Gmp change control by amsavel

cGMP:cGMP:

CChange Control Managementhange Control Management

GMP IntroductionGMP Introduction

What is tested is not sold What is tested is not sold

What is sold is not testedWhat is sold is not tested

So,So,

Quality is not testing of Quality is not testing of product. It product. It should to be built should to be built in each stage in each stage of of process/operation.process/operation.

Objective of GMPObjective of GMP

Principle of GMPsPrinciple of GMPs

Product QualityProduct Quality depends on: depends on:

Quality, Safety, and Effectiveness Quality, Safety, and Effectiveness must be designed and built into must be designed and built into

the product;the product;

Each step in a manufacturing process Each step in a manufacturing process must bemust be controlled controlled to maximize the to maximize the probability that the finished product will probability that the finished product will meet all its quality and design meet all its quality and design specifications.specifications.

Brief GMP HistoryBrief GMP History

1957:1957: First GMP issued as a First GMP issued as a government regulation (government regulation (by the Canadian by the Canadian Specifications Board for drug supplied to the Specifications Board for drug supplied to the Canadian military)Canadian military)

1963/1978:1963/1978: US FDA GMP US FDA GMP 1967:1967: WHO GMP WHO GMP 1968/1973: 1968/1973: UK GMPUK GMP 1984: 1984: GMP in more than 25 countriesGMP in more than 25 countries

Why GMP RequiredWhy GMP Required

It is to ensure to avoid It is to ensure to avoid – Mistakes Mistakes – Mix-upsMix-ups– Cross-contaminationCross-contamination– ConfusionConfusion– Rejection/reworkRejection/rework

GMP: Become NecessityGMP: Become Necessity

To meet regulatory requirementTo meet regulatory requirement Authorities/Agencies become watch dog Authorities/Agencies become watch dog Audits/approval by agencies & customersAudits/approval by agencies & customers Customers are more demandingCustomers are more demanding Competition and quality is becoming Competition and quality is becoming

significantsignificant

Achieving quality is a rewarding experience.Achieving quality is a rewarding experience.

Changing ApproachChanging Approach

Initiated Initiated

‘‘Risk AssessmentsRisk Assessments & &

““Quality ManagementQuality Management” approach” approach

Extensive guidelines on specific activities Extensive guidelines on specific activities

Rigorous inspection and document reviewsRigorous inspection and document reviews

GMP GuidanceGMP Guidance

GMP GuidanceGMP Guidance

– ICH- Q7AICH- Q7A– FDA- CFR-210 &211 FDA- CFR-210 &211 – WHO-GMPWHO-GMP– CEFIC and EFPIA , GMP for active ingredients CEFIC and EFPIA , GMP for active ingredients

(1996)(1996)– PIC/S, GMP guide for API,PIC/S, GMP guide for API, (draft of Sept. 1995)(draft of Sept. 1995)

ICH: Q7A Contents (Chapters)ICH: Q7A Contents (Chapters)

1.0. Introduction 1.0. Introduction

3.0 Personnel3.0 Personnel

2.0 Quality 2.0 Quality Management Management

5.0 Process equipment5.0 Process equipment

4.0 Building and 4.0 Building and premisespremises

7.0 Materials 7.0 Materials ManagementManagement

6.0Documentation & 6.0Documentation & RecordsRecords

9.0 Packaging and 9.0 Packaging and labellinglabelling

8.0 Production & in-8.0 Production & in-process process ControlsControls

11.0 Laboratory 11.0 Laboratory ControlControl

13.0 Change control

10.0 Storage & 10.0 Storage & DistributionDistribution

15.0 Complaints and 15.0 Complaints and recallsrecalls

14.0 Rejection and re-14.0 Rejection and re-use use of materials of materials

12.0 Validation12.0 Validation

16.0 Contract 16.0 Contract manufacturingmanufacturing

Quality managementQuality management

ICH Q7AICH Q7A

1.1. Quality ManagementQuality Management

Define Responsibilities & AuthoritiesDefine Responsibilities & Authorities Responsibilities of Quality UnitResponsibilities of Quality Unit Quality Control / AssuranceQuality Control / Assurance

Independent of ProductionIndependent of Production Responsibilities of Production Responsibilities of Production

activitiesactivities Internal AuditsInternal Audits Product Quality ReviewsProduct Quality Reviews

Change controlChange control

ICH Q7AICH Q7A

13.013.0 Change ControlChange Control A formal change control system should be A formal change control system should be

established to evaluate all changes that could established to evaluate all changes that could affect the production and control of the affect the production and control of the intermediate or API.intermediate or API.

