TITLE: QUALITY GMP GLOSSARY AND ACRONYMSvalidation1.com/wp-content/uploads/2017/02/GMP-Glossary.pdf · A convenient vehicle for summarising the definitions of acronyms, terms, and

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TITLE: QUALITY GMP GLOSSARY AND ACRONYMS

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Table of Contents Page

PURPOSE ………………………....................................................... 2

SCOPE ………………………....................................................... 2

DEFINITIONS ………………………....................................................... 3

ACRONYMS ………………………....................................................... 234

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PURPOSE

The purpose of this Procedure is to provide:

A convenient vehicle for summarising the definitions of acronyms, terms, and phrases, and interpretation of common vocabulary to assure consistency of understanding and use.

SCOPE

The Validation_1 GMP Glossary of Pharmaceutical, Biotechnology and Medical Device Terminology contain thousands of GMP terms that are of relevance within these highly regulated industries. It is the result of much effort in collating materials across professional organisations to industrial magazines and includes definitions across quality assurance, validation, quality control, manufacturing, warehouse and distribution. Where possible, definitions have been aligned with the relevant pharmacopoeia and international regulatory documents published within the relevant framework.

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DEFINITIONS

- A -

Abbreviated NDA (ANDA)

An application, usually for duplicates of a drug product previously approved under a full application, in which reports of most non-clinical laboratory studies and most clinical investigations may be omitted. Clinical studies dealing with in-vivo bioavailability of the drug product must be included unless the FDA has determined that the information already available is adequate to ensure the drug’s safety and effectiveness or is unnecessary.

ANDAs are frequently filed by manufacturers wishing to market a generic equivalent to an established, approved product. However, an ANDA may be filed for any product that is the same in active ingredient, dosage form and strength, route of administration and conditions of use as any item specified on the FDA list of drug products for which abbreviated applications are suitable.

Accelerated Stability

Studies designed to increase the rate of chemical degradation or physical change of a drug substance or drug product by using exaggerated storage conditions as part of the formal stability studies.

Data from these studies, in addition to long term stability studies, can be used to assess longer term chemical effects at non-accelerated conditions and to evaluate the effect of short term excursions outside the label storage conditions such as might occur during shipping. Results from accelerated testing studies are not always predictive of physical changes (from ICH Q1A).

Acceptable Daily Exposure (ADE)

The amount of a material an individual could consume on a daily basis for life without the likelihood of adverse health effects.

Acceptable Quality Level/Limit (AQL)

1) When a continuing series of lots is considered, a quality level that, for the purposes of sampling inspection, is the limit of a satisfactory process average; the maximum percentage of nonconforming units in a lot or batch that, for the purpose of acceptance sampling, can be considered satisfactory as a process average.

2) The AQL is the quality level that is the worst tolerable process average when a continuing series of lots is submitted for acceptance sampling.

3) The threshold value used during the Statistical Sample Inspection to differentiate between a lot that passes inspection and a lot that requires further investigation.

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Acceptable Residual Limit (ARL)

1) The maximum quantity of residual compound permitted (in units of µg/swab for swab samples and µg/mL for rinse samples).

2) The pre- determined amount of product, degradate, intermediate, excipient, raw material/reactant or cleaning agent that may reside on any equipment surface following completion of a validated cleaning procedure.

Acceptable Source

Official documentation of data/content, which has been second reviewed, approved, or validated, that is in its final form from which a regulatory submission is compiled. Acceptable sources provide traceability of data/content in regulatory submissions, and must have appropriate author, second reviewer and/or approver signatures affixed to the document, as relevant per its type (i.e. primary vs. secondary source) to ensure authenticity.

Acceptance Criteria

A predefined parameter which must be met to successfully complete a test phase.

Acceptance Sampling

Inspection of a sample from a lot to decide whether to accept or not accept that lot.

There are two types:

1) Attributes Sampling and 2) Variables Sampling. In attributes sampling, the presence or absence of a characteristic is noted in each of the units inspected.

In variables sampling, the numerical magnitude of a characteristic is measured and recorded for each inspected unit; this involves reference to a continuous scale of some kind (see ANSI/ASQC 21.4 for procedures for inspection by attributes; see ANSI/ASQC 21.9 for procedures for inspection by variables).

Acceptance Sampling Plan

A specific plan that indicates the sampling sizes and the associated acceptance or non-acceptance criteria to be used. In attributes sampling, for example, there are single, double, multiple, sequential, chain and skip-lot sampling plans. In variables sampling, there are single, double and sequential sampling plans.

For detailed descriptions of these plans, see the standard ANSI/ISO/ASQC a3534-2, Statistics--Vocabulary and Symbols--Statistical Quality Control.

Acceptance Testing

Formal testing conducted to determine whether or not a system satisfies its acceptance criteria and to enable the customer to determine whether or not to accept the system.

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Provides verification that the integrated system performs its intended functions, in accordance with approved specifications for its intended use, and satisfies stakeholders’ or business owners’ acceptance criteria.

Accepts

The population of containers in a 100% visual inspection process that is evaluated and determined to be free of visual nonconformities.

Accountability

A procedure used to reconcile the input of raw materials, ingredients or components with the output quantity of product after a significant processing step.

Accreditation

Certification by a duly recognised body of the facilities, capability, objectivity, competence and integrity of an agency, service or operational group or individual to provide the specific service or operation needed.

For example, the Registrar Accreditation Board accredits those organisations that register companies to the ISO 9000 series standards.

Accuracy

The closeness of agreement between the value, which is accepted either as a conventional true value or an accepted reference value and the value found.

Note distinction from precision.

ACS Grade

Purity grade, which meets reagents grade specifications and additional specifications, established by the American Chemical Society.

Note difference to reagent grade.

Act

The 1938 US Federal Food, Drug and Cosmetic Act, as amended (21 U.S.C 301 et seq.).

Action Level

Microbial or particulate level specified for a given environmentally controlled area which, when met or exceeded, indicates a drift from normal operating conditions.

Action level occurrences must be investigated, and corrective actions should be taken.

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Action Level

Action levels are established to ensure that matter does not exceed a level at which material could potentially be unsafe or impact the overall quality of an API, intermediate or NSPBI.

Action Tolerance (Action Limits)

Tied to process performance and represents the level at which the potential for product impact exists and a Deviation Investigation is required.

Active Pharmaceutical Ingredient (API)

See ‘Drug Substance’.

Active Pharmaceutical Ingredient (API)

Any pharmaceutical chemical or drug substance used as active ingredient in finished pharmaceutical products. The preformulated drug substance which may be subsequently formulated with excipients to produce the drug product.

Active Thermal Protection System

Commonly referred to as an “active container”, is a temperature controlled container with refrigeration and/or heating capabilities as well as associated calibrated temperature controlling devices.

This term includes commonly used containers like active ULD (for air freight – Envirotainer®, PP360®, etc.), temperature controlled trucks/trailers, temperature-controlled ocean containers, etc.

Active Supplier

Are all other suppliers which are regionally or locally managed but that we do not wish to manage through a formal governance and supplier management program.

Active Unit Load Device (ULD)

A Unit Load Device container used to consolidate cargo on aircraft that contains electrical or battery-powered temperature control systems for transporting temperature sensitive materials.

Add-Back

The planned and approved addition of material, which meets all quality attributes of final product from a previous batch into a subsequent formulation of the same product.

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Additive Materials

Materials that do not come in direct contact with the product but are used to facilitate the manufacturing process.

For example: additive chemicals used for water system sanitation.

Adjustment

The operation intended to bring a measuring instrument into a state of performance and freedom from bias suitable for its use.

Adsorption

The retention of solutes, suspended colloidal particles or microorganisms to fluid contact surfaces, e.g. the surfaces of pores in filtration membranes.

Advanced Aseptic Processing (AAP)

Manufacturing method where the process is isolated from direct intervention by personnel using Advanced Aseptic Processing Technologies.

Unlike traditional aseptic processing that requires a Grade A environment, advanced aseptic processing (e.g. sterile tube welding) can take place in as low as a Grade C environment if supported by process validation data demonstrating container closure.

Advanced Aseptic Processing (AAP) Technologies / Advanced Aseptic Technique

Physical barriers and enclosed environments that provide separation of operators from sterile products.

Although these systems are not able to be maintained ‘closed’, these technologies provide the ability to protect the process from the environment and the personnel by eliminating or minimising human intervention.

Advanced aseptic processing technologies ensure that the product and product contact surfaces (including sterilised containers and closures) are not exposed to viable and particulate contamination that can exist in conventional cleanroom operations. AAP technologies include isolators, RABS, and sterile connection systems (e.g. tube welding).

AAP technologies provide ingress control to ensure an improvement over traditional open aseptic processing.

Note: Does not include traditional laminar flow hoods, biosafety cabinets, or curtained areas in a grade C environment as these do not provide positive barriers to ingress.

Adverse Event (AE)

Any unfavorable and unintended change in the structure (signs), function, systems or chemistry (laboratory data) of the body, which may be associated with any use of a product, whether or not considered related to the use of the product.

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In the United States, Food and Drug Administration regulations require the detailed reporting of adverse experience information. Similar requirements are imposed by drug regulatory authorities in other countries in which our products are used.

Adverse Reaction

A negative side effect, toxicity, injury or sensitivity reaction, which occurs following product use.

The term may also be used to describe the absence of the expected pharmacologic effect following treatment with the drug product. Adverse reaction must be reported whether or not a direct cause-and-effect relationship has been established between the product and the reaction. An adverse reaction is also an ADE.

Advocate

The individual or group who wants to achieve a change but does not possess the necessary legitimisation power.

Aerobiology Microbial Challenge

A microbial challenge evaluating the effectiveness and integrity of a sterile boundary to prohibit microorganisms from entering from the surrounding environment through atomising or aerosolised Bacillus Atrophaeus over the boundary under evaluation.

Affected Materials

The actual material being changed by the PCR (raw material, API, intermediate APIs, formulated product, etc).

Airlock

An enclosed space with two or more doors, only one of which may be open at any one time.

An airlock or vestibule provides a separation of space and work activities to achieve control of bioburden, cross contamination, and containment for biohazards, where applicable.

Within classified spaces, the airlock controls the airflow between two rooms while allowing for the movement of either personnel or materials.

An airlock also controls the airflow between two rooms of different classification.

Alarm or Temperature Alarm

An observation or an event where temperature data captured by a monitor is outside the predetermined allowable temperature and time ranges and indicates a Temperature Excursion has occurred.

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Alarm Activated (also called Temperature Alarm)

Observed when temperature/time data captured by a TempTale® monitor is outside the preconfigured temperature/time ranges and indicates a Temperature Excursion has occurred.

Alcohol

A hydroxyl derivative of any hydrocarbon.

Where the term ‘alcohol’ is used with no further designation or labeling, the use of ethanol is implied.

Alert Level

A level at which there is an indication of a potential drift in normal operating conditions.

Alert levels are set below the action level and are to be based on historical data and a 95% frequency distribution.

Trending evaluations, rather than investigations when an alert level is hit or exceeded, are usually performed to determine if it is a spurious result or part of a trend, recurring, etc. If it is recurring, then an investigation should be performed.

Alert Level are established based on process capability, i.e. levels for the numbers and types of matter allowed based on the experience with a process. These alert levels can be those as established in SAT 57 for APIs, or other appropriate guidance for NSPBIs, or set by a site based on experience with a particular process or equipment train.

Alert Limits

Represent the range of expected control or performance.

1) Depending on the process specifics, these limits may be identical with or tighter than the CPP/CQAs or the regulatory limits. Performances outside the Alert Limits are atypical events, which must be monitored and investigated.

2) Acceptance criteria against which test results generated at long term storage conditions are compared to data generated at the previous time point.

Also called Maximum Allowable Difference (MAD).

Allowable Shipping Temperature Range

Typically defined as a time and temperature range, supported by stability studies, within which a product can be transported for a short duration of time without adverse effect on product quality.

Alpha Sites

Sites where the change will be implemented first. Alpha and beta sites are grouped according to process types/similarities.

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Alternate Method

An analytical procedure which has been validated against the regulatory or compendial method and shown to be at least equivalent to the regulatory method. It may require regulatory approval before using to determine the conformity of an API, intermediate, raw material, or finished product to regulatory specifications.

Ambient Conditions

The uncontrolled temperature and humidity conditions existing in a workplace or other location.

Ambient Shipping

Shipping without any means of product protection.

Ambient Temperature (also referred to as Environmental Temperature)

The temperature of the surrounding area or environment.

Note that ambient temperatures are influenced by location e.g. indoors, outdoors, proximity to heating and cooling sources and duration of exposure.

Ambient Temperature Profile

An accurate representation of the expected ambient temperature exposure that a TPS may experience during shipment based on geography, historical weather data, or other general information about the distribution environment.

Amendment

A change to an application, either an original NDA or a supplement to an NDA, submitted prior to final approval of the application.

The submission of a major amendment, which contains significant new data or a detailed analysis of previously submitted data, whether initiated by the applicant or an FDA request, extends the date by which the agency is required to make a decision. This extension may not exceed 180 days. The submission of a minor amendment will not extend the review period. Note distinction from ‘supplement’.

American Society for Quality (ASQ)

A society of individual and organisational members dedicated to the ongoing development, advancement and promotion of quality concepts, principles and technologies.

The Society serves more than 130,000 individuals and 1000 corporate members in the United States and 63 other countries.

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Ampule or Ampul

A sealed glass container for one dose of a sterile product to be administered by injection. Sometimes used for the packaging of reference standards and seed stocks.

Analysis of Means (ANOM)

A statistical procedure for troubleshooting industrial processes and analysing the results of experimental designs with factors at fixed levels. It provides a graphical display of data.

Ellis R. Ott developed the procedure in 1967 because he observed that non-statisticians had difficulty understanding analysis of variance.

Analysis of means is easier for quality practitioners to use because it is an extension of the control chart.

In 1973, Edward G. Schilling further extended the concept, enabling analysis of means to be used with non-normal distributions and attributes data where the normal approximation to the binomial distribution does not apply.

This is referred to as analysis of means for treatment effects.

Analysis of Variance (ANOVA)

A basic statistical technique for analysing experimental data.

It subdivides the total variation of a data set into meaningful component parts associated with specific sources of variation in order to test a hypothesis on the parameters of the model or to estimate variance components. There are three models: fixed, random and mixed.

Analytical Change Request (ACR)

A formal request to create or change a Quality Standard, SAT or associated documents. The system for review of ACRs ensures that each request has the proper technical and regulatory review and that the impact on all sites is evaluated.

Analytical Evaluation Threshold (AET)

An upper limit, at or above which, identification and quantification of an unknown extractables and leachables should be performed and reported for potential toxicological assessment.

This is not applicable to special case compounds such as polyaromatic hydrocarbons (PAH, also known as polynuclear aromatic hydrocarbons, PNA), mercaptobenzothiazole (MBT) and N- Nitrosamines, which must be evaluated individually.

Analytical Instrumentation

That equipment which measures / transmits / records quality attributes of materials or products e.g. most laboratory instruments.

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Ancillary Piping System

Piping configuration associated with another system but may be sterilised separately e.g. filler drop piping, u-bend connections and sample devices.

Ancillary Supply

All non-drug supplies used in the conduct of a clinical trial, but not limited to medical supplies/devices equipment, printed materials, recruitment materials, and drug components.

Annual Lot

A representative batch / lot of drug substance or drug product manufactured at a given manufacturing site on a given calendar year, which is placed on stability to satisfy regulatory, quality and GMP requirements for ongoing stability programs.

Annual Product Review

GMP-mandated evaluation of the standards for each active pharmaceutical ingredient (API), drug product or biologics to determine the need for changes in drug product specifications and/or manufacturing, control procedures or manufacturing processes.

The evaluation must be performed yearly and must include a review of changes to master and batch production records, complaints, recalls, returned or salvaged drug products due to quality defects or failing specifications, product-related investigations, process changes, stability results and statistical analysis of analytical results.

Annual Report

A document which must be forwarded to the FDA each year within 60 days of the anniversary date of approval of the new drug application or biological license.

This report must include a brief summary of significant new information, obtained since the last submitted report that might affect the safety, effectiveness, or labeling of the drug product.

It must also contain a brief description of actions the applicant has taken or intends to take as a result of this new information.

Distribution data, current labeling, chemistry, manufacturing and control changes, stability data, nonclinical laboratory studies, clinical data, and status reports on any post-marketing studies must also be included.

Note distinction from periodic report and annual review.

Annual Review

GMP-mandated evaluation of the standards for each drug product or biologics to determine the need for changes in drug product specifications and/or manufacturing or control procedures.

The evaluation must be performed yearly and must include a review of batch records, complaints, recalls, returned or salvaged drug products and product-related investigations.

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Annual Stability Review

Report which summarises the long-term and accelerated (if available) stability data for each drug substance, or drug product to verify if the stability data continue to support the registered expiry or retest period.

ANSI

American National Standards Institute

Antimicrobial Activity

Inhibitory properties of a material which are detrimental to the proliferation of microorganisms; classified during method validation as total, partial or none.

Total: a dilution of 1:1000 or greater of the material is required to recover all of the microorganisms used for the method validation;

Partial: a dilution of 1:100 or greater of the material is required to recover some of the microorganisms used for the method validation;

None: a dilution of less than 1:100 of material can be used to recover all the microorganisms used in the method validation.

API Critical Intermediate

An intermediate in which at least one essential molecular characteristic, usually involving the proper sterochemical configuration required for structure or pharmacological/physiological activity, is first introduced into the molecular structure.

API Intermediate

A material produced during steps of the processing of an API that undergoes further molecular change or purification before it becomes an API. Intermediates may or may not be isolated.

API Key Intermediate Supplier

Source of any substance produced by chemical, physical, or biological action in which at least one essential molecular characteristic is first introduced in the production of an API.

API Key Raw Material

A substance in which the quality is of critical importance in the production of an API, and/or material which is used in the final processing step of an API or become part of the actual molecule of the API.

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API Key Raw Material Supplier

Source of any substance in which the quality is of critical importance in the production of an API, and/or materials which are used in the final processing step of an API or become part of the actual molecule of the API.

API Raw Material

A commercially available material used in the manufacture of an API (i.e. HCl, sodium chloride, etc.) which may be manufactured in a non-GMP environment. Such material should be manufactured under appropriate raw material good manufacturing practices.

API Starting Material

Raw material, intermediate, or API that is used in the production of an API and that is incorporated as a significant structural fragment into the structure of the API.

API Starting Materials are normally of defined chemical properties and structure. (Per ICH Q7 Good Manufacturing Guidance for Active Pharmaceutical Ingredients/EudraLex Volume 4 Part II.

API Starting Materials

Raw materials, intermediates, or APIs that are used in the production of an API and that are incorporated as a significant structural fragment into the structure of the API (per ICH Q7A Good Manufacturing Guidance for Active Pharmaceutical Ingredients (EU GMP Guide Part II)).

Application

Software installed on a defined platform/hardware providing specific functionality

Approvable Letter

Written communication from the FDA to an applicant which states that their application will be approved if specific additional information or material is submitted or specific conditions are met.

This letter does not give approval to any part of the application nor does it allow the new drug to be marketed.

Note distinction from ‘Approval Letter’.

Approval Letter

Written communication from the FDA to an applicant which states that their application is approved.

This letter allows marketing of the drug product described in the application.

Note distinction from ‘Approvable Letter’.

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Approved or Authorised By

Authorises, via a hand-written signature, the use of the record for subsequent activities that are contingent on the content of the record.

Approved Target Composition

The components and amount of each ingredient for a drug product used in an approved pivotal clinical study or bioequivalence study.

Archive

Long term, permanent retention of completed data and relevant raw data, metadata and audit trail data in its final form for the purposes of reconstruction of the process or activity.

Article

Any drug product, drug substance, or excipient for which a compendial monograph exists.

See also ‘Official Article’.

Artwork

A digital prepress file containing type (text), graphics, diagrams, graphs, tables, etc. from which printed labeling and packaging components are derived.

As Built

As built is the condition where the facility and HVAC installation is complete and in operation, but manufacturing equipment has not been installed.

As Close as Possible

Final filtration (sterile boundary filtration) occurs on the filling line.

For processes where sterile boundary filtration cannot occur on the filling line, it is to occur at the last process step where the item can be filtered or where ingredients are added to a sterile stream and no further downstream sterilisation is possible.

As Found

Measurement data from the instrument collected at the beginning of a calibration procedure before any PM, adjustment or replacement of the instrument’s parts; these data are required to determine whether or not the equipment was out of tolerance while in use for its intended function.

See ‘Out-of-Tolerance Notification’.

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As Left

Measurement data collected during an instrument calibration if no adjustment was required or after adjustment, data that demonstrates that the instrument is calibrated.

See ‘Calibration’.

Aseptic

Free from disease-producing microorganisms.

An operation performed in a controlled environment designed to prevent contamination through the introduction of microorganisms.

Aseptic Area (also ‘Controlled Area’ / ‘Core’)

A room or suite of rooms within a ‘Clean Area’ designed, constructed, and maintained with the intention of limiting microbial bioburden and particulates.

These areas are supplied with specially treated and filtered air and maintained with disinfection procedures and monitored in order to produce a manufacturing zone of low bioburden.

Aseptic Core

See ‘Aseptic Processing Area’.

Aseptic Fill

Process by which the drug or biologic product, container, and closure are sterilised separately then assembled together under strict environmental conditions.

Aseptic Filling

Part of aseptic processing where a pre-sterilised product is filled and/or packaged into sterile containers and closed.

For processes using live bacteria or virus (Axenix manufacturing), the process must exclude contamination by extraneous microorganisms.

Aseptic Processing

Handling sterile materials in a controlled environment, in which the air supply, materials, equipment and personnel are regulated to control microbial and particulate contamination to acceptable levels to protect the sterility of the product or bulk material.

Aseptic Processing Area

A room or suite of rooms within a GMP area designed, constructed, and maintained for the purposes of carrying out aseptic processing with the intention of limiting microbial bioburden and particulates.

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An aseptic area requires Grade A conditions either through the use of Grade A room design or advanced aseptic technologies.

Critical considerations for designing an aseptic processing area include the design of the sterile boundary, the ability to supply material to the critical area, and the flow of people and material to and from the aseptic processing area.

Aseptic Processing Suite

A Grade B filling room containing a Grade A critical zone.

Assay

The quantitative measurement of how much of a specific entity is present in a drug product, raw material, manufacturing intermediate or other substance under test.

Assessment Shipments

Temperature monitored shipments made as part of Transportation Lane Risk Assessments and then subsequently during seasonal extremes and executed to provide temperature data to demonstrate temperature profiles of a transportation lane.

Assignable Cause

The specific reason for the generation of atypical or out-of-specification data

At Risk Design Location

Locations identified within a controlled temperature unit based on unit design with the greatest potential for temperature variation, fluctuation, instability or excursion.

At Risk Location

Locations identified within a controlled temperature unit based on temperature mapping data with the greatest potential for temperature variation, fluctuation, instability, or excursion.

Atomic Absorption

A method for the elemental analysis of solution, especially trace metals, based on the absorption of radiant energy by atoms when a liquid sample is introduced into a flame.

Atomic Emission

A method for the elemental analysis of liquids or solids, especially for the metallic elements, based on the radiation emitted by a sample when it is introduced into an electrical discharge.

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Attenuated

Living but weakened organisms unable to cause disease in a healthy host, which are used to make a vaccine.

Attribute

A characteristic or property that is appraised in terms of whether it does or does not exist, with respect to a given requirement.

Attribute Data

Go/No-Go information.

The control charts based on attribute data include percent chart, number of affected units chart, count chart, count-per-unit chart, quality score chart, and demerit chart.

Atypical

Previously not observed or observed at a level above the historical levels e.g. safety clinical studies and/or process capability.

Atypical Matter

An unexpected impurity that is found associated with an APIs, API intermediates and their raw materials, and non-sterile powder biologic intermediates.

Atypical matter includes both extraneous matter and inherent matter and can be in particulate or chemical form.

Atypical matter does not include degradates of the API and other expected impurities known to occur as part of the manufacturing process.

For API degradates and known impurities, consult relevant ICH Q3A and Q3B guidance.

Atypical Result

Any test result or set of results on a product quality indicating test (all tests not designed exclusively for process control purposes) which falls outside of the typical range but within the specification or acceptance criteria.

Examples include Out of Process Capability Limit results, Out of Trend results, Alert Limits, etc.

Audit

Non-statistical formal sampling review to assure compliance with departmental procedures and Good Manufacturing Practices (cGMPs).

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Audit Terms:

Automation Audit

An audit performed to assess the compliance of automation systems used to support GMPs.

Audit Trail

GxP audit trails are metadata that are a record of GMP critical information, for example the change or deletion of GMP relevant data, which permit the reconstruction of GMP activities, to trace from original data to the relevant records, reports or events; or from records, reports or events back to the original data.

Data Review of Regulatory Submission

An audit performed to determine the accuracy of data contained in a regulatory submission.

Due Diligence Audit

An audit performed for a business unit to assess the current status of GMP compliance of a potential business partner.

For-Cause Audit

An audit performed to evaluate a potential quality concern or a special circumstance.

GMP Audit

An audit performed of the operations and activities supporting the manufacturing, packaging, storage, distribution or testing of materials. The facilities and records are audited to applicable GMP regulations that correspond to the operation or activity.

Sometimes GMP audits are referred to as ‘Full’, ‘Limited’ or ‘Walk-through Audits’.

Full GMP audit indicate that all GMP systems (Quality, Facilities and Equipment, Materials, Production, Packaging and Labeling, and Laboratory) are audited.

Limited GMP audit indicates that not all GMP systems are audited.

Walk-through GMP audit indicates the audit was limited to a walk-through during which GMP activities were observed and on-the-floor documentation reviewed and deficiencies are promptly reported.

Pre-Approval Inspection (PAI) Audit

A GMP audit that will additionally include a review of areas described in planned regulatory filings.

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System-Based Audit

System-based audits are typically seen as a “top-down” audit approach of looking first at the high level controls in place for ensuring GMP compliance.

These controls include managerial oversight along with policies, guidelines or SOPs. System-based audits will also include observing operations, interviewing operators and reviewing various GMP records to determine whether policies and procedures are being followed.

In addition, deficiencies noted at the operational level are viewed as to whether they represent a system defect or failure. Therefore, system-based audits mean evaluating whether specific deficiencies even if for different operations or products may be indicative of a larger system failure.

Risk-Based Audit

A term frequently used to describe decisions based on taking into account the risks associated with the outcomes of the decision.

When used in association with audits, it means focusing the greatest attention on controls where if deficient would present the greatest risk to product quality and patient health. The term when associated with planning or scheduling of audits means auditing at an increased frequency those firms or suppliers that present the greatest risk if controls at the firm or supplier are deficient.

1st, 2nd and 3rd Party Audits

1st party audits are self-audits by of their own facilities.

2nd party audits are those of business partners and contracted operations.

3rd party audits are those of suppliers from which company is purchasing materials but for which you are not contracting operations.

Audit Report

A document generated after auditing a site or certain data or information that contains specific observations or findings.

Author

1) Any creator/originator of data/information or the user that creates the regulatory support document. In practice, the author is often titled chemist, engineer, pharmacist, regulatory compliance coordinator, operator, technician, scribe, etc.

2) Any creator/originator of an acceptable source or regulatory submission document.

Author (Initiator/Originator)

Any creator/originator of a GMP document.

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Auto Analyser

A multi-component instrumentation system consisting primarily of a sampler, pump, detector and recorder whereby an operator can perform routine stepwise wet chemical analysis rapidly and uniformly using an automated, segmented, continuous flow system.

Autoclave (Steam Steriliser)

Pressurised chamber surrounded by a steam jacket using steam as a sterilising medium in which components are loaded onto a rack or other appropriate container and exposed to steam for a predetermined amount of time.

Automated Equipment

Equipment whose functions and operations are controlled by a programmable computer.

Automated Inspection

Automated presentation of product and automated evaluation of product for defects.

Availability

The ability of a product to be in a state to perform its designated function under stated conditions at a given time.

Availability can be expressed by the ratio:

Uptime divided by (uptime + downtime) being when the product is operative (in active use and in standby state) and downtime being when the product is inoperative time (while under repair, awaiting spare parts, and so on).

Average Chart

A variables control chart in which the subgroup average, X-bar, is used to evaluate the stability of the process level.

Axenic

It refers to processes such as live bacterial or viral vaccine manufacturing where all inputs and equipment used in the bulk and final product manufacturing must be sterilised to ensure the product remains a pure culture.

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- B -

Backup

A copy of current (editable) data, raw data, metadata, audit trail data and applicable variable system configuration settings maintained for the purpose of disaster recovery.

Bacterial Retention

A test to evaluate the capability of a filter to retain bacteria from a suspension.

Barcode

(1)an established, machine-readable symbology consisting of a series of alternating heavy and light lines and spaces. The order of the lines represents digitally encoded information, which provides a unique identification of the item. (2) Different types of bar code symbology (encoding standard) include EAN, UPC, code 39, code 128, Interleaved 2 of 5, Pharmacode, and others, each having different coding conventions and uses in industry.

Barrier System

A physical partition that affords aseptic processing area (ISO 5) protection by partially separating it from the surrounding area.

Basket Dissolution

A dissolution test using USP Apparatus 1 <711>, which uses a shaft with a basket attachment as the stirring element. (Note distinction from paddle dissolution).

Batch Certification

The certification in a register or equivalent document by a Qualified Person, as defined in Article 51.3 of Directive 2001/83/EC, before a batch is released for sale or distribution within the EU.

Batch Number

For the purposes of this procedure, the term "batch number" is equivalent to the term, "lot number".

Batch Production Record

An executed/completed Batch Record, Batch Sheet or Floor Copy. May also be referred to as Batch Record, Production Batch Record, Batch Processing Record and Batch Production Sheet.

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Batch Record(s)

A collection of documents associated with the manufacture of a batch of bulk or finished product. They provide a history of each batch of product and of all circumstances pertinent to the quality of the final product.

Batch Sheet (Floor Copy)

An exact copy of the Master Batch Sheet or Working Master Batch Sheet issued for use in production, with a single and unique work order number that corresponds to the lot or batch number.

Batch / Llot

A specific quantity of a drug product, intermediate or API intended to have uniform character and quality, within specified limits, and produced according to a single manufacturing order during the same cycle of manufacture. For supplies, a definite quantity of some product or material produced under condition that is considered uniform. The terms batch and lot can mean the same but not always. For example, a lot can never consist of more than a single batch but a batch can be divided into multiple lot numbers.

Benchmarking

An improvement process in which a company measures its performance against that of best-in-class companies, determines how those companies achieved their performance levels, and uses the information to improve its own performance. The subjects that can be benchmarked include strategies, operations, processes, and procedures. Benchmarked companies do not necessarily have to be in the same industry.

Bespoke / Customised (Computerised System)

A computerised system individually designed to suit a specific business process

Best Practice

A process, design consideration, model, or method that may be considered for division-wide implementation. While best practices are not intended to identify new policies/guidelines/procedures or regulatory requirements, they do, however, provide additional clarification or alternative means of meeting requirements, usually in a more efficient and effective manner. Consideration should be given for incorporating the content of best practices into related policies/guidelines/procedures at the next scheduled document update.

Beta-Lactam Antibiotic Compound

Beta-Lactam Antibiotic Compounds: Antibiotic compounds that contain a Beta-Lactam ring. Penicillins have been widely reported as having produced serious hypersensitivity reactions (including anaphylaxis) in sensitive individuals. Non-penicillin Beta-Lactams, such as cephalosporins, penems, carbacephems, and monobactams and associated process

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intermediates, also have sensitisation potential because of the presence of a Beta-Lactam ring.

Beta Sites

Sites where the change will be implemented after the alpha site. (Alpha and beta sites are grouped according to process types/similarities.)

Bill of Materials (BOM)

document created and maintained by Packaging Technology that lists the approved packaging materials and any additional package requirements for APIs.

Bioavailability

The rate and degree to which the active drug ingredient is absorbed from the drug product in vivo and is available at the site of the drug action.

Biobatch

A batch of drug product manufactured at a minimum of 1/10th of proposed manufacturing scale or 100,000 units (theoretical), whichever is greater, for the purposes of pharmacokinetic evaluation in a bioavailability (BA)/bioequivalency (BE) study, and by the manufacturing process intended to be used for the marketed product. This batch provides a bridge between product used during development and the marketed commercial product. The biobatch lots should also be representative of the drug product used in pivotal studies to demonstrate safety and efficacy of the product.

Bioburden

1) Population of viable microorganisms in a fluid prior to sterilising filtration.

2) Population of viable microorganisms in a sample, in a substance or on a surface.

Bioequivalence

Chemical equivalents that, when administered to the same individual in the same dosage regimen, result in equivalent concentration of active ingredient in blood and tissue.

Bio-Hazardous Material

Any complaint sample that has potentially been contaminated with a biological material, such as blood or other bodily fluids.

Biological Active Pharmaceutical Ingredient

See ‘Drug Substance’.

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Biological Critical Reagent (BCR)

Any reagent, control, or reference standard used in testing of Biotech or Vaccine products, that has Critical Quality Attributes (CQA) essential for both the performance of a release or stability assay and quality or quantity of the reportable results. A critical reagent requires qualification and assignment of any of the following items prior to use: a qualified value for a reagent, a qualified use condition for the reagent such as dilution, or a qualified performance range for the reagent. Critical reagents include: Primary Reference Standards, Secondary Reference Standards, reference standards, control samples, monoclonal and polyclonal antibodies, polyclonal antisera, primers and probes, cell lines/banks and miscellaneous reagents. A reagent requiring a suitability check prior to use is not considered a critical reagent and should be evaluated prior to use by the testing laboratory.

Biological Indicator

A system containing microorganisms of known concentration and resistance which can be expected to follow a predictable spore death rate when exposed to particular physical parameters.

Example Bacillus stearothermophilis.

Biological Product

(1) The biological dosage form in the primary packaging (e.g., vial, syringe, etc.) or secondary packaging (e.g., outer carton) intended for marketing. (2) Any virus, therapeutic serum, toxin, antitoxin, cellular component of microorganisms or biotechnologically derived material, or analogous product applicable to the prevention, treatment or cure of diseases or injuries of humans. Biological products are produced using biological processes, e.g., extraction of natural product or fermentation. The manufacturing process is part of the definition of the product.

Biologics License Application (BLA)

For biological products, facility and product specific dossier filled with US regulatory agency.

Biometrics

To mean a method of verifying an individual's identity based on measurement of the individual's physical feature(s) or repeatable action(s) where those features and/or actions are both unique to that individual and measurable.

Bisection

Tablet defect in which the tablet score line or engraving is not sharply defined.

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Black Zone

A GMP area within the facility that has no potential for product exposure to the environment or personnel and no potential for product contact surface/component exposure. Examples include mechanical spaces, general warehouses, shipping and receiving.

Blemish

An imperfection that is severe enough to be noticed but should not cause any real impairment with respect to intended normal or reasonably foreseeable use. See also "defect," "imperfection," and "nonconformity."

Blistering

Filmcoating defect characterised by small bubbles on the surface of the tablet. The evaporation of the solvent from the core and the high temperatures used during the process affect the strength, elasticity, and adhesion of the film coat.

Blister Packaging

A packaging design that uses vinyl films and metallic foils. The unit cell is normally a preformed vinyl blister or bubble in which a single dose is placed and then encased or mounted on a card of foil coated roll board.

Block Diagram

A diagram that shows the operation, interrelationships, and interdependencies of components in a system. Boxes, or blocks (hence the name), represent the components; connecting lines between the blocks represent interfaces. There are two types of block diagrams: a functional block diagram, which shows a system’s subsystems and lower-level products, their interrelationships, and interfaces with other systems; and a reliability block diagram, which is similar to the functional block diagram except that it is modified to emphasise those aspects influencing reliability.

Block Flow Diagram

A diagram, which shows the process flow through all unit operations. A material and energy balance are not included. Unit operations are shown simply as blocks (squares). The simplest of diagrams that is used to describe an operating system.

Blowback Feature

A circular depression in the crown of a glass vial engineered to prevent the stopper from dislodging.

Boiling Point

The temperature at which a specified liquid vaporises when subjected to direct heat or pressure changes.

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Bolus

An animal health dosage form resembling a large capsule-shaped tablet.

Boundary Value Testing

A testing technique using input values at, just below, and just above the defined limits of an input domain, and with input values causing outputs to be at, just below, and just above the defined limits of an output domain. (FDA Glossary of Computerized System and Software Development Terminology)

BPDR

Biological Products Deviation Report (official alert to FDA)

Branch

(1) Acomputer program construct in which one of two or more alternative sets of program statements is selected for execution. (2) A point in a computer program at which one of two or more alternative sets of program statements is selected for execution. (3) Any of the alternative sets of program statements in (1). (4) To perform the selection in (1).

Branch Testing

Testing designed to execute each outcome of a decision point in a computer program.

Bracketing

(1) A reduced design for a stability schedule where only samples on the extremes of certain design factors (i.e., strength, container size, fill size, etc.) are tested at all time points as in a full design. This design assumes that intermediate levels of each bracketed factor are represented adequately by the extremes. Refer to the ICH guidelines, Q1A (R2) Stability Testing of New Drug Substances and Products or other applicable regulatory guidelines for additional guidance. (2) Using the three lot results from suitability testing different strengths of the same drug product to allow for equivalency-based suitability testing of intermediate strengths.

Brainstorming

A technique that teams use to generate ideas on a particular subject. Each person in the team is asked to think creatively and write down as many ideas as possible. The ideas are not discussed or reviewed until after the brainstorming session.

Bridging

Filmcoating defect, which occurs during the drying stage. Filmcoating shrinks and pulls away from the sharp corners of a bisect or engraving forming a “roof” over the depression. This

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term can also be used to describe a granulation flow characteristic where air pockets form within the mass of granulation and halt the flow. This phenomenon is sometimes seen when a granulation is fed to tablet presses.

Broken Tablet

Tablet defect where the tablet is not a whole entity.

Broker / Agent

A licensed firm holding a legal power of attorney from the importer that files the importation documentation and information with the authorities on behalf of the importer. No material is held or stored by the broker/agent.

Bubble Point (Test)

A non-destructive test to determine filter integrity with specific, validated, pressure values, wetting liquid and temperature for specific pore-size (and type of) filters. The differential gas pressure at which a wetting liquid is pushed out of the largest pores of a wetted porous membrane and a steady stream of a gas bubbles or bulk gas flow is detected is measured. Bubble Point test method is best suited for small (less than 10 inches) cartridge or capsule filters. A combination of bubble point and diffusive flow (enhanced bubble point or combination test) integrity test method must be used to ensure reliable results due the presence of diffusive airflow obscuring the true bubble point for larger filters (greater than 10 inches). This combination test may be conducted using automated integrity test equipment from filter manufacturers.

Buffered

Referring to data that is temporarily stored.

Buffers

Solutions or suspensions used in the production of vaccines or biologic products that do not have grown promoting qualities (static or inhibitory).

Bulk Biological Intermediates

See "drug substance intermediate".

Bulk Drug Product (also Bulk Finished Pharmaceutical Drug Product)

A finished pharmaceutical dosage form (drug product in its final dosage form, for example bulk sterile powders, coated tablets awaiting packaging, and unpacked solid dosage forms) that is still pending further packaging into the primary market package or clinical package.

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Bulk Drug Substance

See “drug substance”.

Bulk Media Challenges

See "bulk sterile challenge".

