1 3. Validation (and Qualification) Basic Principles of GMP.

129
1 3. Validation (and Qualification) Basic Principles of GMP

Transcript of 1 3. Validation (and Qualification) Basic Principles of GMP.

Page 1: 1 3. Validation (and Qualification) Basic Principles of GMP.

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3. Validation

(and Qualification)

Basic Principles of GMP

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Validation, Qualification

Two phylosophies:• Validation, qualification (and

calibration) are different, although interrelated activities (e.g. EU GMP)

• Qualification and also calibration belong to validation activities (e.g. WHO GMP)

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Qualification or validation? • A system/equipment must be qualified

to operate in a validated process

• Qualify a system and/or equipment

• Validate a process• Qualification versus validation, e.g. you

qualify the autoclave, while you validate the whole sterilization process

• (and calibrate a measuring instrument!)

Terms

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Validation

IntroductionThree basic principles of Quality

Assurance:

• Quality, safety, efficacy

• Cannot inspect quality into a product

• Processes must be under control (for this, they should be validated, whether they can be under control!

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Validation

Objectives• To review the definition and types of

validation• To understand the requirements for

documentation and key stages in the process of validation

• To consider models for process validation

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Validation

Definition

Validation is the documented act of proving that any procedure, process, equipment, material, activity or system actually leads to the expected result

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Qualification and validation work require:

• Collaboration of experts

• Budget

• Meticulous and careful

planning

A Validation

Master Plan helps

the manufactur

er and inspectorat

e

Validation

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Validation

Essential Part of GMP• Predetermined protocols• Written reports• Processes and procedures• Periodic revalidation• Specific attention:

– processing process validation

– testing analytical method validation

– cleaning cleaning validation

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ValidationTypes of Manufacturing Process Validation

• Experimental approach– Prospective validation– Concurrent validation

• Analysis of historical data– Retrospective validation

• Revalidation– Periodic revalidation– Revalidation after change

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Prospective validation

• Before starting a new manufacturing process (or after its significant change), or revalidation:

• Manufacturing 3 batches only for validation purposes, all data documented. Reason: to see that the process is under control

• As a rule, these batches are not marketed later, except special decision to do that

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Concurrent validation

• In case of rarely produced medicines (e.g. 2 batches per year: no reason to produce 3 „validation” batches)

• Concurrent validation: during the manufacture of „normal” batches to be marketed

• Strict documentation!

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Retrospective validation

• This validation means the assessment of data generated during previous batch manufacturing

• Only for established technologies, the GMP is strictly applied, defects are rare

• Assessment of data of 10-30 batches, including defective ones (their data are very valuable to see how the process can run out of control!)

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QualificationTypes (Stages) of Qualification

• Design qualification (DQ)• Installation qualification (IQ)• Operational qualification (OQ)• Performance qualification (PQ)

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Design qualification DQ

• E.g. of a manufacturing equipment• Before purchasing!• Collection of data about the similar

equipments available on the market, assessing our needs, resources to buy and to operate, space and maintenance they would need, etc.

• Making the decision

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Installation Qualification IQ

• E.g. of a manufacturing equipment• After purchasing (or critical repair)• Put it on its intended place, connect

with other equipments, electric power, material flow devices

• Collect its documents incl. Operation Manual, etc.

• Its formal „release”: it is ready for working with

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Operational Qualification OP

• E.g. of a manufacturing equipment• „Model manufacturing” experiments

with model materials, similar to those to be used in the real manufacture

• E.g. qualifying an autoclave we use culture-media

• Permit the acceptable fluctuations of parameters, even set the „worst conditions”

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„Worst conditions”

• say, an equipment must be operated within the limits of– temperature: 20 and 35 oC– pressure: 0.9 and 1.2 atm

• The worst cases, when it operates at– 20 oC and 0.9 atm– 35 oC and 1.2 atm– 20 oC 0.9 and 1.2 atm– 35 oC and 0.9 atm

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Performance Qualification PQ

• Similar to the Operational Qualification, but the real manufacture is running

• Permit accepted fluctuations up to their limits (incl. worse conditions, if occur)

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DQ IQ OQ PQ

Certification

GMP Processunder control

Reviewperiodically

TrainingCalibration

Changecontrol

QualificationQualification

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Validation Priorities for Process Validation

