New approach to Process Validation 4

A NEW APPROACH TO PROCESS VALIDATION

(INLIGHTOF

ICH Q8-Q11)

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What is QbD?1. QbD is a systematic , holistic and proactive

approach to Pharmaceutical Development.2. Begins with predefined objectives.3. Emphasizes product and process

understanding and process control.4. Based on sound science and Quality Risk

Management.(ICHQ8R2)5. A Quality by Design (QbD) principle can be

simply stated as follow….. “Once a system has been tested to the extent

that the test results are predictable, further testing can be replaced by establishing that the system is operating within a defined design space”

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Introduction of QbD?

ICH-concepts1. Quality by Design 2. Design Space3. Design of Experiments4. Critical Quality Attributes (CQA)5. Critical Process Parameters(CPP)6. Control Strategy

Quality by Design (QbD) is a concept first outlined by Juran

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Quality by Design

1. Continuous improvement is hallmark of quality by design– G. Taguchi on Robust Design : design

changes during manufacture can result in the last product produced being different from the first product.

2. In pharmaceutical manufacturing, we don’t want this-patients and physicians must count on each batch of drug working just like the batches that come before .

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Why QbD?

Generic industry business model: Regulator’s perspective

File first, learn later Major amendments during review

process -Exhibit batch stability failure,

formulation revision Longer time for generic product approval Approved product may not be marketed Post approval changes-prior approval

supplements

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How QbD will help improve? Ensure higher level of assurance of

product quality for patient Improved product and process design &

understanding Monitoring, tracking & trending of product &

process. More efficient regulatory oversight Efficiency and cost saving for industry

Increase efficiency of manufacturing process Minimize / eliminate potential compliance actions

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INTRODUCTION OF PROCESS VALIDATION

Regulators have the authority and responsibility to inspect and evaluate process validation performed by manufacturers. cGMP regulations for validating pharmaceutical manufacturer require that drug substances be produced with high degree of assurance of meeting all the attributes they are intended to possess. In the Federal register of May,1987;FDA issued a notice announcing the availability of a guidance entitled “Guideline on General Principles of Process Validation” (the 1987 guidance)

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INTRODUCTION Since then, regulators have obtained additional experience that allowed to update recommendations to industries on this topic. A revised guidance published in Jan,2011; conveys FDA’s current thinking on process validation and is consistent with basic principles, first introduced in 1987 guidance. A revised guidance also provides recommendations that reflect some of goals of FDA’s initiative entitled “Pharmaceutical cGMP for the 21st century; A Risk – Based Approach”, particularly with regard to the use of

• Technological advances in pharmaceutical manufacturing

• Implementation of Risk management Quality system tools and management

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GUIDELINESA new approach of process validation is

based on following guidelines• ICH Q7 GMP for APIs• ICH Q8(R2) - Pharmaceutical Development• ICH Q9 - Quality Risk Management• ICH Q10 - Pharmaceutical Quality System• ICH Q11 - Development and manufacture of

drug substancesand, FDA Guidance for Industry - Process Validation: General Principles and Practices.

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WHY PROCESS VALIDATION IS REQUIRED?

It is a requirement by law. Effective process validation contributes to assuring drug quality.The basic principle is that “A drug should be

manufactured that is fit for its intended purpose”.

• Quality, Safety and Efficacy should be designed or built in to the product.Quality can’t be adequately assured merely by in-process and finished product inspection or testing.

• Each step of a manufacturing process should be controlled to assure that the finished product meets all quality attributes and specifications.

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Tradit ional definit ion of process validat ion for

APIs (ICH Q7)Process Validation (PV) is the

documented evidence that the process, operated within established parameters, can perform effectively and reproducibly to produce an intermediate or API meeting its predetermined specification and quality attributes.

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TRADIT IONAL APPROACH TO PROCESS VALIDAT IONAND PROCESS DEVELOPMENT

The magic number is 3…Three (3) successful consecutive validation batches = process validationIn Process Development phase, final production process was based on development through the clinical phases, usually with a science or technical driven approach with a focus on-

• improving synthesis, often the synthetic strategy• scale-up• improving a unit operation/process step• solving equipment related/technical issues

Chemometers (attributes and parameters related to chemistry) was introduced as a tool during the 70s and 80s, mainly to support the (above described) science/technical based approach to process Validation.

New definit ion of process validation

13 /GE /

The collection of data, from the process design stage through commercial production, which establishes scientific evidence that a process is capable of consistently delivering quality product.

Process validation involves a series of activities taking place over the lifecycle of the product and process.

Process Development

GLPPhase I

Phase II

Phase III

Commercia lProduction

Process Validation

Life Cycle Management

Submission

Process Design ICH Q8 and Q9

Process Performance Qualification

Continued Process/ Quality Verification

Process Validation

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New approach to process validat ion

The new approach of process validation activity is linked with a “Product lifecycle concept” and with guidelines ICH Q8 to Q11.

• The lifecycle concept links• product and process development• qualification of the commercia l manufacturing process• maintenance of the process in a state of control during

routine commercial production

• Thus, the new guidance on process validation supports• process improvement, and• innovation through sound science

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FLOW DIAGRAM OF PROCESS VALIDATION APPROACH

PDR

MBR

Process (synthesis and purification) development, analytical method developmentand validation

Synthesis, purification,analytical methodsfor biological studies

Verify design space

Synthesis route scouting, purification method testing,and early analytical methods (PA T ? )

GLP

Clinical Phase

Deviations Changes

FinalPDR

Final MBR

Factorialdesign

Risk management Process design

Document rationale behind choices

The keyDocument: Process Development Report

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GENERAL CONSIDERATION FOR PROCESS VALIDATION

• Life cycle approach• Good project management• Good archiving• An Integrated team approach• Studies based on sound scientific principles• Risk based decision making• Evaluation of attributes (quality, product,

component) and parameters (process, operation and equipment) in terms of their roles in the process and impact on the product or in-process material.