Bulk Pharmaceuticals (BPs)

Materials (both pharmacologically active and inactive) which are intended for use as a component of a drug or biological product. These include materials manufactured by processes such as: 1) chemical synthesis, 2) fermentation, 3) recombinant DNA or other biotechnology methods, 4) isolation/recovery from natural sources, or 5) any combination of these processes.

Bulk Pharmaceutical Product

A sterile material, derived from chemical, fermentation or semi-synthetic sources, which is final packaged or stored in bulk form. The bulk material may be an active pharmaceutical or excipient. Bulk materials can be solids, solutions or suspensions.1

Bulk Product Hold Time

The time from the completion of the sterilisation or aseptic transfer of sterile bulk product or intermediates into a holding vessel (i.e., tank, carboy, bag) to the initiation of the next aseptic step.

Bulk Sterile Challenge

Testing of a bulk manufacturing process to demonstrate sterility assurance when simulating all aseptic processing steps, activities, conditions, and characteristics that take place after the final product sterilisation and those which may have a bearing on the possibility of microbial ingress into systems during routine production process and hold times.

Business Agreement / Contract

Agreements including purchase agreements, supply agreements, purchase orders, secrecy agreements, letters of intent, agreement in principle, other contractual understandings (such as letter agreements, memoranda of understanding) and/or Amendments, supplements, renewals, documents, notices and other instruments that explicitly define the obligation and/or responsibilities of one or more parties.

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- C -

Calibration

A comparison of two instruments or measuring devices, one of which is a standard of known accuracy (traceable to national standards) to detect, correlate, report or eliminate by adjustment, any discrepancy in accuracy of the instrument measuring device being compared to the standard.

Calibration Frequency

The established time period for recalibration i.e. once per month, once per quarter or once per year.

Calibration Procedure

A defined technical method for performing a calibration or verification. A written procedure for performing and documenting calibration work.

Calibration Reference Standard

Instrument or device used to calibrate other instruments, whose calibration is traceable back to accepted national standards. The calibration reference standard must have a greater precision, accuracy, and repeatability than that of the instruments being calibrated.

Calibration Sticker

A label applied directly to an instrument, or in the vicinity of its use that is intended to provide information on the calibration status of the instrument.

Calibration System

The management system of resources and responsibilities for equipment calibration.

Also known as calibration program.

This will normally include the functions related to calibration, including computer systems, and the activities supporting calibration, e.g. the system installed to accomplish the requirements of this guideline.

Calibrator Tablets

Tablets supplied by the USP, which are utilised to determine the mechanical suitability of dissolution apparatus.

Campaign

A continuous period of days for the manufacture of API products.

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Campaign Length

The duration of manufacturing a product and/or the number of lots produced between cleanings.

CAPA

Acronym which stands for Corrective Actions and Preventative Actions. A systematic approach that includes actions needed to avoid recurrence (‘Corrective Action’), and eliminate the cause of potential non-conforming product and other quality problems (‘Preventative Action’).

CAPA Effectiveness

Evaluation to determine the degree to which occurrence of the same root cause or observation of a non-conformity, defect or other underlying situation was eliminated or reduced.

Capacity Factor

A chromatographic parameter defined as the ratio of the time spent by a substance in the stationary phase to the time spent by the substance in the mobile phase. It is represented by the symbol k.

Cap and Seal

The application of an aluminum banding seal with attached flip-top cap to a filled and stoppered vial of vaccine or sterile pharmaceuticals. The aluminum seal is subsequently crimped to prevent the stopper from being removed.

Capping

1) Tablet defect characterised by the separation of the top or bottom crowns from the main body of the tablet.

2) The act of applying an overseal to a stoppered vial or other unit (e.g. Ocumeter) and sealing it onto the unit. This is normally carried out as a single mechanical process.

Capsule Filter

A self-contained filter device or assembly

Capsules

Solid, oral dosage forms in which a hard or soft, gelatin ‘shell’ encloses the drug product.

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Carcinogenic

A substance, which produces or incites cancer.

Carrier Gas

The mobile phase in gas chromatography, usually inert in nature.

Carton

The secondary container enclosing a bottle, vial, ampule, tube, etc. of drug product and the appropriate circular.

Cartridge Filter

A filter device requiring a housing for use.

Category I

Analytical methods for quantitation of major components of active pharmaceutical ingredients (APIs), drug substance ingredients (including preservatives) in finished pharmaceutical products, key raw materials or process intermediates.

Category I Chemical Assay (USP)

Analytical methods for quantitation of major components of bulk drug substances or active ingredients (including preservatives) in finished pharmaceutical products.

Category I, II, III, IV

USP / EP differentiation for analytical methods.

Category II

Analytical methods for the determination of impurities in APIs, key raw materials, process intermediates or degradation compounds in APIs or finished pharmaceutical products. These methods include quantitative assays and limit tests.

Category II Chemical Assay (USP)

Analytical methods for determination of impurities and degradation compounds in bulk drug substances or in finished pharmaceutical products. These methods include quantitative assays and limits tests.

Category III

Analytical methods for determination of performance characteristics e.g. dissolution, drug release.

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Category III Chemical Assay (USP)

Analytical methods used for determination of performance characteristics i.e. dissolution, drug release.

Category IV

Identification tests.

Category IV Chemical Assay (USP)

Identification tests or physical properties.

Cause-and-Effect Diagram

A tool for analysing process dispersion.

It is also referred to as the Ishikawa diagram, because Kaoru Ishikawa developed it, and the fishbone diagram, because the complete diagram resembles a fish skeleton.

The diagram illustrates the main causes e.g. people, machines, material measurement, method and/or environment, and subcauses leading to an effect (symptom).

The cause-and-effect diagram is one of the seven tools of quality.

Cause of Failure

Probable cause for the potential failure mode or unwanted event. There may be multiple causes for each failure type.

Cavitated Tablet

Tablet defect characterised by large, uneven depressions in the tablet surface.

CCI Documentation Package

Consists of a project plan (when appropriate), a protocol, raw data package and a final report.

Cell Bank

A collection of containers comprising microbial cells, cells derived from human or animal sources, or recombinant cells that possess the full potential for generation of the desired biotechnological / biological products, and whose contents are of uniform composition and stored under controlled conditions.

Each container represents an aliquot derived from a single, homogenous pool of cells. Microbial sources include bacteria, fungi, and yeast; animal sources of cells include all those of metazoan origin.

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Certificate of Analysis (COA)

1) An official report of test results for a particular lot of material as compared to specifications (NDA, contract, etc.).

2) MRSs Certificates of Analysis (COAs) provide pertinent analytical data, a purity assignment, storage conditions, handling conditions, and the scheduled retest date.

CFU

Colony Forming Unit - Unit of measurement for microbiological monitoring. The assumption is that a colony on an agar plate is derived from a single microbial organism, though in actuality a single CFU may be derived from a clump of two or more cells.

cGMP

Current Good Manufacturing Practices

Challenge

Any test intended to demonstrate integrity.

Challenge Module

A discreet unit operation within a process that is challenged and evaluated individually.

Chamber Setpoint Excursion

Deviation of a controlled environmental parameter (e.g. temperature, humidity) for a stability chamber outside of the defined tolerance limits for the setpoint.

Change Control

Procedure for documenting and reviewing / approving changes to manufacturing, formulation, filling, packaging, and testing processes for drug substance, intermediate and/or finished product.

Change Control Action Plan

A Change Control Action Plan is a document which outlines to the trainee the detail core training requirements to be completed for a job position. It is supplied to new employees or existing employees who have moved to an alternative position at the site.

Change Document

A document that outlines the planned personnel changes being proposed.

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Changing Room

1) A designated room where employees change from street clothes into company issued uniforms and additional protective clothing. Changing rooms should be located adjacent to designated production areas and should be designed to allow personnel movement through the area in sequential order from entry to exit.

2) A room specifically dedicated to facilitate personnel gowning. Changing rooms are located adjacent to designated manufacturing and packaging areas and should be designed to allow personnel movement through the area in sequential order from entry to exit.

Changing Station

1) A designated area or station where employees can add or remove additional clothing required to cross between hygienic zones. Posted signs should indicate where special gowning requirements apply.

2) A designated space within a room or corridor designated to facilitate personnel gowning.

Characteristic

A property that helps to identify or to differentiate between entities and that can be described or measured to determine conformance or non-conformance.

Characterisation Tests

Assays that are scientifically suitable for use but may not have a defined specification.

These assays provide information on the S&CB; not all methods support lot release decisions.

Charge

A quantity of ingredient material placed into a piece of manufacturing equipment.

Check Test

The process of re-evaluating the original sample preparation.

Normally done as part of the initial investigation into laboratory atypical or OOS results.

Examples are the re-injection of a solution into a chromatograph, re-weighing of a crucible, taking a new weight from an original grind of tablets, etc.

Check Testing or Re-Analysis

Additional testing on the same exact initially prepared test sample (e.g., different injection of the same vial or different UV scan of the same sample preparation), or another preparation/analysis from the original solutions that were used in the initial test (e.g. remixing/dilution of same stock solution or re-pour from same solution).

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Chemical Name

A term that uniquely and unambiguously identifies a chemical entity based on rules of systematic nomenclature e.g., IUPAC.

Note distinction from common name, nonproprietary name and tradename.

Chemical Reaction

A process that involves a chemical transformation of a starting material or intermediate to form a new compound e.g., bond formation, oxidation, reduction.

Child Resistant

A type of packaging designed to comply with the regulations set forth in the Poison Prevention Packaging Act. Its purpose is to decrease the chance that a child may obtain access to poisons and to protect them from serious injury or illness resulting from the handling, using or ingesting of such a substance.

Chipping

Filmcoating defect that occurs when tablets stick together and then break away during the film coating process.

Circular

Periodically updated bulletin of information, which comprises part of the labeling and/or packaging of a finished product.

It contains a description of the product, its clinical pharmacology, indications and usage, contraindications, warnings, precautions, adverse reactions, dosage and administration routes, and how supplied information.

Class I Recall

A situation in which there is a reasonable probability that the use of, or exposure to, a violative product will cause serious adverse health consequences or death.

Class II Recall

A situation in which the use of, or exposure to, a violative product may cause temporary or medically reversible adverse health consequences or where the probability of serious adverse health consequences is remote.

Class III Recall

A situation in which the use of or exposure to, a violative product is not likely to cause adverse health consequences.

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Class 100 Area

Required for aseptic manipulations of an API that is considered sterile e.g. bulk packaging of sterile API.

Class 100,000 Area

Required for all non-aseptic steps in the final purification process for sterile APIs except for the charging of the starting materials, where particulate classification is not required.

Classified Area (also Classified Space or Suite)

GMP production and support areas that have been designed and are maintained to meet a specific environmental classification or grade i.e. Grades A, B, C and D.

Clean Area

A room or suite of rooms with defined levels of particulate contamination and bioburden.

It is constructed of materials appropriate for limiting the particulates generated within the room and is not adversely affected by special materials, which are used to clean and disinfect.

Additionally, special air handling systems are used which utilise HEPA or ULPA filters in order to limit the amount of particulates and bioburden within the air.

Clean Hold Time

The time interval between the end of cleaning and equipment re-use.

Cleaning

The process of using an agent (detergent or solvent) to remove dirt, impurities or contamination from surfaces.

Cleaning Agent

An agent to aid in the removal of product residues that may inactivate sanitising agents or harbor microorganisms from facility and equipment surfaces.

Cleaning Record / Log

A complete record of:

1) The products processed using the designated processing area or equipment

2) Subsequent cleaning after processing is completed, and

3) Inspection prior to initiation of processing of another product. Cleaning and inspection entries require the initials of the person accomplishing the action and the date of the action.

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The record or log should be attached to the equipment if possible, or kept in the immediate vicinity for ready reference.

Cleaning Validation

The process of establishing documented evidence that a particular cleaning procedure will consistently reduce equipment surface residuals (i.e., product and cleaning agents) to a predetermined acceptable level.

Cleanroom

A clean, controlled environment designed to reduce or eliminate contamination that may be caused by processes, process materials, equipment or people.

Climatic Zones

The four zones in the world that are distinguished by their characteristic prevalent annual climatic conditions. Storage conditions are based on Mean Kinetic Temperature and the Yearly Average Percent Relative Humidity in each climatic zone.

Clinical Stock Quarantine

Action taken to prevent further dispensing to patients Clinical Supply Material in clinical site inventory or in transit to a clinical site. This excludes actions taken concerning Clinical Supply Material inventory at intermediate locations prior to shipment to clinical sites.

Clinical Stock Recovery

Action taken to retrieve and reconcile Clinical Supply Material in clinical site inventory or in patient possession, or in transit to a clinical site in order to prevent use by human patients for reasons other than routine study conduct activities.

Clinical Supply

GMP Activities (including processes, procedures, and facilities) related to the manufacturing, processing, packaging, holding, transporting, and testing of Active Pharmaceutical Ingredients (API), Drug Substance, intermediates, bulk, and finished dosage forms of sterile and non- sterile drug products, and medical devices (or combinations thereof) that are intended to support or be used in a clinical trial.

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Closed Aseptic Process

Manufacturing method where the aseptic process is isolated from the environment through containment within the processing equipment (either reusable or single-use systems).

During closed sterile processing, there are no open aseptic manipulations or interventions to the system. The system is defined as a series of components e.g., tanks, pumps, filters, bags, bottles, tubing.

All of the following criteria must be met when defining the system as closed:

Components and the assembled system must have been sterilised using a validated sterilisation process. Alternatively, pre-sterilised disposable components can be used. The supplier of pre-sterilised components must have a validated sterilisation process.

The system must undergo post-sterilisation / pre-use leak testing each time the system is used or have container closure validation for those components that cannot be pressurised (bags, bottles, tubing). An appropriately sensitive leak rate specification must be established, as well as a time-limitation between the pre-use leak testing and use.

The system must have controls in place to maintain and document positive pressure after the post sterilisation / pre-use leak testing and throughout processing or have container closure validation and an alternative method for confirming integrity pre-use for those components that cannot be pressurised (bags, bottles, tubing).

The system must have design documentation establishing the absence of aseptic connections and operational documentation providing guidance for the prevention of aseptic interventions.

Product is separated from the surrounding room environment using engineering controls including the equipment as the primary product protection of which a sterilising grade vent filter is integral part. All sterilising grade product and vent filters (liquid and air) contained in the system must be pre- and post-use integrity tested.

Where necessary, the system must enable fluid transfer in and/or out while maintaining the sterile state.

The system must have satisfactory process simulation results.

The system must have established comprehensive preventive maintenance and calibration programs.

An environmental monitoring program must be in place during process simulation and ongoing operations.

Closed Equipment Operations (e.g. Wet Processing Streams)

Can also be considered as a means of segregation as long as there are sufficient procedures to prevent cross-contamination or product dissemination when the equipment is opened.

Closed Sterile Process

Manufacturing method where the process is isolated from the environment using containment (either reusable or single-use systems). During closed sterile processing, there are no open aseptic manipulations or interventions to the system. The system is defined as a series of components e.g. tanks, pumps, filters, bags, bottles, tubing.

All of the following criteria must be met when defining the system as closed.

Components and the assembled system must have been sterilised using a validated

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sterilisation process. Alternatively, pre-sterilised disposable components can be used. The supplier of pre- sterilised components must have a validated sterilisation process.

The system must undergo post-sterilisation / pre-use leak testing each time the system is used or have container closure validation for those components that cannot be pressurised e.g. bags, bottles, tubing. An appropriately sensitive leak rate specification must be established, as well as a time-limitation between the pre-use leak testing and use.

The system must have controls in place to maintain and document positive pressure after the post sterilisation / pre-use leak testing and throughout processing or have container closure validation and an alternative method for confirming integrity pre-use for those components that cannot be pressurised e.g., bags, bottles, tubing.

The system must have design documentation establishing the absence of open aseptic connections and operational documentation providing guidance for the prevention of open aseptic interventions.

Product is separated from the surrounding room environment using engineering controls including the equipment as the primary product protection of which a sterilising grade vent filter is integral part. All sterilising grade product and vent filters (liquid and air) contained in the system must be pre- and post-use integrity tested.

Where necessary, the system must enable fluid transfer in and/or out while maintaining the sterile state.

The system must have satisfactory process simulation results.

The system must have established comprehensive preventive maintenance and calibration programs, where appropriate.

An environmental monitoring program must be in place during process simulation and ongoing operations.

Closed System

A closed system is one that does not contain any aseptic manipulations or interventions by design or operation and does not allow microbial ingress.

All of the following criteria must be met when defining the system as closed. Unless these criteria are met, the system is not considered a closed system. Any deviation from these criteria must be scientifically justified, approved and documented:

The system must have validated sterilisation cycles

The system must undergo post-sterilisation / pre-use leak testing each time the system is used. An appropriate sensitive leak rate specification must be established, as well as a time limitation between the pre-use leak testing and use.

The system must have controls in place to maintain positive pressure after the post sterilisation / pre-use leak testing and throughout processing, or the system must undergo post-use leak testing using an appropriate sensitive leak rate specification, each time the system is used.

The system must have documentation establishing the absence of aseptic connections and aseptic interventions.

All sterilising product and vent filters (liquid and air) contained in the system must be pre and post-use integrity tested.

The system must be adaptable for fluid transfer in and/or out while maintaining the sterile state.

The system must have an established comprehensive preventive maintenance program.

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Closed System Sanitary Processing

Is defined as having the following characteristics:

The separation of product from the external room environment by sterilising grade vent filters.

Filter integrity is verified prior to use. Verification could be performed by review of the CoA upon receipt and release by QA. Post-use testing is necessary only for fermentation systems. For vent filters that are installed and then used for multiple lots, verification of integrity is required only prior to the first use.

Life-cycle studies should be used to justify the number of uses.

HEPA filtered air for locally controlled areas e.g. isolators and bio-safety cabinets.

Validated cleaning cycles

Pre-use leak (vessel integrity) testing

The use of closed methods (e.g. tubing welders using sterilised connection) for sampling.

Fermentation requirements: o The use of media that is heat or filter sterilised prior to use. Note that the

purpose of the sterilisation is to ensure purity of the fermentation culture. o Integrity testing of vent filters post-use o Validated fermentor SIP cycles, if the fermentor does not undergo full-vessel

sterilisation o Media hold tests o Established comprehensive preventive maintenance and system integrity (leak

test) program

Closure

A sealing (e.g., lidding, PS-22 liner, rubber stopper) or covering (child resistant cap) affixed to or on a container for the purpose of retaining the contents and preventing contamination.

Includes Primary Closure Components, such as stoppers, a stopper/plunger assemblies or screw caps (or screw cap/dropper tip assemblies as in ophthalmic products) that are applied to sterile products.

CO2 Free Water

Purified water or ‘Aqua Purification’ that has been boiled vigorously for 5 minutes or more and allowed to cool while protected from absorption of carbon dioxide from the atmosphere.

Code of Federal Regulations

A codification of both general and permanent rules, which have been published in the Federal Register by various departments and agencies of the Federal government. Fifty titles, which represent the different areas subject to government regulations, comprise the Code. Title 21 deals with FDA regulations. Title 40 deals with Environmental Protection.

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Coefficient of Variation

See ‘Relative Standard Deviation (RSD)’.

Co-Loading during Shipment

Typically in a truck, trailer or larger freight container is the co-mingling of pallets of products of different origins and types, and usually from different manufacturers. This practice may be permitted under certain conditions which will not compromise the quality of the product.

Colony Forming Unit (CFU)

Visible outcome of growth of microorganisms arising from a single cell or multiple cells. One colony forming unit is expressed as 1 CFU.

Colour Additives

A colour, pigment, or other material deliberately added to give colour to a product in order to enhance the appearance, value, marketability, or consumer acceptability of that product. They may also be used to facilitate identification of the product and/or its strength.

Colorimeter

A spectrophotometer, which functions only in the visible spectrum.

Colour Variation

Filmcoating defect characterised by a mottled or spotted appearance; a noticeable difference in the colour of two lots of material when compared to one another.

Combination Product

A product that contains both a drug or a biologic, and a device constituent part. A constituent part of a combination product is an article in a combination product that can be distinguished by its regulatory identity as a drug, device, or biological.

Commercial Distribution

Any distribution of a human drug and animal drug or animal feed bearing or containing an animal drug for non-investigational uses. The term does not apply to a human drug for investigational use and does not include internal or interplant transfer of a bulk drug substance between registered domestic establishments within the same parent, subsidiary, and/or affiliate company.

Commercial off the Shelf (COTS) Software

Software commercially available, whose fitness for use is demonstrated by a broad spectrum of users.

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Commissioning

A well planned, documented, and managed engineering approach to the start-up and turnover of facilities, systems, and equipment to the end-user that results in a safe and functional environment that meets established design requirements and stakeholder expectations.

Commitment Batches

Production batches of a drug substance or drug product for which the stability studies are initiated or completed post approval through a commitment made in the registration application (from ICH Q1A).

Commodity Product (Non-Regulated Product)

Consumer care product that does not require registration with a Health Authority or Regulatory Agency.

Common Causes

Causes of variation that are inherent in a process over time. They affect every outcome of the process and everyone working in the process (see also ‘Special Causes’). Common causes can only be eliminated by improving the process.

Common Printing Plates

Printing plates that are used for multiple different printed component items.

Comparability Protocol

A prior approval supplement submitted to the Center for Biologics Evaluation and Research which establishes the tests to be done and acceptable limits to be achieved to demonstrate the lack of adverse effect for specified types of manufacturing changes on the safety and effectiveness of a product. At the time the Comparability Protocol is approved, the reporting category (prior approval, changes being effected in 30 days, and annual report) for the manufacturing changes covered by it will be established (generally one category lower).

Comparative Data

Results generated by performing tests for a specific ingredient on the same sample using different assay methods. The results are statistically evaluated to determine if the different methods are equivalent.

Comparison Sample

A reserved portion from a lot of suitable, previously released, typical production material so designated at the site of manufacture.

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The reserved sample should be from a current lot of production material, if at all possible. It is to be analysed concurrently with and used as a means of judging the qualitative acceptability of the lot undergoing testing. It may also be used as a means of evaluating the system used to perform the testing. This test and system evaluation could include (but is not limited to) the following: HPLC Area %, HPLC WT %, TLC, Titration, Melting Points, etc.

Compatibility

1) Proof that no adverse interaction between the filter and the process fluid has occurred.

2) A measure of the extent to which a PPC, PCM, and/or proximal material will interact with a dosage form. Such interaction should not be sufficient to cause unacceptable changes in the quality of either the dosage form or the packaging component. Such interactions may include (ab)adsorption of the active drug substance, reduction in the concentration of an excipient, leachable-induced degradation, precipitation, changes in drug product pH, discolouration of the dosage form or packaging component, etc.

Compendia

Any of several official publications that contain legally recognised standards of identity, strength, quality, and purity for drug products, drug substances and excipients. There are over 30 active compendia or pharmacopeias in the world, representing national, regional, or international requirements. The major compendia are generally considered to be the United States Pharmacopeia-National Formulary (USP-NF), the European Pharmacopoeia (Ph. Eur.), and the Japanese Pharmacopoeia (JP).

Compendial Compliance

Meeting the appropriate requirements contained in the general notices, general methods, and individual monographs of one or several compendia.

Compendial Method

An analytical test procedure described in an individual compendial monograph or general chapter. It is the legally recognised procedure used by regulatory authorities to determine compliance with appropriate compendial requirements for drug products, drug substances, and excipients.

See also ‘Regulatory Methods’.

Compendial Monograph

A specific set of tests, procedures, and acceptance criteria published in the compendia as a public standard that helps ensure the identity, strength, quality, and purity for specific drug products, drug substances and excipients.

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Compendial Name

Non-proprietary nomenclature for a drug product, drug substance, or excipient as designated by the compendia.

Compendial Reference Standard

A reference standard supplied by the compendia.

Compendial Requirements

Public standards consisting of tests, analytical procedures, and acceptance criteria contained in the various compendia, in the form of general notices, general chapters, and individual monographs, to help ensure the identity, strength, quality, and purity of medicines.

Compendial Specifications

Tests, methods, and acceptance criteria defined by the compendia in order to determine whether an article may be labelled and marketed as a compendial material.

See also ‘Regulatory Specifications’. Note distinction from ‘Internal Specification’.

Compendial Testing

Performance of one, several, or all of the tests included in the compendia for a drug product, drug substance, or excipient, using appropriate analytical procedures, to ensure compliance with compendial requirements.

Competitive Decision Making

The practice of making timely decisions based on sound scientific facts and good understanding of all risks to be managed associated with the decision.

Complaint Category

A value selected from a list of available options that allows for high level description of the PQC facilitating trending.

Complaint Priority

Complaint categorisation based on risk to user, product quality and government expectation.

Complaint Sample

Any sample of product or packaging components returned by a customer relating to a particular PQC or AE.

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Compressed Gas

Pressurised Gas distributed to manufacturing points of use including but not limited to argon, nitrogen, carbon dioxide, oxygen, clean dry air, process air and instrument air.

Complaints per Million (CPM)

A ratio depicting the reported number of affected containers divided by the number of packaged containers sold/distributed. CPM is the PQC metric calculation for human health products.

Completion of Manufacturing

Usually established as the date at which the active ingredient is added to the formulation unless an exceptionally long cycle time is required due to the dispersed nature of the manufacturing operation across many sites.

In those cases, the manufacturing date can be set as the date of QO release but appropriate stability data should exist on all the intermediates (e.g. granulation, pellets, bulk tablets, etc.) to support the expiry period.

Compliance / Management Plan

The Compliance Plan is a document that outlines all compliance activities on site and is utilised by the Quality Council to monitor progress.

Component

Any ingredient intended for use in the manufacture of a drug product, including those that may not appear in the final drug product. This also includes final container closure systems.

Component (Product Contact)

Any ingredient or raw material intended for use in the manufacture of a drug/biologic product or API, including those that may not appear in such product. Component also refers to container/closure systems used as primary containers for drugs, biologics, or APIs.

Component also means any raw material, substance, piece, part, software, firmware, labelling or assembly which is intended to be included as part of the finished, packaged and labelled device.

Component (Product Contact - Equipment)

Elements or parts of manufacturing or utility systems that contact product, product streams, or product components.

Component Number (Item Number)

Unique identifier for a packaging component.

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Composite Assay

The quantitative analysis for active ingredient, which is determined in a homogeneous mixture of multiple units, typically 10 - 20 units, from a lot as designated in the QSs.

Note distinction from ‘Dose Uniformity’.

Compound(s)

Used as a general term encompassing all categories of materials that must be considered as part of a risk assessment for cross contamination, including intermediates, drug substance/API, and drug product.

Compressing

The process by which lubricated granulation is converted into tablet dosage forms.

Computer System Transaction

A computer system transaction is a single operation or sequence of operations performed as a single logical ‘unit of work’. The operation(s) that make up a transaction may not be saved as a permanent record on durable storage until the user commits the transaction through a deliberate act (e.g., pressing a save button), or until the system forces the saving of data. The metadata (i.e., user name, date, and time) is not captured in the system audit trail until the user commits the transaction.

Computer systems collections of hardware and software components organised to perform a specific function or set of functions.

Computerised System

The term ‘System’ generally refers to information systems, manufacturing automation systems, and laboratory systems that store GMP/GLP data and/or control GMP/GLP processes. These ‘systems’ use a combination of hardware and software to perform a specific GMP/GLP function. A system maybe a simple single application or complex combination of several applications interfaced or depended upon the data from another.

Concurrent Process Validation

The compilation of documented evidence that a process does what it was designed to do based on information generated during actual implementation of the process.

Condensed Process or Condensed Hold Time

A shortened process or hold time used during the sterile challenge/media challenge, which must include all aseptic manipulation and interventions that may occur during routine manufacturing.

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Conditional Use

The use of material on a ‘risk’ basis, concurrent with a parallel function prior to full Quality Release e.g. example, the use of a bulk or intermediate material while the material is undergoing laboratory testing.

Confidence Interval

A range of values, which includes the true value of a population parameter with a given probability.

Confidence Level

The probability that an assertion about the value of a population parameter is correct.

Confidence Limits

The upper and lower boundaries of the confidence interval.

Configuration Control

An element of configuration management consisting of the evaluation, coordination, approval or disapproval, and implementation of changes to configuration items after formal establishment of their configuration identification.

Configuration Identification

1) An element of configuration management consisting of selection the configuration items for a system and recording their functional and physical characteristics in technical documentation.

2) The current approved technical documentation for a configuration item as set forth in specifications, drawings, associated lists, and documents referenced therein.

Configuration Item

An aggregation of hardware, software, or both that is designated for configuration management and treated as a single entity in the configuration management process.

Also referred to as ‘System Element’.

Confirmatory Stability Study

Study intended to confirm an already implemented or approved parameter e.g. limit, process, hold time, expiry and storage condition.

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Confirmatory Test

A test used to verify the initial CCI validation which requires one lot of components that have been processed using the identical manufacturing conditions as previously validated.

Conformance

An affirmative indication or judgment that a product or service has met the requirements of a relevant specification, contract, or regulation.

Consecutive Challenge

The process simulation test is conducted immediately after completion of filling production batches at the end of the routine production campaign; thereby, testing the ability of the system to maintain sterility under the stressed environmental conditions that exist after the end of the filling campaign.

Constitution

The conversion of a powdered dosage form into a solution or suspension by the addition of a liquid. Note distinction from ‘Reconstitution’.

Container Closure

Any well-defined boundary created by one or more components that prevents microbial ingress into a container.

Container Closure Integrity (CCI)

The ability of a package to prevent product loss, to block microorganism ingress, and to limit entry of detrimental gases or other substances, thus ensuring that the product meets all necessary safety and quality standards.

Container Closure Integrity Testing (CCIT)

Any package leak test (either physicochemical or microbiological) that detects the presence and/or size of a breach or gap in a package that is capable of permitting loss of product contents or critical headspace gases, and/or capable of permitting entry of microorganisms, reactive gases, or other substances. The term CCIT is synonymous with ‘package leak test’ or ‘package integrity test’.

Container Closure System (CCS)

The sum of packaging components that together contain, protect, and deliver the dosage form. This includes primary packaging components and secondary packaging components if the latter are intended to provide additional protection relative to product stability to the drug product e.g. foil pouch.

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Container / Closure Integrity Validation

Demonstration that the closure system is integral and capable of preventing microbial ingress under the specified process/storage conditions.

Containers

Any product contact vessels used to hold, store, transport materials, for example drums, totes, carboys, bags, bins, tanks, primary packages e.g. plastic bottles etc.

Contaminant

Any substance present that is not indigenous to the material being examined.

Note distinction from ‘Extraneous Matter’.

Content Uniformity

One of two methods to demonstrate uniformity of dosage units based on the assay of individual content of active ingredient(s) in a number of individual dosage units to determine whether the individual content is within the limits set.

Note distinction from ‘Mass Variation’ and ‘Weight Variation’.

Continued Process Verification (CPV)

Stage 3 of Process Validation - Continual assurance that the process remains in a state of control (the validated state) during commercial manufacture.

Continuous Improvement

The process of continually and incrementally improving controls and documentation for a system over time.

Continuous Monitoring

Uninterrupted environmental sampling throughout the processing period, ensuring that collection of data occurs constantly.

Contract

The legal arrangement detailing all responsibilities and expectations in the manufacture of product owner product by the third parties.

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Contract Laboratory

An external entity that performs analytical testing related to the release, characterisation, qualification, or validation of products, product intermediates, raw materials, and components.

A non-government operated lab performing confirmatory testing for local release of imported products, where required by a specific country's law, is also included in the definition of a contract laboratory.

Contract Manufacturer

An external entity that manufactures owner products or product intermediates in accordance with specifications and/or technology approved by company where the company is the Marketing Authorisation Holder and exerts control over the product and contract manufacturer via a Quality Agreement. In this sense, the contract manufacturer may be considered an extension of the company’s manufacturing operations.

Contract Operations

Manufacturing, packaging, labeling, and/or testing operations performed under contract by external manufacturer where product license owner retains certain legal, quality, and financial responsibilities for the product or service provided and exerts control over the product and contract manufacturer via a Quality Agreement.

See also ‘Contract Manufacturer’.

Contract Personnel

Personnel who are not direct site employees, but are employed on a contractual basis by the company to carry out specific tasks as directed.

Control

A regulating mechanism, which monitors the operation of a machine, apparatus or system.

See also ‘Control Sample’.

Control and Manufacturing Data

The chemistry, manufacturing and control section of an NDA or MAA or Biological License which describes the composition, manufacture, and specifications of both the drug substance and the drug product. This section may also contain a statement as to the environmental impact if the application is approved and the drug produced.

Control Chart

A chart with upper and lower control limits on which values of some statistical measure for a series of samples or subgroups are plotted. The chart frequently shows a central line to help detect trends and shifts of plotted values.

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Control Limits

Statistical control limits are the upper and lower boundaries on a control chart which are used as criteria for signalling the need for action, or for judging whether a set of data does or does not indicate a ‘state of statistical control’.

Control Sample

A typical sample of known value (preferably several months old) of a particular product used as a reference point when performing a test on an unknown sample of that product.

It is used to determine if atypical results are product or test related; a biological sample of known value supplied with certain biological products for concomitant chemical testing to ascertain that the chemical test is functioning properly; an acceptable product, manufactured prior to a production change, which is subjected to the same conditions and tested at the same time as a sample representing the production change under evaluation in a given stability study. Results obtained for test and control samples are then compared and may be used to adjust potency assay value.

Control Strategy

A planned set of controls, derived from current product and process understanding that assures process performance and product quality.

The controls can include parameters and attributes related to drug substance and drug product materials and components, facility and equipment operating conditions, in-process controls, finished product specifications, and the associated methods and frequency of monitoring and control. (ICH Q10).

Controlled Area

An area where the level of microbial and particulate contamination are greatly reduced and measured. Aseptic environments are classified according to the maximum allowed particulate contamination that may exist in the work area.

Controlled Copy

A copy of document reproduced from a master document and its distribution (location or recipient) is tracked so that users can be notified of the availability of a newer version or the retirement of the master document.

Controlled Job Aid

A document that provides step-by-step instruction for completing a GMP task. It is controlled and managed under the SOP management system.

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Controlled Room Temperature

(USP definition): ‘Controlled room temperature’ indicates a temperature maintained thermostatically that encompasses the usual and customary working environment of 20°C to 25°C (68°Fto 77°F); that results in a mean kinetic temperature calculated to be not more than 25°C; and that allows for excursions between 15°C and 30°C (59°F and 86°F) that are experienced in pharmacies, hospitals, and warehouses.

Provided the mean kinetic temperature remains in the allowed range, transient spikes up to 40°C are permitted as long as they do not exceed 24 hours. Spikes above 40°C may be permitted if the manufacturer so instructs.

Articles may be labeled for storage at “controlled room temperature” or at “up to 25°C”, or other wording based on the same mean kinetic temperature. The mean kinetic temperature is a calculated value that may be used as an isothermal storage temperature that simulates the non-isothermal effects of storage temperature variations.

An article for which storage at controlled room temperature is directed may, alternatively, be stored and distributed in a cool place, unless otherwise specified in the individual monograph or on the label.

Controlled Substances Act

The law that regulates the manufacture, distribution and dispensing of drugs which have the potential for abuse as defined by the Drug Enforcement Agency.

Controlled Temperature Unit (CTU)

A storage unit throughout which specific temperature tolerances are maintained via active environmental temperature controls.

Controlled Worksheets

Pre-printed worksheets that are issued in a controlled manner either by a supervisor or a serial number system. Controlled worksheets are tracked to ensure accountability of raw data.

Continued Process Verification

Assuring that during routine production the process remains in a state of control. (FDA Process Validation: General Principles and Practices).

Conventional System

A system which does not meet one or more of the criteria which define a closed system.

Conversion Factor

A mathematical term for a number used to change from one basis to another; the ratio of the molecular weights of two similar compounds used to calculate the amount of one substance from the amount of the other present.

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Correction

Repair, rework etc. of Medical devices. For (Medical) Devices the organisation shall deal with nonconforming product by one or more of the following ways:

by investigating and taking appropriate action to eliminate the detected nonconformity

by authorising its use, release or acceptance under concession

by taking action to preclude its original intended use or application Rework of Medical Devices, means action taken on a nonconforming product so that it will fulfil the specified DMR requirements before it is released for distribution.

Corrective Action(s)

Action taken to eliminate the causes of an existing non-conformity, defect or other undesirable situation in order to avoid recurrence.

Count

The number of tablets, capsules, or units stored in each package type.

Count Chart (c Chart)

An attribute control chart for evaluating the stability of a process in terms of the count of nonconformities occurring in a sample.

Count-Per-Unit Chart

An attribute control chart for evaluating the stability of a process in terms of the average count of nonconformities per unit occurring in a sample.

Counterfeit

Unauthorised use of trademark, trade name, other identifying mark, imprint, or device, or any likeness thereof to adulterate, falsely purport, or represent that the product was manufactured or distributed by the identified manufacturer or distributor.

Cracking

Filmcoating defect characterised by fine lines or breaks in the filmcoating surface.

Cream

Preparation comprised of a viscous liquid or semisolid emulsion. There are two types: oil-in-water and water-in-oil. They are usually applied topically.

Note distinction from ‘Ointment’.

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Crimp

Means of sealing a metal ointment tube, aerosol container, or glass vial; defect where the capsule is pinched or wrinkled.

Critical Area

Grade A aseptic area where the sterilised drug product, containers, and closures are exposed to controlled environmental conditions that were specifically designed to maintain product sterility.

Critical Aspects

Functions, features, abilities, and performance or characteristics necessary for the manufacturing process and systems to ensure consistent product quality and patient safety.

They should be identified and documented based on scientific product and process understanding (ASTM E2500).

Critical Aspects include elements of the system that control a CPP, support assessment of product quality or ensure GMP data integrity. Critical Aspects form the basis of the qualification activities.

Critical Computer Systems

Applications of 1) computers used to control vital manufacturing process parameters, 2) computers used to collect, process, store, or provide information which is used to make product quality related decisions.

Critical Data

Data which is determined to have a high impact on product quality or patient safety. This determination is made via an appropriate risk assessment.

Examples of critical data include:

QC analytical data where the data is used for final product release

Adverse Event data

Critical Excipient

A substance used as a vehicle for a drug product whose quality characteristics can control the quality of the final dosage form.

See also ‘Excipient’.

Critical Functions

Those functions of the system that if they were to fail, not be used, or be removed would adversely impact [affect] the quality of the product and/or its cGMP records of the product.

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Critical Information

Designation for information complete enough to be substantially useful to a competitor and which, if disclosed, would be highly detrimental to the company’s interest.

Note distinction from restricted information.

Critical HVAC Parameters

GMP area HVAC parameters which have the potential to adversely impact product quality e.g. critical room conditions.

Critical Instrumentation

A critical instrument is defined as any instrument employed in the production or testing of bulk pharmaceutical chemicals, drug or biologics product that controls and/or is used to measure a parameter that affects the validation state of the product (i.e. Critical Process Parameters, Critical Quality Attributes) and any other quality parameter designated as such by the site.

Critical Laboratory Systems

Come in contact with the samples and can affect test/data validity or patient safety. These systems require calibration and/or qualification.

Critical, Major, and Minor Defects

Defect categorisation based on impact to user, product quality and government expectation.

Critical Material(s)

Those materials, identified during validation activities, as requiring precise measurement or deemed critical to an API process and/or bulk biologics (e.g. a key intermediate would be considered critical; filter aid would not).