Type of process• New

• Existing Sterile products

Non-sterile

Requirement• Every new process before approval for

routine

• All processes affecting the sterility, and manufacturing environment including sterilization stage

• Low dose tablets and capsules: mixing and granulation, content uniformity (possible other parameters)

• Other tablets and capsules: uniformity of mass(possible other parameters)

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Validation

Types of Documentation

• Validation Master Plan (VMP)• Validation protocols (VP)• Validation reports(VR)• Standard Operating Procedures

(SOPs)

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Validation

The Validation Master Plan could consist of:

– Approval page and table of contents– Introduction and objectives– Facility and process description– Personnel, planning and scheduling– Responsibilities of committee members– Process control aspects– Equipment, apparatus, processes and systems to be validated– Acceptance criteria– Documentation e.g.validation protocols and reports– SOPs– Training requirements

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ValidationProtocol

– Objectives of the validation and qualification study

– Site of the study– Responsible personnel– Description of the equipment– SOPs – Standards– Criteria for the relevant products and

processes

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ValidationReport

– Title– Objective of the study– Refer to the protocol– Details of material– Equipment– Programmes and cycles use– Details of procedure and test methods

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Let us spend some time on the Validation Master

Plan now

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Validation

The Validation Master Plan

(VMP)

• Philosophy

• Content

• Strategy

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Validation

Validation Master Plan • Recommendation only• Cover manufacturer’s validation policy and

needs • Provides information on validation

organization

• It should describe:

– why?

– what?

– where?

by whom?

how?

when?

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Validation

Validation Master Plan

• Prospective validation

• Concurrent validation

• Retrospective validation

• Revalidation

• Change control

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Validation

The VMP

• Identifies validation items (products, processes, systems)

• Defines nature and extent of testing expected

• Outlines test procedures and protocols

• Summary document

• Management agreement

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Validation

The VMP helps:

• Management

• Validation team members

• Project leaders

• GMP inspectors

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Validation Activities in VMP• Every validation activity included

• Revalidation

• Validation of new process cycles

• Large validation projects have separate VMPs

• Include reasonable unexpected events

Validation

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Validation

The VMP:

• Enables overview of entire validation

project

• Lists items to be validated with the planning schedule as its heart

• Is like a map

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Validation

The “Introduction” to the VMP• Validation policy• Project scope• Location and timing (including

priorities)• Validation procedures• Standards

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Validation

VMP should state who is responsible for:• Preparing the VMP

• The protocols and SOPs

• Validation work

• Report and document preparation and control • Approval/authorisation of validation protocols

and reports in all stages of validation process

• Tracking system

• Training needs in support of validation

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Validation

VMP should contain:• Cross references to documents

• Specific process considerations

• Specific characteristics briefly outlined

• Validation list (What to validate)– premises, systems and equipment– processes – products

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Validation

VMP should contain, 2:• Descriptions of

– plant (where to validate)– processes – products

• Personnel attributes – expertise and training

• Key acceptance criteria

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VMP should contain, 3:• Format for protocols and other

documentation• List of relevant SOPs (How)• Planning and scheduling (When)• Location (Where)• Estimate of staffing requirements

(Who)• A time plan of the project (When)• Annexes

Validation

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Validation

VMP should contain change control

• Policy and procedure

• Risk assessment

• Authorization

• Failure to properly document changes to the

system means invalidation of the process

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Validation

Changes that require revalidation• Software changes; Controllers• Site changes; Operational changes• Change of source of material• Change in the process• Significant equipment change• Production area changes• Support system changes

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Validation

In summary, a VMP should contain at least:• Validation policy• Organizational structure• Summary of facilities, systems, equipment,

processes to be validated• Documentation format for protocols and

reports• Planning and scheduling• Change control• Training requirements

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Finishing Validation Master Plan, something about the

Validation Protocol and Report

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Validation

WHO Model for Validation Protocol and Report, 1

• Part 1 – Purpose and prerequisites• Part 2 – Presentation of the process• Part 3 – Validation protocol

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Validation

WHO Model for Validation Protocol and Report,

2

• Part 4 – Installation qualification• Part 5 – Qualification protocol/report• Part 6 – Product characteristics