• Exercise degree of control on attributes and parameters commensurate with their risk to the process and process output.

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PROCESS VALIDATIN AND DRUG QUALITY

Effective process validation contributes significantly to assuring drug quality. The basic principle of quality assurance is that a drug should be produced that is fit for its intended use. This principle incorporates-

• Quality, Safety and Efficacy are designed or built in to the product.

• Quality can’t be adequately assured merely by in-process and finished product inspection or testing.

• Each step of manufacturing process is controlled to assure that the finished product meets all quality attributes including specifications.

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APPROACH TO PROCESS VALIDATION

A new guidance of USFDA defines Process Validation as the collection and evaluation of data, from the process design through commercial production, which establishes scientific evidence that a process is capable of consistently delivering quality product. Process validation involves a series of activities taking place over the life cycle of the product and process. This guidance describes process validation activities in three stages.

Stage-1 : Process Design Stage-2 : Process Qualification Stage-3 : Continued Process Verification

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APPROACH TO PROCESS VALIDATION(Contd..)

Stage-1 : Process DesignThe commercial manufacturing process is defined

during this stage based on knowledge gained through development and scale-up activitiesStage-2 : Process Qualification

During this stage, the process design is evaluated to determine if the process is capable of reproducible commercial manufacturing.Stage-3 : Continued Process Verification

Ongoing assurance is gained during routine production that the process remains in a state of control. -- This guidance describes activities typical of each stage, but in practice, some activities might occur in multiple stages.

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GENERAL CONSIDERATION FOR PROCESS VALIDATION

In all stages of product life cycle, good project management and good archiving that captures scientific knowledge will make the process validation program more effective and efficient. The following programed practices should ensure uniform collection and assessment of information about the process and enhance the accessibility of such information later in the product life cycle.1 FDA recommends 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• Quality Assurance

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GENERAL CONSIDERATION FOR PROCESS VALIDATION (Contd…)

Through out the product lifecycle various studies can be initiated to

• Discover impacts of extended time cycle at various conditions and operations, improvements in process.

• Observe impact of equipments design and inprocess tests and trends.

• Correlate process data with pilot batch, laboratory trials and commercial runs with yield, quality and impurities.

• Confirm information with previous experience at pilot scale and commercial batches, about the product and process.

All studies should be‒ Planned‒ Conducted

According to-‒ Sound scientific principles‒ With appropriate documentation‒ Approve in accordance with established procedures appropriate

for the stage of the lifecycle.

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GENERAL CONSIDERATION FOR PROCESS VALIDATION (Contd…)

With a lifecycle approach to process validation that employs risk decision making through out that lifecycle. All attributes and parameters should be evaluated in terms of their roles in the

‒ Process‒ Impact on the product‒ In process tests and materialsand re-evaluated as new information is 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. Many products are single-source or involve complicated manufacturing processes. Validation offers assurance that a process is reasonably protected against sources of variability that could affect production output, cause supply problems and negatively affect public health.

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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.

Building: Capturing Process Knowledge and understanding. Generally, early process design experiments do not need to be

performed under cGMP conditions required for drugs intended for commercial distribution that are manufactured during stage -2 ( Process qualification ) and stage – 3 (continued process verification ).

Process design experiments should, however, be conducted in accordance with sound scientific methods and principles including good documentation practices (ICHQ10)

Decisions and justification of the controls should be sufficiently documented and internally reviewed to verify and preserve their value for use for adaption later in the lifecycle of the process and product.

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STAGE -1: PROCESS DESIGN (Contd…) Process design experiments are often performed at small –

scale laboratories, so, most viral inactivation and impurity clearance studies cannot be considered at early stage.

Product development activities provide key inputs to the process design stage, such as the

‒ Selection of the route ( scouting )‒ Selection of raw materials, catalysts, solvents ‒ General manufacturing pathway‒ Quality attributes‒ Expected impurity profile‒ Functionality and limitations of commercial manufacturing

pathway‒ Variability of environmental conditions.‒ Expected measurement and monitoring system during

commercial manufacturing‒ Requirement of specific quality of personnel to handle operations.

Designing of efficient process with an effective process control approach is dependent on the process knowledge and understanding obtained.

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STAGE -1: PROCESS DESIGN (Contd…) Design of experiments (DoE ) study can help develop process knowledge by revealing.

• Relationships of variables to quality attributes.• Multivariable impact on quality attributes• In-process tests and limits• Requirement of isolation of intermediates or in situ route

Risk analysis tools can be used to screen potential variables for DoE studies to minimize the total number of experiments conducted to get maximum knowledge regarding process. The results of DoE studies can provide justification for establishing

• Ranges of incoming components quality• Ranges of quantity of components• Equipment parameters ( MoC, ancillary requirements )• In process and intermediate materials quality attributes.• FDA generally does not expect manufacturers to develop and test

the process until it fails.

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STAGE -1: PROCESS DESIGN (Contd…) Other activities, such as experiments and demonstrations at laboratory or pilot scale to

‒ QA‒ Process engineering‒ Production

also assist in evaluation of certain conditions and predictions of performance of the commercial process. Such experiments or demonstrations also provide information to simulate the commercial process. It is essential that all informations collected during these experiment and demonstrations be documented with review, conclusion and decisions.

For example, manufacturer should document the variables studied for a unit operation and the rationale for these variables identified as significant. All the information collected during this process can be related during commercial manufacturing.

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STAGE -1: PROCESS DESIGN (Contd…) Establishing a Strategy for process control : Process knowledge and understanding is the basis to establish an approach to process control for each unit operation and the process overall, for example.