Critical Observation

Audit finding which meets one or more of the following criteria:

product is at risk (identity, strength, purity)

elements of quality system missing

violation to contractual agreements/commitments

recurrence of previous audit findings

fraudulent data/information

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Critical Product Contact Gas Application

Direct or Indirect gas use within Sterile Boundary - Point of use locations, where the gas is released into or from the sterile boundary where sterile gas is required, specifically downstream of the final sterile boundary filtration. The gas filter is the system Sterile Boundary and should be located as close as possible to the sterilised product or sterilised product contact surface in order to minimise the size of the sterile boundary.

Critical Process

A set of interdependent aseptic steps or manipulations involving final sterilised product, aseptically prepared product, or sterilised components utilising the same setup.

Examples range from a single aseptic connection to a product lot fill.

Critical Process Parameters (CPP)

1) A process parameter whose variability has an impact on a critical quality attribute and therefore should be monitored or controlled to ensure the process produces the desired quality (ICH Q8).

2) A process parameter that must be controlled and /or monitored within an established range to ensure consistency and repeatability of the validated sterilisation cycle.

Critical Process Steps

Those manufacturing steps in which operations (i.e. reactions, purifications) are performed that directly impact whether an intermediate or API meets its predetermined specifications and critical quality attributes. Critical Process Parameters (CPPs) and Critical Quality Attributes (CQAs) are identified within these critical process steps.

Critical Processing Area

The area in which aseptic manipulations/incursions are performed that can include aseptic connections, samplings, or additions.

Critical Quality Attribute(s) (CQA)

A critical quality attribute (CQA) is a physical, chemical, biological, or microbiological property or characteristic that should be within an appropriate limit, range, or distribution to ensure the desired product quality (ICH Q8).

Critical RCA

RCA classification denoting a serious observation that would most likely result in a regulatory action and/or market recall.

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Critical Site(s)

Environmental monitoring sites within a critical zone that are monitored during a critical process and reviewed for product lot release.

Critical sites are subdivided into product-contact and non- product-contact sites.

Critical Site Results Review

A process to review critical site testing data and take appropriate action related to product disposition.

Critical Stability Attribute

The particular stability-indicating attribute or test of a high stability risk drug substance or drug product that has demonstrated either a known history of stability issues or an increased risk of stability failure.

Critical Steps

Manipulations associated with process parameters, critical quality attributes and validated manufacturing steps.

Critical Supplier

A single or sole source for an excipient/component, a supplier of an excipient or primary component used in multiple product families or sites.

Critical Surface(s)

Surfaces that may come into contact with or directly affect a sterilised product or its containers or closures; critical surfaces are rendered sterile prior to the start of the manufacturing operation, and sterility is maintained throughout processing.

Critical Zone

A classified area or zone where sterilised product or product-contact equipment or components that are not subsequently subjected to a sterilisation process are exposed. These are Grade A areas.

Cross-Contamination

Contamination of a material or of a product with another material or product.

Crude API

Term used to refer to the API prior to its final purification step.

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Culture Medium (Media: plural form)

Sterilised nutritive substance for cultivating microorganisms.

Cumulative Sum Control Chart

A control chart on which the plotted value is the cumulative sum of deviations of successive samples from a target value. The ordinate of each plotted point represents the algebraic sum of the previous ordinate and the most recent deviations from the target.

Current Good Manufacturing Practices (cGMPs)

Regulations which were enacted into U.S. Federal Law (21 CFR 210-211) to outline the minimum standard that must be met in the manufacture of human and veterinary drugs and devices.

Custom Engineered CTU

Controlled temperature units that require custom assembly on site.

Customer

See ‘External Customer’ and ‘Internal Customer’.

Customer Complaint

Any report registered by a customer communicating displeasure with a product or package.

Customer Feedback

Any written, electric or oral communication by a customer, reporter, medical practitioner or distributor that does not allege a product defect but provides a suggestion or opinion on a product.

Any question, suggestion, or remark regarding a medical device, which may trigger an improvement in the functionality or quality of the medical device.

Customer Interface (CI) / Seller

Serves as the intermediary for communications between the Origin Site and Receiving Sites that do not have Origin Site contact information (i.e. notifies Origin Site when the Receiving Site notifies the Customer Interface (CI) / Seller of a temperature alarm).

Customer Satisfaction

The result of delivering a product or service that meets customer requirements.

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Customer Supplier Partnership

A long-term relationship between a buyer and supplier characterised by teamwork and mutual confidence. The supplier is considered an extension of the buyer’s organisation. The partnership is based on several commitments. The buyer provides long-term contracts and uses fewer suppliers. The supplier implements quality assurance processes so that incoming inspection can be minimised. The supplier also helps the buyer reduce costs, improve product and process designs, and improve product quality.

Cut Label

Printed components containing regulatory text (e.g. labels, inserts, cartons) that are stored as individual units e.g. sheet labels.

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- D -

D Chart

See ‘Demerit Chart’.

D Value

1) The time in minutes required under specific conditions (i.e. temperature) to reduce the spore population by 90% or one logarithm cycle. Prior to initiating product sterilisation studies, the D- value of the challenge organism/product combination must be established and may be utilised to support a ‘worst case’ approach if considering a matrix approach. For gamma irradiation sterilisation, the D- value is described as the dose in MegaRad required to reduce the spore population by one log.

2) The time in minutes required for a one logarithm, (i.e. 90%), reduction of the population of microorganisms under specified lethal conditions, also known as DT Value.

Data

Paper or electronic record that contains Information derived or obtained from raw data. Raw data is a subset of data.

See also ‘Original Record’, ‘Raw Data’ and ‘Records’.

Data Archival

The process of moving data to long term storage in such a way that the authenticity of data records is preserved.

Data archival schemes must include a mechanism for retrieving the data and these schemes must also account for life spans of the media on which the archive data will be stored. This will often include periodic media ‘refreshing’ to preserve the data integrity. Typically (but not always), archived data is ‘off-line’ in that is cannot be inspected or reviewed without first retrieving it in some manner. Provision should be made for purging of archived data at the end of the required retention period. If the lifecycle of the electronic media for storage is shorter than the required retention period, then media ‘refreshing’ must be defined.

Data / Content

Statements of fact (numeric and text), interpretations and conclusions, that can be verified/supported by acceptable source documents.

Examples of numeric data include stability data, assay specifications, and other measured values. Examples of text are product/generic/chemical names, lot numbers, method identifiers, storage information, packaging information, shelf life, manufacturing site information, and process flow diagrams.

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Data Conversion

The process of changing the format or type of stored data. This is typically accomplished using one or more conversion algorithms and may or may not involve a data conversion program. The meaning, accuracy and completeness of converted data are preserved.

Data Integrity

The extent to which all data are complete, consistent and accurate, used to describe the objective and factual status of all data values throughout the data lifecycle.

Data Lifecycle

All phases in the life of the data (including raw data) from initial generation and recording through processing (including transformation or migration), use, data retention, archive / retrieval and destruction.

Data Migration

The process of moving data from one system or medium to another. Data migration may or may not involve data conversion but must include some form of verification of the successful migration.

Date of Manufacture (DOM) for Drug Product

Date on which the expiry assignment is based.

Typically the date when active ingredient is added to formulation, or as defined in registration.

De Minimus Limits

The amount of a compound a patient could be exposed to daily for life without a likelihood of adverse health effects as discussed in Dolan et al. (2005) and ISPE (2010):

≤1 μg/day for compounds that are likely to be mutagenic

≤10 μg/day for compounds that are likely to be potent or highly toxic

≤100 μg/day for compounds that are not likely to be potent, highly toxic or carcinogenic.

Dolan, D.G., Naumann, B.D., Sargent, E.V., Maier, A., and Dourson, M., Application of the threshold of toxicological concern concept to pharmaceutical manufacturing operations. Regul. Tox. Pharm. 43: 1-9, 2005.

ISPE (2010). Risk-Based Manufacture of Pharmaceutical Products (Risk-MaPP) – A guide to managing risks associated with cross-contamination. Chapter 5, Risk Identification. Volume 7. First Edition. September 2010. International Society of Pharmaceutical Engineers (ISPE), Orlando, FL.

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Deadleg

Branches from a main piping path with lengths greater than 6 times the pipe diameter that do not have continuous flow.

Debossed

Imprinted with a mark below the dosage form surface.

Decision Matrix

A matrix used by teams to evaluate problems or possible solutions. After a matrix is drawn to evaluate possible solutions, for example, the team lists them in the far-left vertical column. Next, the team selects criteria to rate the possible solutions, writing them across the top row. Third, each possible solution is rated on a scale of 1 to 5 for each criterion and the rating recorded in the corresponding grid. Finally, the ratings of all the criteria for each possible solution are added to determine its total score. The total score is then used to help decide which solution deserves the most attention.

Decommissioning

The process of retiring a computer application and/or computer hardware from production use.

Note: Upgrading an application is usually not considered a decommissioning activity.

Decommissioning Package

All of the documentation created or assembled as part of the decommissioning process.

This will typically include a System Decommissioning Plan, data restoration test protocols and all other SLC documentation applicable to the system.

Decommissioning / Recommissioning

Actions taken to convert a previously dedicated facility or piece of equipment by cleaning and renovation to allow manufacture of another product.

Decontamination

A process that reduces or removes contaminating substances such as chemical residues, harmful bacteria or other organisms in or on objects to some lower value but not zero.

Dedicated Production / Manufacturing

1) Refers to an area or process where cross-contamination or product dissemination is prevented by restricting operations within the facility or equipment train solely to produce a specific product, while being adequately segregated from other operations. Dedication can be accomplished by using a facility or equipment for its lifetime for one product or product family.

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2) Refers to an area or process where cross-contamination is prevented by restricting operations within an equipment train that is used solely to produce a specific product while being adequately segregated from other operations. Dedication can be accomplished by using a facility or equipment for its lifetime for one product, product family or product type and by prohibiting different products from utilising the same processing facility and/or equipment.

Defect

1) A product’s or service’s nonfulfillment of an intended requirement or reasonable expectation for use, including safety considerations. Quality attributes not met.

2) Any non-conformity found in a unit of product during inspection.

Defined Load Pattern

A load pattern consisting of a collection of Groups of Items with Items from each Group placed in defined locations within the autoclave. All Items within the Group are interchangeable within the assigned locations.

Degradate

A molecule resulting from a chemical change in a substance brought about over time and/or by the action of, e.g. light, temperature, pH, or water or by reaction with an excipient and/or the immediate container/closure system.

Also called ‘Degradation Product’ or ‘Decomposition Product’.

Degradation Product (Degradate)

A molecule resulting from a chemical transformation or decomposition of the active drug substance brought about over time and/or by the action of, e.g. light, temperature, pH, or water or by reaction with an excipient and/or the immediate container/closure system. The term "degradate" is a subcategory of the term ‘Impurities’.

Delayed Release

A modified-release dosage form in which the active ingredient is released some time other than immediately after administration of the drug product.

Deliverable Volume

Test intended to assure that oral solutions and suspensions packaged in multiple-unit containers will, when transferred from the original container, deliver the claimed volume as stated on the label.

Both liquid preparations and liquid preparations that are constituted from solids with a designated volume of a specific diluent are governed by this test’s requirements.

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Delivery Sheets

Delivery sheets also provide storage conditions and other additional information specific to the particular reference standard lot.

Demerit Chart

A control chart for evaluating a process in terms of a demerit (or quality score), i.e. a weighted sum of counts of various classified nonconformities.

Demonstration Lot

Batches or lots manufactured to evaluate a proposed, non-validated process. Lots are manufactured prior to the initiation of a validation study so any inherent problems in manufacturing can be solved. See also ‘Engineering Batch’. Note distinction from ‘Validation Lot’.

Dented

Defect characterised by at least one depression in an otherwise smooth surface.

Dependability

The degree to which a product is operable and capable of performing its required function at any randomly chosen time during its specified operating time, provided that the product is available at the start of that period. Non-operation-related influences are not included.

Dependability can be expressed by the ratio: time available divided by (time available + time required).

Depth and Centering Check

A maintenance function performed on dissolution apparatus, in which the position of the paddle or basket shaft assemblies, relative to the dissolution vessel, are measured and adjusted as needed.

Depyrogenation

Refers to the removal or destruction of Pyrogens from a solution or from a surface intended to have direct contact with product or process operations.

Design Changes

Any modification or alteration of or addition to design inputs and/or design outputs once the design inputs have been approved.

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Design History File (DHF)

A DHF is maintained for each type of device subject to design controls.

It is a compilation of records which describes the design history of a finished medical device. It contains or references the records necessary to demonstrate that the design was developed in accordance with the approved design plan and regulatory requirements.

Design Input

The physical and performance requirements of a device that are used as a basis for device design.

Design of Experiments (DOE)

A branch of applied statistics dealing with planning, conducting, analyzing, and interpreting controlled tests to evaluate the factors that control the value of a parameter or group of parameters.

Design Output

The results of a design effort at each design phase and at the end of the total design effort.

The finished design output is the basis for the Device Master Record.

The total finished design output consists of the device, its packaging and labeling and the Device Master Record.

Design Plan / Project Plan

Documentation that defines the design and development activities and responsibilities for implementation.

Design Planning

The documented and approved activities, deliverables, roles, responsibilities and interfaces, and milestones and/or schedules for any given medical device project.

Design Qualification (DQ) [Design Validation]

Documented verification that the proposed design of facilities, equipment or systems is suitable for the intended purpose.

Design Review

Documented, comprehensive, systematic examination of a design to evaluate the adequacy of the design requirements, to evaluate the capability of the design to meet these requirements, to identify problems, and to propose necessary actions.

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Design Space

Design Space is the multidimensional combination and interaction of input variables and process parameters that have been demonstrated to provide assurance of quality (ICH Q8).

Design Specification

Documentation that provides explicit information about the requirements for a product and how the CCS is to be put together in support of product sterility assurance. A CCS design specification must include all necessary drawings, dimensions, environmental/ storage factors, aesthetic factors, that will be needed to properly identify the CSS prior to validation.

Design Test Report

The summary of Design Testing results to support Qualification development.

Design Testing

A scientific method of evaluating active/passive TPS under controlled conditions to identify components, assembly, and methods to establish the criteria for qualification testing.

Design Transfer

The correct translation of the design specifications into production specification, procedures and requirements.

Design Validation

Establishing by objective evidence that device specifications conform to user needs and intended use(s).

Design Verification

Confirmation by examination and provision of objective evidence that specified requirements (design outputs meet design input requirements).

Designing in Quality vs. Inspecting in Quality

See ‘Prevention vs. Detection’.

Desktop Publishing (DTP) Suppliers

The reference to the internal and external functions for artwork composition. May also be referred to as Labelling or Graphic Designers.

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Detectability

The ability to discover or determine the existence, presence, or fact of a hazard.

Detection

1) Identification and separation of defective product.

2) The ability that the current process controls and/or planned tests and inspections to remove defects or detect failure modes

Detection Limit (DL) or Limit of Detection (LOD)

The lowest amount of analyte in a sample that can be detected, but not necessarily quantitated, under the stated experimental conditions.

Development Studies

Study (or studies) conducted to determine critical process parameter conditions for initial PQ studies.

Deviation(s)

1) An Event requiring an investigation as it may affect the quality of the product, process, equipment or quality management system. Any unexplained discrepancy or the failure of a batch or any of its components to meet any of its specifications.

Deviations require a full investigation in all cases including determination of root cause, trending, CAPA analysis and product impact assessment. Quality formally approves all Deviation investigations.

2) Any unplanned or unexpected direct production, packaging or testing event or result that has the potential to impact the validity of the analytical data or affect product quality.

3) Any unplanned event that may affect product quality.

Device Master Record (DMR)

1) A document that describes how to perform specific functions related to the production of a device including but not limited to product specification, list of components, manufacturing/packaging/labelling instructions and production controls.

2) A compilation of records containing the procedures and specifications for a finished device.

Diagnostic Journey and Remedial Journey

(ASQC) A two-phase investigation used by teams to solve chronic quality problems.

In the first phase, the diagnostic journey, the team journeys from the symptom of a chronic problem to its cause. In the second phase, the remedial journey, the team journeys from the cause to its remedy.

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Diffusive Flow (Test)

A non-destructive test to determine the integrity of a filter.

The movement of a dissolved gas across a liquid-wetted membrane based on the pressure differential is measured.

Diffusive flow test method is better suited to large filters (greater than 10 inches) or multiple filters. The large area allows for more air diffusion through the wetted membrane. If the filter is small, there may not be sufficient air diffusion to be able to reliably measure the flow.

Digital Signature

A digital signature is a type of electronic signature method that employs cryptographic technology to authenticate the individual, verify the signature, encapsulate the signature with the content, and encrypt signed content to confirm that the signed information has not been altered. Public Key Infrastructure (PKI) is one example of a digital signature technology.

Diluent

An agent/liquid added to a product to achieve the appropriate concentration for dosage.

Dilution Factor

Mathematical term for the number expressing the amount of dilution of a standard and sample in a test method. These numbers are used in the calculation to correct the quantity of a substance at the final test level to the basis as it was used initially in the test.

Dioctyl Phthalate (DOP)

A substance that produces aerosol particles of uniform size and weight suitable for integrity and efficiency testing of high efficiency filters.

Direct Impact

A system that has the potential to directly impact product quality or patient safety.

Direct Procurement

The sourcing of all items that are part of finished products, such as raw material, excipients, active pharmaceutical ingredients, packaging components.

Direct Supplier

A supplier of items that are part of finished products, such as raw material, excipients, active pharmaceutical ingredients, packaging components.

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Dirty Hold Time

The time interval between the end of manufacturing to the time cleaning begins.

Disaster Recovery Plan

A written plan that defines back-up facilities, alternate power sources, monitoring and alarm devices, procedures for restarting environmental chambers, data recovery and sample disposition in case of failure of stability chambers and/or units due to a natural or other type of disaster.

Disinfectant

A chemical or physical process that removes, destroys or deactivates microorganism but may not kill bacteria or fungal spores on objects or surfaces.

Disinfection

The process of using an agent that destroys disease or other harmful microorganisms but may not kill bacterial spores. Certain cleaning agents can act as disinfectants.

Disintegration

The breaking up of a tablet or bolus into separate particles so that it becomes a soft mass with no palpable core.

Disintegration Test

The measurement of the time required to cause the physical change from a normal tablet or bolus to a soft mass with no palpable core when subjected to specified test conditions using the disintegration apparatus as described in the compendia.

See also ‘Disintegration Time’.

Disintegration Time

The time required for a tablet to change to a soft palpable mass, when placed in a disintegration apparatus containing the appropriate immersion fluid.

Dispensing

The allocation of material (e.g. raw material, API, excipient) to a specified manufacturing batch, or to a work/processing order as defined by the batch record or Bill of Materials.

Disposable Aseptic Connector (DAC)

A single use device designed to enhance the assurance of a sterile connection between two separate, pre-sterilised components, an example of an advanced aseptic technique

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Disposition

What happens to data, documents, hardware and software after the computer system is decommissioned. Data disposition may include archiving, migrating, converting or purging; document disposition may include storing/archiving or purging; hardware disposition may include retiring, replacing or continuing in production use; software disposition may include storing/archiving or purging.

Dissolution Test

A measure of drug release by an analytical method of the rate at which the active ingredient dissolves in the dissolution medium when subjected to the specified test conditions. The test conditions include medium description, volume, and temperature, type of dissolution apparatus, rotation speed of stirring element and sample time. The dissolution test is very sensitive to formulation factors and the data from it can be used to monitor variations in manufacturing and the impact of process changes.

Dissolution Time

Usually expressed in minutes, the length of time a dosage form is subjected to dissolution testing and the time at which sampling is performed. Acceptance criteria will specify the percent dissolved at a given dissolution time.

Distribution Filter

A sterilising grade compressed gas filter located downstream of the source filter and either in a classified room or outside a classified area e.g. processing suite.

Distribution Temperature

The temperature range, supported by stability studies, within which a product can be transported for a short duration of time without adverse effect on product quality.

Distributor

Distributes a product under custom or own label. The product is manufactured and/or labelled by a registered establishment.

Distribution Thermocouples

Thermocouples, which are placed inside a system in order to determine temperature uniformity and control throughout the process.

Diversion

The transfer or sale of products or materials outside of their intended distribution channels that result in a violation of a law or contract.

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DMAIC

Define, Measure, Analyse, Improve, Control (5 phases of 6-Sigma projects)

DMR Index

Is a table of contents that represents a compilation of records containing device-specific procedures and specifications used to produce and evaluate a finished device.

Document Accuracy

Free from mistakes or errors that could change the content or meaning; data represents the true values obtained and the record is correct in the reported steps/actions performed.

Document Completeness

All required data are recorded and all required steps have been performed to include recording of all relevant actions and occurrences.

Document Development

Initial document preparation by an author (initiator/originator).

Document Effective Date

The date by which the document must be in use.

Document Execution

Use of the document for its intended purpose and includes data entry in support of the process being documented.

Documented Emergency Change

An immediately implemented change made to a batch sheet and insert sheet/form to address a short-term processing problem or equipment failure and generally impacting only one batch.

Documented Pre-Approved Change

A change made to a Working Master Batch Sheet or on a per batch record basis intended to be used regularly for future batches excluding format and typographical errors. Approval of a change request that then results in changes to a batch record is considered documented pre-approval. Changes that have no processing or product quality impact but may related to safety or environmental issues are considered pre-approved changes.

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Dosage Form

Finished or partially finished preparation or product of one or more official substances formulated for use on, or for, the patient e.g. tablet, capsule, ointment.

Dose Uniformity

See ‘Uniformity of Dosage Units’.

Double Wall (Plate) or Double Tube Sheet Heat Exchanger

A type of heat exchanger that does not allow the intrusion of the heating/cooling medium into the process stream and is fully drainable on the process side.

Drift

The change in a chromatographic baseline with respect to time.

Drug Delivery Systems

Is a system for transporting a pharmaceutical compound in the body as needed to safely achieve its desired therapeutic effect.

Drug Master File (DMF)

A compilation of pertinent information submitted to the FDA by a company, which describes the facilities and operating procedures used to manufacture and/or package a drug substance or drug product. The DMF eliminates the need to provide standard information used in all NDAs or biological licenses e.g. lot numbering convention, quarantine procedures, etc., in each submission.

The FDA does not approve all or part of the DMF. Rather, they review information only when it is referenced in an NDA. If discrepancies are found, the holder will be notified at that time. The DMF may be referenced by the holder in his own applications, or the holder may authorise others to rely on the information as part of their applications. Information contained in the DMF is available to the FDA only. Others who are authorised to reference the document are not authorised to have access to the file.

Drug Product

The dosage form in the final immediate packaging intended for marketing (from ICH Q1A).

Drug Product Excipient

See ‘Excipient’.

http://en.wikipedia.org/wiki/Pharmaceutical

http://en.wikipedia.org/wiki/Therapeutic_effect

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Drug Product Intermediate

A material containing the drug substance that is produced during the manufacturing process for a drug product, which is not the drug product, but is used in the subsequent manufacturing steps towards the drug product.

Drug Product Listing

A list of every drug in commercial distribution, including bulk drug substances and Type A articles for use in the manufacture of animal feeds, as well as finished dosage forms, by established name and by proprietary name.

Drug Product Reclamation

Taking rejected product and trying to reclaim it as good material (e.g. re- metal detection of rejected tablets from metal detector, re-check weighing of rejected capsules from check weigher, re-inspection of rejected vials due to product defects, etc.).

Drug Release

USP test which measures the dissolution profile of extended-release or enteric coated items; the disassociation of a drug from its formulation thereby allowing the drug to be distributed into the skin or be absorbed into the body where it may exert its pharmacological effect.

Drug Substance

Any substance or mixture of substances intended to be used in the manufacture of a drug (medicinal) product and that, when used in the production of a drug product, becomes an active ingredient of the drug product. The drug substance may be produced by chemical synthesis, fermentation, recombinant DNA processes, extraction, or recovery from natural materials or any combination thereof, and is not further chemically modified, but may be subsequently formulated with excipients to produce the drug product. Such substances are intended to furnish immunological or pharmacological activity or other direct effect in the diagnosis, cure, mitigation, treatment, or prevention of disease or to affect the structure and function of the body.

Drug Substance Intermediate

A material produced during the manufacturing process for a drug substance whose manufacture is critical to the successful production of the drug substance or the drug product. Intermediate material may undergo further molecular or physical modification or be held for an extended period of time prior to further processing.

Dry Heat Sterilisation

Processes that use dry heat technology for the purpose of achieving sterilisation.

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Due Diligence Audit

An inspection/assessment performed for a business unit to determine the potential of a new firm to perform a specified service or supply specified materials.

Durham-Humphrey Statement

Precaution required to appear on the carton and label of all prescription drugs.

It states: CAUTION: Federal (USA) law prohibits dispensing without prescription.

Dynamic Alarms

Alarms which are modified (e.g. inactivated, set point changed) via computer sequencing to reflect changing process conditions (e.g. alarm may be critical during only one phase of the operation).

Dynamic Testing (In Operation)

Confirms that the environment remains under control during processing or within an active shift. Environmental monitoring is normally to be performed dynamically except when static testing is required e.g. part of a requalification procedure, where process is particle generating, etc.

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- E -

Early Warning System (EWS) (also Real Time Stability Trend Monitoring)

An approach to active, real time monitoring of stability trends implemented at stability testing sites to detect aberrant results and trends in a timely manner at time of data generation, and to ensure appropriate action and notification upon identification of aberrant data and trends.

EEC Guidelines

EEC Guide to Good Manufacturing Practice for Medicinal Products

Effective Filtration Area

The total surface area of the filter available to the process fluid.

Ejects

Output from an inspection system that is not accepts or rejects.

Examples of eject populations are ‘Uninspected’ containers on automated equipment or the container population from the first pass of a two-pass process that must proceed to the second pass for the accept/reject decision.

Electronic Identity Evidence (EIE)

The necessary actions and collection of data/information to assure the identity of an individual and when connected to a document or data/information, the level of authenticity on an electronic transaction necessary for business transactions.

This evidence should be sufficient to establish the identity of the individual (such as userid and password).

Note: an EIE is not equivalent to an electronic signature as defined by FDA regulation 21 CFR Part 11.

Electronic Record(s) (Electronic Data)

Any combination of text, graphics, data, audio, pictorial, or other information representation in digital form that is created, modified, maintained, archived, retrieved, or distributed by computerised system. See also Data; Original Record; Raw Data.

Electronic Signature

An electronic signature is a generic technology neutral term defined as a computer data compilation of any symbol executed, adopted or authorised by an individual, generated within certain systems/applications and associated with a specific ceremony, to be the legally binding equivalent of the individual’s handwritten signature.

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The Electronic signature serves as a method of authentication for the identification of the undersigned, and indicates the acknowledgment of the undersigned with regard to the contents in said electronic data.

Electronic Verification System

Electronic or electro-mechanical device or equipment that verifies one or several packaging processes have been successfully completed on line.

The Electronic Verification System must have automated response actions that are capable of performing individual product rejection or stopping the packaging line.

Elegance Evaluation

A statistical, visual assessment of material for appearance acceptability at any step during the manufacturing or packaging process.

Elixirs

Oral dosage form comprised of clear, sweetened, hydroalcoholic liquids.

In addition to the active ingredient, most elixirs also contain flavours.

Embossed

Imprinted with a mark raised above the dosage form surface.

Emergency Change

An immediately implemented change made to a batch sheet to address a one-time processing problem or equipment failure and generally impacting only one batch. An operator, supervisor or shift engineer normally makes these changes. Changes that impact future batches are considered pre-approved changes and must follow the appropriate guidelines for approval.

Employee Involvement

A practice within an organisation whereby employees regularly participate in making decisions on how their work areas operate, including making suggestions for improvement, planning, goal setting, and monitoring performance.

Empowerment

A condition whereby employees have the authority to make decisions and take action in their work areas without prior approval.

For example, an operator can stop a production process if he detects a problem or a customer service representative can send out a replacement product if a customer calls with a problem.

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Emulsion

A system in which small droplets of one liquid are dispersed in a second immiscible liquid.

End-Market Inspection

Subjecting material that has undergone 100% visual inspection during manufacturing to a second 100% inspection in the end-market to satisfy market specific expectations.

End-market inspection is not performed to address a deviation.

Endotoxin Challenge

A system containing bacterial endotoxin of known concentration that can be expected to follow a predictable rate of degradation when exposed to particular physical parameters.

Example Escherichia coli (E. coli) Lipopolysaccharide (LPS).

Endotoxins

High-molecular-weight complexes associated with the outer membrane of gram negative bacteria. Endotoxins are common Pyrogens.

Engraved

Imprinted with a code that is cut into the dosage form surface after it has been completed.

Engineering Batch

A production scale batch manufactured in the intended commercial production facility with the intent of evaluating and/or optimising the process.

This batch or batches are generally not intended for sale thereby giving freedom to adjust the process as necessary.

Equilibration Time

The period that elapses between the attainment of the minimum sterilisation temperature at the reference measurement point and the attainment of the minimum sterilisation temperature at all points within the load.

Equipment Qualification (EQ)

Documented evidence that provides a high degree of assurance that equipment and systems meet the critical installation and operational requirements necessary to ensure consistent product quality.

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Equipment Suitability

Establishing confidence that process equipment and ancillary systems can consistently operate within established limits and tolerances.

Equipment / Instrument Logbook

A bound notebook with pre-numbered pages that is used to chronologically record the routine usage and associated calibration/maintenance activities, related to a specific equipment/instrument, as they occur by the respective individuals performing the activity.

Equivalency Study

The manufacturing of one batch with validation testing throughout each appropriate step of the manufacturing process. The equivalency lot must be bridged back to the most recent prospective validation study.

Established Name

FDA recognised, non-proprietary nomenclature for a substance.

It may be either the compendial name of the drug, or if there is no compendial name, the common or usual name as listed in USAN and the USP Dictionary of Drug Names.

Establishment

A place of business under one management at one general physical location.

An establishment is defined as each individual site in CFR §207.3(b).

Establishment Inspection Report

A report that is issued by the FDA at the completion of an inspection of a facility.

EIRs of any facility inspected by the FDA can be obtained under the Freedom of Information Act.

EtO Sterilisation

Sterilisation of items, typically heat or gamma sensitive, via exposure to ethylene oxide gas in a sealed chamber.

A typical cycle would include air removal, conditioning (temperature and humidity) of the load, injection of sterilant, exposure to ethylene oxide (dwell), removal of ethylene oxide, and aeration.

EU Annex 11

Computerised Systems, refers to the European Commission's Good Manufacturing Practices (GMP) guidelines for computer systems used in manufacturing of medicinal products.

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European Pharmacopoeia (official abbreviation: Ph. Eur.; common abbreviation: EP)

Official compendium of standards in Europe for assurance of the identity, strength, quality, and purity of drug products, drug substances, and excipients; published officially in both English and French.

The Ph. Eur. includes general monographs on dosage forms which are applicable to all drug products of the type defined.

Event

Any and all unexplained discrepancies or unplanned events resulting in a departure from current Good Manufacturing Practices (cGMPs), Standard Operating Procedures (SOPs), manufacturing/testing instructions, validation or other GMP protocols, product or material specifications/limits and/or regulatory requirements.

Events include product, process and quality system non-conformances.

Excessive Heat

Any temperature above 40°C (104°F).

See current USP General Notices: Preservation, Packaging, Storage and labelling.

Execution Date

The first event at which material is manufactured/packaged with the proposed change and accompanying requirements.

Excipient

Any substance other than the API which has been intentionally included in a drug delivery system; a component constituent forming matrix of a drug product, which acts as a vehicle for the active ingredient.

Excursion

A result that is equal to or greater than an alert or action level.

Experimental Design

A formal plan that details the specifics for conducting an experiment, such as which responses, factors, levels, blocks, treatments, and tools are to be used.

Expiration Date

The date placed on the container label of a drug product designating the time prior to which a batch of the product is expected to remain within the approved shelf life specification if stored under defined conditions, and after which it must not be used.

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Expiration Dating Period / Expiry Period

See ‘Shelf-Life’.

Exposure Phase

The phase of the sterilisation cycle in which the appropriate parameters are maintained within a defined range for the time and temperature determined to be necessary to achieve the desired lethality.

Synonym: Dwell Time, Dwell Period.

Extended Release

A modified-release dosage form, which reduces the dosing frequency by at least one- half, as compared to the conventional, dosing regimen for that drug product.

External Customer

A person or organisation who receives a product, a service, or information but is not part of the organisation supplying it.

See also ‘Internal Customer’.

External Manufacturer

An External Manufacturer is defined as a company who manufactures, tests or packages regulated intermediate or finished pharmaceutical, biological, or Medical Device products for commercial end-markets on behalf of the Marketing Authorisation holder.

Business arrangements include: contract manufacturers, business alliance agreements, joint ventures. Licensees are excluded.

External Partner (ExP)

An External Partner is defined as a company that is a business partner who manufacture, test, package or distribute regulated intermediate or finished pharmaceutical, biological, or Medical Device products for commercial end-markets, but in addition is under a specific type of business arrangement such as: product license arrangements, contractual business alliance agreement, joint venture, public private partnership, acquisition etc.

External Party (EP)

Contract manufacturers and/or packagers for Marketing Authorisation holder of both sterile and non-sterile API's, intermediates, bulks and finished dosage forms of drug products, biologics, drug delivery systems and medical devices.

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Extractables (E)

Chemical compounds that are removed from a material by exertion of an artificial, exaggerated force e.g. solvent, temperature, or time.

This is a material specific characteristic and is independent of the drug product with which the material is used.

Extraction Sample

A solvent sample in which a small piece of manufacturing or packaging equipment e.g. filling needle, has been soaked.

Extraneous Matter

Any material or compound, including leachates, chemical or any substance, such as metal, plastic, glass, rubber, wood, etc., that is not either:

1) An intended product component

2) A known (though not necessarily identified) process impurity or degradants.

Extraneous matter may be either extrinsic (foreign to the process) or intrinsic (inherent to the process) whether visible, sub visible, soluble or insoluble.

For the purposes of this definition, extraneous matter does not include microbiological contaminants, product / formulation agglomerates, precipitates, and/or charred product.

Extraneous Matter Contamination

Contamination of drug product by foreign material e.g. dust, dirt, fibres, originating from external environments such as the outdoors or adjacent areas such as mechanical space or interstitial building space.

Extrapolation

The use of the statistical model to infer or imply the performance of the dependent variable (e.g. assay) when the independent variable (e.g. age of batch) is outside of the range that has been studied.

An example is the statistical projection of the stability trend beyond the available real time stability data, as allowed per ICH Guideline Q1E.

Extrinsic

As defined in USP <1788> - additive, foreign, and unchanging, and not part of the formulation, package or assembly process.

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F0

The measure of the microbial kill capability of a saturated steam sterilisation process. The F0 is calculated by integrating the time and temperature heating conditions of the product/component to be sterilised in terms of equivalent time at 121.1°C using a Z value of 10.0°C.

F-Value

A measurement of sterilisation effectiveness. The lethality factor (F-value) is the calculated equivalent lethality in terms of minutes at a reference temperature delivered by a sterilisation cycle to the system.

Facility

A general term used to signify the immediate buildings and equipment used to process a drug product, biologics or API.

Factory Acceptance Test (FAT)

Testing activities conducted at the vendor/supplier facility. FAT may include any combination of unit, integration, or system testing.

Factory / Facility Distribution

The section of the water system that starts at the factory/facility take-off from the site system and ends at the point-of-use.

Fail Safe

A mode of operation whereby the system considers the inspection a failure unless it is verified to be good. Also the design is to default to the safest mode in an event of an identified failure.

Failure

1) Event in which an article does not perform one or more of its required functions within the specified limits under specified conditions

2) The condition or fact of not achieving expected results

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Failure Mode Analysis (FMA)

A procedure to determine which malfunction symptoms appear immediately before or after a failure of a critical parameter in a system. After all the possible causes are listed for each symptom, the product is designed to eliminate the problems.

Failure Mode Effects Analysis (FMEA)

A systematic method for identifying, analysing, prioritising, and documenting potential failure modes, their effects on system, product, and process performance, and the possible causes of failure in order to prevent defects from occurring. (PDA Technical Report 54).

Failure Mode Effects and Criticality Analysis (FMECA)

A procedure that is performed after a failure mode effects analysis to classify each potential failure effect according to its severity and probability of occurrence

False Alarm

Any temperature monitor alarm condition that does not represent actual temperature and time exposure outside allowable limits during transportation e.g. excursion data obtained post shipment receipt.

False Rejects

Containers meeting all pre-determined specifications that are rejected during the inspection process.

Falsified Medicinal Product:

Any medicinal product with a false representation of:

Its identity, including its packaging and labelling, its name or its composition as regards any of the ingredients including excipients and the strength of those ingredients

Its source, including its manufacturer, its country of manufacturing, its country of origin or its marketing authorisation holder; or its history, including the records and documents relating to the distribution channels used. This definition does not include unintentional quality defects and is without prejudice to infringements of intellectual property rights. [Article 1(33)]

Family Matrix

A grouping of different strengths of the same product, or multiple pieces of identical equipment that have been demonstrated to be equivalent during qualification.

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Federal Register

A daily publication by the Office of the Federal Register, National Archives and Records Administrations, which makes available to the public, regulations and legal notices issued by Federal agencies. Notices are published to request comments, enact regulations, fulfill congressional acts and provide general information.

Feedwater

Water complying with US EPA NPDWR drinking water quality specifications or comparable regulations of the European Union, Japan, World Health Organisation, or other applicable regulatory body. This is the water that feeds the pre-treatment system of a high purity water system.

Fermentation System

System includes the fermentor and bioreactors used in cell culturing, the peripheral piping and vessels dedicated to support the fermentor/bioreactor.

Field Alert

The applicant shall submit information of the following kinds about drug products or articles to the FDA district office that is responsible for the facility involved within three working days of receipt.

Information concerning any incident that causes the drug product or its labeling to be mistaken for, or applied to, another article. Information concerning any bacteriological contamination, or any significant chemical, physical, or other change or deterioration in the distributed drug product, or any failure of any one or more distributed batches of the drug product to meet the specifications established for it in the application.

FIFO

Abbreviation for ‘First In, First Out’, which is materials management procedure whereby the oldest lots are processed and distributed first.

File Sample

A sample of an appropriate quantity of units collected after secondary packaging used to investigate issues concerning packaging operations such as label adherence, missing or incorrect lot and expiry, and other types of packaging defects. File samples should not be used as retention samples or should not be collected with the intention of testing them as retention samples.

Fill

An Rx, or the portion of an Rx, of biological or sterile pharmaceutical product placed into ampoules, bottles, vials, etc. during a given period; the actual number of tablets or capsules, volume of elixir or syrup, or weight of non-sterile powder placed in a primary container.

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Fill-In

Filmcoating defect that occurs during the filmcoating process whereby the engraving on the tablet is difficult to read or illegible due to the collection of the coating solution into the engraving.

Note distinction from ‘Bridging’.

Filling Operation

The procedure by which a product is placed into bottles, blister cards, tubes, vials, etc.

Film Coated Tablet

Compressed tablets, which are covered with a thin layer or film of solvent or water- soluble material.

Filmcoating

The manufacturing process during which a thin, usually coloured coating is applied to the exterior surface of a pellet or compressed tablet.

Filter (noun)

A device used to remove particles from a fluid process stream that consists of a porous medium and a support structure.

Filter (verb)

To pass a fluid through a porous medium whereby bacteria or other particles are removed from the fluid.

Filtration

The process by which particles are removed from a fluid by passing the fluid through a porous material.

Filtration Time

Total time that a process fluid flows through the filter.

Final Bulk Product

The final drug product after chemical or biological processing and purification, ready for concentration, drying, and filling into containers prior to dispensing and final filling.