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Validation

WHO Model for Validation Protocol and Report, 3

• Part 7 – Evaluation• Part 8 – Certification• Part 9 – Summary

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Special validation types

Validation of

•cleaning

•manuf. process

•QC related processes

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Cleaning validation

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Cleaning validation

ObjectivesTo review:

• General requirements

• Validation protocol requirements

• How to check limits

• Analytical requirements

• Sampling methods

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Cleaning validation

Why cleaning validation is so important (1)

• Pharmaceuticals can be contaminated by potentially dangerous substances

• Essential to establish adequate cleaning procedures

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Cleaning validation

Why cleaning validation is so important (2)

• “Particular attention should be accorded to the validation of … cleaning procedures” (WHO)

• “Cleaning validation should be performed in order to confirm the effectiveness of a cleaning procedure” (PIC/S)

• “The data should support a conclusion that residues have been reduced to an ‘acceptable’ level” (FDA)

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Possible contaminants• Product residues• Cleaning agent residues and breakdown• Airborne matter• Lubricants, ancillary material• Decomposition residues• Bacteria, mould and pyrogens

Cleaning validation

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Cleaning validation

Strategy on cleaning validation

• Product contact surfaces

• After product changeover

• Between batches in campaigns

• Bracketing products for cleaning

validation

• Periodic re-evaluation and revalidation

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Cleaning validation

Cleaning validation protocol (1)

Should include :

• Objective of the validation

• Responsibility for performing and approving validation study

• Description of equipment to be used

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Cleaning validationCleaning validation protocol (2)

Should include: • Interval between end of production and cleaning,

and commencement of cleaning procedure• Cleaning procedures to be used• Any routine monitoring equipment used• Number of cleaning cycles performed

consecutively

• Sampling procedures used and rationale

• Sampling locations (clearly defined)

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Cleaning validationRecord of cleaning validation

Should include : • Data on recovery studies

• Analytical methods including Limit of Detection and Limit of Quantitation

• Acceptance criteria and rationale

• When revalidation will be required

• Must have management and QA involvement

• Management commitment and QA involvement

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Cleaning validation

Results and reports

• Cleaning record signed by operator, checked by production and reviewed by QA

• Final Validation Reports, including conclusions

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Cleaning validation

Personnel

• Manual cleaning methods are difficult to

validate

• Cannot validate people; can measure

proficiency

• Must have good training

• Must have effective supervision

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Cleaning validation

Microbiological aspects

• Include in validation strategy

• Analyse risks of contamination

• Consider equipment storage time

• Equipment should be stored dry

• Sterilization and pyrogen contamination

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Cleaning validation

How to take samples

• Swab/swatch

• Rinse fluid

• Placebo

• The sample transport and storage conditions should be defined

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Cleaning validation

Swab samples • Direct sampling method• Reproducibility• Extraction efficiency• Document swab locations • Disadvantages

– inability to access some areas– assumes uniformity of contamination surface– must extrapolate sample area to whole surface

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Cleaning validation

Rinse samples

• Indirect method

• Combine with swabs

• Useful for cleaning agent residues

• pH, conductivity

• Insufficient evidence of cleaning

• Sample very large surface areas

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Cleaning validation

Analytical method (1)

• Validate analytical method

• Must be sensitive assay procedure:– HPLC, GC, HPTLC

– pH

– conductivity

– UV

– ELISA

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Cleaning validation

Analytical method (2) Check: • Precision, linearity, selectivity• Limit of Detection (LOD)• Limit of Quantitation (LOQ)• Recovery, by spiking• Consistency of recovery

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Setting limits (1) • Regulatory authorities do not set limits for

specific products

• Logically based

• Limits must be practical, achievable and verifiable

• Allergenic and potent substances

• Limit setting approach needed

Cleaning validation

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Setting limits (2) • Uniform distribution of contaminants not

guaranteed

• Decomposition products to be checked

• Setting limits; cleaning criteria:– visually clean

– 10 ppm in another product

– 0.1% of therapeutic dose

Cleaning validation

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Setting limits: “Visually clean” • Always first criteria• Can be very sensitive but needs

verification• Use between same product batches of

same formulation• Illuminate surface• Spiking studies

Cleaning validation

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Setting limits: “10 ppm”• Historical• In some poisons regulations• Pharmacopoeias limit test• Assumes residue to be harmful as heavy

metal• Useful for materials for which no available

toxicological data• Not for pharmacologically potent material

Cleaning validation

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Setting limits: not more than 0.1%• Proportion of MINIMUM daily dose of

current product carried over into MAXIMUM daily dose of subsequent product

• Need to identify worst case

Cleaning validation

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Other issues• Clean-In-Place (CIP) systems

• Placebo studies

• Detergent residues; composition should be known

• Scrubbing by hand

Cleaning validation

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Cleaning validationQuestions for the GMP Inspector to askQuestions for the GMP Inspector to ask

• How is equipment cleaned?