– Reduce input variation– Adjust input variation using inprocess tests during manufacturing.– Intermediate tests and limits– Equipment monitoring at significant processing points (RPM.

Temperature , pressure, vacuum etc.) FDA expects controls to include both –

• Examination of material quality• Equipment monitoring

Special attention to control the process through operational limits and in-process monitoring is essential in two possible scenarios –

• When product attribute is not readily measurable due to limitations of sampling or detectability. ( e.g. viral clearance or microbial contamination ).

• When intermediates and products cannot be highly characterized and well-defined quality attributes cannot be identified.

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STAGE -1: PROCESS DESIGN (Contd…) 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 system with PAT can provide a higher degree of process control than non-PAT system.

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Quality Target Product Profile-QTPP

What is QTPP?1. A set of elements that defines the

drug product2. The target or goal set in advance3. A guide to Drug Product developmentWhen to define QTPP?4. At the start of development5. Knowledge gained in development

may change some elements

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Components of QTPPComponents related to safety, efficacy, identity,

purity and potency

Critical and non-critical components, e.g. Critical: Assay, content uniformity, Impurity Profile Non-critical: Appearance

Fixed and variable components Fixed elements must be present e.g. Dosage Form, Strength Variable elements may have a range of acceptable

values e.g. Tablet weight, assay

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Critical Quality Attributes- CQAs CQAs are a subset of the QTPP Quality Attributes that must be controlled

within predefined limits. CQAs deliver assurance that Drug Product

meets its intended safety, efficiency, stability and performance

CQAs are monitored throughout the DP development.

CQAs ensure that DP remains within safe and effective levels.

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Factor affecting CQAs (Critical Quality Attributes)

CMAs (Properties of input materials)

Identify Critical Material Attributes

-Particle Size

CPPs(Critical Process Parameter)

Identify Critical Process Parameters

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QTPP and CQAsQTPP components

Dosage Form

Route of administration

Strength

Weight

Pharmacokinetics

Appearance

Identity

Assay

Impurities

Content uniformity

Friability

Dissolution

Residual solvents

CQAs

Assay (efficacy)

Impurities (safety)

C.U. (efficacy)

Dissolution (efficacy)

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Critical Material Attributes(CMAs)

Risk Assessment of the drug substance attributes

Solid state form and particle size of DS are CMAs

Drug ProductCQAs

Solid State Form

Hygroscopicity

Particle Size

Residual Solvents

Process Impurities

Chemical Stability

Physical Attributes (size and splitability)

LOW LOW LOW LOW LOW LOW

Assay LOW LOW LOW LOW LOW LOWContent Uniformity

LOW LOW LOW LOW LOW LOW

Drug Release HIGH LOW HIGH LOW LOW LOW

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Control Strategy

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

ICH Q8 (R2) & Q10

Control Strategy includes following elements (but not limited to):

Input material attributes(e.g. drug substance, excipients, container closure)

Equipment operating conditions (process parameters) In-process controls Finished product specifications Controls for each unit operations Methods and frequency of monitoring and control.

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QTPP and SpecificationsQTPP• Desired target for

developmental work• Components of QTPP

may or may not be in specification- Not in spec- Dosage

form, strength- In spec- Assay,

impurities• Does not include

acceptance criteria

Specification • Includes all of the CQAs • Specification is a list of

- Tests- References to analytical

procedures- Acceptance criteria

• Establishes the set of criteria to which DP should conform to be considered acceptable for its intended use.

Defining a QTPP does not mean setting all acceptance criteria or the product specifications before development work begins.

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Control StrategyDeveloping Control Strategy

Formulation & Process Design & Understanding

Risk Assessment

CQACPPCMA

Acceptance Ranges(CMA & CPP)Limits for CQA

Control Strategy

Ingredients

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Control StrategyControl Strategy Implementation Options

Enhanced Approach

Traditional ApproachLevel 3

End product testing + tightly constrained material attributes

and process parameters

Level 2 Reduced end product testing

+ Flexibility for critical material attributes and

critical process parameters within design space

Level 1Real-time

automatic control +Flexible process

parameters

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QbD Tools - DoEDesign of experiments (DoE) Useful for screening of variables with significant impact

on DP CQAs Classical approach uses OFAT (One Factor At A Time) Limited number of experiments gives limited information. DoE helps study effects of interaction of multiple factor at

a time. Used in optimization studies, enable creation of “design

space’’ “Design space” is proposed by the applicant and subject

to regulatory assessment and approval. “Design space’’ developed at lab or pilot scale can be

proposed for commercial scale, but needs to be verified at production for scale dependant parameters.

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QbD Tools – Risk Assessment

Why risk assessment in product development? To identify relative risk levels at the beginning

of product development. To prioritize limited development resources To document the decision making process

throughout development To assess the needs of additional studies for

scale up and technology transfer To identify appropriate specifications, critical

process parameters and manufacturing controls To decrease variability of critical quality

attributes .

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Risk AssessmentRisk assessment for Formulation-starting material properties,

levels of components Manufacturing process

Step for risk assessment List out all components / processes Prepare the process flow chart Identify all potential failure modes for each

item with risk query (what might go wrong?)

Risk analysis Risk evaluation

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Risk AssessmentVarious formal methodologies available for risk

assessment Failure Mode Effect Analysis & Failure Mode

Effects & Criticality Analysis Hazard & Operability Analysis Supporting statistical tools

It is neither always appropriate nor always necessary to use a formal risk management process…. The use of informal risk assessment processes can also be considered acceptable . – ICH Q9

A risk-based justification based on experience and data is always necessary!