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Final Intermediate

The last compound isolated and controlled during the manufacturing process, before the final step that produces the drug substance. There may be more than one final intermediate depending on the nature of the synthesis or process. The final step forming the drug substance must involve covalent bond formation; ionic bond formation (i.e. making the salt of a compound) does not qualify. In addition, the final step forming the drug substance should not involve reactions that form hydrates, solvates, or deprotect.

Final Printed Labelling

Actual printed labelling components available for use in packaging operations.

Final Rule

A standard or law, which has been enacted by a government agency after a period of open debate.

Final Treatment System

The Final Treatment System begins after any microbial control agent (e.g. chlorine) is removed from the system and includes unit operations for improving the quality of the water to achieve the final, desired purity.

Examples of final-treatment include distillation, reverse osmosis and ultrafiltration. Final treatment may consist of several steps comprising the primary purification step, followed by one or more polishing steps to provide a higher degree of assurance of quality. An example is reverse osmosis followed by continuous deionisation.

Finding

A conclusion of importance based on observations.

Fingerprint Batch

A batch of drug product manufactured at a minimum of 1/10th of proposed manufacturing scale or 100,000 units (theoretical), whichever is greater, and by the manufacturing process intended to be used for the marketed product. This batch is subjected to extended testing to provide a full characterisation dataset to facilitate bridging between product used during development and the marketed commercial product. Biobatch requirements may be fulfilled by use of developmental fingerprint batches, only as an exception, and in absence of a linkage to clinical performance i.e. where a biowaiver is used for an intermediate potency. Fingerprint batches should not be referred to as biobatches in WMA submissions.

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Finished Dosage Forms

1) See ‘Bulk Drug Product’

2) A drug or biologic product in its final dosage form, including for example bulk sterile powders, bulk vaccines, solution products in sealed but unlabeled ampoules/vials/syringes, and unpacked solid dosage forms.

Finished Goods Code

A unique identifier for each distinct finished product.

Finished Market Images

The complete package including all product and packaging components that comprises the saleable unit.

Finished Product

A drug product or finished medical device that has undergone all stages of production and is packaged in its final container/closure system.

Finishing Step

Steps in API production from the point of final filtration forward to the bulk packaging operations.

First Air

Air that has passed through a HEPA or equivalent filter within a classified area, and which arrives at the location of the product (or product-contact material) within Grade A, without first contacting any other surface or potentially contaminating object. In this way, the filtered air is minimally likely to carry contamination to the product.

Fishbone Diagram

See ‘Cause-and-Effect Diagram’.

Fitness for Use

A term used to indicate that a product or service fits the customer’s defined purpose for that product or service.

Fixed Load Pattern

A load pattern consisting of a unique, specified collection of Items with each Item placed in a defined location within the autoclave.

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Flat Files

A 'flat file' is an individual record which may not carry with it all relevant metadata e.g., pdf, txt, csv, dat, doc.

Flow Rate

The volumetric rate of flow of a solution, expressed in units of volume per time e.g. L/min or g/day.

Flowchart(s)

A graphical representation of the steps in a process. Flowcharts are drawn to better understand processes. The flowchart is one of the seven tools of quality.

Food and Drug Administration

Agency of the federal government responsible for assuring the safety and efficacy of foods, drugs and cosmetics. As a branch of the government, it establishes and enforces the laws, which regulate these substances.

Food Chemicals Codex (FCC)

An official publication that contains recognised standards for the quality of food-grade chemicals in terms of identity, strength and purity.

Foreign Operations Control Number

See ‘Product Information Notice (PIN)’.

Foreign Matter

Substance, which is not characteristic of the material in which it is found.

Foreign Tablet or Capsule

Any tablet or capsule found in proximity to but differing from an identified in- process lot.

For Information Only

A designation indicating that a test is performed to acquire additional knowledge about an intermediate product or process capability but is not a release criteria.

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Force Field Analysis

A technique for analysing the forces that aid or hinder an organisation in reaching an objective.

An arrow pointing to an objective is drawn down the middle of a piece of paper. The factors that will aid the objective’s achievement, called the driving forces, are listed on the left side of the arrow.

The factors that will hinder its achievement, called the restraining forces, are listed on the right side of the arrow.

Form

A standardised document with blank fields for insertion of data or information. It serves to organise, codify or summarise data/information in the execution of a GMP task. Worksheets and templates are analogous terms.

Formal Stability Studies

Long term and accelerated (and intermediate) studies undertaken on primary and/or commitment batches according to a prescribed stability protocol to establish or confirm the retest or expiry period of a drug substance or the shelf life of a drug product.

Formulation

A listing of the ingredients and composition of the dosage form.

Forte

Designates the higher potency of an existing product for which there is more than one strength.

482 (Form FD482)

Notice of inspection form presented by an U.S. Food and Drug Administration inspector prior to an inspection.

483 (Form FD483)

Colloquial expression for specific observations made by a FDA investigator during an inspection. The term originates from the number of the government form upon which such observations are noted. The observations represent the opinion of the investigator that conditions observed may, after all pertinent facts are reviewed, be classified by the FDA as violations.

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Fractional Times

The exposure time (or dosage) that allows some of the biological indicators to survive and some of the biological indicators to be destroyed. Fractional time (or dosage) results are required to calculate a D-value.

Freedom of Information Act

The US law defining the disclosure of records or information held by a government agency. A written request to that agency is recorded in the public log as well as the requester, nature of the request, action taken on the request and any information supplied as a result of the request. The agency makes the distinction between disclosable and non-disclosable information and attempts to distribute only disclosable information.

Frequency

The period between scheduled calibrations.

Frequency Distribution

A quantitative analysis determined by ranking all of the data for commonly classified areas or systems respectively from the lowest result to the highest result and using a percentage to determine an alert level or action level criterion.

Friability

Ease by which a substance may be chipped, eroded or broken by impact.

Frit

A small screen of fine porosity, which is fitted to the front and back of an HPLC column for the purpose of containing the packing material.

Full Production Cycle

The full-length cycle for a load, based on evaluation of typically three to four fractional cycle studies, which allows for a safety margin in terms of sterilisation. If an “overkill” cycle is being validated this cycle ensures that the product achieves a sterility assurance level of at least 10-

6 and a theoretical lethality of at least a twelve log reduction.

Full Validation

A prospective study with validation testing throughout each appropriate step of the manufacturing process.

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Functional (Black-Box) Testing

Testing that ignores the internal mechanism of system software or a software component and focuses solely on the outputs generated in response to selected inputs and execution conditions. Testing conducted to evaluate the compliance of the system with specified functional requirements.

Funnel Experiment

An experiment that demonstrates the effects of tampering.

Marbles are dropped through a funnel in an attempt to hit a flat-surfaced target below. The experiment shows that adjusting a stable process to compensate for an undesirable result or an extraordinarily good result will produce output that is worse than if the process had been left alone.

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Gamma Irradiation

A method of sterilisation, which may be used on items, which are heat sensitive. The components are placed in a chamber with Cobalt-60 which emits gamma radiation to kill microorganisms.

Gang Printing

Gang-printed labelling means labelling derived from a sheet of material on which more than one item of labelling is printed i.e. taking several print jobs together on the same sheet or the lining-up of several print jobs together on large single runs.

Gas Chromatography

A chromatographic method of analysis in which the mobile phase is a gas. The stationary phase is usually a liquid but may be a solid or a combination of solid and liquid.

The sample is vaporised upon introduction to the system.

See also chromatography.

Gel

A semi-solid system in which a liquid phase is constrained within a three dimensional, cross-linked matrix. The drug substance may be either dissolved or suspended within the liquid phase.

General Stability Protocol (GSP)

A guidance document that outlines the regulatory stability testing requirements for the on-going stability program for a drug substance or finished product, for use as the basis for batch-specific stability study protocols.

The GSP should be specific to a given active ingredient and dosage form/material type, and must include at minimum the specific tests required, test method references, storage conditions and stability testing intervals. The study protocol requirements and schedules for initial production/validation, major process changes, routine long-term studies and accelerated studies are outlined, as appropriate.

Generic

Pertaining to a general characteristic of a group or class. The term is frequently used in place of ‘non-proprietary’ when discussing drug nomenclature.

Note distinction from ‘Generic Equivalent’ and also ‘Generic Name’.

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Generic Equivalent

A drug product sold under its non-proprietary name and usually manufactured by a company other than the innovator, which is considered to be both pharmaceutically and therapeutically equivalent to the innovator’s product.

Generic Name

A non-proprietary designation for a drug substance or product, which identifies that substance or product and may be used by the public free from the restrictions associated with registered trademarks.

See also ‘Non-Proprietary Name’.

Glass Breakage Event

Any event during washing, depyrogenation, filling, lyophilisation, or any other processing step with open containers that causes glass final product containers to be

1) completely broken and/or

2) create loose glass fragments

The identification of a damaged container with missing glass during the operations listed above has the potential to create loose glass fragments and therefore is considered a glass breakage event. Loose glass fragments identified with or without a known cause during the operations listed above are also considered a glass breakage event.

Multiple containers broken at the same time due to the same mechanism are considered a single glass breakage event.

Cracked glass containers are not classified as a glass breakage event unless the cracked container is also missing glass in which case it should be treated as a glass breakage event.

The following are examples which are not required to be classified as a glass breakage event because they do not create the potential for glass intrusion in the final product containers:

1) Broken glass containers or glass fragments created during capping/sealing, final container inspection or any other closed container processing step. For this Standard a closed container is a container that has been fully stoppered (vial, syringe or cartridge) or sealed (ampoule) such that there is no potential for glass intrusion.

2) Broken glass containers or glass fragments located in reject bins.

3) Dropped glass containers that break below line operating levels where there is no concern for glass intrusion into glass containers.

4) Broken glass created during a manual line clearance.

5) Broken glass identified prior to loading of empty containers on to the filling line.

6) Broken glass containers or glass fragments identified while performing cleaning, maintenance or set-up activities if rationale or procedures can establish segregation between manufacturing and these activities (e.g. documented line walk down to verify absence of broken glass containers or glass fragments at end of manufacturing).

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GMP Activity

Any activity that has a direct impact on product quality, integrity, purity and or safety of the product.

GMP Alarms

Automated alarms for in-line instruments on GMP equipment/facilities and GMP product contact utilities (e.g. high purity water, clean steam, compressed gases, HVAC etc) that are associated with parameters that help ensure product quality and regulatory compliance for manufacturing, packaging and warehouse facilities.

There are two sub-categories of GMP alarms: Quality Critical Alarms and Quality Non-Critical Alarms.

GMP Area

1) Any area used in the manufacture, processing, packing, testing or holding of a pharmaceutical product, active pharmaceutical ingredient, or vaccine product, their ingredients, or any component thereof.

2) Any area used in the manufacture, processing, packing, holding, transporting and testing of Active Pharmaceutical Ingredients (API), bulk, intermediates and finished dosage forms of drug products, biologicals and medical devices or combination thereof.

GMP Documents

Records that provide evidence of and support product quality, conformance to cGMPs, and compliance to the corresponding regulatory filings.

Includes, but is not limited to, batch records/sheets, laboratory test records, atypical investigations, preventative maintenance records, calibration records, qualification (IQ, OQ, and PQ) and validation documents, warehousing records, operations procedures and System Life Cycle documentation.

GMP Equipment

All equipment that affects product safety, efficacy, suitability for use, or product performance to pre-defined specifications is considered to be GMP equipment.

At a minimum this includes equipment that comes in contact with product during processing, provides process or finished product control and/or measures process or finished product performance.

In general, GMP equipment includes equipment intended for contact with the manufacturing and/or packaging process; equipment used in controlling and maintaining environments for manufacturing and quality operations; equipment used for the storage of raw materials, intermediates, products, and market package components if such storage and environments are considered critical to maintaining product quality and equipment used for raw material in-process performance monitoring or finished product laboratory testing.

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GMP Inspection

The act of verifying the conformance of facilities, processes, manufacturing systems, procedures, material, structure, component or system to Good Manufacturing Practices requirements.

GMP Job Related training

Any additional training that is relevant to the job to ensure that a safe, pure and effective product reaches the market e.g. Standard Operating Procedures training or periodic review, job skills training including: on-the-job (OJT), competency-based-training (CBT) and process specific training (PST).

GMP Supplies and Services

Maintenance, laboratory, and engineering supplies or services that can affect the quality of the API or drug product such as, but not limited to, filters used in production, lab standards, biological test medium, calibration services, filter system services, water and HVAC system services.

Other examples include gloves and garments in sterile operation.

GMP System(s) (Includes Equipment / Instrumentation

Automated equipment and computerised control systems used in the production of drug products and drug substances in various phases of material handling, manufacturing, and testing which may affect the product quality or release status of the material.

GMP Task

A GMP task is any task that has a direct impact on product quality, integrity, purity and or safety of the product.

Good Distribution Practices (GDPs)

The guidelines for the proper distribution of medicinal products for human use.

GDP is a set of quality systems, which include requirements for receiving, storage and transportation of drugs intended for human consumption. GDP regulates the division and movement of pharmaceutical products from the premises of the manufacturer of medicinal products, or another central point, to the end user thereof, or to an intermediate point by means of various transport methods, via various storage and/or health establishments.

Good Documentation Practices (GDP)

1) Self-defined expectations for ensuring that test records and associated documentation are properly documented to provide proof of regulatory compliance and adherence to GEP. GDP ensures the control of document creation, review, approval, distribution, and storage.

http://en.wikipedia.org/wiki/Distribution_%28business%29

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2) The handling of written or pictorial information describing, defining, specifying and/or reporting of certifying activities, requirements, procedures or results in such a way as to ensure data integrity. (ISPE)

Good Engineering Practice (GEP)

1) Established engineering methods and standards that are applied throughout the project to deliver appropriate, cost-effective solutions. GEP is design and installation that takes full account of GMP, safety, health, environmental, ergonomic, operational, maintenance, recognised industry guidance, and statutory requirements. It is professional project management, design, procurement, construction, installation, and commissioning including appropriate documentation.

2) Established engineering methods and standards that are applied throughout the project lifecycle to deliver appropriate cost-effective solutions (ISPE).

Gowning Shift

The maximum length of time a person can be in the area were aseptic operations are performed without a break.

Grade A Area

Class 100 laminar flow area where aseptic manipulations are performed, product considered sterile and sterility test sampling required e.g. bulk packaging of sterile API.

Grade B Area

Class 100 background area (room) for Grade A area. Requirements should be met when room is at rest e.g. filling room outside laminar flow hood.

Grade C Area

Class 10,000 area e.g. bulk preparation area – product is subsequently sterile filtered.

Grade D Area

Class 100,000 area e.g. bulk preparation for terminally sterilised products, closed system.

Gray Zone

A GMP area within the facility that has no potential for product exposure to the environment or personnel and limited product contact surface/component exposure.

The Gray Zone designation may refer to non-working spaces or working spaces. Examples of areas designated as Gray (non-working) Zones are transition zones and support corridors. Examples of Gray (working) Zones are secondary packaging and in processing storage areas.

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Gross Weight

The total weight of a container and its contents.

Note distinction from ‘Net Weight’.

Group

A Group is a collection of Items that are similar in design and are loaded into the autoclave in the same way.

Growth Promotion Test

Test performed to demonstrate that media will support microbial growth.

Guideline (Quality Manual)

Describes the quality-related activities, which are recommended for consistent implementation at the manufacturing sites. Deviation is permitted with documented scientific justification.

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Harm

1) Damage to health, including damage occurring from loss of product quality or availability

2) Physical injury or damage to the health of people, or damage to property or the environment.

Hazard

The potential source of harm.

Hazardous Situation

Circumstance in which people, property, or the environment are exposed to one or more hazard(s).

Hazing

Filmcoating defect in which the resulting tablet finished has a dull luster.

Headspace

The atmosphere above the contents of a container that may or may not be altered in order to maintain the quality of a product.

Health Authority (Labeling)

The relevant organisations that are responsible for labeling approvals and establishing the implementation requirements for such changes in the particular country.

Health Authority Submission Timeline

The maximum time between receipt of the Company Core Data Sheet and submitting the labeling dossier to the relevant Health Authority for approval.

Timelines will vary depending on labeling priority and specific market requirements.

Heat Up Time

The period required for all temperature monitoring locations to reach the sterilisation cycle minimum temperature set point.

Synonym: Come Up Time

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Helium Leak Test

A physical challenge evaluating the effectiveness and integrity of a boundary by pressurising the container with helium.

Hermetic Seal

An airtight seal that prevents the invasion of oxygen, moisture, humidity, and any outside contaminant to enter the sealed package.

HIAC

A commercially available instrument, which determines the amount of sub-visible particulate matter in small volume injectable products via light scattering principles.

Hierarchy of Standards Principle

The calibration tolerance of a given reference standard or calibration equipment must be as tight as or tighter than the intended tolerance of the instrument to be calibrated.

High Dose API

API whose maximum daily dosage in the product is greater than 2 grams per day.

High Dose Formulation

Pharmaceutical product whose maximum daily dosage is greater than 1 gram per day.

High Efficiency Particulate Air (HEPA)

Air filters capable of removing particles of 0.3 micrometer size with a minimum efficiency of 99.97%.

Highly Active Compound(s)

1) Compounds that produce significant adverse effects at low doses. Highly active compounds are genotoxic compounds that are known to be, or highly likely to be, carcinogenic to humans; compounds that can produce reproductive and/or developmental effects at low dosages; and compounds that can produce serious target organ toxicity or other significant adverse effects at low dosages (Clinical doses < 10 mg/day or dosages in animal studies < 0.2 mg/kg/day).

2) Genotoxic compounds that are known to be, or highly likely to be, carcinogenic to humans. Compounds that can produce reproductive and/or developmental effects at low dosages.

Compounds that can produce serious target organ toxicity or other significant adverse effects at low dosages.

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Clinical doses <1 - 10 mg/day or dosages in animal studies <0.2 – 1 mg/kg/day.

Professional judgment is required with precedence given to human data.

This definition is consistent with the ISPE definition for Highly Hazardous Drugs (ISPE, 2010).

High Performance Liquid Chromatography (HPLC)

See ‘High Pressure Liquid Chromatography’.

High Performance Water System (HPWS)

A water system that has been in operation for a minimum of 24 months and meets all management and performance criteria identified in local quality requirements.

Designation of a water system as an HPWS may allow microbiological testing frequencies to be reduced below the standard minimum levels required for newer (< 2 years of operation) systems.

High Pressure Liquid Chromatography (HPLC)

A liquid chromatographic system where the mobile phase is pumped under high pressure to achieve a higher flow rate for high-speed separations. The sample is introduced to the system as a liquid.

See ‘Liquid Chromatography’.

High Priority Packaging Systems

Packaging systems or components that contact or identify product but do not affect efficacy or dosage.

High Purity Water System

Any water system that produces water specified as Process Water 500 (PW500), Process Water 100 (PW100), Purified Water, Endotoxin Reduced Water (ERW), or Water for Injection (WFI).

High Risk Non-Critical Product Contact Gas Application

Indirect prior to Sterile Boundary surface sterilisation (with no Further Liquid Filtration.

Point of use locations, where the gas contacts non- sterile surfaces of equipment prior to equipment sterilisation. In these applications, the equipment is intended for sterile use and becomes part of the sterile boundary after sterilisation. The sterile liquid that touches these surfaces will have no further liquid filtration.

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High Stability Risk Product

A drug substance or drug product that has demonstrated either a known history of stability issues or an increased risk of stability failure.

Histogram

A graphic summary of variation in a set of data.

The pictorial nature of the histogram lets people see patterns that are difficult to see in a simple table of numbers. The histogram is one of the seven tools of quality.

Histograms are also called a relative frequency graph. Processes that are in a state of statistical control have histograms that exhibit a bell shape.

Hold Time

The period of time in which a material can be held in bulk storage under appropriately controlled storage conditions before it is completely consumed or is further processed in the next manufacturing step before it is no longer considered acceptable for use.

Homogeneity

A test in which across the lot bulk samples are assayed, and must fall within specified limits.

Conforming assay results indicate that the lot is well mixed.

Homogenisation

A method of atomisation and thereby emulsification of one liquid in another in which the liquids are pressed between a finely ground valve and seat under high pressure e.g. up to 5,000 psi.

Hydrophilic

Having a tendency to mix with, dissolve in, or be wetted by water.

Hydrophobic

Literally ‘water fearing’. A filter that repels aqueous and other high-surface tension fluids and therefore cannot be wetted unless subjected to a high pressure differential. When pre-wetted with a low surface tension fluid, such as alcohol, the membrane will allow water flow at a low pressure differential.

Hygienic Zoning

Formal segregation of a non-sterile pharmaceutical production facility into discrete and clearly identified zones which require a specific gowning regime in order to prevent extraneous matter contamination and product to product contamination.

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I/O

Input / Output

ICH

International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use is a joint initiative involving both regulators and research-based industry from Europe, Japan and the United States focusing on the technical requirements for medicinal products containing new drugs.

ICH/USP Climatic Zones

Defined by temperature & relative humidity, where Zone I is Temperate (21C/45%RH). Zone II is Mediterranean, Subtropical (25C/60%RH), Zone III is Hot, dry (30C/35%RH), and Zone IV is Hot, humid (30C/70%RH)

Identity Tests

Tests which verify that a material is in fact the entity it is claimed to be.

Impact Assessment

The process of evaluating the impact of operation, contact, data, control, alarm, and failure conditions of a system with respect to product quality or patient safety.

Impacted Products

Are all finished products (i.e. regulatory/generic product name) and product identifiers (e.g. codes/numbers) potentially impacted by the change. Impacted products could also be affected materials.

Imperfection

A quality characteristic’s departure from its intended level or state without any association to conformance to specification requirements or to the usability of a product or service

See also ‘Blemish’, ‘Defect’ and ‘Nonconformity’.

Impermeable Containers

Containers that provide a permanent barrier to the passage of gases or solvents e.g. sealed aluminum tubes for semi-solid, sealed glass ampoules and vials for solutions.

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Importer

A firm that is responsible for the importation of foreign articles, and maintains the records of importation in accordance with the regulations.

Imprint Code

Any single letter or number or any combination of letters and numbers including, e.g. words, company name, NDC or a mark, symbol, logo, or monogram assigned by a drug firm to a specific drug product.

Imprinting

Marked with an identification code by means of embossing, debossing, engraving, or printing with ink.

Impurity

Any component (except water) of the product which is not the active pharmaceutical ingredient (API) or an excipient in the product.

Impurity Profile

A description of the impurities present in a typical lot of an API or biological API produced by a given manufacturing process. The description includes the chemical identity, the range of each impurity observed, and the classification of each identified impurity.

Incident

Any temperature/time related event that occurs during the transportation of product that may adversely affect the quality.

Examples include: temperature excursion, missing temperature monitor when required, shipment time exceeds the qualified pack out duration, wet or crushed packaging.

In-Control Process

A process in which the statistical measure being evaluated is in a state of statistical control, i.e. the variations among the observed sampling results can be attributed to a constant system of chance causes.

See also ‘Out-of-Control Process’.

In-Market Quality Responsible Person

Is the local/site person responsible for the initial assessment of quality issues with potential market action impact. This is normally the site quality head.

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the Qualified Person (QP). Also specific to recall activities in European countries, the Quality Responsible Person (QRP) is responsible for recall execution in the country in scope of the recall event, in close coordination with the QP or site Quality Head. The QRP is also responsible for any required agency notifications. In EU, must ensure that the site Qualified Person (QP) is notified once a quality issue is detected.

Indicator Solution

Any solution used to determine the specified end-point in a chemical reaction.

Indirect Impact

A system that does not have the potential to directly impact product quality or patient safety, but typically supports a Direct Impact system that does.

Indirect Procurement

The sourcing of all goods and services for a business that enable its activity, such as equipment, personal protective equipment, marketing services, information technology.

Indirect Supplier

A supplier of goods and services for a business that enable its activity, such as equipment, personal protective equipment, marketing services, information technology.

Individual Learning Plan

Is a document that describes required training for an individual.

Induction (New Hire) Training

Formal non-job specific training for new employees to the site and covers at a minimum GMP, Safety, Environmental, Health, Communications and Employee Legislation.

Infectious Substances

An infectious substance is defined as a substance containing a viable microorganism, such as a bacterium, virus, rickettsia, parasite or fungus that is known or reasonably believed to cause disease in humans or animals. (WHO/EMC/97.3).

Information

When important facts, such as manufacturing, packaging, process, labeling development, planning or laboratory documentation other than laboratory data (assay/test results), are originally recorded (i.e. primary source document).

Examples of information include, but are not limited to, text, words, graphs, sentences, etc.

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Infrared Spectroscopy

Spectroscopic method of analysis dealing with wavelengths in the region of 4000 to 400 cm-1.

See ‘Spectroscopy’.

Infrastructure

Refers to a series of hardware and foundation software that provide a platform to application programs so as to enable the functions of said application programs.

For example, network software and operating systems

Ingredient

A constituent part of a drug product. If the substance contributes to the therapeutic effectiveness of the product, it is an active ingredient. If it has no therapeutic action, it is an inactive ingredient e.g. an excipient.

In-House Specification

See internal specification.

Initials

The first letters of the full name (i.e. first and last at a minimum) of a person, hand-written by the person on a record.

In-Process Control

Established standards used during various stages of manufacturing to evaluate the performance of the process against expected outcomes and to predict the conformance of the product to regulatory requirements.

In-Process Material

Any formulation between the commencement of the first manufacturing step and the final manufacturing step as specified on the Manufacturing Process Description; that which is in the state of being processed, e.g. the contents of a fermenting tank, a reaction vessel, etc. An intermediate is the product of in-process material.

Insert Sheets / Forms

A controlled instruction/form added to the Batch Sheet or Floor Copy.

In-Situ Intermediate

An intermediate that is not isolated, however, requires adequate in-process controls before proceeding to the next step in the manufacturing process.

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Inspection

1) Measuring, examining, testing, and gauging one or more characteristics of a product or service and comparing the results with specified requirements to determine whether conformity is achieved for each characteristic.

2) Measuring, examining, testing, and gauging one or more characteristics of a product and comparing the results with specified requirements to determine whether conformity is achieved for each characteristic.

Inspector Days

The amount of time spent by regulatory investigators to perform an inspection. The term day does not denote a specific amount of time; rather it represents the number of business days each investigator spends on plant site. The total number of inspector days is cumulative based on the number of investigators and business days.

Installation Qualification (IQ) [Installation Validation]

Documented evidence that equipment and systems meet critical installation requirements.

Instrument Tolerance Limits

Established limits that define the acceptable amount of error for a given instrument reading against a reference standard reading.

Integral

Impermeable to a challenge organism, or meeting an acceptable test parameter.

Integral (per CCI Technology) Package

A packaging system that protects the articles from contamination by extraneous matter, limits entry of detrimental gases, and/or loss of the product within the package.

See also the definition for ‘CCI’.

Integration testing

Testing in which software components, hardware components, or both are combined and tested to evaluate the interaction between them.

Integrity

Quality of being complete, accurate and in compliance with appropriate regulations, policies, and procedures.

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Integrity Test (IT)

A non-destructive physical test that can be correlated to the bacterial retention capability of a filter/filter assembly.

Intended Use

Intended purpose; used for which a product, process, or service is intended according to the specifications, instructions, and information provided by the manufacturer.

Interface Testing

Testing conducted to evaluate whether systems or components pass data and control correctly to one another.

Interferent

Any component of a sample that contributes peaks to the sample chromatogram but is not the analyte of interest. May include cleaning agents or extractables from plastic sample collection tubes or plastic gaskets or tubing that are part of the manufacturing or cleaning equipment.

Intermediate

A material produced during a manufacturing process that must undergo further molecular change or processing before it becomes an API.

Intermediate Drug Product

Any product not in its finished form i.e. granulation material or tablet cores prior to coating.

Intermediate Precision (Intra-lab Ruggedness)

Expresses laboratory variation, as on different days, with different analysts and/or equipment within the same laboratory.

Internal Customer

The recipient, person or department, of another person’s or department’s output (product, service, or information) within an organisation.

See also ‘External Customer’.

Internal Phase

The internal phase or the dispersed phase of an emulsion comprises the droplets that are found in the emulsion.

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Internal Specification

Tests, analytical procedures, and acceptance criteria which are not be required by a governing regulatory license which were instituted to assure product quality and integrity or to monitor the production process.

Internal Standard

A reference substance combined in known quantity with an unknown sample under test to correct for variable in analytical technique. The ratio of the known quantity to the unknown quantity is used to adjust the experimentally determined value of the unknown.

International Marketing Application (IMA)

Product-specific regulatory dossier filed with non-US regulatory agencies.

International Pharmacopoeia

A collection of recommended analytical procedures and specifications for the determination of drug products, drug substances, and excipients. The International Pharmacopoeia is published by the World Health Organization, focusing on the needs of developing countries, and generally recommending only simple, classical chemical techniques for evaluation of drug quality. The International Pharmacopoeia does not have legal status unless expressly introduced into appropriate legislature by a national authority.

Intervention

An aseptic manipulation or activity that occurs in the Grade A critical area.

Inherent interventions - activities that are required parts of the aseptic process and necessary in every batch.

Corrective interventions - activities that address failures of the equipment, or components to perform as expected and may not be a part of every batch.

Intrinsic

As defined in USP <1788> - inherent in the product and process- formulation, package, and commercial assembly steps.

In Use Period

The length of time directed by the product labelling that a drug product can be used following opening or reconstitution.

Invalid Test

A test conducted outside its validated parameters as demonstrated by an investigation. An invalid test may include, but is not limited to: use of an inappropriate number of test samples, a test conducted in such a manner that results in the growth of contaminants in both the

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samples and negative control portions of the test improper handling, storage and manipulation of test samples etc.

Investigation

A complete review of facts and conditions related to a processing problem, OOS, or atypicals associated with the processing, packaging, storage, or distribution of a drug product. The purpose is to ascertain the reason(s) for the occurrence in order to take appropriate corrective and preventive action. Investigations are normally accomplished by the person(s) responsible for direct supervision of the area where the incident occurred, with assistance from technical and quality groups as required. The investigation should include a statement of facts related to the problem, assignment of cause, actions taken to study or control the problem, and corrective action to prevent recurrence. Follow-up procedures should determine whether the corrective action was effective. Final conclusions should be drawn, a report should be issued, and the investigation should be reviewed and approved by Quality.

Investigational Materials

Any API, drug product (including vaccines/biologics) or medical device intended for clinical trials, including comparator products, placebo, or commercial product used in clinical trials (clinical supplies).

Investigational New Drug (IND)

A new pharmaceutical, antibiotic, or biologic drug, which is used in a clinical study; a biological product use in vitro for diagnostic purposes. Procedure to conduct human testing.

Investigative Testing

Additional testing that is performed to generate data to support root cause identification.

In Vitro Release Rate

Rate of release of the active drug from its formulation, generally expressed as amount/unit area/time

ISO 9000 Series Standards

A set of five individual but related international standards on quality management and quality assurance developed to help companies effectively document the quality system elements to be implemented to maintain an efficient quality system. The standards, initially published in 1987, are not specific to any particular industry, product, or service. The standards were developed by the International Organization for Standardization (ISO), a specialised international agency for standardisation composed of the national standards bodies of 91 countries. The ANSI is the American standards body.

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Isolated Intermediate

A material removed from the manufacturing equipment and held for a specific time period prior to further processing i.e. solid intermediate, concentrated intermediate in solution, granulation, bulk product prior to packaging. Isolated intermediates typically have unique number identifiers and unique container/closure systems.

Isolator

A decontaminated unit, supplied with Grade A or higher air quality that provides uncompromised, continuous isolation of its interior from the external environment e.g. surrounding clean-room air and personnel.

There are two major types of isolators:

Closed isolator systems exclude external contamination from the isolator's interior by accomplishing material transfer via aseptic connection to auxiliary equipment, rather than use of openings to the surrounding environment. Closed systems remain sealed throughout operations

Open isolator systems are designed to allow for the continuous or semi-continuous ingress and/or egress of materials during operations through one or more openings. Openings are engineered (e.g. using continuous overpressure) to exclude the entry of external contamination into the isolator.

Item

An Item is the smallest individual piece of equipment that is sterilised. An Item can be a single piece, or consist of several pieces assembled into one whole. In terms of autoclave load patterns, Items include the wrapping or packaging used during sterilisation. Examples of Items include tubing manifolds, gaskets, bottle assemblies, filter skids and portable tanks.

Item / Component Number

See ‘Component Number (Item Number)’.

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Japanese Pharmacopoeia (JP)

Official compendium of standards in Japan for assurance of the identity, strength, quality, and purity of drug products, drug substances, and excipients; published in both Japanese and English.

Japanese Pharmacopoeial Forum (JPF)

A publication containing proposed revisions to the JP.

Joint Venture

An arrangement which implies that both parties share equally in all aspects of the related manufacturing operations, including legal, financial, technical, and quality areas.

Justification

Reports containing scientific data and expert professional judgment to substantiate decisions.

Just-In-Time Manufacturing (JIT)

An optimal material requirement planning system for a manufacturing process in which there is little or no manufacturing material inventory on hand at the manufacturing site and little or no incoming inspection.

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Karl Fisher Moisture

A titrimetric method for determination of the total water content of substances especially hydrates or water in an adsorbed form.

Key API Raw Materials

Raw materials that directly contribute to the final chemical structure of the API in the validation steps, solvents used in the final solution step and all ingredients added subsequently to the isolated API.

Key Raw Material

A key reactant which directly contributes to the chemical structure of the drug substance and solvents used in the final step of the synthetic process.

Key Operating Parameter (KOP)

Parameter whose variability has an impact on a Key Process Attribute and therefore should be monitored or controlled to ensure the desired consistency of performance.

Key Process Attribute (KPA)

Process and/or product attributes that is a primary measure(s) of the consistency of performance for a process module/step.

Key Raw Material

Any final processing solvent, or any molecule that retains its complete molecular structure in the final active pharmaceutical ingredient or intermediate.

Kill Time

The minimum exposure time (or dosage) that demonstrates kill of the biological indicator

Know-How

Information and data determined to be necessary to manufacture the product, whenever disclosed to the site, including but not limited to information contained in information binders referred to as Technical Know-How initially provided to a site and all later updates.

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Label

Any written, printed or graphic matter on the immediate container of any article or on a package containing any consumer commodity.

Note distinction from ‘Labelling’.

Label Claim

See ‘Labelled Amount’.

Label Validation

Examination of labelling materials for suitability and correctness prior to packaging operations.

A 100% visual inspection performed by an objective reviewer of one-up labelling art or stepped printer’s proofs against an original ‘Reference Standard’.

Labelled Amount

The quantity of an ingredient of a drug product, which is explicitly stated on a product, label, circular or carton as being present.

The term may be applied to either an active ingredient or a preservative.

Note distinction from ‘Target Amount’.

labelling

Any written, printed, or graphic matter on the container or carton or that may otherwise accompany the product.

Note distinction from ‘Label’.

labelling Change

A drug product labelling change includes changes in the package insert, package labelling or container label.

Physician sample labelling, promotional labelling, non-regulated labelling (i.e. shipper end labels), and advertising should be consistent with labelling changes implemented in trade labelling.

labelling Component(s)

Printed professional literature such as Physician or Package Inserts, Patient Information Leaflets, Medication Guides, etc. used in the packaging of finished drug product.

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See also ‘Printed Packaging Component’, ‘Label’, ‘labelling’, and ‘Primary Packaging Component’.

Laboratory Atypical Event

Any laboratory event, which can impact the validity of analytical data e.g. calibration failure.

The identification of a laboratory atypical event also includes the determination of an adverse shift or trend which, if not corrected, may lead to a laboratory OOS or atypical result.

Laboratory Atypical Result

Any test result or set of results on a product quality indicating test (all tests not designed exclusively for process control purposes) which falls outside of the typical range but within the specification.

A confirmed laboratory atypical result triggers a notification to manufacturing which must have a written investigational response.

Laboratory Data Sheet

A uniquely numbered form for recording specific laboratory data or information used in support of assuring the quality of products or adherence to GMPs.

Laboratory Expiration Date

The calendar date through which a laboratory (purchased or prepared) reagent, solution or media is expected to remain ‘Fit For Use’ if stored under appropriate pre-determined conditions, and beyond which may not be used unless it can be re-standardised.

An expiration date listed in a month/year format is interpreted as the last day of the month indicated.

Laboratory Expiration Period

The period of time that a laboratory (purchased or prepared) reagent, solution or media is expected to remain ‘Fit For Use’ if stored under appropriate pre-determined conditions.

This period is determined by laboratory generated hold time data (stability) or data provided by the vendor (for purchased material). For purchased items, the expiration period starts on the date of receipt and should not exceed the vendor assigned expiration period unless laboratory generated hold time data (stability) is available.

For prepared items, the expiration period starts on the date of preparation.

Laboratory Instrument Logbook

A bound notebook with pre-numbered pages that is used to chronologically record the routine usage and associated calibration/maintenance activities, related to a respective laboratory instrument, as they occur by the respective individuals performing the activity.

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Laboratory Notebook

A bound notebook with pre-numbered pages that is used to record raw data. The laboratory notebook should be identified with a unique numbering system so that it is tracked to ensure accountability and traceability of raw data.

Laboratory OOS Result

Any test result or set of results on a product quality indicating test which falls outside of a Quality Standard (QS) specification.

A confirmed laboratory OOS result triggers a manufacturing investigation.

Laboratory Reagent

Any chemical, solvent, or solution purchased or prepared in the laboratory.

Lack of Response

A type of adverse reaction report (ARR) filed when a drug product fails to achieve the desired therapeutic effect in a particular patient.

Laminating

Tablet defect characterised by the separation of the tablet into two or more layers.

Laminar Air Flow

HEPA filtered air supplied to an aseptic area under specified velocity range and a single direction (unidirectional), then exhausted from the area to provide a sweeping motion of air.

Laser Headspace Testing

A quantitative, non-destructive CCIT designed to measure the gas composition within the headspace of a filled container at atmospheric or reduced pressures.

LD50

The dose of a particular drug that is lethal to 50% of a particular experimental population.

Leachables (L)

Chemical species that migrate from or through a contact surface into a drug product or process stream during storage or normal use conditions.

These are specific to the combination of material and drug product with which the material comes in contact.

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Leadership

An essential part of a quality improvement effort. Organisation leaders must establish a vision, communicate that vision to those in the organisation, and provide the tools and knowledge necessary to accomplish the vision.

Leading (Line Spacing)

In relation to artwork/labelling, a measure of vertical space between lines in topography which is measured in points.

Legal Sample

A complete market package taken from each lot manufactured, which is sealed, labelled as Legal Sample and stored for the exclusive use of the company Legal Department. These packages are taken with retention samples and are stored in the retention area and should not be opened for reasons other than those determined by the Legal Department.

Legally Binding Signature

A signature applied to a record identifying the record originator, reviewer, or approver of the record that invokes legally enforceable accountability on the person who applied the signature to the record, as it relates to the content of the record and in terms of the definition of the specific signature transaction.

Legibility

Relative to labelling/artwork, refers to the ease of distinguishing individual letters.

Lethal Medium

The medium used for the purpose of sterilisation of equipment, parts or surface e.g. clean steam, hot air, gamma radiation.

Lethality Factor

The factor that is related to or causing death (inactivation of spores) in reference to a sterilisation process.

Letter Spacing

In relation to artwork/labelling, the placement of space between each letter of a word.

Leveraging

Using test results from elsewhere in the network to complete the criteria for suitability testing.

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Licensee

A firm that holds the local market registration for the product license holder developed product for local marketing under their own trademark.

Lifecycle

1) All phases in the life of the system from initial requirements until retirement including design, specification, programming, testing, installation, operation, and maintenance.

