ayush reportnew 1 (2)

8/6/2019 ayush reportnew 1 (2)

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Pranveer singh institute of technology, kanpur

Institute of pharmacy

CERTIFICATE

This is to certify that the project work entitled is a project work done

by Mahendra Kr. Verma under the supervision ofMr. Swatantra

Kushwaha, Assit. Professor, institute of pharmacy,PSIT,Kanpur.

Date: Mr. A. K. RAI

DIRICTOR OF PHARMACY

Place : PSIT, Kanpur


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LIST OF CONTENTS

Serial

no.

Content Page no.

1 Introduction 1


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Introduction

A process is a series of interrelated functions and activities using a

variety of specified actions and equipment which is designed to produce

a defined result. To validate the reproducibility and consistency of a

process, the full defined process is carried out using validated

equipment, under the established procedure usually at least 3 times The

process must successfully and consistently meet all acceptance criteria

each time to be considered a validated process. In many cases, "worst

case" conditions are used for the validation to ensure that the process is

acceptable in the extreme

case. Sometimes worst case conditions for systems can only really be

tested over time and hence must be evaluated using a rigorous long

term monitoring programme.

Examples of processes which must be validated in pharmaceutical

manufacturing are:

Cleaning,Sanitization,Fumigation,Depyrogenation,Sterilization

Sterile filling,Fermentation,Bulk production,Purification

Filling, capping, sealing Lyophilization

This guideline outlines the principles and approaches that SFDA

considers important for the process validation of manufacturing

processes. It provides that activities align with process validation during

the product and process development, including all terms/ definitions

used in the validation.It should be noted that the recommendations

suggested in this guideline are not intended as requirements under all

circumstances as the requirement of


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the SFDA. Alternate means, scientifically justified and documented are

equally acceptable.Each process to be validated must be a specific

process clearly described in a Master Formula or in an SOP. It is very

important that the specifications for a process undergoing validation be

pre-determined. It is also important that for all critical processingparameters for which specifications have been set, there must be

equipment to measure all of the separateness during the validation

study.

Process Validation studies examine a process under normal operating

conditions to prove that the process is in control. Once the process has

been validated, it is expected that it remains in control, provided no

changes are made.

In the event that modifications to the process are made, or problemsoccur, or equipment or systems involved in the process are changed, a

re-validation of the process would be required. Very often validation

studies require that more measurements are made than are required for

the routine process. The validation must prove the consistency of the

process and therefore must assess the efficiency and effectiveness of

each step to produce its intended outcome.The controls and tests and

their specifications must be defined. To be considered validated, the

process must consistently meet all specifications at all steps throughout

the procedure at least three times

Objective and purpose

Process validation of pharmaceutical manufacturing process especially

tablet manufacturing process with special reference to the

requirements stipulated by the US Food and Drug Administration (FDA).

Quality is always an imperative prerequisite when we consider any

product. Therefore drugs must be manufactured to the highest quality

levels. End product testing by itself does not guarantee the quality of theproduct. Quality assurance techniques must be used to build the quality

in to the product at every step and not just tested for at the end. In

pharmaceutical industry, Process validation performs this task to build

the quality into the product because according to ISO


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9000:2000, it had proven to be an important tool for quality

management of pharmaceuticals.

The purpose of this guideline is limited to non-sterile dosage form,

although the principles and

Elements specified are equally applicable to sterile products. There are

various additional

Guidelines, such as steam sterilization, aseptic processing, radiation

sterilization, etc., that

should be considered when the manufacture of sterile products is

subjected to the process

validation. This guideline is not intended to specify how validation is tobe conducted, but to

indicate what the expectations of SFDA from the manufacturers are.

APPROACH TO PROCESS VALIDATION

For purposes of this guidance, process validation is defined as thecollection 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 product.

guidance describes process validation activities in three stages.

y Stage 1 Process Design: The commercial manufacturing process is defined during this stage based on knowledge gained

through development and scale-up activities.

y Stage 2 Process Qualification: During this stage, the processdesign is evaluated to determine if the process is capable of

reproducible commercial manufacturing.y Stage 3Continued Process Verification: Ongoing assurance

is gained during routine production that the process remains in a state

of control


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Before any batch from the process is commercially distributed for use

by consumers, a manufacturer should have gained a high degree of

assurance in the performance of the manufacturing process such that it

will consistently produce APIs and drug products meeting those

attributes relating to identity, strength, quality, purity, and potency.The assurance should be obtained from objective information and data

from laboratory-, pilot-, and/or commercial-scale studies. Information

and data should demonstrate that the commercial manufacturing

process is capable of consistently producing acceptable quality

products within commercial manufacturing conditions.

A successful validation program depends upon information and

knowledge from product and process development. This knowledge

and understanding is the basis for establishing an approach to control

of the manufacturing process that results in products with the desired

quality attributes. Manufacturers should:

Understand the sources of variation

Detect the presence and degree of variation

Control the variation in a manner commensurate with the risk it

represents to the process and product

GENERAL CONSIDERATIONS FOR PROCESS

VALIDATION

In all stages of the product lifecycle, good project management and good

archiving that capture scientific knowledge will make the processvalidation program more effective and efficient. The following practices

should ensure uniform collection and assessment of information about

the process and enhance the accessibility of such information later in

the product lifecycle.