Since process is validated and quality being Since process is validated and quality being defined for an intermediate or API, (specification) defined for an intermediate or API, (specification) it is essential to maintain this quality, it is essential to maintain this quality, as there as there is interrelationship between "is interrelationship between "QualityQuality" and the two " and the two other essential properties of an API, other essential properties of an API, "safety and "safety and efficacy", efficacy",

ANY change which may affect the ANY change which may affect the Quality Quality of the of the intermediate or API may also change the safety intermediate or API may also change the safety and efficacy.and efficacy.

13.0 Change Control (Cont..)13.0 Change Control (Cont..)Written procedures should provide for the identification, Written procedures should provide for the identification, documentation, appropriate review, and approval of documentation, appropriate review, and approval of changes of the,changes of the,

Raw materials, Raw materials, Specifications, Specifications, Analytical methods,Analytical methods, Facilities, Facilities, Support systems, Support systems, Equipment (including computer hardware), Equipment (including computer hardware), Processing steps, Processing steps, Labeling and Labeling and Packaging materials, and Packaging materials, and Computer software.Computer software.

13.0 Change Control (Cont..)13.0 Change Control (Cont..)

Any proposals for GMP relevant changes should be Any proposals for GMP relevant changes should be drafted, reviewed, and approved by the appropriate drafted, reviewed, and approved by the appropriate organizational units and reviewed and approved by the organizational units and reviewed and approved by the quality unit(s).quality unit(s).

Propose any change to those, who are best able to pass Propose any change to those, who are best able to pass judgment by reviewing the implications on the proposal.judgment by reviewing the implications on the proposal.

– Department headDepartment head– Quality Unit. Quality Unit. – Regulatory AffairsRegulatory Affairs

Others as requiredOthers as required– stability testing unit, stability testing unit, – purchasing,purchasing,– production, production, – EngineeringEngineering


Ensure the documents affected by the changes are Ensure the documents affected by the changes are revised,revised,

E.g. DMF, in-house documents & other Regulatory E.g. DMF, in-house documents & other Regulatory documents, information given to customers etcdocuments, information given to customers etc

In-house instructions, and procedures:In-house instructions, and procedures:– MI, BPR, Specifications if requiredMI, BPR, Specifications if required– SOPs (operation, cleaning, relevant sops), analytical SOPs (operation, cleaning, relevant sops), analytical

method, Change control log. method, Change control log.

The potential impact of the proposed change on the The potential impact of the proposed change on the quality of the intermediate or API should be evaluated.quality of the intermediate or API should be evaluated.


Classify the changes as minor or major. Classify the changes as minor or major.

– Major changes are those affecting the “impact Major changes are those affecting the “impact the quality” of product.the quality” of product.

“ “Impact the qualityImpact the quality” is different from ” is different from “meeting the specification” Some physical “meeting the specification” Some physical characteristics of an API are not characteristics of an API are not easily/routinely measured)easily/routinely measured)

This may help in determining the level of testing, This may help in determining the level of testing, validation, and documentation, which are needed validation, and documentation, which are needed to justify changes to a validated process. to justify changes to a validated process.


Scientific judgment should determine what Scientific judgment should determine what additional testing and validation studies are additional testing and validation studies are appropriate to justify a change in a validated appropriate to justify a change in a validated process.process.

Scientific judgment: Scientific judgment: it is difficult to explain or impossible it is difficult to explain or impossible in such a guide to prescribe exactly how each type of in such a guide to prescribe exactly how each type of change should be dealt with. Each case should be judged change should be dealt with. Each case should be judged on its merits. Include the reasoning why the proposed on its merits. Include the reasoning why the proposed change is being approved.change is being approved.

– Changes in the impurity profile or Chemical & physical Changes in the impurity profile or Chemical & physical characteristics of the product.characteristics of the product.

– This is because there are still too many physical characteristics This is because there are still too many physical characteristics of an API, which cannot easily or routinely measured. of an API, which cannot easily or routinely measured.

13.0 Change Control (Cont..)13.0 Change Control (Cont..) After the change has been implemented, there After the change has been implemented, there

should be an evaluation of the first batches should be an evaluation of the first batches produced or tested under the change.produced or tested under the change.