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Quality Risk Management ICH Q9

QUALITY RISK MANAGEMENT Quality risk management is a systematic process for

the assessment, control, communication and review of risks to the quality of the medicinal product. It can be applied both proactively and retrospectively

The quality risk management system should ensure that

- the evaluation of the risk to quality is based on scientific knowledge, experience with the process and ultimately links to the protection of the patient.

- the level of effort, formality and documentation of the quality risk management process is commensurate with the level of risk.

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Pharmaceutical Quality Systems Q10

1. Knowledge Management2. Describes systems that facilitate

establishment and maintenance of a state of control for process performance and product quality.

3. Facilitates innovation and continual improvement

4. Applies to drug substance and drug product throughout product lifecycle

5. Control strategy

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Pharmaceutical Quality System (PQS) ICH Q10

PharmaceuticalDevelopment

TechnologyTransf

er

Commercial

Manufacturing

Product Discontinuatio

n

Investigational

product Good Manufacturing Practice

Management Responsibilities Process Performance & Product Quality Monitoring

System Corrective Action / Preventative Action System Change Management system Management review Knowledge Management Quality Risk Management

PQSelements

Enablers

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Development and Manufacture of Drug Substances- ICH Q11

Provides further clarification on the principles and concepts described in ICH guidelines on-

• Pharmaceutical Development (Q8),• Quality Risk Management (Q9)• Pharmaceutical Quality System (Q10) As they pertain to the development and

manufacture of drug substance.

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Development and Manufacture of Drug Substances –ICH Q11

Traditional approach- Set points & operating ranges- Process reproducibility and testing to

meet acceptance criteriaEnhanced approach- Risk management & science- Process parameters and unit operations

that impact on CQA- Further studies, design space & control

strategies over the lifecycle.

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Development and Manufacture of Drug Substances- ICH Q11

A company can choose to follow different approaches in developing a drug substance.

For the purpose of this guideline, the terms “traditional” and “enhanced” are used to differentiate two possible approaches.

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Process Analytical Technology (PAT)

Timely measurements during processing Critical quality and performance attributes Raw and in-process materials

At-line, on-line or in-line measurements Founded on “Process Understanding”

Opportunities for improvement More reliable and consistent processes (&

product) Less failures, less reworks, less recalls

Flexibility w.r.t. scale and equipment Better / faster Quality Systems Process Enhancement Opportunities

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PAT in Tablet manufacturing Stage Technique Measurement

Dispensing NIR / Raman

Identification of raw materials

Wet Granulation

NIR Moisture distribution

Drying NIR Moisture content

Blending NIR Blend Uniformity

Compression Strain gauges

Compression force

NIR Content Uniformity

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PAT Examples

Spectral Probe NIR Analyzer installed on top of vessel .

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PAT Examples

Real-time Blend Uniformity by using TruProcess TM Analyzer

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STAGE -1: PROCESS DESIGN (Contd…) PROCESS DEVELOPMENT / DESIGN :Risk based approach to process development / design :ISHIKAWA DIAGRAM :

Substance

Raw Materials Synthesis Purification

Equipments Work-up Analysis, Stability

RM-1

RM-2Purity Ratio

ReactionTime

Temperature

Reactor InprocessDistillation

cfg.

36”

Solvent

48”

WashingLocation Limits

Instruments

GC HPLC

Choice of solventCatalyst

Water Quality Purity Ratio

RM Ratio

Catalyst

Solvent

Class 1 Class 2 Class 3

Recovery

Dissolution

Ratio

Solvent

Class 1 Class 2 Class 3

SS GLR

size

Stirrer

Column

Column

MOC Capacity

QTY

Ratio Temp.

cfg .

PH

Extraction

Final analysis

purity Impurity

Stability data

Long term

Accelerated

Critical quality

attributes

Target Product Profile

Rate

DRY

Temp

Temp.

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STAGE-2 : PROCESS QUALIFICATION During the process qualification (PQ), stage of process validation, the process design is evaluated to determine if it is capable of reproducible commercial manufacturing. This stage has two elements-

• Design of the facility and qualification of equipments and utilities.

• Process performance qualification(PPQ)

During stage-2, cGMP compliant procedures must be followed. Successful completion of stage-2 is necessary before commercial distribution. Product manufactured during this stage, if acceptable, can be released for distribution.

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STAGE-2 : PROCESS QUALIFICATION (CONTD…)

Design of a Facility and Qualification of equipments and utilities : Proper design of manufacturing facility is required under part 211, subpart C, of the cGMP regulations on Building and Facility. It is essential that activities performed to assure proper facility design and commissioning precede PPQ. Here, the term “QUALIFICATION”, refers to activities undertaken to demonstrate that equipment and utilities are suitable for the intended use and perform properly. This activities necessarily precede manufacturing products at the commercial scale.

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Qualification of utilities and equipment generally includes the following activities-

• selecting utilities’ and equipment’s construction material, operating ranges, capacity and performance characteristics based on whether they are appropriate for their specific uses.

• Verifying that utilities and equipment are built and installed in compliance with design specifications (built as designed with proper materials, capacity, functions and properly connected and calibrated )• URS• DQ

o SATo FAT

• IQ

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• Verifying that utility system and equipment operate in accordance with the process requirements in all anticipated operating ranges.

• This should include challenging the equipment or system. Functions while under load comparable to that expected during routine production.

• It should also include the performance of interventions, stoppage and start-up as expected during routine production.

• Operating ranges should be shown capable of being held as long as would be necessary during routine production.

• Qualification of utilities and equipment can be covered under individual plans or part of an overall project plan.

• The plan should consider the requirements of use and can incorporate risk management.

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• The plan should identify the following aspects• The studies or tests to use.• The criteria appropriate to assess outcome.• The timing of qualification activities• The responsibilities of activities to be done by relevant

departments and the quality unit.• The procedures for documenting and approving the

qualification.