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y We recommend an integrated team approach to process validation that

includes expertise from a variety of disciplines (e.g., process

engineering, industrial pharmacy, analytical chemistry, microbiology,

statistics, manufacturing, and quality assurance). Project plans, along

with the full support of senior management, are essential elements forsuccess.

y Throughout the product lifecycle, various studies can be initiated to

discover, observe, correlate, or confirm information about the product

and process. All studies should be planned and conducted according

to sound scientific principles, appropriately documented, and

approved in accordance with the established procedure appropriate for

the stage of the lifecycle.

y The terms attribute(s) (e.g., quality, product, component) andparameter(s) (e.g., process, operating, and equipment) are not

categorized with respect to criticality in this guidance. With a lifecycle

approach to process validation that employs risk based decision making

throughout that lifecycle, the perception of criticality as a continuum

rather than a binary state is more useful. All attributes and parameters

should be evaluated in terms of their roles in the process and impact on

the product or in-process material, and reevaluated as new information

becomes available. The degree of control over those attributes or parameters should be commensurate with their risk to the process and

process output. In other words, a higher degree of control is appropriate

for attributes or parameters that pose a higher risk. The Agency

recognizes that terminology usage can vary and expects that each

manufacturer will communicate the meaning and intent of its

terminology and categorization to the Agency.

y Many products are single-source or involve complicated

manufacturing processes. Homogeneity within a batch and

consistency between batches are goals of process validation activities.Validation offers assurance that a process is reasonably protected

cause supply problems, and negatively affect public health.


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TYPES OF PROCESS VALIDATION-

process validation are divided in 3 category-

y

Prospective validationy Concurrent validation

y Retrospective validation

PROSPECTIVE VALIDATION-

In Prospective Validation, the validation protocol is executed before the

process is put

into commercial use. During the product development phase the

production process

should be broken down into individual steps. Each step should be

evaluated on the

basis of experience or theoretical considerations to determine the

critical parameters

that may affect the quality of the finished product. A series of

experiments should be

designed to determine the criticality of these factors. Each experiment

should be

planned and documented fully in an authorized protocol.

All equipment, production environment and the analytical testing

methods to be used

should have been fully validated. Master batch documents can be

prepared only afterthe critical parameters of the process have been identified and machine

settings,


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component specifications and environmental conditions have been

determined.

It is generally considered acceptable that three consecutive

batches/runs within the

finally agreed parameters, giving product of the desired quality would

constitute a

proper validation of the process. It is a confirmation on the commercial

three batches

before marketing.

The matrix approach generally means a plan to conduct process

validation on

different strengths of the same product, whereas the family approach

means a plan

to conduct process validation on different products manufactured with

the same

processes using the same equipment. The validation process using these

approaches must include batches of different strengths or products

which should be selected to represent the worst case conditionsor scenarios to demonstrate that the process is consistent for all

strengths or products

involved.


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CONCURRENT VALIDATION-

Concurrent validation may be the practical approach under certaincircumstances.

Examples of these may be when:

A previously validated process is being transferred to a third party

contract

manufacturer or to another manufacturing site.

The product is a different strength of a previously validated product

with the same

ratio of active/inactive ingredients

The number of lots evaluated under the Retrospective Validation were

not

sufficient to obtain a high degree of assurance demonstrating that the

process is

fully under control.

The number of batches produced are limited (e.g. orphan drugs).

Process with low production volume per batch ( e.g.

radiopharmaceuticals, anticancer).

Process of manufacturing urgently needed drugs due to shortage (or

absence) of supply.

It is important in these cases however, that the systems and equipment

to be used

have been fully validated previously. The justification for conducting

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validation must be documented and the protocol must be approved by

the Validation

Team. A report should be prepared and approved prior to the sale of

each batch and a final report should be prepared and approved after the

completion of all concurrent batches. It is generally considered acceptable that a

minimum of three consecutive batches within the finally agreed parameters,

giving the product the desired quality would constitute a proper

validation of the process.

RETROSPECTIVE VALIDATION-

In many establishments, processes that are stable and in routine use

have not

undergone a formally documented validation process. Historical data

may be utilized

to provide necessary documentary evidence that the processes are

validated. The steps involved in this type of validation still require the

preparation of a protocol,

the reporting of the results of the data review, leading to a conclusion

and

recommendation.

Retrospective validation is only acceptable for well established detailed

processes that include operational limits for each critical step of the

process and will be inappropriate where there have been recent


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changes in the formulation of the product, operating procedures,

equipment and facility. The source of data for retrospective validation

should include amongst others, batch documents, process control

charts, maintenance log books, process capability studies, finished

product test results, including trend analyses, and stability results. Forthe purpose of retrospective validation studies, it is considered

acceptable that data from a minimum of ten consecutive batches

produced be utilized. When less than ten batches are available, it is

considered that the data are not sufficient to demonstrate

retrospectively that the process is fully under control. In such cases the

study should be supplemented with data generated with concurrent or

prospective validation.