2) All phases in the life of a medical device, from the concept acceptance to final decommissioning and disposal.

LIFO

An abbreviation for Last In, First Out, which is a materials management procedure whereby the most recent material lots received are used first.

Light Sensitive Material

Raw materials, intermediate, or finished product, which are chemically or physically altered upon exposure to light. Such material must be protected against such exposure during storage, processing, testing and shipping.

Limit Expression

USP Term meaning specification, tolerance, or other limit, which has been established.

Limit of Detection

The lowest concentration of analyte in a sample that can be detected, but not necessarily quantitated, under the method’s experimental conditions.

The limit of detection (LOD) is usually expressed as the concentration of analyte (e.g. percentage, parts per billion) in the sample and must be less than the limit of quantitation (LOQ).

Limit of Quantitation (LOQ)

The lowest amount of analyte in a sample, which satisfies all other validation criteria.

Linearity

The ability of an analytical method to obtain test results that are directly proportional to the concentration of analyte in samples within a given range; usually expressed in terms of the correlation coefficient (R) around the slope (m) of a regression line.

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Linearity and Range

The ability of an analytical method to elicit test results that are directly, or by a well- defined mathematical transformation, proportional to the concentration of analyte in samples within a given range.

The range of an analytical method is the concentration interval of analyte that has demonstrated acceptable precision, accuracy, and linearity. The regression line is calculated according to established mathematical relationships from test results obtained by analysis of samples with varying concentrations of analyte at suitable intervals around the specification. The range is normally expressed in the same units as test result obtained by the analytical method.

Liquid Chromatography

A chromatographic method of analysis in which the mobile phase is a liquid and the stationary phase is a solid.

See also ‘High Pressure Chromatography’.

Liquid Ingress

A physical challenge evaluating the effectiveness and integrity of a closure or boundary while immersing the system in a dye-or tracer containing solution. The test includes a vacuum step that exposes the closure to a pressure differential during the challenge.

Locally Approvable Changes

Changes that are not expected to have any quality or regulatory impact and can be reviewed and approved locally using an appropriate change control system e.g. process, equipment, automation, site master formula, etc.

Load Mapping Study

A study performed to determine the worst case locations in the load to be sterilised.

Long Term Stability

Studies designed to evaluate the physical, chemical, and microbiological characteristics (if applicable) of an API, drug product, or biological product covering the expected duration of the shelf- life and retest period, which are claimed in the regulatory filings and may appear on the labelling.

Lot / Batch

A definite quantity of starting material or product processed in one process or a series of processes so that it can be expected to be homogeneous. In the case of a drug product manufactured by continuous process, it is a specific identified amount produced in a unit of time or quantity in a manner that ensures homogeneity of the material.

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Lotion

An externally applied dosage form comprised of a thixotropic gel or suspension.

Lot Number

An identifying combination of numbers, letters or symbols from which the complete history of the manufacturing, packaging, warehousing and distribution of a lot of drug product or other material can be determined.

Low Dose API

API whose maximum daily dosage in the product is less than or equal to 2 grams per day.

Low Dose Formulation

Pharmaceutical product whose maximum daily dosage is less than or equal to 1 gram per day.

Lower Control Limit (LCL)

Control limit for points below the central line in a control chart, normally based on the mean minus 3 standard deviations. The probability of a sample value exceeding the limits due to random variation is very small.

Lyophilisation

A process in which the product is first frozen and while in the frozen state, the major portion of the water and solvent system is removed by sublimation and desorption.

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Maintainability

The probability that a given maintenance action for an item under given usage conditions can be performed within a stated time interval when the maintenance is performed under stated conditions using appropriate procedures and resources. Maintainability has two categories: serviceability, the ease of conducting scheduled inspections and servicing, and repairability, the ease of restoring service after a failure.

Maintenance Record / Log

A complete record of maintenance and repair activity performed on any equipment used in the processing of a drug product. These records are to be available for routine review to assess the impact of maintenance on drug processing operations for significant equipment only.

Major Impact

A change that impacts the way an existing process or computer system functions so much so that it cannot be considered the same process or to have the same functionality.

Major Observation

An audit observation that meets one or more of the following criteria:

Product might be at risk

Quality system elements exist but they are not applied consistently and/or effectively applied

No action plan or corrective/remedial plan

Management Review

Periodic, scheduled and documented evaluation of quality objectives, quality plans, quality policy and quality system procedures by management with executive responsibility to ensure that the quality system has been effectively established and is being effectively maintained. The review shall include assessing opportunities for improvement.

Manual Inspection

Manual presentation of product and human evaluation of product for defects.

Manual Method

Any chemical analysis or physical measurement performed on non-automated instrumentation.

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Manufacturer

Holder of a Manufacturing Authorisation as described in Article 40 of Directive 2001/83/EC3.

Manufacturing Batch Record

Record demonstrating that the batch of a product was manufactured in accordance with the approved master batch documents.

Manufacturing Materials

Includes primary components, excipients, intermediates, active pharmaceutical ingredients (API), bulk biological products, bulk dosage forms and finished dosage forms.

Manufacturing or Processing

For the purpose of drug listing, the term includes manufacture, packaging and repackaging or otherwise changing the container, wrapper, or labeling of any drug package to further distribution of the drug from the original place of manufacture to the person who makes final delivery or sale to the ultimate consumer.

Manufacturing Process

All manufacturing unit operations and storage steps in the creation of the finished product from the weighing of components through formulation, including but not limited to, the following: mixing, granulating, milling, molding, formulating, lyophilising, tableting, encapsulating, coating, sterilising, and filling.

Manufacturing Process Description (MPD)

The formulation instruction for processing a drug product or biologics that specify the amount of raw materials, equipment, and processing parameters; the document also records the accomplishment of required action, the identity of personnel performing and checking processing operations, accountabilities and yields, process control data, and final review by a competent authority.

Manufacturing Site

The site manufacturing the API, pharmaceutical product or biological product.

Market Action

A firm's removal or correction of a distributed product (including market withdrawal and recall).

Market Package

Final unit of packaged product sold or distributed.

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Market Withdrawal

A firm’s removal or correction of a distributed product which involves a minor violation that would not be subject to legal action by the governing regulatory agency or which involves no violation e.g. normal stock rotation practices, routine equipment adjustments and repairs, etc..

Note distinction from ‘Recall’.

Marketing Trial Blanks

Manufactured for use by Marketing for customer acceptance trials or demonstrations to medical professionals. Contains no active ingredient. Not for human or animal consumption, except on an exception basis.

Mass Variation

See ‘Weight Variation’.

Master Artwork File

A ‘reference standard’ against which printer’s proofs or final printed labelling is compared.

A document authorising the printing and use of labelling components in packaging. The attachment represents a full-size, exact copy of the labelling artwork including copy, graphics, colour specifications, bar codes, etc.

Master Batch Record

A document that includes specifications for raw material, for packaging material and for packaged dosage form; master formula (including composition and instructions as described in the definition above), sampling procedures, and critical processing related standard operating procedures (SOPs), whether or not these SOPs are specifically referenced in the master formula.

Master Batch Sheet(s)

A document which includes detailed instructions for the manufacture of product at the site.

Master Cell Bank (MCB)

An aliquot of a single pool of well characterised cells propagated under defined conditions, dispensed into multiples containers, and stored under controlled conditions. The MCB is used to derive Working Cell Banks.

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Master Document

The original document, paper based or electronic that is fully signed and dated by all the signatories. It serves as a master from which copies of the original document can be made.

Master Production and Control Records (Master Production Records)

A document or set of documents specifying the raw materials with their quantities and the packaging materials, together with step-by-step instructions required to produce a specified quantity of a finished product, including the in-process controls with space provided for documenting the execution of the steps. It is used as a master for making executable copies for manufacturing/packaging of a product.

Master Seed (MS)

An aliquot of a single pool of virus propagated under defined conditions, dispensed into multiples containers, and stored under controlled conditions. The MS is used to derive Working Seeds.

Material Handling Supplies

Pallets, crates, frames, casks, shafts, wedges, bracing, and dunnage.

Material of Construction

The substances (e.g. glass, high density polyethylene (HDPE), resin, metal) used to manufacture a packaging type.

Material Safety Data Sheets (MSDS)

A document, provided by the supplier, for each chemical substance containing a complete description of the chemical, physical constants, toxicity levels, spill cleanup procedures, safety and first aid information. MSDS are required by law to be available for use by employees who work with the chemical.

Matrix

1) A grouping of different product soils or equipment, which is related but may not be identical.

2) The sample analyte and the other physical/chemical components of the sample constitute the matrix of a sample.

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Matrixing

Matrixing is the design of a stability schedule such that a selected subset of the total number of possible samples for all factor combinations would be tested at a specified time point. At a subsequent time point, another subset of samples for all factor combinations would be tested. The design assumes that the stability of each subset of samples tested represents the stability of all samples at a given time point. The differences in the samples for the same drug product should be identified as, for example, covering different batches, different strengths, different sizes of the same container closure system, and possibly, in some cases, different container closure systems.

Maximum Allowable Difference (MAD)

Acceptance criteria against which stability test results generated at long term storage conditions are compared to data generated at the previous time point(s) of a stability study. The MAD is based on the test method and the stability profile. MAD is an approach to real time stability monitoring system used for stability data.

Maximum Expiry or Maximum Expiration Period

The longest time period that stability data will support that the product remains within its specifications.

Mean

The sum of N numbers divided by N. It is a measure of central tendency. Also known as Average or X- Bar.

Mean Kinetic Temperature (MKT)

Considered as an isothermal storage temperature that simulates the non-isothermal effects of storage temperature variation. MKT is calculated from the temperatures within a storage facility based on the formula stated in the USP General Information Chapter <1150> Pharmaceutical Stability.

Mean Time Between Failures (MTBF)

The average time interval between failures for repairable product for a defined unit of measure, for example, operating hours, cycles, and miles.

Measurement Precision

The reproducibility (%RSD) of multiple measurements of one sample.

Also called Injection Precision when referring to HPLC or GC.

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Mechanical Equipment (also called Active Temperature Control System)

Temperature controlled transportation including temperature controlled trucks, trailers and ocean containers that are equipped with refrigeration and heating units as well as associated calibrated temperature recording devices.

Media

Solutions or suspensions used in the production of vaccines or biologic products that has growth promoting qualities.

Media Hold Qualification

Evaluates all appropriate pure culture processing steps, activities, conditions, and characteristics relating to the fermentation system that may result in the introduction of foreign growth during the fermentation process. A media hold qualification tests the fermentation system to ensure that normal processing is not compromised by foreign growth.

Medical Device

An instrument, apparatus, implement, machine, contrivance, implant, in vitro reagent, or other similar or related article, including a component part, or accessory which is intended for use in the diagnosis of disease or other conditions, or in the cure, mitigation, treatment, or prevention of disease, in man or other animals, or intended to affect the structure or any function of the body of man or other animals, and which does not achieve any of its primary intended purposes through chemical action within or on the body of man or other animals and which is not dependent upon being metabolised for the achievement of any of its primary intended purposes.

Membrane

A thin, microporous medium used to remove particles and microorganisms from a fluid stream under pressure.

Mesh Analysis

A test used to determine particle size distribution by passing the sample through a series of sieves of known dimensional porosity.

Metadata

Data that describe the attributes of other data or raw data, and provide context and meaning.

Typically, these are data that describe the structure, data elements, inter-relationships and other characteristics of data. It also permits data to be attributable to an individual. This also includes the electronic audit trial information.

See also ‘Data’, ‘Original Record’ and ‘Raw Data’.

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Metal Detect

A validated method used to remove material that is suspected or known to be contaminated with metal. This process is capable of detecting and removing material contaminated with minute pieces of several types of metals and/or alloys associated with the manufacturing process.

Method Comparison

Part of a method validation in which the proposed method’s results are compared directly to results obtained using a compendial method or current analytical method. If no compendial method exists, the proposed method may be compared to the applicable validated Quality Standard method.

Method Precision

The reproducibility (%RSD) of multiple preparations of each sample and standard (if employed) used for assay quantitation.

Methods Validation

The documented evaluation of an analytical method that provides a high level of assurance that the method will consistently yield reliable and accurate results, within previously established specifications; the protocol followed during evaluation of a proposed analytical testing method to prove consistency and reproducibility. A valid method must be accurate, precise, rugged and usually linear over a specific concentration range. A method comparison is performed against a compendial method as required.

Microbial Challenge Liquid Immersion

A microbial challenge evaluating the effectiveness and integrity of a sterile boundary to prohibit microorganisms from entering from the surrounding environment through immersion of the item into a Pseudomonas Aeruginosa liquid broth for 24 hours.

Microbial Limits Test

An analysis performed in which bacterial, fungal and yeast content of a lot is quantitatively determined and evaluated against acceptance criteria.

MicroEnvironment

An enclosure around an operation where product is exposed having appropriate conditioned supply air, airflow direction and filtration to minimise the potential for product contamination.

Minimal Cycle

Validation cycle which represents a fraction of the full production cycle in terms of sterilisation dwell time and is typically run at a lower set point temperature for thermal loads.

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Minimum Fill

A USP test applicable to containers of creams, ointments, pastes, and powders of less than 150 grams, in which the net content is determined and evaluated against acceptance criteria.

Minor Deviation(s)

An event which, upon assessment, is determined to have no impact on the quality of the product, process, equipment or quality management system and as such, a full investigation may or may not be warranted. The level of documentation required as well as the scope and depth of the investigation would be dependant on the complexity of the event and number of occurrences. Corrective and Preventative actions may or may not be required depending on the specifics of the event. Quality formally approves all Non-Quality Impact Event investigations.

Minor Impact

A change that enhances or corrects an existing process or existing functionality.

Minor Observation

An audit finding, which meets one or more of the following criteria:

Product is not at risk

Departures from planned arrangements (one-time events)

Corrective and remedial action was already self-initiated

Mix-Up

Cross-contamination of a product, component or label from a batch or product other than the one being processed. cGMPs require physical and spatial separation to prevent mix-ups. Refer to 21 CFR 211.130.

Mobile Phase

The moving component of any two component chromatographic systems.

Modification

A modification is a change to a portion of an area (for example, the repair of a wall or floor surface) that may cause a localised breach of room or HVAC system integrity. A modification is not associated with an IQ/OQ. A modification can be of moderate to small scale.

Modified-Release

A dosage form for which the drug release characteristics of time course and/or location are chosen to accomplish therapeutic or convenience objectives not offered by conventional dosage form.

See also ‘Delayed Release’ and ‘Extended Release’.

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Moist Heat Sterilisation

Processes that use saturated steam, steam-air mixtures or superheated water as the medium for the purpose of achieving sterilisation.

Molded Glass

A container formed by the injection of molten glass into a cavity or mold and the use of pressure to form the vessel around the constrictions of the cavity.

Note distinction from ‘Tubing Glass’.

Monograph

The statement of requirement, specifications, and test procedures for a particular product which appears in the USP or NF or other compendia and which must be met in order to claim compendial status.

Mother Liquor

A medium for synthesis containing unreacted starting materials, intermediates and impurities that may be reused for further processing, in the synthesis of an intermediate or API.

Mottling

A tablet defect characterised by an unequal distribution of colour in a tablet with light or dark areas standing out in an otherwise uniform surface.

Multidose Container

See ‘Multiple Unit Container’ and/or ‘Multiple Dose Container’.

Multi-Product Facility

A facility that supports production of two or more products, either in a campaigned or concurrent manner.

Multiple Alert Level

An alert level result where another alert or action level has occurred with the environmental monitoring associated with the same lot, indicating that there is a possible correlation. It is independent of test type, and is incorporated in a contextual review of the environment associated with the area in question.

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Multiple-Dose (Multi-Dose)

A packaging system that permits withdrawal of successive portions of an article for parenteral administration without changing the safety, strength, quality, or purity of the remaining portion.

Multiple Dose Container

A type of multiple unit container designed to hold more than one dose of a drug product which is intended for parenteral administration only. The drug product will normally contain a preservative.

Note distinction from ‘Multiple Unit Container’.

Multiple Unit Container

A container that permits withdrawal of successive portions of the contents without changing the strength, quality or purity of the remaining portion.

Note distinction from ‘Multiple Dose Container’.

Multivariate Control Chart

A control chart for evaluating the stability of a process in terms of the levels of two or more variables or characteristics.

Must

If the intent is not to allow flexibility in implementation/interpretation of a requirement, use the term ‘must’.

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- N -

National Drug Code Number (NDC number)

A 10-character code consisting of the Labeller Code, Product Code, and Package Code. The Labeller Code is assigned by the FDA and identifies the registered establishment (manufacturer or distributor). The Product Code and Package Code configurations are used to describe drugs in the product line or added to the product line and are assigned by the manufacturer or distributor. The Product Code identifies the drug formulation. The Package Code identifies the trade/sample package and type of package.

National Formulary (NF)

See United States Pharmacopeia-National Formulary (USP-NF).

National Stock Number

Thirteen-digit code assigned by the US Federal Government to a drug product purchased under procurement based on its USP name. This code applies to both the innovator’s product and generic substitutes.

NDA Approval

See ‘Approval Letter’.

NDA Field Alert Report

Report by an NDA holder to the local U.S. Food and Drug Administration district office within 3 days of receiving any information about any incident that causes the drug or its labeling to be mistaken for another article or information concerning any bacterial contamination or other significant deterioration of a drug or failure of one or more batches of a drug to meet its NDA specifications. Refer to 21 CFR 314.81.

NDE

Non-destructive Evaluation.

See ‘Non-destructive Testing and Evaluation’.

Near Infrared Spectroscopy

A spectroscopic method of analysis dealing with wavelengths in the region 780 nm to 2500 nm.

See ‘Spectroscopy’.

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Near Miss (or Near-Miss)

A serious class of error is defined as: all artwork errors that have the potential for a market action. The error shall be in the printable area of the artwork file.

Net Contents

The weight of the material within a container, disregarding the weight of the container.

Note distinction from ‘Gross Weight’.

Net Weight

See ‘Net Contents’.

Network

A system, including transmission channels and supporting hardware and software, which connects several controllers and computers.

New Animal Drug Application (NADA)

Product specific regulatory dossier for a veterinary product filed with US regulatory agency.

New Chemical Entity (NCE)

A never before used synthetic chemical to treat a disease condition.

New Drug Application (NDA)

Product specific dossier filed with US regulatory agency.

See also individual types of applications: ‘Abbreviated NDA (ANDA), ‘Amendment’ and ‘Supplement’.

New Drug Substance

Any substance that, when used in the manufacture, processing, or packing of a drug, causes that drug to be a new drug, but does not include intermediates used in the synthesis of such substance [21 CFR 310.3(g)].

New Installation

The introduction of a new facility, room, air handler, unidirectional e.g. laminar airflow unit, or utility system etc., to a manufacturing process. A new installation is associated with an IQ/OQ.

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No-Load Temperature Distribution Test

The method by which thermocouples are placed inside a system in order to determine temperature uniformity throughout the system.

Non-Conformity

The non-fulfilment of a specified requirement.

See also ‘Blemish’, ‘Defect’, and ‘Imperfection’.

Non-Conformance

A non-conformity means the non-fulfilment of a specific requirement.

All non-conformances must be investigated, root cause determined and evaluated for CAPAs.

Non-Critical, Non-Product Contact, Environmentally Controlled Applications

Applications where the gas must meet particulate and microbial environmental requirements of the classified space where it is released. Gas travels through filters which are upstream of point of use applications where gas is released. Examples where gas is released in a classified area include:

Instrument Air

Non product contact equipment cleaning and blowdowns

Post-use integrity testing of gas and liquid filters

Pre-Sanitisation / Sterilisation Pre-use integrity testing of gas filters

Non-Critical Instruments

Instruments that control, measure or test non-critical parameters that help maintain the process in a consistent and controlled state. Non-critical instruments may not be associated with Critical Process Parameters (CPPs) or critical quality attributes (CQAs). Non- critical instruments may serve as redundant, back-up systems to critical instruments.

Non-Critical Parameter

Process control parameters which are not critical from a quality standpoint.

Non-Critical Product Contact Gas Application

Direct or Indirect upstream of Sterile Boundary (with Further Liquid Filtration) - Point of use locations, where the gas is released into or from a system that is upstream of the final sterile boundary application where low particulate and bioburden gas is required. The gas exiting the point of use filter is in contact with product which will undergo further liquid sterile filtration and/or equipment that is upstream of the system sterile boundary.

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Non-Critical Systems

Are not expected to come in contact with samples, affect test/data validity or patient safety, but typically will support a ‘Critical’ system. These systems typically require commissioning according to Good Engineering Practices (GEP).

Non-Destructive Testing and Evaluation (NDT)

Testing and evaluation methods that do not damage or destroy the product being tested.

Non-GMP Alarms

Alarms for non-GMP parameters are normally associated with Safety and Environmental (e.g. emissions, effluent, etc) compliance, non-GMP utilities or productivity.

Non-Investigational Medicinal Products (nIMPs)

Any product (other than the product that is the object of investigation, placebo, or active comparator), supplied to patients participating in a clinical trial and used according to the protocol. nIMPs include rescue or support medication or medication used to induce a physiological response per the protocol.

Non-Investigative Incidents/Errors

An incident or error that is determined to have no effect on the quality of the product, process, equipment or quality management system concerned and is addressed in site procedures with instructions for documentation and remediation. Non-Investigative incidents/errors may be documented and justified at the time of identification directly in the GMP record (batch record, lab notebook, etc.), site notification form (Notice of Event, QN, Deviation Alert, etc.) or other appropriate GMP document (logbook, etc). Quality approves these site procedures or records as part of their routine review process.

Non-Isolated Intermediate

A material held within manufacturing equipment while awaiting in-process testing, or during normal processing short term ‘Hold Times’, the intermediate remaining in a piece of equipment (i.e. drier, centrifuge) continuously used in a production campaign. Non-isolated intermediates typically have do not require unique number identifiers.

Non-Printed Packaging Components

Packaging components that contain no printed, or graphic matter.

For example: vials, bottles, caps, and blister film.

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Non-Product Quality Complaint (Non-PQC)

The designation for specific situations where the reported event does not describe a product quality defect.

Non-Product Contact Gas Application, Exhausts in Grades A or B

Point of use locations where gas is released / exhausted into Grade A or B space. In these applications the gas must meet particulate and microbial environmental requirements of the classified space where it is released.

Non-Product Contact Gas Application, Exhausts in Grades C or D

Point of use locations where gas is released/exhausted into Grade C or D space. In these applications the gas must meet particulate and microbial environmental requirements of the classified space where it is released.

Non-Proprietary Name

Non-trademarked nomenclature for a substance or product of potential or proven therapeutic usefulness. The name is often derived as a contraction of the specific chemical name or chemical class of the drug substance. Its use is entirely in the public domain.

Non-Quality Impact Events

An Event which, upon assessment, is determined to have no impact on the quality of the product, process, equipment or quality management system and as such, a full investigation may or may not be warranted. The level of documentation required as well as the scope and depth of the investigation would be dependant on the complexity of the event and number of occurrences. Corrective and Preventative actions may or may not be required depending on the specifics of the event.

Non-Quality Indicating Measurements

Batch manufacturing instructions, measurements and ranges that do not have a direct product quality impact e.g. equipment set-up instructions, operating limits and ranges that exist solely for safety or environmental reports. These exceptions should be clearly identified in the manufacturing instructions.

Non-Regulated Product

See ‘Commodity Product’.

Non-Regulatory Method

An analytical procedure used to determine the conformity of an API, intermediate, raw material, or finished product to a non-regulatory (internal) specification or in-process control.

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Non-Regulatory Specification

See ‘Internal Specification’.

Non-Routine Repackaging

This repackaging takes place as a consequence of an unusual event that requires repackaging of a product before the product can be supplied to the market e.g. new regulatory requirements or labelling changes that require immediate implementation, correction of packaging errors, etc.

Not or Non-Approvable Letter

Written communication from the FDA to an applicant which states that their application is not approvable because of one or more deficiencies in the submission.

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- O -

Objective Evidence

Qualitative or quantitative information, records, or facts pertaining to the quality of an item or service.

Observation

A statement of fact made during an audit and substantiated by objective evidence.

Occurrence

The FMEA rating scale that defines the potential frequency of a failure mode.

Ocumeter

Small plastic container for dispensing a measured amount of liquid medication.

Official Article

Terminology used within the USP-NF to designate a drug substance or excipient (both of which are ‘Official Substances’), or a drug product (‘Official Preparation’) for which a compendial monograph is provided.

See also ‘Article’.

Official Method

See ‘Regulatory Methods’.

Official Reference Standards (ORSs)

ORSs are certified reference standards obtained from an agency of official legal status. These organisations include, but are not limited to, the United States Pharmacopoeia (USP), the National Institute of Standards and Technology (NIST) and non-US compendia. These standards should be used as reference standards when conditions warrant comparison of a sample against such Official Reference Standards.

Ointments

Semi-solid preparations intended for external application to the skin or mucous membranes.

On-Going Monitoring

See ‘Performance Monitoring’.

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Open System

An environment in which system access is not controlled by persons who are responsible for the content of electronic records that are on the system. 21CFR 11.3(9).

Operating Procedure

A written procedure that provides specific directions for performing certain operations that impact product identity, strength, quality or purity, e.g. cleaning, gowning, sampling of environment, testing, equipment operation.

This includes, but is not limited to Standard Operating Procedures, posted instructions, and operating instructions. This excludes actual processing records such as batch records.

Operational Qualification (OQ) [Operation Validation]

Documented evidence that critical operating measurements and system functionality meets pre-determined requirements.

Operational Test (OT) Templates

Test script templates that can be leveraged for future projects of the same system type and intended use to promote standardisation and efficiency in test script development.

Ophthalmic Solutions

Sterile solutions suitably compounded and packaged for instillation into the eye.

Operating Characteristic curve (OC curve)

A graph used to determine the probability of accepting lots as a function of the lot’s or process’s quality level when using a specific sampling plan. There are three types:

Type A curves, which give the probability of acceptance for an individual lot coming from finite production (will not continue in the future)

Type B curves, which give the probability of acceptance for lots coming from a continuous process

Type C curves, which, for a continuous sampling plan, give the long-run percentage of product accepted during the sampling phase

Optical Character Recognition (OCR)

Electronic translation of text images into machine-encoded text.

Optical Character Verification (OCV)

Electronic inspection of content and/or quality of printed text.

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Orange Book

British Guide to Good Pharmaceutical Manufacturing Practices; also the FDA list entitled: Approved Drug Products with Therapeutic Equivalence Evaluations.

Origin Site (OS) (also referred to as Shipping Site)

The site in which a shipment originates from.

Origin Site Contact

The person at the origin site designated to manage oversight of temperature- monitored shipment alarms.

Original Record

Data as the file or format in which it was originally generated, preserving the integrity (accuracy, completeness, content and meaning) of the record, e.g., original paper record of manual observation, or electronic raw data file from a computerised system.

Also see ‘True Copy’.

Otic Solutions

Solutions for instillation in the outer ear. They may be aqueous, in glycerin or in other solvents and dispersing agents.

Out-of-Control Process

A process in which the statistical measure being evaluated is not in a state of statistical control, i.e. the variations among the observed sampling results cannot be attributed to a constant system of chance causes.

See also ‘In-Control Process’.

Out-of-Specification (OOS) Result

A term used to indicate that a unit does not meet a given specification; an examination, measurement or test result that does not comply with pre-established criteria.

See also ‘Laboratory OOS’.

Out of Tolerance Notification

A formal notification that an instrument has exceeded its instrument tolerance limits. This notification is based on calibration data obtained prior to adjustment of the equipment (‘As Found’).

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Out Of Trend (OOT) Results

An examination, measurement, or test outcome that is within specifications but is inconsistent with previous data, established trends, or other results for the same batch or other stability batches.

The diagnosis that a result is out of trend may be based on comparison to an expected pattern, or on the application of limits derived specifically to diagnose such results.

Overage

The additional or excess amount above 100% of labeled amount of active ingredient or preservative which is included in the formulation to compensate for production and/or stability losses.

Overarching Management Reviews

A process by which Management with executive responsibility reviews the suitability and effectiveness of the quality system and product conformity at defined intervals and with sufficient frequency according to established procedures.

Overkill Sterilisation Process

A process, which is sufficient to provide at least a 12-log reduction of microorganisms, having a minimum D value of 1 minute.

Overseal

The overseal is the final physical component (caps, crimps, Ocumeter bands, etc.) which protects the final container closure seal during storage and transportation.

Oversize

A tablet in which the thickness tolerance is exceeded. The term does not necessarily imply that the tablet is overweight.

Note distinction from ‘Overweight’.

Overweight

A tablet or capsule which exceeds the target weight if no range is listed or which exceeds the upper limit of a range if one is specified.

Overwrap

Thin sheet of plastic used to bundle market packages, packers of market packages or incoming components.

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- P -

Pack (Packaging) Site Rotation

A reduced stability scheme that represents different packaging sites that package a drug product manufactured at a single manufacturing site into the same/equivalent primary package configuration on a rotational basis within the ongoing stability program at least once every three years.

Package Configuration

All primary packaging components including a description of the fill, size, and count.

Package Type

The API or pharmaceutical primary container.

For example, a glass bottle and an HDPE bottle would be considered different package types. Also PVC and a PVDC blister would be considered different package types due to differences in film permeability.

Packaging Area

The physical space or room where packaging activities take place.

Packaging Batch Record

Records demonstrating that the batch of a drug was packaged in accordance with the approved master production documents.

Packaging Component

Any single part of the package, an element of the container/closure system or packaging materials used to contain the product for delivery to the customer. Typical components are containers (e.g. ampules, bottles), container liners, closures (e.g. screw caps, stoppers), closure liners, stopper overseals, container inner seals, overwraps and container labels.

Packaging Order

The batch sheet (paper or electronic) that is used during the packaging process to complete a package lot.

Packaging Site

The site packaging the pharmaceutical drug or biological product in the primary or secondary (if secondary package impacts stability) package.

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Packaging Staging Area

An area where packaging components and/or product is brought while waiting further processing.

Packer

The final outside corrugated cardboard box in which a specified quantity of market package units are enclosed for appropriate storage and shipping.

Paddle

The stirring element consisting of a blade and a shaft that conforms to the specifications listed in the appropriate compendia.

Paddle Dissolution

A dissolution test using a stirring element consisting of a blade and a shaft.

Paddle Sample

A homogeneous mixture of tablet or capsule samples, taken at regular intervals over the duration of the compressing operation, which representative of the overall quality of the lot; during packaging operations, the samples or market packages to check for appearance and count by the use of special paddles.

PAI

See ‘Pre-Approval Inspection’.

Parallel Testing

The testing of a supplier’s product by receiving site and comparison of test results to a supplier’s certificate of analysis.

Parameters

Factors that are important to control, may have impact on filtration performance and product sterility and are product/process specific. These parameters are defined and validated during product filter validation.

Pareto Chart

A graphical tool for ranking causes from most significant to least significant. It is based on the Pareto principle, which was first defined by J. M. Juran in 1950. The principle, named after 19th-century economist Vilfredo Pareto, suggests that most effects come from relatively few causes; that is, 80% of the effects come from 20% of the possible causes. The Pareto chart is one of the seven tools of quality.

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Part

For coated tablets, those tablets which are coated and polished, if necessary, as a unit; for compressed tablets, that portion of the formula which is mixed, granulated, dried, and ground as a unit. Subsequently, all parts are blended, lubricated, compressed, sampled and tested as a single unit and part identity is lost.

Particle Count

The number of discrete particles of a particular size present in the sample examined.

Particle Size

A measurement of a particle’s dimensions. The instrumentation used determines the method of measurement. When determined by the manual microscopic method, the particle size is determined by the longest axis or effective linear dimension.

Passive Temperature Control System

A set of components including thermal container, spacers, dunnage, refrigerants, packaging and product payload configured in a specific manner to function as a qualified temperature controlled system for a specified time frame.

Passive Thermal Protection System

Typically an insulated thermal container in combination with shipping refrigerants (gel pack, gel brick, dry ice, etc.) which when assembled will provide thermal protection for its payload from outside temperatures during shipping. A set of components including thermal container, spacers, dunnage, shipping refrigerants, packaging and product payload configured in a specific manner to function as a qualified temperature controlled system for a specified time frame.

Pastes

Two classes of ointment-like preparations intended primarily for external application.

One class is made from a single phase gel, the other class, fatty pastes, consist of thick, stiff ointment that do not ordinarily flow at body temperature. Veterinary pastes may be given internally.

Path

In software engineering, a sequence of instructions that may be performed in the execution of a computer program.

Path Testing

Testing designed to execute all or selected paths through a computer program.

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Payload

Often referred to as a core-pack, it’s the volume of space which encompasses the area being temperature protected.

Peeling

Filmcoating defect characterised by a bumpy or an orange peel appearance. The coating can be lifted and pulled away from the body of the tablet.

Penetration Thermocouples

Thermocouples that are placed within piping/vessels or a liquid product/media to determine the temperature and F value received during the heating and sterilisation process.

Percent Chart (P Chart)

An attribute control chart for evaluating the stability of a process in terms of the percent of the total number of units in a sample in which a non-conformity occurs. The Percent Chart is also referred to as a Proportion Chart.

Performance Monitoring

A process that enables important operating parameters to be monitored to determine that the system is operating within a state of control, to detect and manage undesirable trends before they reach unacceptable levels or significantly impact system performance and to correct problems.

Performance Monitoring Data

Data that are collected during performance monitoring. This data indicates the operational health of the computer system.

Performance Qualification (PQ)

Documented evidence that provides a high degree of assurance that the equipment and/or system functions accurately and consistently according to predetermined specifications in its operating environment.

Periodic Evaluation

An evaluation, performed on periodic time basis, to confirm that a process/method/system remains able to consistently produce a result meeting pre-determine acceptance criteria.

The evaluation can involve execution of field studies (See definition ‘Periodic Revalidation’) or an assessment of pertinent data (See definition ‘Periodic Review’).

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Periodic Report

Document containing information regarding adverse drug experiences, which must be filed with the FDA quarterly for three years from the date of approval of the application, and then at annual intervals. Note distinction from ‘Annual Report’.

Periodic Revalidation

Re-execution of validation studies, performed on a periodic basis, to verify systems and processes remain able to consistently produce a result meeting pre-determine acceptance criteria through execution of a lab or field study.

Note: For sterilisation processes, Periodic Revalidation is referred to as Annual Revalidation due to the clear expectations on frequency.

Periodic Review

A documented review of pertinent data as appropriate (for example, manufacturing performance trend data, change history, deviation history) to confirm that a process/method/system continues to consistently produce a result meeting pre-determined acceptance criteria. See definition ‘’Validation’.

Periodic Stability Trend Monitoring

System in place at stability testing sites to proactively review stability data and trends on a regular basis, at minimum, on an annual basis e.g. stability annual review.

Permanent Inspection Readiness (PIR)

A formalised system that documents the structure, responsibilities and procedures required to achieve effective quality management. Provides a platform for establishing GMP compliance. Robust Quality Systems ensure sustainable compliance. Quality Systems in a good state of control are fundamental to taking risk based decisions

Personnel Training

Encompasses documented training of all personnel related to fermentation processing, in aseptic techniques, operating procedures, and other areas as applicable.

pH

The negative logarithm of the effective hydrogen ion concentration of hydrogen ion activity in gram equivalents per litre. It is used to express the acidity or alkalinity of a solution.

pH values are scaled from 0 to 14, with 7 designating neutrality, values less than 7 indicating increasing acidity and values greater than 7 indicating increasing alkalinity.

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Pharmaceutical Alternatives

Drug products that contain the same therapeutic moiety but are different salts, esters, or complexes of that moiety or are different dosage forms or strengths.

Note distinction from ‘Pharmaceutical Equivalents’.

Pharmaceutical Equivalents

Drug products that contain the same active ingredient(s), are of the same dosage form, route of administration and are identical in strength or concentration. The drug products are formulated to contain the same amount of active ingredient in the same dosage form and to meet the same or compendial or other applicable standards (i.e. strength, quality, purity, and identity), but may differ in characteristics such as shape, scoring configuration, release mechanisms, packaging, excipients (including colours, flavours, preservatives), expiration time, and within certain limits, labelling.

Note distinction from ‘Pharmaceutical Alternatives’.

Pharmaceutical & Medical Device Agency (PMDA)

Japan's regulatory group responsible for control of pharmaceuticals, biologicals and medical devices for sale in Japan.

Pharmaceutical Water System

A pharmaceutical water system begins at the point where potable-grade water enters and ends at the point of use (POU) where water is delivered meeting the quality attributes applicable to the specific water type (based upon its intended use).

Pharmacode

A one dimensional, variable length bar code symbology (encoding standard) commonly used in the pharmaceutical industry for on-line verification of inserts, cartons and other printed package components.

Pharmacopeia

See ‘Compendia’.

Pharmacopeial Discussion Group (PDG)

Comprised of representatives of the USP, Ph. Eur., and JP who meet to work toward harmonisation of compendial monographs and general chapters.

Pharmacopeial Forum (PF)

A publication containing proposed revisions to the USP-NF

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Pharmacovigilance (PV)

Detection and investigation of the effects of the use of medicinal products, mainly aimed at safety and efficacy in animals and safety in human(s) exposed to the products.

Pharmeuropa

A publication containing proposed revisions to the Ph. Eur.

Physical Manipulation

A process that does not involve a chemical reaction that changes the purity or the physical properties of the material, including but not limited to, crystallisation, gel filtration, chromatography, milling or blending.

Physician’s Sample (also, Physician Sample or Physicians Sample)

A type of pharmaceutical package intended to be dispensed to a patient directly by a physician in order to start and evaluate therapy with that product.

Picking

Tablet defect in which material from a tablet is removed from the tablet’s surface and sticks to a punch. The defect frequently occurs with punch tips with engraving for the letters “B”, “A” and “O”.

Pills

A solid dosage form, in the shape of a small ball or pellet, containing a medicament. They are to be administered orally and are formed by rolling rather than by molding or compressing.

Pilot Lot

Small-scale demonstration batch or lot usually processed in research.

Pilot Scale

The manufacture of either drug substance or drug product by a procedure fully representative of and simulating that used for full manufacturing scale. For solid oral dosage forms this is generally taken to be, at a minimum, one-tenth that of full production, or 100,000 tablets or capsules, whichever is larger

Pilot Scale Batch

The manufacture of drug product by a procedure fully representative of and simulating that intended to be used for full manufacturing scale.

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Piping and Instrumentation Diagram (P&ID)

A diagram, which shows the detailed piping and instrumentation design for all unit operations. Equipment and piping sizes are show as well as controls for the instrumentation. This diagram is only symbolic of the equipment, piping, and instrumentation. It does not represent the spatial orientation of the items depicted.

Pivotal Intermediate

An intermediate that may be prepared by more than one manufacturing process to provide material of suitable quality for use in the production of a drug substance.

Placebo

Contains all components of the formulation except the analyte of interest.

Plan-Do-Check-Act Cycle

A four-step process for quality improvement.

In the first step (Plan), a plan to effect improvement is developed.

In the second step (Do), the plan is carried out, preferably on a small scale.

In the third step (Check), the effects of the plan are observed.

In the last step (Act), the results are studied to determine what was learned and what can be predicted. The plan-do-check-act cycle is sometimes referred to as the Shewhart cycle because Walter A. Shewhart discussed the concept in his book Statistical Method From the Viewpoint of Quality Control and as the Deming cycle because W. Edwards Deming introduced the concept in Japan. The Japanese subsequently called it the Deming cycle.