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Qualification activity should be documented and summarized in the form of protocol and report with conclusion. Quality unit must review and approve the qualification plan and report. Process performance Qualification: The Process performance qualification (PPQ) is the second element to stage-2 process qualification. The PPQ combines the actual

Facility Utility Equipment (each now qualified) Monitoring and measuring tools (Calibrated) Validated analytical methods Commercial manufacturing process Control procedures Inputs and componentsto produce commercial batches.


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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 by data from commercial scale batches. Data from laboratory and pilot studies can provide additional assurance that the commercial manufacturing process performs as expected. The approach of PPQ should be based on sound science and manufacturer’s overall level of product and process understanding and demonstrable controls. The cumulative data from all relevant studies i.e.

– Designed experiment– Laboratory batches– Pilot batchesShould be used to establish the manufacturing conditions in the PPQ.

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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 extent to which some materials such as

– Recycled solvents– Column resins– Molecular filtration mediacan be reused without adversely affecting product quality can be assessed in laboratory and /or pilot studies.

The usable life times of such materials should be confirmed by an ongoing PPQ protocol during commercial manufacturing. The goal of validating any manufacturing process will be to establish scientific evidence that process is reproducible and will consistently deliver quality products.

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PPQ protocol : A written protocol that specifies the manufacturing

• Equipments• Conditions• Controls• Testing• Expected outcomesis essential for this stage of process validation.

FDA recommends that the protocol should discuss the following elements. The manufacturing conditions, including operating parameters, processing limits, raw materials or components inputs and equipment. The data to be collected at different stages of operations and when and how it will be evaluated, is to be addressed in protocol.

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Tests to be performed.– in process– Intermediates– Final productrelease, characterization and acceptance criteria for each significant test.

Sampling should be precisely mentioned in protocol as-– Sampling plan– Sampling points– Number of samples– Frequency of sampling– Acceptance criteria

The number of samples should be adequate to provide sufficient statistical confidence of quality, both within a batch and between batches. Sampling during validation stage should be more extensive than is typical during routine production.


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Criteria and process performance indicators that allow for a science and risk based decision about the ability of the process to consistently produce a quality products. The criteria should include-

– A description of the statistical methods to be used in analyzing all collected data (e.g. statistical metrics defining both intra and inter batch variability).

– 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 a documented, science based justification.(Any data can be disregarded but cannot be deleted/OOS).

Design of facility; qualification of utilities and equipment; personal training; qualification and verification of sources of materials if not previously accomplished. Status of the validation of analytical methods used in measuring the process, inprocess materials and the product. Review and approval of the protocol by appropriate departments and the quality unit.

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PPQ Protocol execution and report: Execution of protocol should not begin until the protocol has been reviewed and approved by all appropriate departments, including the quality unit. Any departure from protocol must be made according to established procedure or provision in the protocol. Such departure must be justified and approved by all appropriate departments and quality unit before implementation. The commercial manufacturing process and routine procedures must be followed during PPQ protocol execution. 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 ( including AHUs and water system ), material, personnel, environment and manufacturing procedures.

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A report documenting and assessing adherence to the written PPQ protocol should be prepared in a timely manner after the completion of activity. This report should

− Discuss and cross – reference all aspects of the protocol− Summarize data collected and analyze the data, as

specified in the protocol.− Evaluate any unexpected observations and additional

data not specified in protocol.− Summarize and discuss all manufacturing non

conformances such as deviations, aberrant test results or information that has bearing on the validity of the process.

− Describe in sufficient detail , any corrective actions or changes that should be made to existing procedures and controls


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− State a clear conclusion whether the data indicates that the process met the conditions established in the protocol and the process is considered to be in a state of control.

− If not, the report should state what should be accomplished before such a conclusion can be reached (CAPA and recommendations )

− 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 and information gained from the design stage through the process qualification stage.

− Include all appropriate departments and quality unit for review and approvals.

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STAGE -3: CONTINUED PROCESS VERIFICATION

The goal of 3rd validation stage is continual assurance that the process remains in a state of control ( the validated state ) during commercial manufacturing. A system for detecting unplanned departures from the process, is essential to accomplish this goal. Adherence to 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 the problem 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 or in process materials or finished product.

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STAGE -3: CONTINUED PROCESS VERIFICATION (Contd…)

The data should be statistically trended and reviewed by trained personnel. The information collected should verify that the quality attributes are being appropriately controlled thoughtout the process. FDA recommends that the statistician or person with adequate training in statistical process control techniques develop the data collection plan and statistical methods and procedures used in measuring and evaluating process stability and process capability. Procedures should describe how trending and calculations are to be performed and should guard against over reaction to individual events as well as against failure to detect unintended process variability The quality unit should review information. If properly carried out, these efforts can identify variability in the process and/ or signal potential process improvements.

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Good process design and development should anticipate− Significant sources of variability and establish appropriate.

• Detection• Control• Mitigation strategy• Appropriate alert and action limits.

Many tools and techniques, statistical and qualitative, can be used to detect variation, characterize it, and determine the root cause. FDA recommends that the manufacturer should use quantitative, qualitative and statistical methods whenever appropriate and feasible. Scrutiny of intra-batch as well as inter-batch variation is part of a

comprehensive continued process verification program. FDA recommends continued monitoring and sampling of process parameters and quality attributes during its life cycle to estimate the state of control of process. Process variability should be periodically assessed

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Variations can also be detected by the timely assessment of ‒ Defects/ complaints‒ Out of specification‒ Process deviation reports‒ Process yield variations‒ Batch records‒ Incoming raw material records‒ Adverse event report

Production line operations and quality unit staff should be encouraged to provide feedback on process performance. FDA recommends that quality unit meet periodically with production staff to

• Evaluate data• Discuss possible trends• Undesirable process variation.and co-ordinate any correction or follow-up actions by

production.