Some of the essential elements for Retrospective Validation are:

y Batches manufactured for a defined period (minimum of 10 last

consecutive batches).

y Number of lots released per year.

Batch size/strength/manufacturer/year/period.

Master manufacturing/packaging documents.

Current specifications for active materials/finished products.

List of process deviations, corrective actions and changes to

manufacturing documents.

y Data for stability testing for several batches.

Trend analyses including those for quality related complaints.


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PROCESS RE-VALIDATION-

Re-validation

becomes necessary in certain situations. The following are examples of

some of the planned or unplanned changes that may require re-validation:

Changes in raw materials (physical properties such as density,

viscosity, particle size distribution, and moisture, etc., that may affect

the process or product). Changes in the

source of active raw material manufacturer.

Changes in packaging material (primary container/closure system).

Changes in the process (e.g., mixing time, drying temperatures and

batch size) Changes in the equipment (e.g. additionof automatic detection system). Changes of equipment which involve

the replacement of equipment on a like for like basis would not

normally require a re-validation except that this new equipment must

be qualified. Changes in the plant/facility.

Variations revealed by trend analysis (e.g. process drifts).

PRINCIPLE OF PROCESS VALIDATION-Stage 1 Process Design

Process design is the activity of defining the commercial manufacturing

process that will be reflected in planned master production and control

records. The goal of this stage is to design a process suitable for routine

commercial manufacturing that can consistently deliver a product that

meets its quality attributes.

1. Building and Capturing Process Knowledge and Understanding.


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Generally, early process design experiments do not need to be

performed under the CGMP conditions required for drugs intended for

commercial distribution that are manufactured during Stage 2 (process

qualification) and Stage 3 (continued process verification). They should,

however, be conducted in accordance with sound scientific methods andprinciples, including good documentation practices. This

recommendation is consistent with ICH Q10 Pharmaceutical Quality

System. Decisions and justification of the controls should be sufficiently

documented and internally reviewed to verify and preserve their value

for use or adaptation later in the lifecycle of the process and product.

Although often performed at small-scale

laboratories, most viral inactivation and impurity clearance studies

cannot be considered early process design experiments. Viral and

impurity clearance studies intended to evaluate and estimate product

quality at commercial scale should have a level of quality unit oversight

that will ensure that the studies follow sound scientific methods and

principles and the conclusions are supported by the data.

Designing an efficient process with an effective process control approach is

dependent on the process knowledge and understanding obtained. Design of

Experiment (DOE) studies can help develop process knowledge by revealing

relationships, including multivariate interactions, between the variable inputs

(e.g., component characteristics 13 or process parameters) and the resultingoutputs (e.g., in-process material, intermediates, or the final product).

Risk analysis tools can be used to screen potential variables for DOE studies

to minimize the total number of experiments conducted while maximizing

knowledge gained. The results of DOE studies can provide justification for

establishing ranges of incoming component quality, equipment, parameters,

and in-process material quality attributes. FDA does not generally expect

manufacturers to develop and test the process until it fails. It is important to

understand the degree to which models represent the commercial process,including any differences that might exist, as this may have an impact on the

relevance of information derived from the models.


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It is essential that activities and studies resulting in process

understanding be documented. Documentation should reflect the basis

for decisions made about the process. For example, manufacturers

should document the variables studied for a unit operation and the

rationale for those variables identified as significant. This information isuseful during the process qualification and continued process

verification stages, including when the design is revised or the strategy

for control is refined or changed.

ESTABLISHING A STRATEG Y FOR

PROCESS CONTROL-

Process knowledge and understanding is the basis for establishing anapproach to process control for each unit operation and the process overall.

Strategies for process control can be designed to reduce input variation,

adjust for input variation during manufacturing (and so reduce its impact on

the output), or combine both approaches. FDA expects controls to include

both examination of material quality and equipment monitoring. Special

attention to control the process through operational limits and in-process

monitoring is essential in two possible scenarios:

y When the product attribute is not readily measurable due to

limitations of sampling or delectability (e.g., viral clearance ormicrobial contamination) or

y When intermediates and products cannot be highly characterized

and well-defined quality attributes cannot be identified.

More advanced strategies, which may involve the use of process analytical

technology (PAT), can include timely analysis and control loops to adjust

the processing conditions so that the output remains constant.

Manufacturing systems of this type can provide a higher degree of process

control than non-PAT systems. In the case of a strategy using PAT, the

approach to process qualification will differ from that used in other process


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PROCESS PERFORMANCE QUALIFICATION

The process performance qualification (PPQ) is the second element of

Stage 2, process qualification. The PPQ combines the actual facility,

utilities, equipment (each now qualified), and the trained personnelwith the commercial manufacturing process, control procedures, and

components to produce commercial batches. A successful PPQ will

confirm the process design and demonstrate that the commercial

manufacturing process performs as expected. Success at this stage

signals an important milestone in the product lifecycle. A manufacturer

must successfully complete PPQ before commencing commercial

distribution of the drug product.