The potential for The potential for critical changescritical changes to affect to affect established retest or expiry dates should be established retest or expiry dates should be evaluated evaluated

If necessary, samples of the intermediate or API produced If necessary, samples of the intermediate or API produced by the modified process can be placed on an accelerated by the modified process can be placed on an accelerated stability program and/or can be added to the stability stability program and/or can be added to the stability monitoring program. monitoring program.

Current dosage form manufacturers should be Current dosage form manufacturers should be notified of changes from established production and notified of changes from established production and process control procedures that can affect the process control procedures that can affect the quality of the API.quality of the API.

Process Change:Process Change:Reasons for the process / Equipment changes:Reasons for the process / Equipment changes:

Design improvement to enhance product quality, Design improvement to enhance product quality, Specific quality requirement by customer, Specific quality requirement by customer, Process improvement to increase productivityProcess improvement to increase productivity CAPA : for oos/deviation resulting to change of CAPA : for oos/deviation resulting to change of

process process operation convenience operation convenience Safety / Statutory requirementsSafety / Statutory requirements

Introduction of new equipment to increase Introduction of new equipment to increase productivity, product quality, etc.productivity, product quality, etc.

Modification of the equipment to improve product Modification of the equipment to improve product quality, increase the productivity, easy operation, quality, increase the productivity, easy operation, safety or Regulatory requirements, etc.safety or Regulatory requirements, etc.

Change implementationChange implementation

Process Change:Process Change: Change made to improve process yields should Change made to improve process yields should

be evaluated for new or higher level of impurities. be evaluated for new or higher level of impurities.

The impurity profiles of the batches should be The impurity profiles of the batches should be comparable of the API batches used in drug comparable of the API batches used in drug safety and clinical testing. safety and clinical testing.

Evaluate analytical method to determine the new Evaluate analytical method to determine the new or higher level of impurities or by products.or higher level of impurities or by products.

If necessary, modify the analytical methods to If necessary, modify the analytical methods to detect and quantify the impurities.detect and quantify the impurities.

Process Change:Process Change:

Classification: A major process changes are;Classification: A major process changes are;– A change in the route of manufacture;A change in the route of manufacture;– Change in the source of starting raw materials Change in the source of starting raw materials

and change of raw material and solvents used in and change of raw material and solvents used in the manufacture;the manufacture;

– Changes to the manufacturing conditions / Changes to the manufacturing conditions / process, which results in changes to the impurity process, which results in changes to the impurity profile or physical characteristics of the product. profile or physical characteristics of the product.

Eg. Critical process parameters or change of Eg. Critical process parameters or change of solvent used for final crystallization.solvent used for final crystallization.

Process Change:Process Change:

Classification: A minor process changes are;Classification: A minor process changes are;

– Changes in the manufacturing conditions, to Changes in the manufacturing conditions, to improve efficiency which do not affect the improve efficiency which do not affect the impurity profile of the product.impurity profile of the product.

– Eg. Process time during work up, tightening the Eg. Process time during work up, tightening the limit, etclimit, etc

Steps can be followed while Process Change:Steps can be followed while Process Change:

Review the process change or operation change for Review the process change or operation change for consequencesconsequences

Draft the proposed process changeDraft the proposed process change Get approval from R&D in-charge, QA in-charge and Get approval from R&D in-charge, QA in-charge and

Production/factory in-charge.Production/factory in-charge. Conduct laboratory experiment if required.Conduct laboratory experiment if required. Make a trial production based on the proposed processMake a trial production based on the proposed process Review the results obtained from the changed processReview the results obtained from the changed process Classify the change in process steps as major or Classify the change in process steps as major or

minor.minor. If the change is major i.e. has a potential effect on the If the change is major i.e. has a potential effect on the

final product quality, conduct a process validation.final product quality, conduct a process validation.

Steps can be followed while Process Change:Steps can be followed while Process Change:

Conduct a stability study, if requiredConduct a stability study, if required Evaluate the pre-approval requirement form Evaluate the pre-approval requirement form

regulatory/customerregulatory/customer If the change in minor document the changes If the change in minor document the changes

with proper justification.with proper justification. Carry out analytical method validation if required.Carry out analytical method validation if required. Evaluate the cleaning procedure for equipment Evaluate the cleaning procedure for equipment

cleaningcleaning Revise the relevant documents with due Revise the relevant documents with due

approval.approval. Permanent implementationPermanent implementation

Reference: Guidelines: Q7A, CMC, BACPAC etcReference: Guidelines: Q7A, CMC, BACPAC etc

Equipment changeEquipment change A major equipment change is defined as a change A major equipment change is defined as a change

involving:involving:– A change in the material of construction;A change in the material of construction;– A change in the speed of the movable parts of the A change in the speed of the movable parts of the

equipment;equipment;– Use of a different type of equipment performing the Use of a different type of equipment performing the

same operationsame operation

A minor equipment change is defined as :A minor equipment change is defined as :– Replacement of an equipment with another of identical Replacement of an equipment with another of identical

nature;nature;(like-for-like replacement)(like-for-like replacement)

– Replacement of equipment with another of identical Replacement of equipment with another of identical nature but different capacity.nature but different capacity.