• Are different cleaning processes required?

• How many times is a cleaning process repeated before acceptable results are obtained?

• What is most appropriate solvent or detergent?

• At what point does system become clean?

• What does visually clean mean?

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Conclusion• The manufacturer needs a cleaning validation

strategy• Assess each situation on its merits• Scientific rationale must be developed

– equipment selection– contamination distribution– significance of the contaminant

• “Visually clean” may be all that is required

Cleaning validation

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Process validation

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Process validationObjectives

To review:

• Validation, risk analysis, and critical steps of processing

• Points to consider in process validation of:– solid dose mixing– tablet compression– sterilization

• Finalization of validation

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Process validationReliable, repeatable, under control

• At least first 3 consecutive batches - repeatable

• Must investigate failures

• The rationale should be documented if experimental method is changed – document deviations, decisions and reasoning

• Does not improve processes

• Should not validate bad processes

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Process validationProcess validationDesign user or process requirements

Install installation qualification

Operate operational qualification

Perform performance qualification

and process validation

Review periodically (+ change control)

DQ, IQ, OQ and PQ

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Process validation

Critical factors or parameters

• Need to be determined

• Need to be monitored during

validation

• May affect the quality of the product

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Process validation

Setting Limits• Marketing authorization limits

– stability specifications

• Release specification• Validation limits

Batch release limits

Marketing authorisation limitsbased on stability specifications

Validation limits

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Determining critical control point: example of a tablet granulation process

• Particle size distribution of the active(s)• Blending time for the powder• Granulating time and speed, • Amount of granulating fluid-binder concentration• Drying time - final moisture content, granule particle size distribution• Granule active content and homogeneity, blending time of external phase

Process validation

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Criticalcontrol

point

Decision as to whether tocompress or not based on

expected yield and actual yield

Process step Operation IQ/OQ/PQ requirements

Criticalcontrolpoint

Measure humidity withhumidity meterXIII

IQ/OQcalibration

Weigh granulate - balanceXIV IQ/OQcalibration

instrumentoperation,

cleaning, careand maintenance

Trainingrecords fortechnician

XV Sieve 3/5

sieve with sieve type 1

XVI Blend3/5

granulatemixer (speed 1, 1 minute)

XVI Blend 2with 3/5

granulate

mixer (speed 1, 30seconds)

IQ/OQ/PQCleaning

validationCleaning, and Blend

uniformity required to beestablished during validation

XVIII Weigh granulate

Process validationDetermining critical control points

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Solid dose mixing (1)• Homogeneity in blending – the

key to quality! • Sampling strategy• Sample site, label, container• Storage • Transport• Sample thief

Process validation

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Solid dose mixing (2)

• In situ analysis

• Methods of analysis

• Statistical analysis – inter-batch

– intra-batch

– within-sample-site

Process validation

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Process validation

Tablet compression variables

• Fill volume • Pre-compression force,

compression force• Turntable speed• Dwell time• Granule size and feed• Ejection force, lubrication

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Process validation

Tablet compressionparameters

Mass

Hardness

Moisture

Friability

Disintegration

Dissolution Thickness

Tablet coating variables Spray rate Inlet and outlet air

temp Coating weight

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Process validation

Sterilization validation (1)

• Sterility test

• Physical measurements

• Chemical and biological indicators

• Loading patterns

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Process validation

Sterilization validation (2)• Cooling fluid or gas• Automated process• Leak tests• Control instrumentation• Steam quality• Heat distribution

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Process validationDry heat sterilization

• Parameters• Air circulation, positive air pressure,

HEPA filter• Advantages

– microorganisms destroyed– depyrogenation possible

• Disadvantages– poor heat transfer– higher temperatures for long periods

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Process validationProcess variation