The decision to begin commercial distribution should be supported bydata from commercial-scale batches. Data from laboratory and pilot

studies can provide additional assurance that the commercial

manufacturing process performs as expected. The cumulative data from

all relevant studies (e.g., designed experiments; laboratory, pilot, and

commercial batches) should be used to establish the manufacturing

conditions in the PPQ. To understand the commercial process

sufficiently, the manufacturer will need to consider the effects of scale.

However, it is not typically necessary to explore the entire operatingrange at commercial scale if assurance can be provided by process

design data. Previous credible experience with sufficiently similar

products and processes can also be helpful. In addition, we strongly

recommend firms employ objective measures (e.g., statistical metrics)

wherever feasible and meaningful to achieve adequate assurance.

In most cases, PPQ will have a higher level of sampling, additional

testing, and greater scrutiny of process performance than would be

typical of routine commercial production. The level of monitoring and

testing should be sufficient to confirm uniform product quality

throughout the batch. The increased level of scrutiny, testing, and

sampling should continue through the process verification stage as

appropriate, to establish levels and frequency of routine sampling and


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monitoring for the particular product and process. Considerations for

the duration of the heightened sampling and monitoring period could

include, but are not limited to, volume of production, process

complexity, level of process understanding, and experience with similar

products and processes.

The extent to which some materials, such as column resins or molecular

filtration media, can be re-used without adversely affecting product quality

can be assessed in relevant laboratory studies. The usable lifetimes of such

materials should be confirmed by an ongoing PPQ protocol during

commercial manufacture.

A manufacturing process that uses PAT may warrant a different PPQ

approach. PAT processes are designed to measure in real time the

attributes of an in-process material and then adjust the process in atimely control loop so the process maintains the desired quality of the

output material. The process design stage and the process qualification

stage should focus on the measurement system and control loop for the

measured attribute. Regardless, the goal of validating any

manufacturing process is the same: to establish scientific evidence that

the process is reproducible and will consistently deliver quality

products.


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PPQ PROTOCOL-

A written protocol that specifies the manufacturing conditions, controls,

testing, and expected outcomes is essential for this stage of process

validation. We recommend that the protocol discuss the followingelements:

y The manufacturing conditions, including operating parameters,

processing limits, and component (raw material) inputs.

y The data to be collected and when and how it will be evaluated.

y Tests to be performed (in-process, release, characterization) and

acceptance criteria for each significant processing step.

y The sampling plan, including sampling points, number of

samples, and the frequency of sampling for each unit operation

and attribute. The number of samples should be adequate to

provide sufficient statistical confidence of quality both within a

batch and between batches. The confidence level selected can

be based on risk analysis as it relates to the particular attribute

under examination. Sampling during this stage should be more

extensive than is typical during routine production.


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y Criteria and process performance indicators that allow for a

science- and risk-based decision about the ability of the process

to consistently produce quality products. The criteria should

include:

y A description of the statistical methods to be used in analyzing

all collected data (e.g., statistical metrics defining both intra-

batch and inter-batch variability).

y Provision for addressing deviations from expected conditions

and handling of nonconforming data. Data should not be

excluded from further consideration in terms of PPQ without adocumented, science-based justification.

y Design of facilities and the qualification of utilities and

equipment, personnel training and qualification, and

verification of material sources (components and

container/closures), if not previously accomplished.

y Status of the validation of analytical methods used in measuring

the process, in-process materials, and the product.

y Review and approval of the protocol by appropriate

departments and the quality unit.


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PPQ PROTOCOL EXECUTION AND REPORT-

Execution of the PPQ protocol should not begin until the protocol has been

reviewed and approved by all appropriate departments, including the quality

unit. Any departures from the protocol must be made according toestablished procedure or provisions in the protocol. The PPQ lots should be

manufactured under normal conditions by the personnel routinely expected

to perform each step of each unit operation in the process.

Normal operating conditions should include the utility systems (e.g., air

handling and water purification), material, personnel, environment, and

manufacturing procedure.

A report documenting and assessing adherence to the written PPQ protocol

should be prepared in a timely manner after the completion of the protocol.This report should:

y Discuss and cross-reference all aspects of the protocol.

Summarize data collected and analyze the data, as specified by

the protocol.

y Evaluate any unexpected observations and additional data not

specified in the protocol. Summarize and discuss all

manufacturing nonconformances such as deviations, aberrant

test results, or other information that has bearing on the validity

of the process.

y Describe in sufficient detail any corrective actions or changes

that should be made to existing procedures and controls.

y State a clear conclusion as to whether the data indicates the

process met the conditions established in the protocol and

whether the process is considered to be in a state of control. If

not, the report should state what should be accomplished beforesuch a conclusion can be reached. This conclusion should be

based on a documented justification for the approval of the

process, and release of lots produced by it to the market in

consideration of the entire compilation of knowledge

.information gained from the design stage.