Plug

1) The undissolved contents of a capsule, which remain upon completion of the dissolution test. The undissolved material is usually bound together and loosely resembles the shape of the capsule. The substance that remains at the bottom of a vial after lyophilisation.

2) Also referred to as ‘Shank – the cylindrical part of the stopper perpendicular to the flange which extends down into the throat of the vial when the stopper is properly seated.

Point of Use Filter

A terminal gas filter located downstream of either source filter (for non-product contact applications) or a distribution filter (for product contact applications).

Policy

A high level strategic statement of quality goals, principles and philosophies which are to be implemented throughout the a set of sites.

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Polymeric Contact Material (PCM)

Also known as process stream contact material such as tubes/hoses, filters, bags and connectors.

Population

Statistical term defining all of the items of a set or all of the items coming from a process. It includes the whole set of items of a specified kind at a specified time.

Pore Size

Filter manufacturer’s claimed estimated size of filter pores.

Porous / Hard Goods Load

A group of items to be sterilised in an autoclave in which the bioburden is inactivated through direct contact with moist heat (saturated steam). Porous/hard goods load items may include, but are not limited to: filters, fill line change parts, equipment assemblies, and equipment change parts.

Positive

Test which exhibits detectable microbial growth after incubation.

Positive Sterility Test Result

A positive sterility test result is defined by the observation of microbial growth in specified test media. Turbidity in the test media typically indicates contamination. The presence of microbial contamination results in failure of the sterility test.

Post-Production

Part of the life-cycle of the product after the design has been completed and the medical device has been manufactured.

Post Release

See ‘Stages’.

Post Shipment Receipt

Time beginning after the customer has assumed custody and responsibility for the goods delivered, usually the time following POD.

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Post Sterilisation Hold Time (PSHT)

The time between the completion of the sterilisation cycle and the use of that equipment, material or component in a production operation.

Post-Sterilisation, Pre-Use (PUPS) Filter Integrity Test

A non-destructive physical test that be correlated to the bacterial retention capability of a filter/filter assembly. This test is performed on the filter/filter assembly after it undergoes sterilisation but prior to use.

Postmarket Safety Monitoring

A process by which the manufacturer collects and reviews information about the medical device, which includes safety surveillance, product quality trending and certain manufacturing controls.

Potency

The therapeutic activity of a drug product. Note distinction from Strength’.

Pre-Approval Inspection (PAI)

An inspection of an establishment that performs manufacturing steps in an approved BLA or NDA for which the applicant has submitted a supplement for a significant manufacturing change or other change that ordinarily requires on-site review of change.

Pre-Approved Change

A change made to the working Master Batch Sheet intended to be used regularly for future batches.

Preassembled CTU

Commercial off-the-shelf (COTS) reach-ins and table top units that require minimal assembly on site.

Precision

1) The variability in a method of measurement. The degree of agreement/reproducibility among individual test results with an analytical method and is usually expressed as a standard deviation (SD) or percent relative standard deviation (%RSD). There are three fundamental components of precision: measurement, method, and ruggedness. Note distinction from ‘Accuracy’.

2) The closeness of agreement between a series of measurements obtained from multiple sampling of the same homogeneous sample under the prescribed conditions.

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Predicate Rules

Federal Food, Drug and Cosmetic Act and the Public Health Service Act requirements and regulations including but not limited to 21 CFR 210, 211, 600, 601, and 610.

Pre-Execution

See ‘Stages’.

Pre-Filter

A sterilising grade, nominal pore size of 0.22 micron (or greater), filter placed prior to the sterile boundary filter and used for bioburden reduction

Pre-Filtration Hold Time

The time between the start of the preparation of a solution and its sterilisation by filtration through a bacteria-retentive filter.

Preliminary Investigation

The initial phase of an investigation into an atypical event, an atypical result or an OOS result conducted to determine if an assignable cause is present.

Preliminary Investigation Report

Report issued before the entire investigation is completed, but before the original due date. The preliminary investigation reports contains the key steps completed to date, the findings, any actions taken and a preliminary risk assessment.

Prepared Solution

Any solution or indicator prepared in the laboratory.

Preservative

An agent that prevents or inhibits microbial growth in a formulation to which it has been added. May also be present to prevent chemical degradation.

Pre-Shipment Samples

Samples of a production lot obtained by the supplier which are representative of the production lot and are shipped separately from the production lot.

Pressure Hold Test

The pressure hold (or pressure decay) test is an indirect method of upstream diffusive flow testing. In this method, the filter housing is pressurised to a predetermined setting and then

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isolated from the pressure source. Gas flow across the membrane is quantitatively measured as decay in pressure over a specific period of time. This test is then indirectly correlated to bacterial retention through its relationship to the diffusive flow test.

Preventive (or Preventative) Action(s) (PA)

An action taken to eliminate the cause of a potential non- conformity, defect or other undesirable situation in order to prevent occurrence.

Preventative Maintenance (PM)

A formalised program to periodically check the routine operation of equipment to ensure that the equipment operates with original design specifications.

Prevention vs. Detection

A term used to contrast two types of quality activities. Prevention refers to those activities designed to prevent non-conformances in products and services. Detection refers to those activities designed to detect non-conformances already in products and services. Another term used to describe this distinction is ‘Designing in Quality vs. Inspecting in Quality’.

Primary Controls

A procedure, method, or physical design feature intended to protect the product from contamination by addressing potential root causes of contamination.

Primary Label

Label applied to the primary container contacting the dosage form to identify the product in the primary container.

Primary Component

Any purchased element of the container/closure system, packaging materials used to contain and/or identify the product for delivery to an internal or external customer and/or a device changed on some recurring basis and with critical specifications (such as a Sterilising Filter) used in the manufacturing and/or packaging process.

Primary Package Type

Package configurations with equivalent materials of construction and equivalent closures. For example, HDPE Bottles with different sizes and counts but with the same induction seal closure are representative of the HDPE Bottle as the primary package type. Similarly, different counts of blister cards are considered the same primary package type since blisters are unit dose packages.

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Primary Packaging

Components that are in direct contact with the product.

Primary Packaging Component(s)(PPC)

A component of the container closure system that potentially comes into direct contact with the drug product formulation (e.g. canisters, pumps, actuators, gaskets, syringe plungers, stoppers, etc.).

Primary Record

The record which takes primacy in cases where data that are collected and retained concurrently by more than one method or system, application, fail to concur.

Primary Source

The original recording of a piece of data or information.

Examples include laboratory raw data, calculated data/results, executed batch records, Quality Standards, specifications.

Primary Source Document

The original recording of a piece of data or information. This includes laboratory raw data, process descriptions, batch records, packaging orders/tickets, Quality Standards, official compendia, previously filed regulatory submissions, packaging/vendor specifications etc.

Printed Packaging Component(s)

Primary, secondary, and tertiary (as applicable) packaging components that display any written, printed or graphic matter and are used in the packaging of a finished drug product.

Examples include: primary container label, primary and/or secondary folding cartons, blister packs, etc.

Probability

The likelihood that a hazard or event will occur.

Process

1) A series of operations and/or actions used to produce a desired result.

2) The relevant manufacturing, formulation, filling, packaging, and/or testing for the relevant drug substance, intermediate and/or finished product.

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Process Analytics Terminology

Calibration Model: The mathematical expression or set of mathematical operations that relates component concentrations or properties to spectra for a set of reference samples.

Library: As in the case of spectroscopic qualitative or identity methods, the set of spectra comprising the positive controls to which a new sample spectrum is compared.

Model Update: A process to modify a calibration model to suit the changed measurement conditions (process, sample, environment, etc.).

Model Verification: On-going, evaluation and testing to ensure the analytical performance of a calibration model.

Model Validation: The process of testing a calibration model with validation samples to determine bias between the estimates from the model and the reference method and to test the agreement between estimates made with the model and the reference method.

Reference Method: The analytical method that is used to estimate the reference component concentration or property value which is used in the calibration and validation procedures.

Validation Samples: A set of samples used in validating a calibration model. Validation samples are not part of the calibration set. Reference component concentrations or property values are known (measured by Reference Method), and are compared to those estimated using the presence of compounds that may be expected to be present, such as impurities, degradation products and matrix components model.

Process Capability

The 6-sigma (6σ) spread in the distribution of the product quality characteristics for a process that is statistically in control and normally distributed compared to engineering or specification limits.

Process Capability Index

The value of the tolerance specified for the characteristic divided by the process capability. There are several types of process capability indexes, including the widely used Cpk and Cp.

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Process Controls

Is an all-inclusive term used to describe the controls used during manufacturing and packaging to monitor and, if appropriate, adjust the process and/or to ensure that an intermediate or an Active Pharmaceutical Ingredient (API) with an established specification or the finished drug product will conform to its respective specification.

The term includes Critical Quality Attributes (CQAs) and Critical Process Parameters (CPPs).

Process Description

A description of a series of operations and/or actions used to produce desired results.

Process Design

Defining the commercial manufacturing process based on knowledge gained through development and scale-up activities. (FDA Process Validation: General Principles and Practices).

Process End-to-End Testing

Testing based on operational methods (business process) and procedures associated with the system and any interfaced system(s). Testing should challenge the full business process focusing on critical functionality and the movement of data (start to finish) throughout these interconnected systems.

Process Flow Diagram (PFD)

A diagram which shows the process flow through all unit operations and provides a material balance, energy balance, and process conditions (temperature, pressure, process stream physical properties) for the process and utility fluids. The unit operations are depicted using the appropriate equipment symbols.

Process Fluid

Any liquid or gas.

Process Instrumentation

An instrument that is required to control/measure/monitor or record variables in the manufacturing, packaging or the production process.

Process Owner

The person responsible for the business process.

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Process Performance Qualification (PPQ)

The second element of Stage 2, Process Qualification which confirms the process design and demonstrates that the commercial manufacturing process performs as expected. (Adaptation of FDA Process Validation: General Principles and Practices).

Process Qualification

Confirming that the manufacturing process as designed is capable of reproducible commercial manufacturing. (FDA Process Validation: General Principles and Practices).

Process Re-qualification

Re-confirmation a manufacturing process, as designed is capable of reproducible commercial manufacturing. This action is taken in response to either a planned or unplanned event that may impact the qualification status. (Adaptation of FDA Process Validation: General Principles and Practices).

Process Simulation

Method of evaluating the effectiveness of an aseptic process to maintain sterile conditions using a microbial growth medium.

Note that Process simulation tests are synonymous with simulations, simulated product fills, media challenge, broth trials, broth fills, etc.

Process Tolerance Limits

The acceptable amount of error for a given instrument reading against a defined and defendable Process Tolerance. The process tolerance being the point at which the potential for product impact has been determined to exist.

Process Validation

The collection and evaluation of data, from the process design stage through commercial production, which establishes scientific evidence that a process is capable of consistently delivering quality products. (FDA Process Validation: General Principles and Practices).

Process Validation Protocol

A written plan describing the requirements for a validation study by stating the objective of the study, providing a process background, clearly defining CPPs and CQAs (for all process steps, intermediate and final product), and detailing sampling and testing requirements, specifications, acceptance criteria and other information of relevance to the process.

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Process Validation Study

The formal study of a process, conducted with the aim of demonstrating that the process is in control (individual steps are well understood) and consistently yields product meeting predefined quality criteria.

Product Contamination

Contamination of a drug product via either product cross contamination or extraneous matter contamination.

Product Cross Contamination

Contamination of one drug product by another.

Product Disposition

Documented notification to a receiving site providing direction on the acceptance/rejection of the subject product.

Product Protection System

Any active or passive temperature control system.

Product Quality Complaint (PQC)

Any communication that describes a potential defect related to the identity, strength, quality, or purity of a product after it is released / distributed for use by a customer.

Product Release

The final authorisation the Quality Operations gives that a raw material, component, intermediate, API, or finished product is ready for distribution for its intended use and market and is in compliance to all specifications, regulations and GMPs of the recipient market.

Product Review Period

A period which must be predefined in the Product Review schedule of twelve continuous months, and within which all commercial batches manufactured for a given product are subject to review and analysis in the Product Review.

Product Type

Categorisation of products with similar characteristics that are grouped together for the purposes of a Standard Investigation Plan. Some examples of Product Types would include Tablets/Capsules, Sterile Injectables, Ophthalmics, Liquids/Ointments/Creams, Oral Liquids/Powders, Medical Devices.

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Product Value Enhancement (PVE)

Represents either a new dosage form for an already marketed product (e.g. chewable tablet for pediatric population) or a combination product with two or more active pharmaceutical ingredients.

Project Validation Master Plan

A project planning document used to describe the overall qualification and validation strategy for a project. This document will plan and guide activities for a new product, process, system, facility or utility. The Project VMP outlines the systems, equipment or utility to be qualified; the systems and processes requiring validation; establishes primary responsibilities for completion; and identifies the project controls which will be implemented to ensure regulatory compliance.

Proof of Delivery (POD)

Is a document, signed by the consignee/receiving site personnel, which confirms delivery and conditions of the goods in a shipment.

Proposed Rule

A standard or law, which has been promulgated by a government agency. The proposal appears in the Federal Register and is open for comments by the general public.

Proprietary Name

A trademarked designation for a substance or product of potential or proven therapeutic usefulness. It has been registered for private use in identifying an individual brand of the substance or product.

Prospective Validation

Validation conducted prior to the distribution of either a new product, or product made under a revised manufacturing process, where the revisions may affect the product's characteristics. Requires that each critical processing step be pre-defined and limits set for both those parameters (CPPs) which ensure the successful execution of that step, and the product’s attributes (CQAs) resulting from the step. A pre-determined number of product lots (usually three to five) are then manufactured and demonstrated to conform to all of the pre-assigned process specifications.

Protocol

A written plan describing the process to be validated including production equipment and stating how validation will be conducted.

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Protocol Deviations

Noted discrepancies (differences) between the approved protocol and the actual work performed which may or may not have the potential to impact the validity of the results or affect product quality.

Proximal Materials

All packaging materials other than the PPC such as ink, adhesive, label, carton, protective packaging materials etc.

PST

Process Specifics Training is the on-going training employees receive to ensure they understand the key GMP, processing, environmental, safety and industrial hygiene requirements for manufacturing processes run at the site. PST is primarily intended for personnel directly involved in manufacturing.

Pure Process

Any API unit operation that can affect the final crystallisation or subsequent processing steps.

Pure Room

A room/area containing any API unit operation that can affect the final crystallisation or subsequent processing steps.

Pure Steam System

Pure Steam systems begin at the point of entry of the feed-water (minimally Purified Water) and ends at the point at which the Pure Steam exits at the point of use e.g. for autoclave applications, the system terminates at the autoclave isolation valve.

Purge

The act of permanently discarding or deleting data, documents or software.

Purification Procedure

A process, such as crystallisation, distillation, or chromatography, intended to improve the purity of an intermediate, API or biologic API.

Pyrogens

A substance that induces febrile reaction in a patient.

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- Q -

Q

Used to determine the dissolution acceptance criteria. It is expressed as a percentage of labeled claim of active ingredient dissolved in a given time

Q9000 Series

Refers to ANSI/ISO/ASQC Q9000 series standards, which is the Americanised version of the 1994 edition of the ISO 9000 series standards. The United States adopted the ISO 9000 series standards as the ANSI/ISO/ASQC Q9000 series.

QA

Quality Assurance.

QMS Flowchart

A process overview map for each of the GMP Quality Management Systems (QMS) that reflects the core requirements and details the roles and responsibilities linkages between responsible functions.

QRD File - Quality Review of Documents

Word file following a given structure as defined by the EMEA containing the text to be printed on one component, part of the Product Information Template.

Qualification (Equipment and Systems)

Action of proving and documenting that equipment or ancillary systems are properly installed, work correctly, and actually lead to the expected results. Qualification is part of validation, but the individual qualification steps alone do not constitute process validation. (Reference ICH Q7)

Qualification (Personnel)

Action of proving and documenting that individual personnel are trained and capable to perform a defined task.

Qualification / Qualified

Action of proving that any equipment works correctly and actually leads to the expected results.

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Qualification Period

The length of time for which a comparison sample is considered approved for use. As the comparison sample is intended to represent current production, a period that should not exceed 24 months is established as the maximum length of time that a sample can be qualified as a comparison sample.

Qualification Threshold (QT)

A level below which a given leachable is not considered for safety qualification (toxicological assessment) unless the leachable presents structure-activity relationship (SAR) concerns.

The QT of 5µg/day has been established for leachable compounds based on total daily intake of Orally Inhaled and Nasal Drug Products (OINDP) only. QT is not applicable to all special case compounds, such as PAH, MBT, and N-Nitrosamines.

Qualified

Persons with the responsibility for a specific activity and the necessary capability, education, and experience to perform the activity.

Qualified Person (QP)

EU requirement as per Directive 2001/83/EC. There are three types of QP:

1) As per articles 41, 46, 48-52 and per EU GMPs Chapters 1, 2, Annex 16, the person – linked to the Manufacturing Authorisation - legally responsible for batch certification and batch release to EU/EEA market, for quality of product in market and the first contact person with (local) agency on quality issues. This person must ensure that the batch has been manufactured and checked in accordance with the requirements of its marketing authorisation and the principles of EC Good Manufacturing Practice; in the case of medicinal products coming from third countries, that each production batch has undergone in the importing Member State a full qualitative analysis, a quantitative analysis of at least all the active constituents and all the other tests or checks necessary to ensure the quality of medicinal products in accordance with the requirements of the marketing authorisation; for active substances used, that they have been manufactured in accordance with good manufacturing practice for active substances and distributed in accordance with good distribution practices for active substances.

2) As per article 79(b), the person - linked to Wholesale Distribution Authorisation - responsible for Good Distribution Practices.

3) As per article 103, the person – linked to the Manufacturing Authorisation - responsible for Pharmacovigilance (there can be only a single Qualified Person for Pharmacovigilance within a Company).

Qualified Test

Test(s) that meet the statistical criteria for a supplier test acceptance.

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Qualify

To declare competent or adequate.

Quality (QA/QC)

An organisational element including both QA and QC, and the Qualified Person (in the EU). QA has the responsibility for GMP compliance throughout the product manufacturing cycle, starting with incoming raw materials through release and distribution of product to the commercial market. QC has the responsibility to test and determine if these materials meet their monograph test specification.

Quality Agreement

A quality agreement is a written contract that helps to delegate the responsibilities for compliance with current Good Manufacturing Practice (cGMP) requirements or Quality Systems Regulations (QSRs), describe any particular requirements regarding the product or service provided through specifications, and establish the responsibilities and procedures applicable to the parties’ respective RA/QA groups.

Quality Alert

A notification utilised to communicate critical information which has had or will probably have an impact on company facilities, practices, operations, etc. All information provided and associated action item requests require immediate attention and usually a formal response from the affected areas and sites.

Quality Assurance

The element of the Quality management system that monitors compliance with New Drug or Marketing Authorisation Applications and local and international regulations, adherence to Quality Standards, application of Quality Control procedures and handling of complaints.

Quality Assurance Audit

An independent quality check performed by a Quality Assurance group to determine the accuracy of data/content within a document.

Quality Audit

A systematic, independent examination and review to determine whether quality activities and related results comply with planned arrangements and whether these arrangements are implemented effectively and are suitable to achieve the objectives.

Quality Bulletin

A notification utilised to communicate important, useful information and a common understanding and awareness of quality and regulatory/compliance issues.

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Quality by Design (QbD)

A systematic approach to development, that begins with predefined objectives and emphasises product and process understanding and process control based on sound science and quality risk management (ICH Q8).

Quality Compliance Tracking System (QCTS)

A database used to track compliance related items such as Audits/Inspections, Observation, Action Plans associated with Audits/ Inspections and Action Plan Extension Requests

Quality Control Department

A separate and distinct operation maintained by a manufacturer that monitors the quality of production operations and exercises control over the quality of materials required for and resulting from those operations.

Quality Council

See ‘GMP Committee’.

Quality Critical Alarms

1) Automated alarms for those parameters that indicate an adverse impact on product quality and/or regulatory filings. If deemed to be valid, these alarms require a deviation investigation. They include such analog alarms as filed regulatory range limits (e.g. NDA), Critical Process Parameter (CPP) limits, other process parameter limits that impact quality (e.g. Critical Sterilisation Parameter, Critical Cleaning Parameters) and discrete device alarms for system integrity (e.g. limit switch failure for critical break valves, detection of foreign component on packaging line).

2) An alarm indicating that a critical environmental control parameter has moved outside its defined control range, and which by doing so, may affect the quality of the material being produced.

Quality Engineering

The analysis of a manufacturing system at all stages to maximise the quality of the process itself and the products it produces.

Quality Indicating

Having a direct impact on the purity, safety, efficacy or potency of the product.

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Quality Management System (QMS)

A formalised system that documents the structure, responsibilities, and procedures required to achieve effective quality management. QMS principles include providing a platform for establishing GMP compliance, embedding Quality Systems thinking into the culture, providing established and robust systems to support risk management, and driving continuous improvement.

Quality Manual Policy

A high level document which defines strategic Quality philosophies, principles and/or goals.

Quality Manual Procedure

A document that provides specific operating instructions to sites and/or functional areas which define detailed what and how requirements are to be implemented to ensure compliance with cGMPs and regulatory agency expectations.

Quality Non-Critical Alarms

Automated alarms which help to maintain the process in a consistent and controlled state and may provide early warning information designed to avoid Quality Critical alarms. They may also be used to define discrete process ‘Events’ (e.g. high level alarm indicates when to manually pump out tank). Alarms for such parameters would have no expected impact on product quality and/or regulatory filings.

Quality Operations

Typically, the unit that independently monitors the quality of production and laboratory operations and determines product release. In some plants, other units or individuals may contribute to the product release process.

Quality Planning

Activities, established by management with executive responsibility, that establish the quality objectives and requirements for quality and application of the quality system.

Quality Responsible Person (QRP)

In the EU, the qualified person responsible for the safeguarding of product users against potential hazards arising from poor distribution practices. The QRP must meet the conditions provided for by the legislation of the Member State concerned.

Quality Risk Management

A systematic process for the assessment, control, communication and review of risks to the quality of the drug (medicinal) product across the product lifecycle.

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Quality Score Chart (Q Chart)

A control chart for evaluating the stability of a process in terms of a quality score. The quality score is the weighted sum of the count of events of various classifications where each classification is assigned a weight.

Quality Standard

Compilation of specifications and their associated analytical methods used to ensure the identity, strength, quality, and purity of products, active ingredients, intermediates and raw materials.

Quality Target Product Profile (QTPP)

A prospective summary of the quality characteristics of a drug product that ideally will be achieved to ensure the desired quality, taking into account safety and efficacy of the drug product. (ICH Q8).

Quantitation Limit (QL) or Limit of Quantitation (LOQ)

The lowest amount of analyte in a sample that can be quantitatively determined with acceptable accuracy and precision.

Quarantine

Status of starting material, intermediates, API or finished products isolated physically or by other means while awaiting a decision on their release status.

Note distinction from ‘Rejection’.

Quarantined Status

A status assigned to a material that is held under quarantine pending a decision on their subsequent final disposition.

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- R -

Range(s)

1) The extent to which or the limits between which acceptable variation exists. The interval between the upper and lower concentrations of analyte in the sample (including these concentrations) for which it has been demonstrated that the analytical procedure has demonstrated acceptable precision, accuracy, and linearity will be demonstrated.

2) The inclusive interval between the upper and lower concentrations of analyte in the sample for which it has been shown that the analytical procedure has demonstrated acceptable precision, accuracy and linearity.

Range Chart (R Chart)

A variables control chart in which the subgroup range, R, is used to evaluate the stability of the variability within a process.

Range for Critical Process Parameter

The range for each critical process parameter generally developed on research or pilot scale batches that encompasses values that are capable of producing intermediates and APIs with acceptable quality attributes.

Raw Data (also referred to as Data Source or Source Data)

A paper or electronic record that contains the first record of an original observation or data (the first time numerical data values/observations are recorded is considered ‘Raw Data’), or a ’True Copy’. Raw data must be contemporaneously and accurately recorded by permanent means. In the case of basic electronic equipment which does not store electronic data, but provides only a printed data output (e.g. balance or pH meter), the printout constitutes the raw data. In the case of basic electronic equipment which displays data but does not store electronic data, and does not provide a printed data output the hand recorded data in the data sheet constitutes the raw data. See also ‘Data’.

Raw Material

Any substance intended for use in the manufacture of an active pharmaceutical ingredient.

Readability

Relative to labelling / artwork, refers to the ease, speed, and accuracy with which information can be read and understood.

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Reagent Grade

Part of an overall chemical purity grading system that includes primary standard, reagent, and technical grades. Reagent grade is usually the highest quality commercially available for that chemical.

Reagents/Test Solutions

Chemicals in solid form, or solution that are used as part of analytical testing procedures.

Real Time Stability Trend Monitoring

System in place at stability testing sites to proactively detect aberrant stability results and trends in a timely manner at time of data generation and to ensure appropriate action and notification. Approaches to real time trend monitoring include Maximum Allowable Difference (MAD), Trend Limits and Early Warning Systems (EWS).

Reapproval Testing (also Re-Testing)

Term analytical evaluation of the stability indicating attributes of a drug substance batch which has exceeded its assigned retest date, to confirm conformance to specifications and to qualify the material for use in the manufacture of a drug product. This is the same as re-test per ICH Q1A and ICH Q7.

Recall

A firm’s removal or correction of a marketed product that the governing regulatory agency considers to be in violation of the laws it administers, and against which the regulatory agency may initiate legal action, e.g. seizure.

Recall is an action that takes place because manufacturers and distributors carry out their responsibility to protect the public health and well-being from products that present a risk of injury or are otherwise defective. This does not include market withdrawal or stock recovery.

Note distinction from ‘Market Withdrawal’.

Recall Classification(s)

The designation to a particular product recall to indicate the relative degree of health hazard presented by the product being recalled.

See also individual classifications: ‘Class I Recall’, ‘Class II Recall’ and ‘Class III Recall’.

Recall Depth

Medical assessment determines the recall class and the recall class facilitates determining the appropriate depth of a recall. Class I recall depth is generally at the physician/consumer level. Class II recall depth is generally at the retailer level. Class III recall depth is generally at the wholesaler/distributor level. The recall depth may be adjusted based on product specific issues or at the request of the authorising regulatory agency.

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Recall Strategy

A planned specific course of action to be taken in conducting a specific recall, which addresses the depth of recall, need for public warnings, and the extent of effectiveness checks for the recall.

Receiving Site (RS)

The destination site of the goods shipment.

Re-Circularisation

The process involving the removal of circulars from the market package and their replacement with the current, approved revision of the circular.

Reconstitution

The conversion of a lyophilised or dehydrated product into a solution or suspension by the addition of a liquid.

Note distinction from ‘Constitution’.

Records

Documents that provide evidence of various actions taken to demonstrate compliance with instructions. See also Data; Original Record; Raw Data.

Recovery

Measures the ability of an analytical method to quantify the concentration of analyte in the appropriate sample matrix.

Recovery Precision

The reproducibility (%RSD) of a set of measurements obtained at individual levels from the accuracy/linearity evaluation.

Recurrence of Event

An event which occurs as a result of the same root cause three times over a six month period of time.

Recurring Alert Level

An alert level result where another alert or action level has occurred in the recent monitoring history of the site in question e.g. 10 previous tests.

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Redlining

A process of making changes that are approved through change control practices. Redlined changes are then applied to the approved GMP SLC deliverables, without re-circulating the entire deliverable each time for revision approval. This may be accomplished electronically or manually e.g. with a red pen.

Reduced Investigation

An investigation that includes only a portion of investigation elements. Reduced investigations can only be performed with a risk assessment has been performed that shows that they are appropriate in the given circumstance.

Redundant Filtration

Sterilisation by filtration unit operation that requires one claimed sterilising filter but uses two sterile boundary filters that are placed one after the other. The sterile boundary is created after the process fluid passes the first sterile boundary filter.

Re-Evaluation Date (RED)

The date assigned to clinical supplies that corresponds to the end of that period of time after the Date of Manufacture for which supporting stability data are available. Prior to this date the product is expected to remain within specification if stored according to label instructions. The date is recorded in month/year or day/month/year format, and will typically be set to the end of the month in which the RED falls unless superseded by local SOP or regulatory requirement. After the RED, the material should be re-evaluated for conformance to specifications.

Reference File / Supplied Text

Human readable computer file that is used as the official source for the text content, including tables, graphs, and graphics, to be printed on one labelling and printed packaging component.

Reference Material

The material which is used for comparison with the biobatch drug product in a biostudy.

For bioequivalence studies, the material may be an innovator’s product or marketed product. For bioavailability studies, the material may be an oral solution or injection of the drug product under investigation.

Reference Standard

A substance that has been shown by an extensive set of analytical tests to be authentic material that should be of high purity. This standard can be:

1) Obtained from an officially recognised source

2) Prepared by independent synthesis

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3) Obtained from existing production material of high purity

4) Prepared by further purification of existing production material

Registered Expiry Period

A period of time, expressed as the number of months which represents a product’s expiry period as registered in a particular country or end market.

Registrar Accreditation Board (RAB)

A board that evaluates the competency and reliability of registrars (organisations that assess and register companies to the appropriate ISO 9000 series standards). The Registrar Accreditation Board, formed in 1989 by ASQC, is governed by a board of directors from industry, academia and quality management consulting firms.

Registration to Standards

A process in which an accredited, independent third-party organisation conducts an on-site audit of a company’s operations against the requirements of the standard to which the company wants to be registered. Upon successful completion of the audit, the company receives a certificate indicating that it has met the standard requirements.

Regression Analysis

A statistical technique for determining the best mathematical expression describing the functional relationship between one response and one or more independent variables; a statistical procedure which demonstrates how two variables are related. Using this method and a small data collection, the value of a dependent variable can be predicted from a known value of the independent variable.

Regression Testing

Selective retesting of a system or component to verify that modifications have not caused unintended effects and that the system or component still complies with its specified requirements.

Regulated Product

A product registered with a Health Authority or Regulatory Agency.

Regulatory Methods

The set of testing procedures used by the regulatory agency/licensing regulatory authority to determine if a drug, drug product or biologic is in conformance with the approved regulatory specifications in the NDA. For compendial articles, the analytical test methods in the compendial monograph or general chapter which are legally recognised and used by the regulatory agencies when determining compliance with the appropriate regulatory requirements are considered regulatory. For non-compendial items, methods appearing in

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the NDA license or MAA or its supplements, and used to measure a specific regulatory specification, are considered regulatory.

Note distinction from ‘Non- Regulatory Method’.

Regulatory Specifications

Tests, analytical procedures, and acceptance criteria defined by the NDA, MAA, or product license, which must be met in order to allow marketing of the drug product.

Note distinction from ‘Internal Specification’.

Regulatory Submission(s)

1) This is the document that is submitted to a Regulatory Agency either directly or by Regulatory Affairs.

2) See ‘Stages’.

Regulatory Submission Document

A document that is submitted to a Regulatory Agency or Health Authority in support of a company product.

Regulatory Support Document

Data / information that has been generated from primary source documents specifically to support a regulatory submission e.g. technical reports, technical memos. Regulatory support documents are a sub-type of secondary source documents.

Regulatory Supported Range

A range which is filed with a regulatory authority, the limits of which are supported by documented laboratory, pilot plant or production data.

Reinspection

Subjecting material that has undergone 100% visual inspection during manufacturing to additional visual inspection due to a deviation in order to remediate the affected material.

Rejection

Status of material, which signifies that some aspect of its quality or manufacturing, has conclusively failed. Materials of this status must be isolated physically or by other means and that is not available for use unless approved by the quality unit.

Note distinction from ‘Quarantine’.

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Rejection Rate

A measure of the amount of product rejected relative to the total amount of product manufactured and dispositioned, during the review period, measured as the number of batches and presented as a percentage e.g. 2 batches rejected/100 batches manufactured = 2% rejection rate.

Rejects

The population of containers in a 100% visual inspection process that is rejected due to the potential presence of a defect. The reject population will be comprised of ‘Defects’ (i.e. true nonconformities) and ‘False Rejects (i.e. conforming material incorrectly identified as defective).

Relational Database

A relational database stores different components of associated data and metadata in different places. Each individual record is created and retrieved by compiling the data and metadata for review.

Relative Standard Deviation (RSD)

A statistical method used to compare amounts of different sizes by normalising the results to a comparable percentage basis. The RSD is equal to the standard deviation divided by the mean, multiplied by 100. Also called ‘Coefficient of Variation’.

Release

The formal Quality Operations approval of a material. Subsequent to release, a material may be used in processing or distributed to the market.

Release Criteria

The sum total of all the testing requirements necessary for lot approval, complete and correct documentation and absence of outstanding quarantines.

Release Limit Evaluation

Statistical analysis of stability data to determine criteria to apply at release and/or stability time zero to ensure that stability data will be expected to remain within the shelf-life specifications throughout the expiry or retest period. Results of the evaluation may form the basis for a release specification or could be used internally to monitor process performance against stability trends. The evaluation incorporates the contribution from quantitative changes in the measured results over time, the variability or uncertainty associated with the estimated rate of change, the variability or uncertainty of the reported results (analytical method variability) and the confidence level (alpha level or stated p-value associated with the risk).

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Release Limits

Established specifications to which a material must conform at the time of its release. These limits are normally based on stability and assay variability data and assure that the product will conform to regulatory specifications throughout its life to expiry. They are generally more restrictive and may never be looser than shelf life limits.

Release Pending

Status to ship materials prior to full Quality Release. Examples include material for which testing has not been completed, material that cannot be released due to regulatory restrictions, material pending close-out of PCR requirements or atypicals. Also known as ‘Hold for Release’.

Release Testing

The physical measurements, chemical analyses, and microbiological assays, which must be performed on a lot in order for it to receive Quality approval.

Reliability

The probability of a product performing its intended function under stated conditions without failure for a given period of time.

Re-Measurement

The process of re-evaluating a sample preparation (i.e. re-injection/re-dilution/re-shaking of samples solutions, re-weighing of a crucible, etc.) in an attempt to confirm the original result. Re- measurement should only be done using the original sample preparation.

Remedial Action (Immediate Action)

Action to eliminate or control a detected non-conformity taken at or near the time of the event and often prior to root cause determination. Remedial Actions typically are one-time fixes. It is an immediate solution such as repair or replacement.

Renovation

A renovation affects a large portion of the entirety of an area or system and is associated with an IQ/OQ. It is differentiated from a modification by its large scale.

Repackaging

The process of physically replacing the primary or secondary packaging components of a drug.

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Repackaging (Packaging Rework)

The process of physically replacing, adding or examining (if not provided via the initial packaging effort) the primary or secondary packaging components of a finished product (drug, biological, vaccine, etc.).

Repeat Test

A test used to replace an invalid test consisting of the original number of sample containers.

Repeatability (Measurement Precision)

The degree of agreement among individual test results when the method is applied repeatedly to multiple measurements of a single standard or sample preparation.

Repeatability (Standard/Sample Method Precision)

The degree of agreement among multiple standard/sample preparations when the method is applied repeatedly.

Reports

Documentation of the conduct of particular exercises, projects or investigations, together with results, conclusions and recommendations.

Reporting Limit (RL)

The level below which results are not reported. The reporting limit is always at or above the limit of quantitation.

Representative Sample

A selection of items from a population by a random process, in which each member of the population has an equal chance of being included.

Reprocessing

The single repetition of a step in the approved sequence of the manufacturing process. An extension or continuation of an in-process step to meet an in-process specification (i.e. drying, concentration volume, pH, impurity level) is not considered reprocessing. Extension or continuation of an in-process step which is not predefined/allowed by the operating procedure and the approved filing should be handled as an atypical event.

Requirements Traceability Matrix (RTM)

The RTM traces requirements to IQ/OQ and/or User Acceptance Test cases, configuration, design, procedures, policies, and/or user manuals.

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Resample

Resampling involves analysing a specimen from any additional units collected as part of the original sampling procedure or from a new sample, collected from the batch, should that be necessary.

Residual

Any product, degradate, intermediate, excipient, raw material/reactant or cleaning agent that may reside on any equipment surface following processing and/or cleaning.

Residual Risk

Risk remaining after risk control measures have been taken.

Residual Seal Force

Due to the viscoelastic relaxation behaviour of rubber stoppers, the force of the closure pressing against a vial decays as a function of time, elastomer composition and as a result of various processing procedures. Residual seal force is the measured force a closure exerts against a vial after the initial seal is made.

Response Level

That result which requires some response or reaction.

Re-Standardisation

The re-qualification of a previously standardised reagent or solution through re-testing or re-evaluation and statistical comparison of the found value to the original (or vendor) value. The process of verifying that a standardised solution can be used for an additional pre-determined period of time after exceeding its expiration period.

Restricted Access Barrier System (RABS)

A Restricted Access Barrier System (RABS) is an aseptic processing system that is used for filling sterile drug product. The RABS provides an enclosed environment which reduces the risk of microbial contamination during filling operations. The RABS is designed to operate with ‘doors closed’ during filling, providing a very low risk of contamination, or permit infrequent ‘open door interventions’ provided appropriate control procedures are taken.

Restricted Information

Designation for valuable data, not otherwise available to competitors, which does not present a comprehensive or conclusive segment of information. Information of temporary vital importance also comes under this category. This designation is the basic protective

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mechanism for most documents under controlled distribution and provides protection against loss, improper use or unauthorised disclosure.

Note distinction from ‘Critical Information’.

Restricted Release

The release of a material/product manufactured under a PCR with multi-market is restricted to the market that has received regulatory approval.

Result

The final reported value(s) of an analytical test.

Retention Sample

A sample consisting of at least twice the quantity necessary to perform all release testing, including sterility and pyrogens (if applicable).

Retest

The analysis of the original, homogenous material that was originally collected from the lot tested and yielded the atypical/ OOS result. An obsolete test historically conducted to verify the results of a valid, failing test. Retests are not permitted to release product, but additional tests may be employed in an investigational mode to assist in determining the source of a contaminant or the bioburden in a product designated for rejection.

Retest Date (also known as Re-Evaluation Date)

The assigned date after which a material should be examined to ensure that it is still in compliance with the specification and suitable for use. (From ICH Q1A)

Re-Test Period (also known as Re-Evaluation Period)

The period of time during which the drug substance is expected to remain within its specification and, therefore, can be used in the manufacture of a given drug product, provided that the drug substance has been stored under the defined conditions. After this period, a batch of drug substance destined for use in the manufacture of a drug product should be evaluated through re-approval testing for compliance with the specification and then used immediately. A batch of drug substance can be re-approved multiple times and a different portion of the batch used after each re-approval, as long as it continues to comply with the specification. For most biotechnological/biological substances known to be labile, it is more appropriate to establish a shelf life than a re-test period. The same may be true for certain antibiotics. (From ICH Q1A)

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Retrospective Validation

Validation of a process for a product already in distribution based upon accumulated production, testing and control data.

Note distinction from ‘Prospective Validation’.

Returned Product

Materials returned from any source-customers, branches, other company plants and other company divisions.

Revalidation

Re-execution of studies within a validation program to confirm that a process/method/system continues to consistently produce a result meeting pre-determined acceptance criteria. (See definition ‘Validation’). Revalidation is performed either in response to a change or as part of periodic monitoring of a process or system (See definition ‘Periodic Revalidation’).

Review By Exception

Methodology whereby data records generated by automated systems are filtered to reduce reviewing acceptable data and trends, to focus upon critical exceptions and the appropriate data and information necessary for decision-making or other human responses.

Reviewed By

Examines the format and content of a record to assure that it is accurate and complete via a hand-written signature on the record.

Reviewer

The party who reviews the Initiator's requested change.