Controllable causes of variation may include:• Temperature, humidity • Variations in electrical supply• Vibration• Environmental contaminants• Light• Human factors • Variability of materials• Wear and tear of equipment

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Process validationChange control

• Must be a review procedure for validated processes

• From time to time changes may be necessary

• Documented change control procedure needed

• “Like for like" changes do not require re-validation

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Mixing validation liquid and solid dose change control and scale up

• Mixer type and size

• Batch size

• Pilot study scale up

• Limit on the proportion of the scale up

Process validation

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Process validationFinalization of validation process

• Final report required• Summarize and reference protocols and

results• Conclusion required: “Is the process valid”

• Final report should be reviewed and approved by – the validation team

– “authorized person”

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Tablet manufacturing flow chart

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Quality Control related validation

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QC related validation

Introduction

• Why is analytical monitoring necessary?

• What is the purpose of analytical validation?

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QC related validation

ObjectivesTo introduce the concepts of :• Protocol development• Instrument qualification• Analytical procedure• Extent of validation• Method transfer• Chemical and physical, biological, and

microbiological test validation

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Validation of analytical procedures requires:• Qualified and calibrated instruments

• Documented methods

• Reliable reference standards

• Qualified analysts

• Sample integrity

QC related validation

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Validation protocol for analytical method

• Statement of purpose and scope• Responsibilities • Documented test method• List of materials and equipment• Procedure for the experiments for each

parameter• Statistical analysis• Acceptance criteria for each performance

parameter

QC related validation

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Qualification of the instrument

• Make, model and maker’s manual

• Modifications

• Installation and operational qualification

• Calibration programs

• Maintenance schedules

QC related validation

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Characteristics of analytical procedures (1)• Accuracy

• Precision

• Repeatability

• Reproducibility

QC related validation

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Inaccurate &imprecise

Inaccurate butprecise

Accurate butimprecise

QC related validation

Relationship between accuracy and precision

Accurate AND Precise

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Characteristics of analytical procedures (2)

• Ruggedness • Robustness• Variability caused by:

– Day-to-day variations– Analyst-to-analyst– Laboratory-to-laboratory– Instrument-to-instrument– Chromatographic column-to-column– Reagent kit-to-kit– Instability of analytical reagents

QC related validation

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Characteristics of analytical procedures (3)

• Linearity and range• Specificity• Sensitivity• Limit of detection• Limit of quantitation

QC related validation

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Linearity of an analyte in a material

0.010

0.015

0.020

0.025

0.030

0.035

0.040

0.01 0.015 0.02 0.025 0.03 0.035 0.04

Reference material mg/mlCal

cula

ted a

nal

yte

in m

g/m

L Table of values (x,y)

x y # Reference

material mg/mlCalculated

mg/ml

1 0.0100 0.0101

2 0.0150 0.0145

3 0.0200 0.0210

4 0.0250 0.0260

5 0.0300 0.0294

6 0.0400 0.0410

QC related validation

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Linearity Statistics • Intercept -0.0002• Limit of Linearity and Range

0.005 – 0.040 mg/mL• Slope 1.0237• Correlation coefficient

– Pearson 0.9978– Olkin and Pratt 0.9985

• Relative procedure standard deviation 3.4%

QC related validation

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LOQ, LOD and SNR

• Limit of Quantitation

• Limit of Detection

• Signal to Noise Ratio

noise

Peak ALOD

Peak BLOQ

Baseline

QC related validation

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Different classes of analytical tests• Class A: To establish identity

• Class B: To detect and quantitate impurities

• Class C: To determine quantitatively the concentration

• Class D: To assess the characteristics

QC related validation

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* A degree of bias may be allowed

Characteristic A B quant.