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STAGE 3 Continued Process Verification-

The goal of the third validation stage is continual assurance that the

process remains in a state of control (the validated state) duringcommercial manufacture. A system or systems for detecting unplanned

departures from the process as designed is essential to accomplish this

goal. Adherence to the CGMP requirements, specifically, the collection

and evaluation of information and data about the performance of the

process, will allow detection of undesired process variability. Evaluating

the performance of the process identifies problems and determines

whether action must be taken to correct, anticipate, and prevent

problems so that the process remains in control.

An ongoing program to collect and analyze product and process data

that relate to product quality must be established. The data collected

should include relevant process trends and quality of incoming

materials or components, in-process material, and finished products.

The data should be statistically trended and reviewed by trained

personnel. The information collected should verify that the quality

attributes are being appropriately controlled.

a statistician or person with adequate training in statistical processcontrol techniques develop the data collection plan and statistical

methods and procedures used in measuring and evaluating process

stability and process capability.

a process is likely to encounter sources of variation that were not

previously detected or to which the process was not previously

exposed. Many tools and techniques, some statistical and others more

qualitative, can be used to detect variation, characterize it, and

determine the root cause. We recommend that the manufacturer use

quantitative, statistical methods whenever appropriate and feasible.

Continued monitoring and sampling of process parameters and quality

attributes at the level established during the process qualification stage

until sufficient data are available to generate significant variability


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estimates. These estimates can provide the basis for establishing levels

and frequency of routine sampling and monitoring for the particular

product and process. Monitoring can then be adjusted to a statistically

appropriate and representative level. Process variability shoul Variation

can also be detected by the timely assessment of defect complaints, out-of-specification findings, process deviation reports, process yield

variations, batch records, incoming raw material records, and adverse

event reports. d be periodically assessed and monitoring adjusted

accordingly.Data gathered during this stage might suggest ways to

improve and/or optimize the process by altering some aspect of the

process or product, such as the operating conditions (ranges and set-

points), process controls, component, or in-process material

characteristics. Maintenance of the facility, utilities, and equipment is

another important aspect of ensuring that a process remains in control.Once established, qualification status must be maintained through

routine monitoring, maintenance, and calibration procedures and

schedules. The equipment and facility qualification data should be

assessed periodically to determine whether re-qualification should be

performed and the extent of that re-qualification.

CONCURRENT RELEASE OF PPQ BATCHES-

In most cases, the PPQ study needs to be completed successfully and a

high degree of assurance in the process achieved before commercial

distribution of a product. In special situations, the PPQ protocol can be

designed to release a PPQ batch for distribution before complete

execution of the protocol steps and activities, i.e., concurrent release.

FDA expects that concurrent release will be used rarely.

Concurrent release might be appropriate for processes used

infrequently for various reasons, such as to manufacture drugs for


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which there is limited demand (e.g., orbhan drugs, minor use and minor

species veterinary drugs) or which have short half lives (e.g.,

radiopharmaceuticals, including positron emission tomography drugs).

Concurrent release might also be appropriate for drugs that are

medically necessary and are being manufactured in coordination withthe Agency to alleviate a short supply.

Conclusions about a commercial manufacturing process can only be

made after the PPQ protocol is fully executed and the data are fully

evaluated. If Stage 2 qualification is not successful then additional

design studies and qualification may be necessary. Full execution of

Stages 1 and 2 of process validation is intended to preclude or minimize

that outcome.

Circumstances and rationale for concurrent release should be fullydescribed in the PPQ protocol. Even when process performance

assessment based on the PPQ protocol is still outstanding, any lot

released concurrently must comply with all CGMPs, regulatory approval

requirements, and PPQ protocol lot release criteria. Lot release under a

PPQ protocol is based upon meeting confidence levels appropriate for

each quality attribute of the drug.

When warranted and used, concurrent release should be accompanied

by a system for careful oversight of the distributed batch to facilitaterapid customer feedback. For example, customer complaints and defect

reports should be rapidly assessed to determine root cause and whether

the process should be improved or changed. It is important that stability

test data be promptly evaluated to ensure rapid detection and

correction of any problems.


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CHANGE CONTROL-

Clearly defined procedure are required in order to control any changes

in the Production processes. These procedures should control all the

planned changes and ensure the presence of sufficient supporting datathat show that modified process will

result in a product of the desired quality. Significant changes to process

(e.g. mixing

time, drying temperature, etc.), using new equipments with different

operating

parameters, etc may require the pre-approval of the SFDA.

If a change is proposed in any of the procedures, product, processes, or

equipment,

which may impact the quality, appropriate written procedures should

be in place.

All changes must be formally requested, documented and accepted by

the Validation

Team. The proposed changes was scientifically assessed and, depending

on the

changes, the need of re-validation will be determined.

Commitment of the company to control all changes to premises,

supporting utilities,

systems, materials, equipment and processes used in the

fabrication/packaging of


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pharmaceutical dosage forms is essential to ensure a continued

validation status of the

systems concerned. It is essential for a company to control all changes

to ensure the validity of thecontinued assurance of validation. The

change control system should ensure that all

notified or requested changes are satisfactorily investigated,

documented and

authorized. Products made by processes subjected to changes should

not be released

for sale without full awareness and consideration of the change by the

Validation

Team.