Rework

Is any manufacturing step performed outside of the normal processing step sequence or outside of the regulatory filing and is used to correct non-conformity. Rework procedures are used to salvage active drug substances, process intermediates, and drug products which do not conform to specifications.

Right First Time

A term used to convey the concept that it is beneficial and more cost-effective to take the necessary steps up front to ensure a product or service meets its requirements than to provide a product or service that will need rework or not meet customers’ needs. In other words, an organisation should engage in defect prevention rather than defect detection.

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Rinse Sample

A cleaning validation sample consisting of an aliquot of the equipment rinse solvent.

Risk

The combination of the probability of occurrence of harm and the severity of that harm

Risk Analysis

The estimation of the risk associated with the identified hazards.

Risk Assessment

A systematic process of organising information to support a risk decision to be made as part of the assessment. It consists of identification of hazards and the analysis and evaluation of risk associated with exposure to those hazards.

Risk Communication

The sharing of information about risk and risk management between the decision maker and stakeholders.

Risk Control

Process in which decisions are made and measures implemented by which risks are reduced to, or maintained within, specified levels.

Risk Evaluation

The comparison of the estimated risk to a given risk criteria using a quantitative or qualitative scale to determine the significance of the risk.

Risk Management File

Set of records and other documents that are produced by the risk management.

Risk Prioritisation Number

A quantitative method for determining the level of risk by multiplying the severity, occurrence, and detectability rankings of the failure or event.

Robustness

A measure of a method’s capacity to remain unaffected by small but deliberate variations in method parameters (different instrument manufacturers, different solvent ratios, temperatures, etc.). It provides reasonable operating tolerances that may be expected during routine use.

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RODAC (Replicate Organism Detection and Count)

The industry-recognised method for evaluating aseptic surfaces, including gowning technique, in which nutrient agar plates are bought into contact with a gowned individual at various pre-specified locations then incubated at a specified temperature for some predefined period before being checked for microbial growth.

RODAC Plate Surface Area

4 sq. inches (25 sq. centimeters). If swab technique is used, the area swabbed should be approximately 4 sq. inches.

Room Temperature

Ambient, uncontrolled temperature conditions denoting the temperature prevailing in the working area. See also ‘Ambient Conditions’. Note distinction from ‘Controlled Room Temperature’. Various compendia define this term differently.

Root Cause

The underlying source of variation causing the deviation. The most basic reason, which if eliminated, would prevent recurrence of the deviation event.

Roughness

Filmcoating defect characterised by a gritty surface. It results when the coating is deposited on the tablet surface as particles instead of finely divided droplets of coating solution.

Routine Testing

The scheduled interval of required testing, such as testing each lot.

Ruggedness

The degree of reproducibility of a test obtained by the analysis of samples under a variety of routine test conditions expected in normal operating conditions (different laboratories, analysts, instruments, lot of reagents, elapsed assay times, assay temperatures, days, etc.).

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- S -

Safety

1) Safe packaging materials do not leach harmful or undesirable amounts of substances to which a patient will be exposed when being treated with the drug product

2) Freedom from unacceptable risk

Safety Concern Threshold (SCT)

A level below which a leachable would have a dose so low as to present negligible safety concerns from carcinogenic and non-carcinogenic toxic effects. The SCT of 0.15µg/day has been established for leachable compounds based on a total daily intake for OINDPs only. SCT is not applicable to all special case compounds, such as PAH, MBT and N-Nitrosamines.

SAL (Sterility Assurance Level)

The probability of microbial survival that corresponds to the process exposure time

Same

Agreeing in kind, amount; unchanged in character or condition.

Sample

1) A representative portion of a batch or lot selected according to a defined sampling plan and may be submitted to the laboratory for testing, examined on-line or maintained by the manufacturing site for possible future reference e.g. retain samples.

2) For the purposes of this document, sample refers to the material to be tested. Samples may include but are not limited to excipients, raw material, process intermediate, drug substance, drug product or finished goods.

Sample Preparation

That portion of the sample initially selected to be used for and subsequently processed in an analytical test.

Sample Pull Window

Time period around a scheduled stability testing interval during which samples are recommended to be removed from the stability storage conditions for testing according to the stability protocol for data to be representative of the scheduled storage duration.

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Sample Size

A group of units taken from a larger collection of units which is assumed to be representative of the collection. The size is determined by the sampling plan employed.

Sample Solution

A solution prepared from a sample (raw material, intermediate, API or drug product) that has been designated for analysis/testing/assay for the purpose of assessing product quality and/or process performance.

Sample Standard Deviation Chart (S Chart)

A variables control chart in which the subgroup standard deviation, s, is used to evaluate the stability of the variability within a process.

Sample Testing Window

Time period during which stability samples should be tested after removal from the stability chambers.

Sample Turnaround

The elapsed time (in calendar days) between the removal of the stability sample(s) from the stability chamber(s), to completion of all testing, including the review and approval of the data.

Sanitisation

A process for the purpose of reducing or controlling bioburden.

Saturated Steam

Steam that is at a temperature and pressure that corresponds to the vaporisation curve of water. It is a state of equilibrium between being a liquid and a gas, with minimal entrained liquid water.

Scale-Up

The process of increasing the batch size.

Scale-Down

The process of decreasing the batch size.

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Scanning Electron Microscope

An instrument, which uses electrons to examine the surface of a substance. The detailed images from the SEM make it especially useful for defect and particle analysis.

Scatter Diagram

A graphical technique to analyse the relationship between two variables. Two sets of data are plotted on a graph, with the vertical (y) axis being used for the variable to be predicted and the horizontal (x) axis being used for the variable to make the prediction. The graph will show possible relationships, although two variables might appear to be related, they might not be. Those who know most about the variables must make that evaluation. The scatter diagram is one of the seven tools of quality.

Schedule I

Drug Enforcement Agency classification for drugs which have a high potential for abuse and no accepted medical use in the United States.

Schedule II

Drug Enforcement Agency classification for drugs which have a high potential for abuse but do have a currently accepted medical use in the United States.

Schedule III

Drug Enforcement Agency classification for drugs which have accepted medical use in the United States but they have a lower potential for abuse than Schedule I and Schedule II drugs.

Schedule IV

Drug Enforcement Agency classification for drugs included in this schedule have a low potential for abuse relative to those in Schedule III.

Schedule V

Drug Enforcement Agency classification for drugs that have the lowest abuse potential of the controlled substances and consist of preparations containing limited quantities of certain narcotic drugs generally for antitussive and antidiarrheal purposes.

Scope Template

Standard form used at the start of the document development/revision process to record the document author, mentor, document drivers, planned application, proposed outline (for a new document) or major issues requiring revision (for an existing document), the need for (or against) supporting impact analysis and/or an implementation plan, and target dates for document chartering and completion.

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Seal(s)

1) A component (e.g. foil induction) used to prevent the passage of gas or moisture into the container

2) Any well-defined boundary created by melted elastomeric material or metal that prevents ingress or egress e.g. tanks, bags, bottles, or tubing.

Second Person Check

A confirmation by a second person for accuracy at close proximity to the executed step and usually required before continuing with a subsequent processing step and/or GMP activity.

Second Person Review

A re-examination of the content of the data/record/report by a second person against raw data (where available) as an independent review in a timely manner to confirm document complies with ALCOA elements (attributable, legible, contemporaneous, original and accurate) and in compliance with current Good Documentation Practices, current GMP standards and established procedures. This includes the review of items that have not been second person Verified or Checked during a GMP activity and for which documented evidence is required to demonstrate compliance with instructions on which quality decisions are taken

Second Person Verification

A direct witness of a step to assure that the step was performed appropriately prior to commencing a subsequent step or an equivalent assurance.

Secondary Container

General laboratory terminology for any vessel such as a wash bottle, dropping bottle, or reagent bottle, which has been filled from a primary container supplied by the chemical manufacturer.

Secondary Controls

A procedure, method, or physical design feature intended to provide an added layer of protection and redundancy to a system or to prevent ‘mix-ups’ and the results of human error in the manufacturing environment.

Secondary Packaging

Components that enclose one or more primary product containers for protection and to form the final market presentation, but which do not make direct contact with the product. This does not include labels.

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Secondary Source

A document or electronic record containing transcribed or summarised information from a primary source. There are two forms; both require second person review as well as an approval (obtain required approvals when governed by procedure). Approvers should have relevant knowledge and authority to enable use of the source.

Seed

A collection of containers comprising live virus, whose contents are of uniform composition and stored under controlled conditions. Each container represents an aliquot from a single, homogenous pool of virus produced from a single cell culture process.

Segregation

1) Refers to an area where potential cross-contamination or product dissemination is significantly minimized or prevented through the presence of physical controls (such as walls, HEPA filters in HVAC systems, separate HVAC systems, isolators such as gloveboxes, vial washing equipment etc.) and procedural controls (such as gowning/degowning, personnel flow, separate operating staffs, material controls, etc.).

2) Refers to an area where potential cross-contamination or product dissemination is significantly minimised or prevented through the presence of physical controls (e.g. walls, HEPA filters in HVAC systems, separate HVAC systems, isolators such as glove boxes, vial washing equipment, etc.) and procedural controls (e.g. gowning/degowning, personnel flow and/or separate operating staffs, material controls, etc.). Closed equipment operations (e.g. wet processing streams) can also be considered as a means of segregation as long as there are sufficient procedures to prevent cross-contamination or product dissemination when the equipment is opened. Segregation does not necessarily mean separated facilities; however, in the case of some compounds it may be necessary or required. Change of product requires validated inactivation/cleaning methods.

Seizure

Legal mechanism by which the regulatory agency prevents further distribution of material it considers to be violative. The manufacturer is given the opportunity to resolve the issue; however, normally the material must be destroyed.

Selectivity

The ability of an analytical method to measure accurately and specifically the analyte in the presence of components that may be expected to be present in the sample matrix. Selectivity may often be expressed as the degree of bias of test results obtained by analyses of samples containing added impurities, degradation products, related chemical compounds, or placebo ingredients when compared to test results from samples without added substances. The bias may be expressed as the difference in assay results between the two groups of samples. Selectivity is a measure of the degree of interference (or absence thereof) in the analyses of complex sample mixtures.

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Semi-Automated Inspection

Automated presentation of product and human evaluation of product for defects.

Semi-Permeable Containers

Containers that allow the passage of solvents, usually water, or gases, usually oxygen, while preventing solute loss. Examples of semi-permeable containers include plastic bags and semi-rigid, low-density polyethylene (LPDE) pouches for large volume parentals (LVPs), LDPE ampoules, bottles and vials.

Sequential Hold Time Study

An experimental design wherein material is manufactured according to the manufacturing directions but is stopped for all potential hold times at each applicable intermediate step prior to further processing. The stability indicating attributes of the held intermediates would be evaluated, as appropriate. In addition, the final product, which represents the cumulative hold time, may be packaged into the market package container closure system and placed into a stability program.

Serial / Series Filtration

Sterilisation by filtration unit operation that requires one claimed sterilising filter but uses one sterile boundary filter preceded by a pre-filter. The sterile boundary is created after the process fluid passes the sterile boundary filter.

Seven Tools of Quality

Tools that help organisations understand their processes in order to improve them. The tools are the cause-and-effect diagram, check sheet, control chart, flowchart, histogram, Pareto chart, and scatter diagram. See ‘Individual Entries’.

Severity

A measure of the possible consequences of a hazard (for PHA) or the significance of the failure effect (for FMEA).

Shear

A strain resulting from applied forces that cause or tend to cause contiguous parts of a body to slide relative to one another in direction parallel to their plane of contact. In emulsification and suspensions, the strain produced upon passing a system through a homogeniser or other milling device.

Low Shear

Processing in which the strain produced through mixing and/or emulsifying shear is modest.

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High Shear

Forceful processes which, at point of mixing or emulsification place a great strain on the product. Homogenisation, by its very nature, is a high shear process, which leads to a small and relatively uniform emulsion droplet size. Depending on their operation, mills and mixers are categorised as either high shear or low shear devices

Shelf Life

Also referred to as ‘Expiration Dating Period’. The time period during which a drug product is expected to remain within the approved shelf life specification, provided that it is stored under the conditions defined on the container label. (From ICH Q1A)

Shelf Life Limit

Established specifications to which a material must conform throughout its shelf life (Expiry Period). These limits are normally based on stability and assay variability data and assure that the product will conform to regulatory specifications throughout its shelf life.

Shewhart Cycle

See ‘Plan-Do-Check-Act Cycle’.

Shipment Under Quarantine (SUQ)

Materials which are transported prior to release between sites and their contracted operations and for which the material may only be released by the Quality Operations or External Quality Assurance having oversight for the site that shipped the material under quarantine.

Routine Shipments Under Quarantine

Shipments of commercial material prior to release that are permitted without per shipment Quality approval.

Non-Routine Shipments Under Quarantine

Shipments of material prior to release that are permitted with Quality approval on a case by case basis.

Shipper

The person or organisation responsible for preparing the goods for transportation with logistic service providers and/or freight forwarders.

Short Dating

An action whereby the length of time of the lot expiration date period may be reduced.

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Should

If the intent is to allow some flexibility in implementation/interpretation of a requirement, use of ‘should’ is acceptable.

Sieve Test

See ‘Mesh Analysis’.

Sigma

A Greek letter which in the upper case (Σ) directs the summation of a series of numbers or results of a mathematical expression; a Greek letter which in the lower case (σ) represents the standard deviation of a population or sample.

Sigma Limits

Statistical boundaries, applied to a normal distribution, which are established by multiplying the standard deviation by 1, 2, or 3 and then adding and subtracting the value obtained from the mean to

give an upper and lower limit. The probability of a value falling within these limits can then be calculated.

Signal-to-Noise Ratio (S/N Ratio)

A mathematical equation that indicates the magnitude of an experimental effect above the effect of experimental error due to chance fluctuations.

Signature

The name of a person, hand-written by the person on a record.

Significant Body of Information

A significant body of information on the stability of the drug product is likely to exist after five years of commercial experience for new molecular entities, or three years of commercial experience for new dosage forms.

Significant Change (as it applies to Stability)

1) For a drug substance – failure to meet specifications

2) For a drug product - In general, defined as a 5% change in assay from its initial value; or failure to meet the acceptance criteria for potency when using biological or immunological procedures; Any degradation product’s exceeding its acceptance criterion; Failure to meet the acceptance criteria for appearance, physical attributes, and functionality test (e.g. colour, phase separation, resuspendibility, caking, hardness, dose delivery per actuation); however,

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some changes in physical attributes (e.g. softening of suppositories, melting of creams) may be expected under accelerated conditions; and, as appropriate for the dosage form; Failure to meet the acceptance criterion for pH; or Failure to meet the acceptance criteria for dissolution for 12 dosage units.

Significant Deviation(s)

An Event requiring investigation, which has a negative effect on the quality of the product, process, equipment or quality management system and has regulatory implications (regulatory notification, market action, product shortage, etc).

The term "Significant Investigation" has also been in use in the EMEA region for several years with a similar intent. Significant Investigations are defined as those which may potentially result in a market action or serious supply problems.

Significant Figures

The digits of the decimal form of a number beginning with the left-most nonzero digit and extending to the right to include all digits warranted by the precision of measuring devices used to obtain the numbers.

Significant Negative Trend (also Significant Atypical Trend or Significant Out of Trend)

An observation which requires relevant agency/authority notification per EU GMP Guide Chapter 6.32 that shows a projection/prediction of potential out of specification (OOS) results within the product shelf-life. The evaluation should represent a meaningful treatment of the stability data based on the product's historical stability profile, including requirements for number of time points or study duration and comparison with the historical profile to identify shifts in trends.

Simulated Container

A container/closure system, which imitates the actual storage system. The simulated container may be smaller than the actual but must be of the same material composition.

For non- isolated intermediates the container/closure system would be the actual production equipment.

Single Dose Container

A container designed to hold one dose of a drug product intended for parenteral administration only.

Note distinction from ‘Unit Dose Container’.

Single-Unit Container

A container designed to hold a quantity of drug product intended for administration as a single dose. The content must be used promptly after the container is opened.

Note distinction from ‘Unit-Dose Container’ and ‘Single Dose Container’.

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Single-Use System (SUS)

Such as bioreactor, mixing bag, filter, tubing, connectors, etc.

Site

An active pharmaceutical ingredient or finished pharmaceutical manufacturing location.

Site Acceptance Test (SAT)

Testing activities conducted at the installed production site. May include any combination of unit, integration or system testing.

Site Distribution

The section of the water system that starts immediately following the last purification step and ends at the factory/facility take-off from the site system.

Site Master Training Plan (SMTP)

Is a site document drafted by training lead, which sets the training plan and strategy for the year's activity.

Site Operating Procedure

Instructions which are maintained by site and functional specific departments which provide detailed methods and action steps to be followed to accomplish a particular task.

Site Validation Master Plan

Umbrella document that describes the site and site operations requiring validation. It defines and organises validation-related activities at the site. The VMP will contain the details of all validation activities or may refer to complementary site validation plans and project validation plans containing more detail. The Site VMP identifies the systems and equipment that are qualified; the systems and processes that are validated; establishes primary responsibilities for qualification and validation activities; and identifies the operational controls which are implemented to ensure on-going regulatory compliance.

Six Pipe Diameters (6D)

The distance from the center-line of the loop piping to the next water isolation point. The diameter used is that of the take-off piping.

Size

Volume of the actual container. Pertains mostly to vials and bottles.

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Skip Lot Testing

A testing procedure in which some lots in a series are accepted without testing (other than possible spot checks) when the testing results for a stated number of immediately preceding lots meet the stated criteria. The lots are chose randomly in accordance with a stated frequency. This is frequently applied to continuous production material.

SLC

See ‘System Life Cycle’.

Snap Cap

Small, threadless closure used on bottles and vials.

Solubility

The mass of a substance contained in a solution, which is in equilibrium with an excess of the substance. Degrees of solubility are defined by the compendia as follows:

Descriptive Term Parts of Solvent Required for 1 Part of Solution

Very Soluble Less than 1

Freely Soluble From 1 to 10

Soluble From 10 to 30

Sparingly Soluble From 30 to 100

Slightly Soluble From 100 to 1000

Very Slightly Soluble From 1000 to 10,000

Practically Insoluble, or Insoluble

10,000 or over

Solution

Preparation that contains one or more soluble chemical substances (solute) dissolved in a liquid (solvent).

SOP

Standard Operation Procedure.

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Sorting

A step in the manufacturing process where product is physically evaluated in order to remove foreign tablets from lots of film-coated material, to remove debris or extraneous matter, or to remove defective packages, etc.

Source Filters

Two filters (1µm followed by 0.2µm) in series located as the compressed gas enters the sterile manufacturing facility.

Special Causes

Causes of variation that arise because of special circumstances. They are not an inherent part of a process. Special causes are also referred to as assignable causes. See also ‘Common Causes’.

Specification

Documented tests, analytical procedures, and acceptance criteria applied to determine the conformance or non-conformance of a batch or lot; the document that prescribes the requirements with which the product or service must conform.

Specification Limits

A collective term for acceptance and release limits; limits that define the conformance boundaries for an individual manufacturing unit or service operation.

See Acceptance Limits, Release Limits.

Specific Gravity

The ratio of the mass of a substance or solution to the mass of an equal volume of water at a specified temperature.

Specificity (Selectivity)

The ability to access unequivocally the analyte.

Specified Objectionable Microorganisms

A microorganism, if present in the product, represents a potential health hazard to the user, when using the product as directed. In addition, a microorganism is considered objectionable if it affects product stability or if it may damage the integrity of the container closure system.

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Spectroscopy

The study of the science of the interaction between radiant energy and matter. Various techniques of analysis have evolved based on the absorption of different wavelengths of light as they interact with a sample.

See also ultraviolet, visible, infrared, and near infrared spectroscopy.

Spike

The addition of a known quantity of a substance to an unknown to determine the accuracy of the test; extraneous sharp peak seen on a recorder during an instrumental analysis due to a system malfunction i.e. air bubble, electrical variation.

Split

Defect characterised by a break extending through the entire wall of the body or cap of the capsule.

Sponsor

The individual or group who orchestrates the communications and consequences within relevant tactical areas of responsibility necessary to ensure successful change implementation. Direct reporting line relationship.

Spore Log Reduction (SLR)

The number of log reductions (10 – fold changes) of spores from the initial population.

Spore Suspensions

Suspensions consist of homogeneous suspension of bacterial spores produced from a specific bacterial strain. These suspensions can be used to prepare liquid biological indicators by inoculating the spores into the medium to be sterilised. Suspensions can also be used to prepare component biological indicators such as stoppers. Once inoculated, the components are dried and physically contained prior to use to confine the spores and to protect the production facility from contamination with resistant spores.

Spore Strips

Commercially prepared biological indicators, which consist of a paper strip inoculated with a spore suspension. The inoculated strips are dried and packaged in steam penetrable glycine bags to protect the production facility from contamination by resistant spores.

Sporicide

An agent that destroys microbial spores.

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Spots and Specks

A phrase categorising a wide variety of sample anomalies including samples with dissimilar areas on the surface (spots) or samples containing extraneous particles (specks).

Stability

The capacity of a drug to remain within specifications established to assure its identity, strength, quality and purity.

Stability Chamber

A storage unit or facility capable of maintaining a controlled environment with specified set points and tolerances for parameters such as temperature, humidity and/or light intensity for the purpose of evaluating stability performance of materials stored within.

Stability Coordinator

Designated personnel at manufacturing and packaging operations sites and at stability testing sites that are responsible for the coordination of stability activities at their site and for the monitoring and management of the stability program.

Stability Indicating Method (SIM)

An analytical procedure capable of separately determining the active drug substance and any of its prevalent or main degradates.

Stability of Solution

Verifying the hold time of a solution, which is diluted using an approved diluent.

Stability Site

The site performing the stability testing.

Stability Study

Over time, an investigation of a product’s characteristics conducted at regular intervals on samples stored under a variety of environmental conditions by assaying for potency, observing for physical changes, and evaluating physicochemical and microbiological attributes for conformance to criteria and/or deterioration over time.

Stability Time Point (also Stability Testing Interval)

The date the stability samples are scheduled to be removed from the stability chamber for testing. Term is also used to denote a scheduled testing interval in a stability study (e.g. the 12-month stability time point).

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Stable Process

The steps or processes have shown to run consistently within the design space with no persistent exceptions across consecutive operations. The process shall have been validated to current standards.

Staged

The positioning of a lot of material prior to the start of the processing step. Subsequent Rx’s may be staged in designated areas prior to the completion of the Rx currently being processed. Both product and components are staged prior to packaging.

Staging Area

An area where materials and/or product is brought while waiting further processing.

Standard Assay and Test

A document containing step-by-step instructions for the performance of a test whose use is common to a large number of raw materials, intermediates and finished products. SATs eliminate the need to repeat the information or procedure in each of the affected Quality Standards.

Standard Check

A manual UV absorbance reading obtained on a reference standard solution for an automated method. It is used to determine that the reference standard has been weighed and prepared within the required degree of accuracy of its theoretical amount.

Standard Deviation

A measure of variation. The SD is a statistical measurement of the degree of dispersion of numerical data around the average.

Starting Material(s)

A commercially available components, obtained by commonly known procedures and well defined in chemical literature, used in the synthesis of an intermediate or an API.

Standard Modules

A multidisciplinary fixed array of equipment containing process designs, equipment arrangement, facility requirements and automation code.

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Standard Operating Procedure(s) (SOPs)

1) Written documents that prescribe the detailed methods and action steps to be followed in order to accomplish a particular task. The U.S. Food and Drug Administration requires SOPs for virtually every aspect of production, control and testing of pharmaceutical products. One of the SOPs should describe the issuance and control of SOPs.

2) A document that provides specific directions or detailed instructions for performing GMP operations and GMP related activities.

Standard Stock Solution

A concentrated standard solution from which working solutions are prepared.

This includes Reference Standards and Check Standards.

Standard Working Solution

A standard solution used in the test method. This includes Reference Standards and Check Standards.

Standardised Volumetric Solution

A solution where the concentration/purity has been determined by titration with a highly pure material.

Statement Testing

Testing designed to execute each statement of a computer program.

State of Control

A condition in which all process parameters that can affect performance remain within such ranges that the process performs consistently and as intended.

State of Statistical Control

Operating a process with only chance causes of variation.

Static Alarms

Alarms which are active at all times with the same alarm set point.

Static Testing (At-Rest)

Ensures that the facility environment continues to perform as designed, with no personnel present and no activities in progress. Static testing is performed after all people have left the area for a designated period (e.g. 20 minutes).

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Statistical Process Control (SPC)

The application of statistical techniques to control a process.

Statistical Sample Inspection

1) Manual inspection of a sample of the conforming product units to determine the level of visible defects present.

2) Manual inspection of a sample of the conforming product units after 100% visual inspection to determine the level of visible defects present.

Status

The quality designation of the material in regards to quality operations release procedures. For example, approved for use, released, quarantined, administrative hold/impounded, rejected, and all other inventory management system terminologies that are recognized as status designations.

Steam Sterilisation

A method of killing microorganisms present in product equipment or components by subjecting them to steam at 121°C and 15 lbs. of pressure for at least 15 minutes to free them of microorganisms.

Stenciling

Guides used to mark labels, cartons, folding boxes, and packers with the proper finishing number, expiration date, circular revision number, and package size as required.

Sterile Boundary

1) Sterile area that begins at the outlet of the sterile boundary filter until the product is in the final container(s) and has engineering and procedural controls in place to maintain and ensure its sterility. 2) The physical barrier that separates the sterile system from the non-sterile environment, for example, on a process skid, it will be defined by the valves, filters and seals that isolate the wetted path and vessel headspace that contacts the wetted path. Where filtration creates the barrier, the sterile side begins at the outlet of the sterile boundary filter until the product is in the final container(s) and has engineering and procedural controls in place to maintain and ensure its sterility.

Sterile Boundary Filter (SBF)

A sterilising grade filter of 0.22 micron nominal pore size (or less) used to render a specific product sterile and creates the sterile boundary.

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Sterile Bulk Biologics

A microbial or viral vaccine, blood component, or therapeutic protein product that has been processed and is being held for further processing into the finished biological product.

Sterile Dosage Form

The finished drug or Biologic product in its closed/sealed container.

Sterile Equipment Hold Time

The time from the completion of the sterilisation of the item through its use in the aseptic operation.

Sterile Manufacturing Facility

A facility used for the manufacture of sterile products using closed sterile processing, aseptic processing or both.

Sterile Product

Product manufactured in such a manner that there is a high degree of assurance of the absence of living material as demonstrated by growth and reproduction in laboratory testing.

Sterility Assurance Level (SAL)

1) Probability of a single viable microorganism occurring on an item after sterilisation.

2) Sterilisation can occur by various methods; depending on the nature of the design, material and/or packaging some methods have advantages over others. In all cases the level of sterilisation is based on the pre-sterilised bioburden. When the sterilisation method is chosen, the method requires validation. The validation method is based on determining the SAL. The sterility assurance level can vary depending on the application of the device and is set by various standards and requirements. For invasive products, the level is usually 10-6 or, in other words, once the sterilisation is completed the probability of finding a non-sterile article will be 1 in a million. A SAL of 10-6 is the minimum requirement for gowning components that are supplied as sterile for use in aseptic processing areas.

Sterility Test Method

The test method used to evaluate the process for microbial integrity. This evaluation is conducted on the test media utilised during the challenge.

Sterilisation

A process used to render a product free of viable organisms with a specific probability.

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Sterilisation Validation

The process of ensuring that a sterilisation method provides a minimum sterility assurance level (SAL) of 10-6 probability of microbial contamination for all product contact surfaces, as well as the test medium if it is sterilised in place.

Sterilise-In-Place (SIP)

The use of moist heat (saturated steam) to sterilise equipment that is fixed in place or placed on a fixed skid, for purposes of sterility assurance.

Sterilising By Filtration / Sterilising Filtration / Sterile Filtration / Sterile Boundary Filtration

Rendering a process fluid sterile by passing through a porous material to remove viable and/or non-viable particles.

Sterilising Grade Filter

1) A filter that will retain 107 cfu (colony forming unit) of Brevundimonas diminuta (B. diminuta) ATCC® 19146TM/cm2 of effective filter surface area under process conditions.

2) A filter that will produce a sterile effluent after being challenged by microorganisms at a challenge level of greater than or equal to 1x107/cm2 of effective filtration area.

Sticking

Tablet material adhering to the die wall or other tooling.

Stock Recovery

A firm’s removal or correction of a distributed product that has not been marketed or that has not left the direct control of the firm i.e. the product is located on premises owned by, or under the control of, the firm or logistics service provider and no portion of the lot has been released for sale and use.

Stock Solution

The initial volumetric preparation of specified solute and solvent used to prepare less concentrated solutions through its subsequent dilution.

Storage Conditions

1) Environment in which a product must be kept in order to preserve product integrity through its expiry dating; normally includes temperature and humidity limitations. If no specific requirements are stated, implicit limitations include protection from moisture, freezing and excessive heat. See also individual USP storage temperatures, i.e. cold, cool, room temperature, controlled room temperature, warm and excessive heat.

2) Environmental conditions a container is exposed to while being stored.

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Storage under Nonspecific Conditions

For USP articles where no specific storage conditions are provided, storage conditions must provide protection from moisture, storage at controlled room temperature and where necessary, protection from light.

Stopper

Normally a synthetic molded plug that is mechanically applied to the necks of open units. The surface at which the seal is made is the horizontal face that mates with the horizontal vial neck during the capping operation. A raised molded bead is normally seen on the sealing surface to assist with the sealing process. For lyophiliser applications, the stopper is partially inserted prior to lyophilisation, at the conclusion of which the stopper is completely inserted by mechanical means.

Strength

Concentration of the active ingredient in a drug product.

Note distinction from ‘Potency’.

Stress Testing

Tests conducted to evaluate a system or component at or beyond the limits of its specified requirements.

Structural (White Box) Testing

Examining the internal structure of the source code. Includes low level and high level code review, path analysis, auditing of programming procedures and standards actually used, inspection for extraneous or dead code, boundary analysis and other techniques. Requires specific computer science and programming expertise. Testing that takes into account the internal mechanism of a system or component. Types include branch testing, path testing and statement testing.

Structure Forming Excipient

An excipient which participates in the formation of the structural matrix which gives an ointment, cream or gel etc. its semisolid character.

Examples are gel forming polymers, petrolatum, certain colloidal inorganic solids (e.g. bentonite), waxy solids (e.g. cetyl alcohol, stearic acid), and emulsifiers used in creams.

Study Initiation Label

A label other than the market label placed on the stability sample prior to placing into the stability chamber in order to properly identify the stability sample(s).

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Study Protocol

A detailed schedule to be followed for a specific lot/batch which specifies storage conditions, test intervals, sample quantity, sample orientation, test procedures or procedure references in order to generate chemical, microbiological, and physical stability data to assess whether a drug product or drug substance has remained within specifications throughout its shelf life (expiry or retest period).

Subdivision

The process of dividing a material (raw material, drug substance, excipient, etc.) into multiple aliquots (e.g. by weighing, counting, etc.) in order to more efficiently use the material.

Sub-Lot / Sub-Batch

A lot / batch that has been divided to complete certain stages of manufacture and/or packaging

Subject Matter Expert

An individual who possesses appropriate skills, knowledge and experience on a particular topic or within a specific job function (e.g. process engineer, supervisor, quality employee, trainer, operator or technician).

Sub-System

Secondary distribution systems derived from common treatment system and originating from the same storage tanks as the main distribution system, are considered ‘Sub-Systems’ (or ‘Sub-Loops’). They may be capable of being isolated from the main distribution system via a break tank or a back-flow prevention device, but the water they contain is typically not subject to any additional purification steps.

Where water in the main distribution loop and any associated sub-loop is separated by a break tank, with no possibility of back flow into the main loop, then, for the purpose of distribution system performance qualification, performance evaluation, change control and deviation management, the sub-loop may be considered a separate distribution system. For example, a WFI loop can feed a break tank for laboratory use as Purified Water.

Suitability

The packaging materials ability to adequately protect the dosage form, be compatible with the dosage form, and be composed of materials that are safe for use with the dosage form and the route of administration. Some packaging may also have a performance requirement, and should therefore function properly.

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Supplemental NDA

A change to an NDA submitted after the final approval of the application. The timing for implementation of the change, and whether prior FDA approval is required, depends on the nature of changes proposed.

Note distinction from ‘Amendment’.

Supplement

Periodic updates to the compendia, which contain corrections, revisions and additional new information that is official before the publication of the next main editions.

Supplemental Investigation

An investigation conducted when new information is learned after the initial investigation has been completed.

Supplier

An entity that manufactures or distributes material or provides a service.

Supplier Lot

A specific quantity of homogeneous material, identified by a combination of numbers, letters or symbols, assigned by the supplier, from which the complete history of the manufacturing, packaging, warehousing and distribution of the material can be determined.

Supplier Performance Management Process (SPMP)

An end-to-end supplier management process developed to ensure reliable and compliant supply as a key enabler for becoming a World Class Supply Organisation.

Supplier / Product Qualification

A supplier/product combination, which meets the conditions for the supplier, test acceptance program.

Supplier Quality Assurance

Confidence that a supplier’s product or service will fulfill its customers’ needs. This confidence is achieved by creating a relationship between the customer and supplier that ensures the product will be fit for use with minimal corrective action and inspection. According to J. M. Juran, there are nine primary activities needed:

1) Define product and program quality requirements

2) Evaluate alternative suppliers

3) Select suppliers

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4) Conduct joint quality planning

5) Cooperate with the supplier during the execution of the contract

6) Obtain proof of conformance to requirements

7) Certify qualified suppliers

8) Conduct quality improvement programs as required

9) Create and use supplier quality ratings

Supplier Test Acceptance Plan

A quality/business/statistical based program, which allows the reduction in the number of release tests performed on a routine basis.

Support Equipment

Equipment that does not affect product quality is considered support equipment. This equipment may be used in support of and/or connected to GMP equipment if appropriate separation, monitoring, alarms, and/or barriers are established and maintained. In general, supporting utilities not intended for contact with the process stream (e.g. instrument air, jacket service utilities, etc. with appropriate monitoring to assure functionality) should be commissioned, documented and managed (e.g. change control) according to good engineering practice and thus will be handled accordingly.

Suppository

Solid, but readily meltable, medicated dosage form that is administered by insertion into the rectal, vaginal, or urethral orifice of the human body.

Survival Times

The maximum exposure time (or dosage) that allows survival of the biological indicators.

Suspending Agent

An excipient added to a suspension to control the rate of sedimentation of the active ingredients.

Suspension

A system in which particles of undissolved drugs are dispersed in a liquid vehicle.

Sustained Release

See ‘Extended Release’.

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Swab

Material used to collect residual target compound from a given surface for the purpose of quantification via assay.

Swab % Recovery

The amount of analyte measured as a percentage of amount spiked onto a swab.

Swab Sample

1) A cleaning validation sample consisting of a swab which has been used to sample an equipment surface.

2) A cleaning validation sample consisting of a swab which has been used to sample.

Swish Thin Layer Chromatography

Sample preparatory technique involving ‘swishing’ or mixing a mainly insoluble sample (frequently, overnight on a vibromixer) to solubilise a desired substance (impurity) for thin layer chromatographic analysis.

Syringe

A device used to inject water, liquids or medication into the body or its cavities. They may also be used to transfer material into a container. There are three types of syringes, named to indicate the mode of action: plunger syringes, bulk syringes, and gravity syringes.

Syringeability Test

A test on sterile injectable suspensions, whereby a syringe needle of a specified gauge is inserted into a filled vial and a fixed volume of suspension is withdrawn. The purpose of the test is to determine if needle clogging will occur due to suspension particle size.

Syrups

An oral dosage form comprised of a solution of concentrated sugar with a medicament. They may also contain flavoring agents.

System Documentation

Documents supporting the validated state of a system i.e. specifications, testing, procedures, etc.

System Life Cycle

The period of time that starts when a system is conceived and ends when it is no longer available for used. The system life cycle typically includes a concept phase, requirements phase, design phase, construction phase, test phase, installation/qualification phase, and

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operation and maintenance phase. It includes any formal system development methodology that governs the specification, development, acceptance, and operation of automated equipment or computer system from initial concept to eventual decommissioning of that system.

System Organ Class (SOC) Query

The Lot by SOC report displays adverse event information related to a specific product family and lot requested by the user. The output includes a tabular summary of the MedDRA preferred terms in each case grouped by system organ class. The individual case numbers associated with each term are also included.

System Owner (SO)

1) The person responsible for quality systems i.e., Quality, Facilities and Equipment, Materials, Production, Packaging and Labeling and Laboratory.

2) The person responsible for the availability, and maintenance of a computerised system and for the security of the data residing on that system.

System Shakedown

A trouble-shooting, commissioning activity that occurs prior to the formal, documented Operational Qualification (OQ) for each system. This activity may include risk minimisation and non- quality impact testing.

System Suitability

1) The effectiveness of a final operating chromatographic system (usually HPLC or GC) to perform the separations desired. A test to determine the method is producing acceptable results based on performance criteria.

2) An integral part of analytical procedures. The tests are based on the concept that the equipment, electronics analytical operations and samples to be analysed constitute an integral system that can be evaluated as such. System suitability test parameters to be established for a particular procedure depend on the type of procedure being validated. See Pharmacopoeias for additional information.

System Suitability Requirements

The parameters set forth in the individual QS methods to ensure adequate performance of the chromatographic system.

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- T -

Tablet

A solid, oral dosage form containing a medicinal substance, usually in combination with other excipient materials that is compressed or moulded into a solid mass of various shapes.

Tablet Hardness

A test in which a tablet is placed in an instrument which applies an even but steadily increasing force, until the tablet matrix is stressed, and the tablet abruptly breaks. The force required to break the tablet is read directly off the instrument in kilopounds, and is the reported tablet hardness value in kilograms.

Tailgate Samples

Samples of a production lot obtained by the supplier which are representative of the production lot and are shipped along with the actual production lot.

Tampering

1) Action taken to compensate for variation within the control limits of a stable system. Tampering increases rather than decreases variation, as evidenced in the funnel experiment.

2) A fraudulent and unauthorised intervention that alters a product's quality or intended representation.

Tamper Resistant

The immediate container and/or the outer container or protective packaging utilised by a manufacturer or distributor for all dosage forms that are not specifically exempt from packaging and labelling requirements of the FDA that are designed to show evidence of any tampering with the contents.

Target Amount

The quantity attempted to achieve; with respect to Quality limits, the quantity of an ingredient of a drug product which is not explicitly stated on a product label, circular or carton, but is the quantity that Manufacturing intends the product to contain. The term is normally applied to a preservative.

Note distinction from ‘Labelled Amount’.

Target Fill

The quantity that the approved process description indicates is to be put into a container.

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Target Limits

The upper and lower boundaries defining the range in which production is expected to remain.

Target Weight

The quantity to which the manufacturing process description indicates a product must be compressed or encapsulated.

Technical Agreement

A written agreement between the stability site and the site of manufacture and/or package/filling outlining roles and responsibilities of each site to ensure conformance to divisional guidelines and site procedures.

Technical Traceability

Implies that the evaluation of a rational behind each API process step is well documented and accessible.

Technology Transfer

Transfer activity includes process specific training of personnel, document preparation and demonstration of the process (along with analyses for quality assurance) at production scale. During process demonstration, via validated processing, material is produced which must demonstrate clinical equivalency and consistency to support licensure.

Technology Transfer Documents

Centrally controlled documents that identify and communicate the authorised packaging materials, profiles, and applicable component specifications that are supported with stability data and reference the regulatory and compendial requirements, as appropriate to the packaging site.