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Data gathered during this stage , might suggest ways to improve and or optimize the process by altering some aspects of the process or product, such as

• Operating conditions ( ranges or set points )• Process control• Components• In process tests and /or material characteristics

Depending on how the proposed change might affect products quality, additional process design and process qualification activities could be warranted. A description of the planned change, a well – justified rationale for the change, an implementation plan and quality unit approval before implementation must be documented. Maintenance of the facility, utilities and equipment is another aspect of ensuring that a process remains in control.

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Maintenance of the facility, utilities and equipment is another aspect of ensuring that a process remains in control. Once established, qualification status must be maintained through

‒ Routine monitoring‒ Maintenance schedule‒ 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 requalification. Maintenance and calibration frequency should be adjusted on feedback from breakdown reports.

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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 a special situation, 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

‒ Due to limited demand‒ Rework processes‒ Short retest period‒ Minor use‒ Manufactured in co-ordination with Agency to alleviate a short

supply. Circumstances and rationale for concurrent release should be fully described in the PPQ protocol.

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CONCURRENT RELEASE OF PPQ BATCHES (Contd…)

Even when process performance assessment based on the PPQ is still outstanding, any lot released concurrently must comply with

‒ GMP‒ Regulatory approval requirement‒ PPQ protocol lot release criteria.

Lot released under PPQ protocol should be 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 facilitate rapid customer feedback. For example, customers complaint and defect reports should be rapidly assessed to determine.

‒ Rootcause for defect or complaint‒ Whether the process should be improved or changed

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CONCURRENT RELEASE OF PPQ BATCHES (Contd…)

Concurrently released lots must be assessed in accordance with any negative PPQ study finding or conclusions and appropriate corrective action must be taken. FDA recommends that each batch in concurrent release program be evaluated for inclusion in the stability program. It is important that the stability test data be promptly evaluated to ensure rapid detection and correction of any problem. Conclusion about a commercial manufacturing process can only be made a after the PPQ protocol is fully executed and the data are fully evaluated. If stage-2 qualification is not successful that is a process

• Does not demonstrate that as designed• Does not capable to produce reproducible and consistent results at

commercial scale.Then additional process design study and qualification may be necessary.

The new product and process understanding obtained from the unsuccessful study can have negative implications if any lot was already distributed. Full execution of stage-1 and 2 of process validation is intended to preclude that outcome.

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ANALYTICAL METHODOLOGY Process knowledge depends on accurate and precise measuring techniques used to test and examine the quality of

• Raw materials• In process tests• Intermediates• Finished product

Validated analytical methods are not necessarily required during product and process development stage or characterization studies but analytical methods should be scientifically sound

• Specific• Sensitive• Accurateand produce results that are reliable.

There should be assurance of proper equipment function for laboratory instruments.

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ANALYTICAL METHODOLOGY (Contd…)

Procedures for ‒ Analytical methods‒ Instruments maintenance‒ Calibrations‒ Documentation practices‒ Practices supporting process development efforts

(reviews, conclusion, recommendations )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 product. Use of this methods is particularly appropriate when they reduce risk by providing greater understanding or control of product quality. However, analytical methods supporting commercial release must follow cGMP.

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STATISTICAL ANALYSIS FDA recommends that the manufacturers should use quantitative, qualitative and statistical methods whenever appropriate and feasible for assessment and evaluation during stage -2 ( Process Qualification) and stage -3

(continued process verification )

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Pareto diagram is a technique of arranging data according to priority or importance and using it in to a problem solving frame work. This helps to find out the “Vital Few” from the “Useful Many” for problem selection. Mr. Vilfred Pareto was an Italian economist, has

developed this technique. Later, Mr. Lorenz the US economist has presented this technique in a theoretical curve. This curve is called Lorenz’s curve.

Example:An annual review performed by quality assurance department

has revealed following data, which indicates reasons for unplanned deviation v/s number of unplanned deviations occurred during calendar year.

PARETO DIAGRAM

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Sr. No Reasons for occurrence of unplanned deviation No.

0102030405060708

Environment control in confined areaManufacturing processAmbiguity in document /records instructionsPreventive MaintenanceInadequate TrainingLack of Man powerAnalytical errorOthers

1014252040151214

• In order to make a Pareto Diagram,• A data available have to be arranged according to the descending order

in terms of numbers, in a next step.• A % of numbers and cumulative % of total to be tabulated.

PARETO DIAGRAM (CONTD…)

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Now, let us make a Pareto Diagram

Draw a Vertical Axis on both sides. Mark

number on left Y axis and % on right Y axis.Draw horizontal X – X

axis to devide in reasons for unplanned

deviations.

Draw a diagram

Draw a cumulative curve or Lorenz curve.


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PARETO DIAGRAM (CONTD…)Sr. No Reasons No. Cum. % Cum.%

1 Inadequate Training 40 40 27 27

2 Ambiguity in document /records instructions 25 65 17 44

3 Preventive Maintenance 20 85 13 57

4 Lack of Man power 15 100 10 67

5 Manufacturing process 14 114 9 76

6 Analytical error 12 126 8 84

7 Environment control in confined area 10 136 7 91

8 Others 14 150 9 100

150 100%

0

15

30

45

60

75

90

105

120

135

150

0

10

20

30

40

50

60

70

80

90

100

40

2520

15 14 12 1014

27

44

57

67

76

84

91

100

Break even


Lorenz Curve

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The Use of Pareto Diagrams

The Common use of pareto diagram is in prioritizing and defining quality related issues. Any production area faces numerous problems.The pareto principle and pareto analysis lead the quality members to focus on those few vital problems that, when carefully addressed, will result in the maximum benefit to the organization.Pareto diagram can also be utilized to statistically evaluated “Vital Few” from “Useful Many” reasons for• Complaints• Training• Process Failuresetc.