DOCUMENTATION-

Documentation at each stage of the process validation lifecycle is

essential for effective communication in complex, lengthy, and

multidisciplinary projects. Documentation is important so that

knowledge gained about a product and process is accessible and

comprehensible to others involved in each stage of the lifecycle.

Information transparency and accessibility are fundamental tenets of

the scientific method. They are also essential to enabling organizational

units responsible and accountable for the process to make informed,

science-based decisions that ultimately support the release of a product

to commerce.


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The degree of documentation is greater for stage 2 (process

qualification) and stage 3(continued process verification) of the stages

of process validation as compared to stage 1(process design). All studies

during these processes should be according the GMP.CGMP documents

for commercial manufacturing (i.e., the initial commercial master batchproduction and control record and supporting procedures) are key

outputs of Stage 1, process design.

Process flow diagrams should describe each unit operation, its

placement in the overall process, monitoring and control points, and the

component, as well as other processing material inputs (e.g., processing

aids) and expected outputs (i.e., in-process materials and finished

product). It is also useful to generate and preserve process flow

diagrams of the various scales as the process design progresses to

facilitate comparison and decision making about their comparability.

For each stage of the process validation, documentation is very

essential.

ANALYTICAL METHODOLOGY-

Although the validated analytical methods may not be required during

the product and

process development activities, the methods used should bescientifically sound (e.g.

specific, sensitive and accurate), suitable and reliable for the purpose.

Process knowledge depends on accurate and precise measuring techniques

used to test and examine the quality of drug components, in-process

materials, and finished products. Validated analytical methods are not

necessarily required during product- and process-development activities or

when used in characterization studies. Nevertheless, analytical methods


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should be scientifically sound (e.g., specific, sensitive, and accurate) and

provide results that are reliable.

There should be assurance of proper equipment function for laboratory

experiments. Procedures for analytical method and equipment maintenance,

documentation practices, and calibration practices supporting process-

development efforts should be documented or described.

New analytical technology and modifications to existing technology are

continually being developed and can be used to characterize the process or

the product. Use of these methods is particularly appropriate when they

reduce risk by providing greater understanding or control of product quality.

However, analytical methods supporting commercial batch release must

follow CGMPs in parts 210 and 211. Clinical supply production should

follow the CGMPs appropriate for the particular phase of clinical studies.

VALIDATION PROTOCOL-

The validation protocol provides a synopsis of what is hoped to be

accomplished. The protocol should list the selected process and control

parameters, state the number of batches to be included

in the study, and specify how the data, once assembled, will be treatedfor relevance. The date of approval by the validation team should also

be noted. In the case where a protocol is altered or modified after its

approval, appropriate reasoning for such a change must be documented.

The validation protocol should be numbered, signed and dated, and

should contain as a minimum the following information:

Objectives, scope of coverage of the validation study.


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Validation team membership, their qualifications and responsibilities.

Type of validation: prospective, concurrent, retrospective, re-

validation.

Number and selection of batches to be on the validation study.

A list of all equipment to be used; their normal and worst case

operating parameters.

Outcome of IQ, OQ for critical equipment.

Requirements for calibration of all measuring devices.

Description of the processing steps: copy of the master documents for

the product.

Sampling points, stages of sampling, methods of sampling, sampling

plans.

Statistical tools to be used in the analysis of data.

Training requirements for the processing operators.

Validated test methods to be used in in-process testing and for the

finished product.

Specifications for raw and packaging materials and test methods.

Forms and charts to be used for documenting results.

Format for presentation of results, documenting conclusions and for

approval of study

Result.


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TEST REPORT-

When the validation carried out, the actual data is recorded, compared

with the requirement

and acceptance criteria(s), and a conclusion is made and authorized in

form of report.

Validation Master Plan-

A validation master plan is a document that summaries the companys

overall philosophy,intentions and approaches to be used for

establishing performance adequacy. The Validation Master Plan should

be agreed upon by management.The validation master plan should

provide an overview of the entire validation operation, itsorganizational

structure, its content and planning. The main elements of it being the

list/inventory of the items to be validated and the planning schedule. All

validation activities relating to critical technical operations, relevant to

product and process controls within a firm should be included in the

validation master plan. It should comprise all prospective, concurrentand retrospective validations as well as re-validation.

The Validation Master Plan should be a summary document and should

therefore be brief, concise and clear. It should not repeat information

documented elsewhere but should refer to existing documents such as

policy documents, SOPs and validation protocols and reports.

The format and content should include:

Introduction: validation policy, scope, location and schedule.

Organizational structure: personnel responsibilities.

Plant/process/product description: rational for inclusions or

exclusions and extent of validation.


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Specific process considerations that are critical and those requiring

extra attention.

List of products/ processes/ systems to be validated, summarized in a

matrix format, validation approach.

Re-validation activities, actual status and future planning.

Key acceptance criteria.

Documentation format.

Reference to the required SOPs.