B Limit test

C D

Accuracy 

  X   X X*

Precision   X   X X

Robustness X X X X X

Linearity and range

  X   X X

Specificity X X X X X

Limit of detection   X    

Limit of quantitation

  X      

QC related validation

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Extent of validation • New methods require complete

validation• Pharmacopoeial methods require

partial validation (or verification)• Significant changes mean partial

revalidation– equipment changes– formula changed– changed suppliers of critical reagents

QC related validation

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Analytical method transfer• Method transfer protocol and procedure

– precision– accuracy– ruggedness

• Written and approved specific test method• Proficiency check• Formal acceptance by new laboratory

QC related validation

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Chemical laboratory validation requirements (1)

• Balances • Chromatography

– HPLC, HPTLC, GC, TLC• Dissolution or disintegration apparatus• Karl Fischer moisture determination• Melting, softening or freezing point apparatus• Ovens, refrigerators, incubators

QC related validation

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Chemical laboratory validation requirements (2)

• pH meter• Polarimeter - optical rotation• Refractometer• Spectrophotometer UV/Vis, IR, FTIR, Raman, AA• Timers• Viscometer• Volumetric equipment

QC related validation

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QC related validation

Typical validation of HPCL assay (1)

• System suitability (performance check)– system precision– column efficiency – symmetry factor– capacity factor

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QC related validation

Typical validation of HPLC assay (2)• Method validation

– specificity – accuracy – precision– linearity – robustness

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Biological assays• Can be difficult to "validate"

• "Validity" on a case by case basis

• Strictly adhere to the Biological Testing monographs in pharmacopoeias

QC related validation

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QC related validation

Microbiological testing requiring validation

• Microbial limit testing

• Microbial count

• Sterility testing

• Preservative effectiveness testing

• Environmental monitoring program

• Biological testing

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Validation of microbial test procedures (1)

• Virtually impossible to completely validate test procedures for every microorganism

• Neutralize /inactivate inhibitory substances, or dilute

• Periodic media challenge• Media QC• Reliable methods

QC related validation

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Validation of microbial test procedures (2)

• Incubation temperature and time

• Media may not grow all microorganisms

• Variations in media may affect recovery

• Inhibitory disinfectants or preservatives

• Sample– procedures

– handling, storage, transport

QC related validation

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Microbiological viable count method validation (1)

• Methods – pour plate / spread plate– membrane filtration– Most Probable Number

• Sample size• Test dilution• Inoculation size

QC related validation

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Microbiological viable count method validation (2)

• Membrane filtration conditions

• Incubation conditions

• Acceptance criteria

QC related validation

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Sterility testing validation requirements

• Media growth promotion, sterility, pH

• Product validation

• Stasis testing

• Environmental monitoring

• Negative controls

• Challenge organisms

QC related validation

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Personnel - Validation team members • Quality Assurance• Engineering• Manufacturing• Other disciplines may be involved depending

on the product and process:– laboratory, technical services– research and development, regulatory affairs– clinical – chemical engineering– purchasing/planning

Validation

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ValidationProtocol development (1)

• Identification of process

• Objective and measurable criteria

• Length and duration of the validation

• Shifts, equipment

• Identification and quality of utilities• Identification of operators and operator

training and qualification

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Validation

Protocol development (2)• Complete description of the process

• Relevant specifications and tests

• Samples and sampling methods

• Special controls or conditions

• Process parameters to be monitored

• Methods for controlling and monitoring

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ValidationProtocol development (3)

• Objective and subjective criteria used to evaluate the product

• Definition of non-conformance

• Statistical methods

• Maintenance and repairs

• Criteria for revalidation

• Criteria for change control

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GMP Inspector’s check list for validation (1)

Check that the manufacturer has:

• A VMP and multi-functional team for validation

• Planned approach, defined requirements

• Identified and described processes

• Analyse the amount of validation work to perform

Validation

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GMP Inspector’s check list for validation (2)

Check that the manufacturer has:

• Selected methods and tools for validation

• Created protocols

• Performed DQ, IQ, OQ, PQ and documented results

• Exerted change control, set revalidation time

Validation

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Validation • A quality tool that makes sense • A prevention-based activity• Expensive• In danger of becoming overwhelming • Risk-based assessment of what needs to

be validated or verified• The process must be under control

Validation: summary

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We are now validated!

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Exam topics

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Validation and Qualification in GMP

• Definitions. What is their difference?

• Their importance

• Describe the 3 process validation types

• Describe the 4 qualification types

• Validation documentation (special emphasis to VMP)

• What is change control, why to do it?

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Validation of clening processes and analytical procedures in

GMP• Cleaning validation

– Its 2 targets– How to perform it (examples)

• Analytical method validation– List the main method characteristics– Classes of testing for validation– Analytical instrument validation (examples)– Microbiology