– Such changes would not shift the process in any Such changes would not shift the process in any discernible manner and might be implemented with discernible manner and might be implemented with minimal testing and re-validation.minimal testing and re-validation.


Changes that could affect in Raw material:Changes that could affect in Raw material:

Synthesis route (benzaldehyde in PAC)Synthesis route (benzaldehyde in PAC) Residual Solvents (benzene/class-1 solvent)Residual Solvents (benzene/class-1 solvent) Change in physical and chemical propertiesChange in physical and chemical properties Impurity profile (process & degradation impurity)Impurity profile (process & degradation impurity) Inorganic salts (heavy metals) may catalyze the Inorganic salts (heavy metals) may catalyze the

degradation, resulting stability issues.degradation, resulting stability issues. Adequacy of the analytical procedures Adequacy of the analytical procedures If our analysis method is not capable of detecting If our analysis method is not capable of detecting

the new impurities, our product will get affected.the new impurities, our product will get affected. Passes in analytical test, if fail in performancePasses in analytical test, if fail in performance

13.0 Change Control (Cont..)13.0 Change Control (Cont..) Especially in final stage, the following may get Especially in final stage, the following may get

affected,affected, chemical propertieschemical properties

– Assay, Assay, – Impurities: Related sub & Residual solvent Impurities: Related sub & Residual solvent – Other (molecule) related properties Other (molecule) related properties

Physical, Physical, – Description ; Crystalline natureDescription ; Crystalline nature– PSDPSD

Polymorphs Polymorphs

By implementing such changes involves cost & By implementing such changes involves cost & timetime– Validation & Stability.Validation & Stability.– Pre-approvalPre-approval– Delay in commercializing the APIDelay in commercializing the API

Other changesOther changes Analytical methods: Analytical methods:

– Suitability or validationSuitability or validation Facilities:Facilities:

– New facility or modification of existing eg.clean New facility or modification of existing eg.clean area AHUarea AHU

Support systems:Support systems:Water system, Environment,Water system, Environment,

LabelingLabeling Packaging materials: Packaging materials:

– Primary & Secondary packing Primary & Secondary packing

Computer software. Computer software.

Thank YouThank You

EfficacyEfficacy :The ability of a substance to produce a desired :The ability of a substance to produce a desired effect effect

Measures the power to produce, in a controlled setting such Measures the power to produce, in a controlled setting such as a clinical trial, a stated effect typically attributable to a as a clinical trial, a stated effect typically attributable to a known physiologic phenomenon. It is important to derive known physiologic phenomenon. It is important to derive measures of efficacy because, with appropriate statistical measures of efficacy because, with appropriate statistical achievements, these data can approximate real-world achievements, these data can approximate real-world effectiveness.effectiveness.

SafetySafety is the state of being safe, the condition of being is the state of being safe, the condition of being protected against physical or consequences of failure, or protected against physical or consequences of failure, or any other event which could be considered dangerousany other event which could be considered dangerous

Audit systemAudit system

– Quality SystemQuality System– Premises and Equipment SystemPremises and Equipment System– Materials SystemMaterials System– Production SystemProduction System– Packaging and Labelling SystemPackaging and Labelling System– Laboratory Control SystemLaboratory Control System

Audit on System, process and productAudit on System, process and product

Class-1 solventsClass-1 solvents Benzene- 2ppm-CarcinogenBenzene- 2ppm-Carcinogen Carbon tetrachloride-3- Toxic& hazardCarbon tetrachloride-3- Toxic& hazard 1,2-Dichloroethane-5- toxic1,2-Dichloroethane-5- toxic 1,1-Dichloroethene-8- toxic1,1-Dichloroethene-8- toxic 1,1,1-Trichloroethane-1500-hazard.1,1,1-Trichloroethane-1500-hazard.

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Gmp change control by amsavel