Time plans of each validation project and sub-project


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PROCESS VALIDATION DURING

CLINICAL DEVELOPMENT OF

BIOLOGICAL MEDICINAL PRODUCTS

Some critical processes will need to be validated even at phase I.

These include:

y Aseptic processing, where possible.

y viral clearance validation should be no less rigorous than for

products authorized for marketing.

y Homogeneity issues.

y Removal of critical impurities (highly toxic, immunogenic,

mutagenic,prions, etc.) to levels below the limit of detection, where

relevant.

Although for phase I full validation will not be required there are initialsteps towards validation that will need to be taken, such as qualification

of equipment and of analytical methods. The FDA guidance Sterile Drug

Products Produced by Aseptic Processing Current Good Manufacturing

Practice provides for validation requirements for aseptic processes and

this is expected to be completed as soon as practicable during the initial

stages of the new drug investigation.


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LATE PHASE-

Late phase is generally defined as post-proof-of-concept, which is close

to the end of phase II and the beginning of phase III. The following is a

recommended outline of activities related to process validation:

y end of phase II/phase III: consider whether any critical parts of the

process should be validated and justify omissions.

y prior to medical administrive activities/new drug application/BLA.

y completion of validation.y revalidation following scale-up.

y manufacture of at least three qualification batches.

Process validation cannot take place until the equipment, facilities and

services have been qualified and standard operating procedures

prepared. stablishing appropriate validation acceptance criteria (VAC)

is one of the greatest challenges in the development of a commercial

biological IMP manufacturing process. Manufacturers with VACs that

are too broad will not be able to demonste adequate process control.

However, if the manufacturer sets its VAC too tight this can result in

failed validation runs, even though the process may be performing

adequately.

In addition, there is a need to understand potential impurities and have

validated methods available to detect these. Target limits will need to be

set and justified for in process control, release and end of shelf-life

testing. These limits should be based on data amassed during biological

IMP production and process development as well as trend analyses,

pharmacopoeial and other regulatory requirements and precedence,

including assessment of safety.


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The following issues are often encountered during inspections

pertaining to process validation and are often quoted in inspection

reports, such as 483 observations, by investigators:

y lack of documented procedures and documented validation results.

y sampling or sample preparation step contributing to overall error.

y accessories and materials used for equipment qualification not

qualified.

y lack of computer system validation (this is in addition to the software

and hardware qualification requirements).

y qualification and validation are carried out at just one particular point

in time.

y adaptation of acceptance criteria for qualification of new system

without adequate justification.

The Process and Its Validation-Validation requirements differ in terms of the specific manufacturing

process involved and whether the process occurs upstream,

downstream or fill and finish.

Upstream-

Fermentation represents the critical component of the upstream

process and is typically scaled-up several times, which may impact on

biological IMP quality, safety and/or efficacy. Thus, to support thescale-

up activities, a comprehensive physico-chemical and biological testing

programme will be required. If differences are detected, supporting

non-clinical and clinical data may be required for late phase changes.

For phase I, the facilities and equipment will need to have been

qualified. Trend analyses will continue with full validation being

conducted on at least three consecutive batches. Upstream

validation will need to justify in-process controls. For example, this canbe performed by testing the process at the extremities of the limits.


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DOWNSTREAM-

Downstream processing involves purification and such critically

important processes as virus clearance, which are required to be

validated even at phase I. During later development phases it will alsobe necessary to validate removal of any critical or toxic impurities. By

medical administrative activities/new drug application/BLA

submission, validation will need to address issues such as: column

loading capacity, regeneration, period of use, sanitisation, potential for

leaching, storage, cleaning and sanitisation. Cleaning/washing and

sanitisation (percentage of ethanol or sodiumhydroxide) of the column

packing will be needed to be both established and verified.

FILL AND FINISH-

Proteins are generally labile, so terminal sterilisation is usually not

possible and reliance on aseptic processing is required. This is acritical

issue that needs to be validated even at phase I. Validation of aseptic

processes presents special problems when the batch size is small; in

these cases the number of units filled may be the maximum number

filled in production. During biological IMP production, filling and sealing

is often a manual or semi-automated operation presenting great

challenges to sterility,so enhanced attention should be given to operatortraining and validating the aseptic technique of individual operators.

Spray drying and lyophilisation are two common processes in the

finishing of dosage forms. Spray drying involves continuous atomisation

of the feed solution into a hot drying gas, most commonly air or

nitrogen. The fine droplets resulting from the atomisation of the feed

solution are immediately exposed to the drying gas leading to super

saturation and resulting in the formation of ultra-fine particles, typically

below 5 and with a tight particle size distribution, which are collectedvia a cyclone. The end product must comply with precise quality

standards regarding particle size, distribution, residual moisture

content, bulk density and morphology.


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Freeze-drying (lyophilisation) has successfully been used for the

preservation and storage of many vaccines, microbial cultures and other

labile biological products. Certain biological preparations are

lyophilised in order to maintain integrity, potency and other properties

of the product, when for that particular product other methods of

preservation, such as freezing alone or addition of a preservative, have

not been found to provide sufficient stability. Residual moisture has

been the term used to describe the low level of surface water, usually

from less than 15%, remaining in a freeze-dried vaccine or other

biological product after the bulk of the aqueous solvent has been

removed during the freeze-drying (vacuum sublimation) process.