Temperature Controlled (TC) Trailer / Truck

An Active TPS that is mechanically controlled and is used for storing and moving goods over road.

Temperature Excursion

Any event during transportation in which product is exposed to temperatures and/or times outside of the approved distribution temperature / time ranges.

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Templates

Standard forms or tools that can be used directly (often in their native form – Word/Excel).

Templates may be referenced from within Quality Manual documents, or may be sections of Quality Manual documents e.g.attachments.

TempTale®

An electronic temperature monitor manufactured by Sensitech, Inc. The TempTale® measures and records temperatures in memory which can then be downloaded for analysis and trending in Cold Chain Manager. The TempTale® monitor display shows when a monitor is recording, when it has been permanently stopped and if an alarm condition has been exceeded. Each TempTale® is configured to record data at specified intervals (e.g. every 9 minutes) and alarm at specified temperatures (e.g., <-20°C and >50°C).

Teratogenic

Agents, which cause developmental malformations upon exposure.

Terminal Sterilisation

Manufacturing method in which the final product is sterilised in a validated sterilisation cycle in its final container closure system.

Testing Protocol

A written plan stating how testing will be conducted, including objective production equipment description and requirements test equipment and procedures, and acceptance criteria.

Test Media

1) Media used to simulate the process which may include a non- restrictive growth promoting culture medium, inert buffer or sterile placebo powder. Each test medium must be qualified for growth promotion prior to implementation if the media does not adhere to United States Pharmacopoeia (USP) or other applicable international standards.

2) Medium used to simulate the process, including non-restrictive growth promoting culture medium or actual fermentation process medium. Any test medium purported to be non-restrictive and growth promoting must be validated as such before or during the use in a media hold qualification.

3) Medium used to simulate the process or used to flush process equipment post-simulation. This may include growth promoting culture medium, inert buffer or sterile manufacturing blank. The medium used must be shown to be appropriately growth-promoting or non-inhibitory as required for its use in the challenge.

Test Method

The test method used to evaluate the process for microbial integrity. This evaluation is conducted on the test media used during the challenge.

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Test Method Medium

The secondary growth promoting culture medium used for incubation of the test filters. This medium must be shown to be appropriately growth-promoting via growth promotion studies following the method listed in USP General Chapter <71> Sterility Tests.

Test Method Validation

1) Each test method must be qualified prior to implementation if the method does not adhere to United States Pharmacopoeia (USP) or other applicable international standards. Parameters to be evaluated include, but are not limited to, the type of filters used, container configuration, suitability of culture medium for direct read method, volume of test medium, growth promotion capability of the culture medium and temperature of incubation.

2) Each test method used to verify the media hold qualification must be validated prior to implementation. All practices and procedures used to accomplish validation must be appropriately documented.

Test Solution

A solution that allows for the determination of a test. This applies to compendial and wet chemistry type tests. Examples include APHA Colour, Chlorides, etc.

Test Specification

A document that specifies the detailed instructions for the set-up, execution, and evaluation of results for a given test case. This includes specification of the test inputs, execution conditions and predicted results.

Test Summary Report

A document summarising testing activities and results. It also contains an evaluation of the corresponding test times.

Test Unit

A set of one or more computer program modules together with associated control data, usage procedures, and operating procedures that satisfy the following conditions:

a) All modules are from a single computer program

b) At least one of the new or changed modules in the set has not completed the unit test

c) The set of modules together with its associated data and procedures are the sole object of a testing process.

Therapeutic Equivalents

Chemical equivalents that, when administered to the same individual in the same dosage regimen, provide essentially the same efficacy and/or toxicity.

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Thermal Protection System (TPS)

Any active or passive temperature control system for the distribution of temperature sensitive products. This term includes commonly used terms like ‘Packout’, ‘Ocean Reefer Container’, ‘Temperature Controlled Truck/Trailer’ etc.

Thermocouple

Consists of two wires made of dissimilar metals fused together at one end to form a junction and connected to an electrical voltage measuring device used to record temperature.

Thermogravimetric Analysis

A destructive analytical technique that measures the amount and rate of change in the weight of a substance over a specific temperature gradient used to measure loss of H2O + volatiles.

Thin Layer Chromatography

A chromatographic method of analysis in which the mobile phase is a liquid and the stationary phase is a thin layer of finely powdered solid applied to a glass plate. The mobile phase (contained in a tank) is allowed to equilibrate before the plate is added. Capillary action moves the mobile phase over the plate. The sample is introduced as a liquid to the dry plate and then dried before the chromatographic procedure.

See also ‘Chromatography’.

Third Party

Parties not directly managed by the holder of the manufacturing and/or import Authorisation e.g. Suppliers, Service Providers.

Threshold of Toxicological Concern (TTC)

The TTC is the daily intake of a genotoxic impurity that is considered to be associated with an acceptable risk (excess cancer risk of <1 in 100,000 over a lifetime) for most pharmaceuticals.

The TTC value for chronically-used drugs is 1.5 ug/day. The TTC value can be higher under certain conditions.

TTC should not be used for carcinogenic impurities where adequate data exist and allow for a compound specific risk assessment.

Time Out of Refrigeration (TOR)

The time that the product is exposed to temperatures outside the defined, refrigerated or frozen storage temperatures.

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Time Out of Storage (TOS)

The time the product is exposed to temperatures outside the product's defined label storage temperatures. Also referred to as ‘Time Out of Refrigeration (TOR)’.

Time Zero (T0 or TZ)

Stability interval corresponding to the initial time point at the start of the stability study.

Data reported as time zero data can be from release testing or from testing of stability samples at the time of study initiation.

Tolerance

The total allowable variation around a level or state (upper limit minus lower limit). A value fixing the limit of allowable error or departure from true performance or value.

Tolerance Limit

Values that define the conformance boundaries for an individual unit of manufacturing or service operation.

Toll Manufacturing

A specific type of contract manufacturing operation where licence holder maintains financial ownership of the starting material and pays the contract manufacturer a fee for only the ‘value-added’ service or conversion work performed on the starting material.

Topical Preparation

A dosage form that is intended for application to the skin.

Torque Tester

An instrument, which measures the force necessary to cause a fracture at a bolus, score mark.

The force is applied at right angles to the score mark, and is measured against an opposing force supplied by a calibrated spring.

The results are red off the instrument in the English unit of measure inch- pounds; instrument used to test caps in the packaging operation. It measures the applied force necessary to loosen the cap.

Total Aerobic Count (TAC)

Quantitative enumeration of viable mesophilic (25°C - 40°C) bacteria and fungi that may grow under aerobic conditions.

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Total Quality Management (TQM)

A term initially coined by the Naval Air Systems Command to describe its Japanese-style management approach to quality improvement. Since then, total quality management (TQM) has taken on many meanings. Simply put, TQM is a management approach to long-term success through customer satisfaction. TQM is based on the participation of all members of an organisation in improving processes, products, services, and the culture they work in. TQM benefits all organisation members and society. The methods for implementing this approach are found in the teachings of such quality leaders as Philip B. Crosby, W. Edwards Deming, Armand V. Feigenbaum, Kaoru Ishikawa, and

J. M. Juran.

Total Wet Time

Total time of initial fluid contact with filter to end of filtration.

Toxic Complaint Sample

A complaint sample that may be harmful to the environment and to human health if inhaled, swallowed, or absorbed through the skin. This may include, but is not limited to chemotherapeutic reagents.

Toxicological Assessment

An evaluation of the estimated Total Daily Intake (TDI, which is considered similar to the Average Daily Intake, ADI) of a chemical species in order to determine if the level of exposure will present a safety concern to the patient. These evaluations include considerations of available literature data for the specific compound or class of compounds, structure-activity relationships, and any qualification data (if available).

Traceability

The property of a calibration whereby it can be related to appropriate measurement standards, generally international or national standards, through an unbroken chain of comparisons.

Trademark

A name, designated by a superscript ®, which has been registered with the Patent Office.

While a trademark is pending registration, the name is designated by a superscript TM.

Trainer

Person delivering the training to site personnel.

Training Documentation

Includes training plans, training records, and training materials.

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Training Matrix

A document that acts as a guide by listing the various policies, procedures and standard operating procedures (SOPs) an employee, defined by a position title, may be required to be trained on. This tool can be used to document training for other types of training.

Training Modules

Normally PowerPoint slide decks that provide summaries of the significant revisions to specific Quality Manual documents. The training module may also provide detailed information on interpretation of the requirements or implementation expectations for specific documents. These modules are not provided for all Quality Manual documents, but only for those identified by the document authors as necessary in cases where there have been significant changes to the requirements or where implementation challenges are anticipated.

Transfer Isolator

A type of closed isolator that surface decontaminates materials for transfer by Rapid Transfer Ports (RTP) into critical isolators.

Transition Zones

Areas designed to facilitate access into an adjacent Hygienic Zone.

Transport Conditions

Environmental and process conditions the container is exposed to while being transported.

Transport and Tertiary Packaging

Components that enclose the secondary package to provide added protection during shipping and transport.

Transportation Lane (also known as Shipping Lane)

Path taken by a shipment between Origin and Destination which includes all of the transportation related factors that can impact product quality e.g. route, product protection measures, mode of transportation with same/similar transit time, transfer points, and origin/destination climatic zones.

Trend

Trends can be a pattern that when compared to historical data may be considered to be an improvement or adverse, typical (e.g. seasonal variation) or atypical (i.e. no previous record).

Trends may be considered positive when the change in the data indicates a possible improvement in control of the measured parameter.

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Trends may be adverse when they change from the normal variability of the data indicating a possible loss of control in the system and the possibility of future data points exceeding the action limit for the parameter measured.

Trend Control Chart

A control chart in which the deviation of the subgroup average, X-bar, from an expected trend in the process level is used to evaluate the stability of a process.

Trend Limits – Stability

A range of values for the reportable value for a stability result that is considered to be consistent with either other stability batches or with other stability results of the same batch.

Trending

The study of the general tendency of a subject to ascertain if it exhibits a specific direction or deviation from the norm, and the frequency of an event’s occurrence.

True Copy

An exact verified (via a Quality approved procedure), copy of an original record/data. The true copy must provide the full content and meaning of the Original Record.

Tubing Glass

Glass formed by drawing the molten silica in a tubing alley and forming a continuous tube of glass which precisely controlled dimensions. The tube is then cooled and cut to workable lengths for additional processing into containers.

Twinning

Tablet defect resulting from the marriage of two tablets during the film coating process. The two tablets stick together and are film coated together.

Two Dimensional (2D) Matrix Code

A machine-readable symbology consisting of a two dimensional area of dark and white squares representing digitally encoded information, commonly referred to as ‘bull's- eye’, ‘postage stamp’, or ‘RSS - Reduced Space Symbology’ code, and is of higher information density than a conventional (linear) bar code.

Type I Error

An incorrect decision to reject something (such as a statistical hypothesis or a lot of products) when it is acceptable. Also called producer’s risk – OC curves can quantify this risk.

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Type II Error

An incorrect decision to accept something when it is unacceptable. Also called consumer’s risk

– OC charts can quantify this risk

Typical Range

For a normal distribution of data, the typical range is ±3 s from the average as indicated on the control chart. If the distribution is non-normal, the appropriate Statistical Support should be contacted for guidance. Where control charts are not available, the minimum and maximum actual lot values, within specification requirements, may be used as the typical range.

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- U -

Ultra Low Penetration Air (ULPA)

A term applied to air filters capable of removing particles of 0.1 micrometer size with a minimum efficiency of 99.99997%.

Ultraviolet Spectroscopy

A spectroscopic method of analysis dealing with wavelengths in the region of 190 nm to 380 nm.

Underfilled

A container with less than the required quantity of contents.

Underweight

A tablet or capsule, which is short of the target weight by lower control limit.

Unexpected OOS

A test result that does not conform to specification requirements. Specification requirements include CQAs, process capability limits, Quality Standards etc.

Unidirectional Air Flow

An airflow moving in a single direction, in a robust and uniform manner and at sufficient speed to reproducibly sweep particles away from the critical processing or testing area.

Uniformity of Dosage Units

The degree of uniformity in the amount of the active ingredient(s) among dosage units.

The uniformity of dosage units can be demonstrated by either of two methods: content uniformity or mass/weight uniformity.

Unique Identifier

An alternative to labelling smaller containers that do not have room to contain all of the required label information is to record a ‘unique identifier’ on the container that corresponds to an identical ‘unique identifier’ that is recorded in the laboratory notebook or on the controlled worksheet or in an alternative validated electronic system next to the required label information.

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Unit Dose Container

A container designed to hold a drug product intended for direct administration, as a single dose, by other than the parenteral route.

Note distinction from single dose container.

United States Pharmacopeia-National Formulary (USP-NF)

Official compendium of standards in the United States for assurance of the identity, strength, quality, and purity of drug products, drug substances and excipients.

The USP-NF also contains packaging and labelling requirements for monograph items.

Unit of Measure

A symbol, word or abbreviation, which immediately precedes or immediately follows a number, and is utilised to give the number meaning or dimension.

Unit of Use

A type of market package designed to be dispensed directly to the consumer.

Unit Operation

A step-wise means of examining the generic processing steps of manufacture including, but not limited to mixing, granulating, drying, milling, lubricating, compressing and encapsulating.

Unit (Component) Testing

Testing of individual hardware or software units or groups of related units.

Unwanted Event

Event results in the generation or introduction of extraneous matter.

Upper Control Limit (UCL)

Control limit for points above the central line in a control chart, normally based on the mean plus 3σ. The probability of a sample value exceeding the limits due to random variation is very small.

Upper Tolerance

Limit applicable to the upper conformance boundary for an individual unit of a manufacturing or service operation.

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US 21 CFR Part 11

Food and Drug Administration (FDA) Guideline for Electronic Records and Electronic Signatures.

US EPA NPDWR

United States Environmental Protection Agency National Primary Drinking Water Regulations.

Usage Factor

A value derived by dividing the raw material target assay by the actual assay value, and multiplying the resulting quotient by 100. This value is used to correct or adjust the quantity of an ingredient used in a formula as a function of its assay in a pure state.

Use Error

Act or omission of an act that results in a different medical device response than intended by the manufacturer or expected by the user.

User Requirements

Requirements defined by the end user that provide the basis for the development of the factory buildings, facilities, equipment or other systems. They combine the product, process, regulatory and business needs of a manufacturing system into a set of specific, measurable and verifiable parameters.

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- V -

Vaccine

A microbiological preparation of killed microorganisms, living attenuated organisms or microbiological components produced by biotechnology or fermentation purification which are introduced into the body to stimulate the production of antibodies and provide immunity to a specific disease.

Vacuum

1) Pressure in a system below 14.7 psia or atmospheric pressure.

2) (per CCI Technology) - any space above a container in which the pressure is lower than atmospheric pressure (i.e. sub-ambient).

Valid Test

A test conducted within its validated parameters.

Validated System Output

Documentation, such as data tables, graphs, or printouts, that is generated directly by a validated manufacturing, laboratory, or information system that stores GMP data and/or controls GMP processes.

Validated Test Method

The process by which it is established by laboratory studies that the performance characteristics of the method meet the requirements

Validation

A documented program that provides a high degree of assurance that a specific process, method, or system will consistently produce a result meeting pre-determined acceptance criteria. Reference ICH Q7.

Note: Validation is a lifecycle program which may include development and qualification activities for one or more elements/systems that form a process.

Validation Lot

One of a pre-determined number of batches made in support of a validation study.

Note distinction from Engineering Lot.

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Validation Protocol

A written plan describing the process to be validated including production equipment and stating how validation will be conducted.

Such a plan would address objective test parameters, product and process characteristics, predetermined specifications and factors, which will determine acceptable results.

Validation / Validated

Action of proving, in accordance with the principles of Good Manufacturing Practice, that any procedure, process, equipment, material, activity or system actually leads to the expected results.

Validity Criteria

Requirements established in the approved protocol that will render the study invalid when not met.

Value-Adding Process

Those activities that transform an input into a customer-usable output. The customer can be internal or external to the organisation.

Valued Supplier

A supplier which has the most strategic and generally high value relationships that we wish to invest significant time and effort in managing in order to drive value. These are usually global relationships.

Variables

An Independent Variable - is a variable whose level(s) is (are) selected. These are also called Regressor or Predictor Variables. An example is a ‘process set point’.

A Dependent Variable - is a variable that shows the observed result(s) of an experiment. These are also called Response Variables. An example is ‘a test result’.

All variables shall have predetermined specifications or desired ranges established.

Variables Data

Measurement information.

Control charts based on variables data include average (X-bar) chart, range (R) chart and sample standard deviation (s) chart.

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Variance

A written and approved justification which allows deviation from the intent, requirements or implementation timing of a Quality Manual core requirement, policy, guideline, or procedure.

Variances are either interim or permanent.

Vendor

A person or company that sells a service, product, raw material or some component to another individual or company.

Vendor Certification

A total quality management system that assures that a supplier’s product is produced under a controlled process that result in consistent conformance to customer requirements.

Version Number

A number used to identify and keep track of subsequent changes to a document or material.

Vestibule

A vestibule is a small entrance hall or room, either to a building, larger room, or to a series of airlocks. Vestibules are not designed to have engineering controls (e.g. interlocking doors or pressure differentials).

Vestibules can act as transition areas from unclassified spaces to classified entrance and exit areas.

Virus

Ultramicroscopic or sub-microscopic infective agents that cause various diseases in man, other animals and plants and cannot replicate outside of a host.

Viscosity

The property of a fluid or semi-fluid that enables it to develop and maintain an amount of shearing stress dependent upon the velocity of flow and then to offer continued resistance to flow.

As a liquid has a greater specific gravity than water or is more viscous than water, the ration of heat transfer within a container can be expected to decline. It is calculated as the ratio of the shear stress to the shear strain at a specified temperature and is normally reported in poise.

Visible Residue Limit (VRL)

The minimum concentration of a known residue which is visually detected by multiple observers, expressed in units of µg/cm2.

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Visible Spectroscopy

A spectroscopic method of analysis dealing with wavelengths in the region of 450 nm to 750 nm.

Visual Code

A code that is human readable.

Visual Inspection

The review of statistically sampled material to determine the levels of visible defects present.

v/v

Percent volume in volume. It is defined as the number of mL of a substance in 100 mL of solution.

Void Volume

The amount of liquid in the interstitial areas of chromatographic columns.

Volume of Fill

The measured amount of product present in a container.

Vital Few, Useful Many

A term used by J. M. Juran to describe his use of the Pareto principle, which he first defined in 1950. (The principal was used much earlier in economics and inventory control methodologies).

The principle suggests that most effects come from relatively few causes; that is, 80% of the effects come from 20% of the possible causes.

The 20% of the possible causes are referred to as the ‘vital few’; the remaining causes are referred to as the ‘useful many.

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- W -

Warning Letter

Letter issued by the U.S. Food and Drug Administration to manufacturer containing adverse findings and giving the manufacturer a certain timeframe in which to reply. It replaced the Regulatory Letter and the Notice of Adverse Findings.

Water Activity (aw)

Water activity is the ratio of the water vapour pressure in the product to that of pure water.

In microbiological terms, water activity determines the amount of “unbound” or “free” water available to sustain the metabolism of microorganisms potentially present within the product.

Since bacteria, yeast and molds require certain levels of available water to germinate, metabolise, proliferate and ultimately survive in a product, water activity becomes a valuable tool for predicting the potential for microbial contamination of a drug product.

Based upon current literature and industry consensus, a water activity value of >0.60 aw will serve as an initial screen and preliminary indication that a product may not be microbiologically inhibitory and requires further analysis (Friedel, Robert R., “The Application of Water Activity Measurement to the Microbiological Attributes Testing of Nonsterile Over-the-Counter Drug Products,” In: Pharmacopeial Forum, Vol. 24, No. 2, p. 6087-6090, 1998).

Water Distribution System

Often referred to as the "distribution loop" (or simply the "loop"), the distribution system can be considered an extension of the storage system; it supplies water to the manufacturing areas where the water is used (via the points of use (POU).

Water Pre-Treatment and Purification

The section of the water system that starts with the feedwater and ends immediately following the last purification step.

Water Pre-Treatment System

The pre-treatment system is responsible for purification of the potable water feed prior to the final treatment system. Pre-treatment is to remove gross impurities and is largely employed to protect and improve the performance (i.e. life, efficiency) of the downstream units.

Typical unit operations associated with pre-treatment systems include, but are not limited to, chlorination/de- chlorination, filtration (macro), UV irradiation and ion exchange (softening).

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Water Storage System

The storage system is used to maintain an available supply of water during times of variable water demand. The water in the storage system is usually maintained in a constant state of recirculation (through the distribution system) to reduce the opportunity for microbial proliferation due to stagnation.

Wave Change

Change that impacts several APIs, product strengths and/or families where the supporting documentation and requirements for implementing the change are the same for each API and/or product.

Waxman-Hatch Act

Law defining the patent term restoration for a patented drug due to the length of the FDA approval process. Another part of the act defines the ANDA generic equivalent approval bill requiring a bioequivalence study prior to the approval of a generic drug.

Web / Die Station

A portion of a flexographic print mat, plate, or cylinder, or portion of other printing equipment that produces a single printed image of a printed packaging component.

Typically in high speed equipment, a multi-station printing process creates multiple printed components simultaneously, during each cycle of the machine on a large continuous web. Similarly multiple components (e.g. cartons) are cut from the web simultaneously at a multi-station die cutting tool.

Weight Uniformity

Test performed which determines the variability of dosage unit weights within a lot.

One hundred dosage units are weighed and evaluated against the following warning limits: Max. 1 unit outside ±15% of the target weight with no unit outside ±25% of the target weight.

(Note distinction from weight variation)

Weight Variation

One of two methods used to demonstrate uniformity of dosage units based on the individual estimated contents of the units utilising the weight of individual units and the ratio of the content of active ingredient to the mean weight of the units used in the Assay method.

See appropriate compendia for specific details concerning the applicability of weight uniformity.

See also mass variation. Note distinction from content uniformity and weight uniformity.

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Wet Chemistry

Manual analytical techniques frequently employing stepwise extraction, dilution or addition of various reagents to create a measurable chemical reaction used to determine the amount of a substance present in the material under test.

WFI (Water for Injection)

Water purified by distillation or by reverse osmosis, so that it contains no added substance.

WFI meets the purity requirements under Purified Water (USP).

Although not intended to be sterile, it meets a test for a limit of bacterial endotoxin.

White Paper

A technical document written on a specific topic in order to provide additional information, details, and clarifications on that topic.

White Papers are not mandatory for implementation, but they support existing mandatory policies/guidelines/procedures.

White High Zone

A GMP area within a facility where there is high potential for product exposure and high potential for product contact surface/component exposure.

Manufacturing areas where there is open processing and dust generating operations are considered White High Zones.

Examples of White High Zones are Glen Bowl Mixing, and primary filling of powders.

White Low Zone

A GMP area within the facility where there is low potential for product exposure and high potential for product contact surface/component exposure.

White Low areas refer to manufacturing areas where there is little risk of dust generation and where closed or enclosed processing occurs.

Examples of White Low Zones are white support corridors for transition into a White High Zone, film-coating and primary packaging.

Wood Supplies

Material handling supplies constructed/composed of solid, untreated wood.

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Working Cell Bank (WCB)

A cell bank prepared from aliquots of a homogenous suspension of cells obtained from culturing the Master Cell Bank under controlled conditions.

The WCB is used to initiate production cell cultures on a lot-by-lot basis or to initiate cell expansion for QC release assays.

Working Master Batch Sheet

A copy of the Master Batch Sheet that indicates the required changes for a Batch Sheet or Floor Copy.

Working Seed (WS)

A viral seed prepared from aliquots of a homogenous suspension of virus derived by propagation of the Master Seed under controlled conditions, dispensed, and stored.

The WS is thawed and used to inoculate production cell cultures on a lot-by-lot basis or as a positive control for QC release assays.

Working Standard

An API or biological API of high quality and purity used as an analytical reference substance for routine laboratory analysis.

The analytical testing needed to document the suitability of the working standard should generally be more extensive than that used for the API, and it is compared with a primary reference standard.

Worksheet / Template

An individualised, standard form, with or without instructions that is used to record laboratory data.

The laboratory worksheet/template should be identified with a unique numbering system so that it is tracked to ensure accountability and traceability of raw data.

Worst Case [Conditions]

1) A set of conditions encompassing upper and lower processing limits and circumstances, including those within standard operating procedures, which pose the greatest chance of process or product failure when compared to ideal conditions. Such conditions do not necessarily induce product or process failure.

2) A set of pre-specified stress conditions encompassing either or both upper and lower processing limits or defined activities within the standard operating procedures, which pose the greatest risk of causing product contamination when compared to routine production conditions. However, these imposed stress conditions must not directly cause product or process failure.

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Worst Case Diluent

The agent which causes the most loss in potency of active moiety or change in stability indicating test.

Worst Case Soil Matrix

The most difficult to clean product in a matrix, for which the same cleaning is used.

Wrapped Components

Those sterilised items which are protected from contamination by being wrapped with autoclave paper or Tyvek® covers or similar, in whole or in part.

w/v

Percent weight in volume.

It is defined as the number of grams of the solute in 100 mL of solution. The solution solvent may be water or any other liquid.

w/w

Percent weight in weight.

It is defined as the number of grams of a substance in 100 grams of solution or mixture.

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- X -

Xenobiotic

A compound foreign to an organism.

Xenograft

Tissue or organs from an individual of one species transplanted into or grafted onto an organism of another species, genus, or family. A common example is the use of pig heart valves in humans.

Xenotransplantation

The transplantation of tissue from one species to another species, typically from non-human mammals to humans. This technology has become very important because of a worldwide shortage of human organs for humans requiring a new organ. The most popular non-human species involved in this technology is the pig.

X-Ray Crystallography

A technique used to determine protein structure in which proteins in a crystalline form are exposed to X-rays. Advanced computer programs analyse the patterns of the X-rays bending through the crystals to create a picture of the protein in three dimensions.

X-Ray Photoelectron Spectroscopy (XPS)

A surface-sensitive technique capable of detecting all elements with an atomic number greater than that of helium. Also known as Electron Spectroscopy for Chemical Analysis (ESCA).

ESCA provides data on the outermost several atomic layers of a material, and has a sensitivity in the order of 0.5 atomic percent. A primary advantage of ESCA is that it can both determine and quantify the chemical state of the elements detected i.e. metallic state or oxide state.

X-Ray Powder Diffraction (XRPD)

X-ray powder diffraction (XRD) is a rapid analytical technique primarily used for phase identification of a crystalline material and can provide information on unit cell dimensions. The analysed material is finely ground, homogenised, and average bulk composition is determined.

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- Y -

Yeast / Mould Count

Quantitative enumeration of viable fungi that may grow under aerobic conditions.

Yield

The ratio of usable output from a process to the value of materials input to the process. Yield is usually expressed as a percentage and may be in terms of total input or a specific raw material. Yield may also be expressed in moles to account for chemical transformation in API production.

- Z -

Z-value

1) The number of degree temperature change required to change the D-value by a factor of 10.

2) The number of degrees of temperature change necessary to change the D-value by a factor of 10.

Zero Defects

A performance standard developed by Philip B. Crosby to address a dual attitude in the workplace; namely that people are willing to accept imperfection in some areas, while, in other areas, they expect the number of defects to be zero. This dual attitude had developed because of the conditioning that people are human and humans make mistakes. However, the zero defects methodology states that, if people commit themselves to watching details and avoiding errors, they can move closer to the goal of zero.

Zone I

Temperate climatic region (e.g. United Kingdom, Northern Europe, Canada, Russia).

Represented by long-term stability storage conditions of 25°C/60%RH (or 25°C/40%RH for liquids in semi-permeable containers) per ICH Q1A and WHO.

Zone II

Mediterranean subtropical climatic region (e.g. United States, Japan, Southern Europe such as Portugal and Greece).


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Zone III

Hot, dry climatic region (e.g. Iran, Iraq, Sudan).


Zone IV (ICH)

Hot, humid, climatic region (e.g. Costa Rica, Egypt).

Represented by long-term stability storage conditions of 30°C/65%RH (or 30°C/35%RH for liquids in semi-permeable containers) per ICH Q1A.

Zone IVA (WHO)

Hot, humid, climatic region. (e.g. Costa Rica, Egypt).

Represented by long-term stability storage conditions of 30°C/65%RH (or 30°C/35%RH for liquids in semi-permeable containers) per WHO.

Zone IVB (WHO)

Hot, very humid, climatic region (e.g. Brazil, ASEAN).

Represented by long-term stability storage conditions of 30°C/75%RH per WHO, ANVISA and ASEAN.

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- A -

ACRONYMS

482 FDA Form FD482

483 FDA Form FD483

ACS American Chemical Society

ADE Acceptable Daily Exposure

AE Adverse Event

AET Analytical Evaluation Threshold

A&IT Automation & Information Technology

ALP Automatic Liquid Packaging

AMC Approved Master Copy

ANDA Abbreviated New Drug Application

ANSI American National Standards Institute

API Active Pharmaceutical Ingredient

APP Approved Printer’s Proof

APR Atypical Process Report, also Annual Product Review

AQL Acceptable Quality Level/Limit

ARL Acceptable Residual Level

ASME American Society of Mechanical Engineers

ASQ American Society for Quality

ASTM American Society of Testing and Materials

ATCC American Type Culture Collection

ATL Addition to the Line, also Across the Lot

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aw Water of Activity

BAS Building Automation System

BCCM Behavioural Coaching and Consequence Management

BCR Biological Critical Reagent

BFD Block Flow Diagram

BLA Biologics License Application or Biological License Application

BOM Bill of Materials

BP British Pharmacopoeia

BPC Bulk Pharmaceutical Chemical

CAD Computer Aided Design

CAPA Corrective Actions and Preventative Actions or Corrective Action / Preventive Action

CBER Centre for Biologics Evaluation & Research

CCI Container & Closure Integrity

CCIT Container & Closure Integrity Testing

CCR Change Control Request

CCS Container Closure System

CDC Centre for Disease Control and Prevention

CDT Counterfeit, Diversion, and Tampering

CFM Cubic Feet per Minute

CFR Code of Federal Regulations

CFU Colony Forming Unit

cGMP Current Good Manufacturing Practices

CHU Complaint Handling Unit

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CI Customer Interface

CIP Clean In Place

COA Certificate of Analysis

COTS Commercial off the Shelf

CP Control Procedure

CPM Complaints Per Million

CPV Continued Process Verification

CPP Critical Process Parameter

CQA Critical Quality Attribute, also Certified Quality Auditor

CQE (ASQC) Certified Quality Engineer

CQM (ASQC) Certified Quality Manager

CR Change Request

CRT Controlled Room Temperature

CSQE (ASQC) Certified Software Quality Engineer

CVM Centre for Veterinary Medicine

DAC Disposable Aseptic Connector

DER Drug Experience Report

DHF Design History File

DHR Device History Record

DI De-ionised Water

DIN German Institute for Standardisation (Deutsches Institut fur Normung)

DL Detection Limit

DMAIC Define, Measure, Analyse, Improve, Control

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DMF Drug Master File

DMR Device Master Record

DOE Design of Experiment

DP Drug Product

DPOC Designated Point of Contact

DQ Design Qualification

DQS Data Quality Services

DS Drug Substance

DSMZ Deutsche Sammlung von Mikroorganismen und Zellculturen

DTC Direct to Consumer

DTP Desktop Publishing or Desktop Publisher

E Extractables

ECR Equipment Change Request

EDP Employee Development Plan

EEC European Economic Community

ELA Establishment License Application

EMEA European Agency for the Evaluation of Medicinal Products

EMEA-QO Regional quality office for EMEA

EMO External Manufacturing Organisation

EMQA External Manufacturing Quality Assurance

EP European Pharmacopoeia, also External Party

EPA Environmental Protection Agency

EQ Equipment Qualification

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E-REC Electronic Records

ERW Endotoxin Reduced Water

E-SIG Electronic Signature

EU European Union, also Endotoxin Units

EWS Early Warning System

ExP External Partner

FAQ Frequently Asked Questions

FAR Field Alert Report (official alert to FDA)

FAT Factory Acceptance Test

FCC Food Chemical Codex

FDA Food & Drug Administration

FD&C Food Drug & Cosmetic Act

FIFO First In First Out

FIO For Information Only

FMA Failure Mode Analysis

FMEA Failure Mode Effects Analysis

FMECA Failure Mode Effects and Criticality Analysis

FOI Freedom of Information Act

FPAC Formula Preparation and Control

FSS Format Stability Studies

FTE Full Time Equivalent

GC Gas Chromatograph

GDP Good Distribution Practices or Good Documentation Practices

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GEP Good Engineering Practices

GLP Good Laboratory Practices

GMP Good Manufacturing Practices

GP Growth Promotion

GPM Gallons per Minute

GSP General Stability Protocol

HAZOP Hazard & Operability Review

HAZMAT Hazardous Material

HDPE High Density Polyethylene

HEPA High Efficiency Particulate Air

HPB Health Protection Branch (Canada)

HPW Highly Purified Water

HPLC High Performance Liquid Chromatography/High Pressure Liquid Chromatography

HVAC Heating, Ventilation & Air Conditioning

HPWS High Performance Water System

HR Human Resources

ICH International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use

IEEE Institute of Electrical and Electronics Engineers

IMA International Marketing Application

IMS Issue Management System

IND Investigational New Drug Application

IQ Installation Qualification

ISO International Organization for Standardisation

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IT Information Technology, also Integrity Test

JIT Just In Time

J-NDA Japanese New Drug Application

JoSHA Job Safety Health Analysis

JP Japanese Pharmacopoeia

JV Joint Venture

KOP Key Operating Parameter

KPA Key Process Attribute

L Leachables

LAL Limulus Amebocyte Lysate

LCL Lower Control Limit

LD50 Lethal Dose 50%

LIFO Last In First Out

LIMS Laboratory Information Management System

LOD Loss on Drying, also Limit of Detection

LOQ Limit of Quantitation

LSS Lean-Six-Sigma

LVV Live Virus Vaccine

MAA Marketing Authorisation Application

MAD Maximum Allowable Difference

MAP Major Accident Prevention

MCA Medicines Control Agency (UK)

MCB Master Cell Bank

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MCF Master Control Form

MET Microbial Enumeration Test

M-HPC Membrane-Heterotrophic Plate Count

MKT Mean Kinetic Temperature

MIL-STD Military Standard

MLT Microbial Limit Test

MMR Measles, Mumps Rubella

MOH Ministry of Health

MPD Manufacturing Process Description

MPN Most Probable Number

MRP Manufacturing Requirements Planning or Materials Resource Planning

MS Master Seed

MSDS Material Safety Data Sheets

NADA New Animal Drug Application

NCE New Chemical Entity

NDA New Drug Application

NDA/WMA New Drug Application/Worldwide Manufacturing Authorisation

NDC National Drug Code

NDT Non-destructive Testing

NF National Formulary

NIH National Institute of Health

nIMPs Non-Investigational Medicinal Products

NIST National Institute of Standards and Technology

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NMT No More Than or Not More Than

OC Curve Operating Characteristic Curve

OCAW Oil, Chemical and Atomic Workers International Union

OCR Optical Character Recognition

OCV Optical Character Verification

OEM Original Equipment Manufacturer

OFC Order Fulfillment Center

OJT On the Job Training

OOC Out of Calibration

OOS Out of Specification

OOT Out of Trend

OQ Operational Qualification

ORSs Official Reference Standards

OS Origin Site

OSHA Occupational Safety & Health Administration

OTC Over the Counter

OVI Organic Volatile Impurity

PA Preventative Action

PAC Pharmaceutical Analysis & Control

PACE Production and Cycle Time Excellence

PAI Pre-Approval Inspection

PCM Polymeric Contact Material

PCR Process Change Request

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PDA Parenteral Drug Association (now the International Association for Pharmaceutical Science and Technology

PDCA Cycle Plan-Do-Check-Act cycle

PDG Pharmacopeial Discussion Group

PDR Physician’s Desk Reference

PEG Polyethylene Glycol

PFD Process Flow Diagram

PhRMA Pharmaceutical Research & Manufacturers of America

Ph. Eur. European Pharmacopeia (see also EP)

PID Packaging Information Document (for licensees)

P&ID Process (or Piping) and Instrumentation Diagram

PIN Product Information Notice

PLA Product License Application

PLC Program Logic Controller

PLR Product Launch Requirements

PM Preventative Maintenance; also Performance Monitoring

PMDA Pharmaceutical & Medical Device Agency

PO Purchase Order

POD Proof of Delivery

POL Policy

PPC Primary Packaging Component

PPD Packaging Process Description

PPE Personal Protective Equipment

PQ Performance Qualification; also Process Qualification; also Product Qualification

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PQC Product Quality Complaint

PR&D Pharmaceutical Research & Development

PSI Pounds per Square Inch

PST Process Specific(s) Training

PT Packaging Technology

PUPS Post-Sterilisation, Pre-Use

PV Pharmacovigilance

PVC Polyvinyl Chloride

PVE Product Value Enhancement

PW Process Water

QA Quality Assurance

QA&P Quality Assurance & Planning

QC Quality Control Department

QL Quantitation Limit

QMS Quality Management System

QO Quality Operations

QP EU-Qualified Person

QS Quality Standard

QT Qualification Threshold

RA Regulatory Affairs

RABS Restricted Access Barrier System

RACI Responsible, Accountable, Contributing (or Consulted), Informed (matrix tool to capture roles and responsibilities)

RCA Root Cause Analysis

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R&D Research & Development

RFT Right First Time

RH Relative Humidity

RL Reporting Limit

RM Raw Material

RO Reverse Osmosis

RODAC Replicate Organism Detection and Count

R&R Roles and Responsibilities

RRF Relative Response Factor

RRT Relative Retention Time

RS Receiving Site

RSD Relative Standard Deviation

SAL Sterility Assurance Level

SAT Standard Analytical Techniques, also Site Acceptance Test

SBF Sterile Boundary Filter

SCDM Soybean Casein Digest Media

SCT Safety Concern Threshold

SI Significant Investigation

SIP Sterilise In Place

SLC System Life Cycle

SLR Spore Reduction Log

SMART Specific Measurable Achievable Realistic Timely

SME Subject Matter Expert

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sNDA Supplemental New Drug Application

SO System Owner

SOP Standard Operating Procedure

SPC Statistical Process Control

SPE Sterile Process Engineering

SPMP Supplier Performance Management Process

SQL Structured Query Language

SSO Sub System Owner

SUS Single-Use System

TC Temperature Controlled

TGA Therapeutic Goods Administration (Australia)

TNTC Too Numerous to Count

TOC Total Organic Compounds

TOR Time Out of Refrigeration

TOS Time Out of Storage

TPS Thermal Protection System

TQM Total Quality Management

TSB Trypticase Soy Broth

TTC Threshold of Toxicological Concern

UCL Upper Control Limit

ULD Unit Load Device

UPS Uninterruptible Power Supply

US EPA NPDWR United States Environmental Protection Agency National Primary Drinking Water Regulations

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USHH United States Human Health

USP United States Pharmacopoeia

USP – NF United States Pharmacopeia- National Formulary

US/PR United States/Puerto Rico

UV Ultraviolet

VHP Vapor-Phase Hydrogen Peroxide; also Vaporized Hydrogen Peroxide

VRL Visible Residue Limit

v/v volume in volume

WCB Working Cell Bank

WFI Water for Injection

WHHM Worldwide Human Health Marketing

WHO World Health Organization

WIP Work in Process

WMA Worldwide Marketing Application

WS Working Seed

w/v weight in volume

w/w weight in weight

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