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What is fishbone diagram? Any defect in a component can be due to one or more reasons

or causes. To find out the relationship between the causes and effect, a diagram is drawn systematically by mapping out all the probable causes influencing the effect. This is called a Cause and Effect Diagram.

Dr.Kaoru Ishikawa first developed this technique in 1953.

Because of its appearance and similarity with skeleton of a fish, it is also termed as fish bone diagram.

FISH-BONE DIAGRAM OR CAUSE AND EFFECT DIAGRAM OR ISHIKAWA DIAGRAM

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How to Draw a Cause and Effect Diagram?

First of all , in a center of a paper draw a thick horizontal arrow about 75% of the length of paper.

Draw a square or rectangular box adjacent to the arrow head.

FISH-BONE DIAGRAM OR CAUSE AND EFFECT DIAGRAM OR ISHIKAWA DIAGRAM (CONTD…)

88

Draw 4 to 6 inclined arrows around 60⁰ angle with the main Arrow.


89

Draw the sub-arrows (horizontal) meeting inclined arrows. Balance sub arrows equally on both sides.


90

Name Main Causes with 4 M’s.‒ Man‒ Machine‒ Material‒ MethodWe may add main reasons apart from 4M.Define the

problem in the box of effect.

Problem(effect)

Man Machine Any Other

Material Method Any Other


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Now start the brain storming session to find the causes responsible for the existing problem.

As soon as cause is proclaimed, decide the main cause under which it can be grouped and write it on the sub-arrow under that main cause.

Continue this activity until the end of the brain storming session, ensuring all the identified causes are entered under proper main causes.


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One Batch During

Validation is Failed

Machine Material Man

MethodOr

Process

Analysis Process Design

Qualification

Calibrationreactors CFs Water

Balances

Vendors Training

Key RM Sampling

Sources Analysis

Recommended in PDR New Process

ValidationEquipment operation

Operational

Dryer AHU

Monitoring instruments

Analysis

AnalysisCleaning

Impurity profile

RM-3RM-2RM-1

Verification ofDocuments/records

Changes

Deviations

Critical parameters

Other operations

Qualification of instruments

Validation of analytical method

Comparison of specification and methods with manual

Standards/reagents

Analytical data

RM In process intermediates

Verification of process parameters

Comparison of RM ratio

Comparison of analytical package

Summary Report


PDR

MOC

Vendor CertificatesCleaning reports

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Fishbone diagram can be used to investigate and identify root cause during


Use of Fishbone diagram

Complaint

Product defect

System failure

OOS

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DESIGN OF EXPERIMENTS (DoE) Design of experiments based on statistical evaluations

Statistical data evaluation , results wide variation in• Critical Parameters• Impurity Profiles • Quality AttributesFactors or parameters influencing wide variations should be identified and optimized to reduce variability in process and prevent potential failures.

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DESIGN OF EXPERIMENTS (DoE) (Contd…)

Example: − A limit of individual

impurity A is <0.1% in specification. Last 10 batch results are.

# Impurity A %1 0.032 0.093 0.064 0.055 0.086 0.077 0.088 0.079 0.04

10 0.07

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0 1 2 3 4 5 6 7 8 9 100

0.01

0.02

0.03

0.04

0.05

0.06

0.07

0.08

0.09

0.1

Scatter Grapgh

Upper Control limit

Central Control limit

Lower Control limit

The Scatter of results indicate 7 out of 10 results are above central control limit (toward upper limit)

Only 3 results are either on central control limit or below.

There is a potential for failure

DESIGN OF EXPERIMENTS (DOE) (Contd…)

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Action to be takenTo identify operational parameters

influencing on impurity A

generation and plan DoE to control.

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Uses of DoE• This technique can be useful in R&D while designing of product.• Retrospective evaluation of established parameters• Systematically choosing certain variables and their individual

effects.• The results of DoE should be evaluated in the form of

Tables Graphically

• DoE can be used to identify impact of deviations and to confirm root cause for OOS.

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SHEWART CONTROL CHARTS Dr. W.A.Shewart, a physicist, from Bell laboratories, explained

that, even after extreme sophistication also , it will be impossible to produce two batches identically same. Various inputs which go in for an output have their inherent

variation, for example – ‒ Raw Materials‒ Process Conditions‒ Manual Operations‒ Machine ConditionUnder these circumstances, obviously output will have variation.

He defined the problem of managing quality as one of between1. Acceptable variation2. Unacceptable variation

Using mathematical formula he established boundaries of variation for a given process. This technique is also called a “Control Chart” .

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SHEWART CONTROL CHARTS (CONTD…)

Example: – A result of Assay

value of 25 batches are graphically presented against upper limit and lower limit.

– Specification of Assay; 98.0 to 100%

– Batch wise Results.

# Assay %

1 98.3

2 99.6

3 98.5

4 98.6

5 98.9

6 99.2

7 98.4

8 98.3

9 99.2

10 98.4

11 99.9

12 98.1

13 99.7

14 98.2

15 99.1

16 98.6

17 98.6

18 98.4

19 98.3

20 98.6

21 98.6

22 98.3

23 99.6

24 99.3

25 98.4

1010 5 10 15 20 25 3097

97.5

98

98.5

99

99.5

100

100.5

Assay v\s Batch No.

Lower Tolerance Limit

Central Limit

Upper Tolerance Limit

Lower Specification

Limit

Upper Specification

Limit

Batch No.

Assay%

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Uses of control charts :•To demonstrate statistical control of process parameters and quality attributes.