Examples of freeze-dried biological products include antihemophilic

factor (human), measles virus vaccine live, streptokinase, Alfa

interferon, typhoid vaccine, meningococcal polysaccharide vaccine

groups A and C combined and wasp venom allergenic extract.Over

drying may cause living cells to lose viability, cause the tertiary

molecular structure of complex proteins to be altered with subsequent

loss of activity, or remove monolayers of water from active sites on

molecules that can then react with traces of oxygen and thus degrade.

Each product needs to be evaluated on a case-by-case basis to

determine the optimum residual moisture level. Therefore, the

approach to process validation should take into considerationdevelopmental data on residual moisture content needed for optimal

stability of lyophilized products. Some of the common inspectional

observations pertaining to freeze drying of biopharmaceuticals include

the following issues:

y failure to adequately ensure that when the results of a process cannot

be fully verified by subsequent inspection and test, that the process

shall be validated with a high degree of assurance and approved

according to established procedure.

y Failure to establish acceptance criteria for validation of the freeze-drying process for the manufacturing of a product prior to initiating

the validation.

y Assessing or varying different parameters but not evaluating the

parameters used during the routine freeze-drying process.


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TYPICAL CONTENT REQUIREMENTS FOR

PROCESS VALIDATIONS IN BIOLOGICALS-

It is vital that during all process validation studies, the processes are

performed in

the "actual" environment under which production is to occur. That is to

say all

routine peripheral activities associated with this process must be in

effect while the

validation is being performed. (e.g. number of personnel in facility, exitand entry

procedures are in effect, environmental and personnel monitoring is

being performed

on the prescribed schedule, air system is operating as for regular

manufacturing.

CLEANING, FUMIGATION, SANITIZATIONPROCESSES-

The validation (or re-validation) of these processes includes chemical

and microbiological testing of samples taken at pre-determined times

and locations within a facility, a system or piece ofequipment.

For validation of some cleaning processes, the equipment or surfaces

can be exposed to an appropriate contaminant (e.g. protein solution,

microbial strain), the process is performed according to defined

approved procedures and specifications and then tested to demonstrate

efficacy.


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Validation includes collecting liquid and swab samples for testing of

residual product.

Typical tests to be performed could include: tests for residual protein,

endotoxin tests, microbial tests (bioburden), chemical tests (including

chlorine and phosphoric acid), residual levels of cleaning agents,

conductivity tests, and pH tests as relevant to the cleaning process

under test. All analytical tests must be validated before being used in the

validation of the process. The main considerations in validating a

cleaning/sanitization/fumigation process are how much of the previous

active product is left, and how much detergent/cleaning agent remains.

However there are many tests that should be performed to detect a

range of different potential contaminants. These include tests for:

microbial presence, excipient presence, endotoxin contamination,particulate contamination, sanitizing agents, lubricants, environmental

dust, equipment related contamination and residual rinse water. Worst

case scenarios should be taken into consideration. For example if any

residual cleaning agent is distributed unevenly across the test surface,

then test points must be chosen appropriately.

STERILIZATION-

Sterile filtration of solutions: Validation of this process should include a

microbial challenge that will both test the filter and simulate the

smallest micro-organism likely to occur in production. Once the filtering

process is validated it is important to ensure that all replacement filters

will perform at the same level. This can be done by performing both

filter integrity tests and performance tests at the same time.

Equipment: Validation for materials sterilized in the autoclave or oven

are covered in the Performance qualification.


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Depyrogenation process-

The validation (or re-validation) of a depyrogenation (dry heat, column

chromatography, other) process would include the validation of the

limits of detection and quantitation of the endotoxin assay, the spikingof samples with endotoxin, running the depyrogenation process

according to the approved procedures, and the testing of samples for

residual endotoxin. The full process should be tested at least three times

to ensure that the process adequately destroys endotoxin and meets the

required specifications.

Sterilizing

Sterile filling tests the filling process for maintenance of asepticconditions by performing the filling process with a nutrient media

which will easily support bacterial and fungal growth. The filling

process is run at full scale according to the Master Formula for at least

one fill size (worst case conditions of large volume and number of vials).

Facility and system monitoring are performed and recorded during the

process. The filled vials are incubated, observed and tested for

contamination by the validated sterility test. The process must be sterile

for three consecutive runs to be considered validated.

Typically the media filled container is incubated for 14 days or more at a

temperature of approximately 25 oC - 35 oC. The media fill is usually

performed twice a year for each shift for each filling/closing line, but

this will depend on the frequency required by the regulatory authority.

The size of the run must be large enough to detect low levels of

contamination (e.g. for a contamination rate of 1/1000, 3,000 units are

needed to provide 95% confidence). Appendix 5 includes the validation

protocol for filling from one of the vaccine manufacturers collaborating

on the preparation of this guide.


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