•Further to this, alert limits and actions limits can be defined to propagate continual improvement in product quality during its cycle.

•To identify potential problems.•To monitor critical parameters.•Provides information to determine.•Process capability•Variability•control

SHEWART CONTROL CHARTS (CONTD…)

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RADAR CHART Radar chart is gating popularity in statistical evaluation techniques.28.20 Example:28.21 Quality assurance department has compared “Review of defects” for consecutive 2 years i.e. 2012-13 and 2013-14 for manufacturing of product A. Following data revealed in comparison study.

Sr. No Cause for defect Number of defects Column1

2012-13 2013-141 Moisture content 3 1

2 Impurity profile (orgainc) 3 4

3 Assay 3 34 Description 2 15 Solubility 2 16 Black particals 4 27 Lump formation 1 08 Partical Size 2 19 Heavy metals 1 0

10 Residual solvent 1 0

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RADAR CHART(CONTD…)

28.22 Now draw a Radar Chart as follows –1. Draw a Circle and divide it in 8 part (equal parts

1

2

4

3

58

7 6

105

Title the vertical line with 10 causes.

Assay

Description

Solubility

Black particals

Lump formation

Partical Size

Heavy metals

Residual solvent

Moisture content

Impurity profile (orgainc)

-10

0

RADAR CHART

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28.22 Calibrate 0 to 10 with 0 at center and 10 at outer circle.

28.25 Conclusion:• Radar chart indicates quantities increase in number of defects due to impurity profile in

organic impurity.

Assay

Description

Solubility

Black particals

Lump formation

Partical Size

Heavy metals

Resideal solvent

Moisture content

Impurity profile (orgainc) -10-9-8-7-6-5-4-3-2-10

2012-132013-14

RADAR CHART

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SPREAD SHEET Following spread sheet can be studied a set of data to plan for the actions-

• Trend analysis of quality attributes• Data of critical process parameters• Trends of yield• Trend of in process results• Trend of equipment performance against breakdown.

Further to this, mean and standard deviation can be derived to study variation of results and identifying border cases and potential problems.

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1. Scatter diagram is a graphical presentation of relationship between two variables.

2. It will be between causes and effect or between two causes.

3. The direction and “tightness” of the scatter gives a clue that there a relationship between both the variables.

Varia

ble

-2

Variable-1

SCATTER GRAPHS

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Patterns of scatter diagrams

Positive Relationship

Negative Relationship

No Relationship

SCATTER GRAPHS (CONTD…)

110

SCATTER GRAPHS (CONTD…) Example :Following is the data of Assay% and maintaining hours , batch wise (inprocess result)

Sr.No

Maintaining Hours Assay % Value Batch wise

#1 #2 #3 #4 #5 #6 #7 #8 #9

1 1 72 74 76 73 77 72 78 75 70

2 2 78 78 81 79 82 79 83 79 76

3 3 83 84 86 85 89 84 88 86 83

4 4 90 92 93 91 94 91 95 93 89

5 5 94 95 96 94 98 94 98 97 93

6 6 98 98 99 99 99 98 99 99 98

111

0 1 2 3 4 5 668707274767880828486889092949698

100

Series1Linear (Series1)Series3Linear (Series3)Series5Linear (Series5)Series7Linear (Series7)Series9Linear (Series9)

Maintaining hours

Assay % Value Batchwise

Uses To correlate two variables

To correlate one variable with effect.

SCATTER GRAPHS

Fault Tree Diagram1. Fault Tree Analysis is a technique for reliability

and safety analysis.2. Bell Telephone Laboratories developed this

concept in 1982 for the US Air Force.3. It was later adopted by the Boeing Company.4. Fault Tree Analysis is one of the many symbolic

“analytical logic technique” found in operations research and in system reliability.

What is Fault Tree Diagram? (FTD)1. Fault Tree Diagram is a logic block diagram

that displays the state of a system (top event) in terms of the states of its components (basic events).

2. FTD uses a graphic model of the pathways with in a system.

3. The pathway connect contributory events and conditions, using standard logic symbols (AND, OR etc.).

4. The basic constructs in a FTD are Gates and Events.

Relationship between FTA and FMEA

Product Failure

Part Failure

FMEAFTA

FTA1. It is a systematic method of system analysis2. Examines system Top Down3. Provides graphical symbols for easy of

understanding4. Incorporates mathematical tools to focus on

critical areas.

FTA used to

Investigate potential faults

It is modes and Causes

And to quantify their contribution to system unreliability in the course of product design.

Symbols

BA

‘AND’ Gate A ∩ B

BA

‘OR’ Gate A B∪

Symbols (Count…)

Basic event

Transfer Out

Transfer in

Thought Process in FTA

FTA is backward looking

Basic Fault Tree Structure

Top Undesired Event

Logic Gates

Intermediate Event

Basic Event

FTA Process

FTA Examples1. Investigation of Laboratory Failure

OOS Resu

lt

or

Production

Lab. error

Others

or

Others

Systematic

Random

or

Calibration

Interface

Others

FTA Examples (Count…)2. FTA for Cleaning process.

Cleaning Change of Product

Product Manufactured

previously

Product to be Manufactured

afterwards

Characteristics of equipment

used

Characteristics of cleaning

process

Solubility in Solvent used

Solubility

Batch Size

Time of Cleaning

Batch Size

Residual Contaminants

Stickyness

Type of surface of equipment

Area

Design

Worst area for cleaning

Type of automisation

Time to be taken for cleaning

Temperature

Time remaining for dirty

FTA Examples (Count…)2. Complaint Entry. Complaint

Entry

QA Review

Investigation required

Report Assessment

ReportibilityInvestigation

CAPA Assessment

Follow-up Reportibility

ClosureActions

US

or

EU Canada

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