Introduction to Good Manufacturing Practice

Rachel BridsonRachel Bridson

Introduction The key aim of any pharmaceutical manufacturing The key aim of any pharmaceutical manufacturing

process is to produce a process is to produce a SAFESAFE, , PUREPURE and and EFFICACIOUSEFFICACIOUS product product

To ensure that this aim is met, quality assurance To ensure that this aim is met, quality assurance procedures must be in placeprocedures must be in place

Definition of QA

“ “..the sum total of the organised ..the sum total of the organised arrangements made with the object of arrangements made with the object of ensuring that medicinal products are of the ensuring that medicinal products are of the quality required for their intended use”quality required for their intended use”

Directive 91/356/EECDirective 91/356/EEC

QA

GMP

QC

QA incorporates GMP and QC

Quality assurance (QA)

Production / control operations are clearly definedProduction / control operations are clearly defined Managerial / team responsibilities are clearly Managerial / team responsibilities are clearly

defineddefined Correct materials are usedCorrect materials are used In-process controls and validation are carried out In-process controls and validation are carried out Finished product is correctly processedFinished product is correctly processed Storage and handling are appropriateStorage and handling are appropriate Self-inspection and audit procedures existSelf-inspection and audit procedures exist

Definition of GMP

“…“…good manufacturing practice shall mean good manufacturing practice shall mean that part of quality assurance which ensures that part of quality assurance which ensures that products are consistently produced and that products are consistently produced and controlled to the quality standards controlled to the quality standards appropriate to their intended use.”appropriate to their intended use.”

You will often see “cGMP” – You will often see “cGMP” – currentcurrent good good manufacturing practicemanufacturing practice

GMP Demands that:Demands that:

All critical steps within the process are defined and All critical steps within the process are defined and validatedvalidated

Only approved procedures are followedOnly approved procedures are followed Detailed documentation is produced to ensure full Detailed documentation is produced to ensure full

traceabilitytraceability Overall objective is to ensure that the material consumed Overall objective is to ensure that the material consumed

by the end user has the following defined attributes:by the end user has the following defined attributes: PurityPurity StrengthStrength IdentityIdentity

GMP: Personnel Should be competent, appropriately qualified and Should be competent, appropriately qualified and

in sufficient numbersin sufficient numbers Everyone should have a clearly defined job Everyone should have a clearly defined job

description description Hierarchical relationships should be shown on an Hierarchical relationships should be shown on an

organisational chartorganisational chart Initial and continuing training should be providedInitial and continuing training should be provided Personnel must follow established hygiene Personnel must follow established hygiene

protocolsprotocols

GMP: premises and equipment Should be entirely suitable for the intended Should be entirely suitable for the intended

operationsoperations

Lay out, design and operation must minimise risk Lay out, design and operation must minimise risk of errors, cross-contamination and anything that of errors, cross-contamination and anything that may have an adverse effect on the productmay have an adverse effect on the product

Premises and equipment that are critical for Premises and equipment that are critical for product quality will be validated (qualified) product quality will be validated (qualified)

Premises cont.

historyhistory neighboursneighbours securitysecurity topographytopography accessaccess

utility generation utility generation and distributionand distribution

transferstransferspeoplepeoplematerialsmaterialsinformationinformation

Each site will have its own unique constraints and problems:-

GMP: documentation

Should be clear, up to date and accurateShould be clear, up to date and accurate Must allow the history of each batch to be Must allow the history of each batch to be

fully tracedfully traced Should be retained for the specified periodShould be retained for the specified period Data storage systems must validated and Data storage systems must validated and

adequately backed-upadequately backed-up

GMP: documentation system

SPECIFICATIONS

PRODUCTION

PRINCIPLES(SOP) RAW MATERIALS

REAGENTS

EQUIPMENT

VALIDATION

PREPARATION

CLEANING RECORDS

IN-PROCESS SAMPLES RECORDS

BATCH DOCUMENTATION

AUDIT REPORTSENVIRONMENTAL

MONITORING RECORDS

cGMP: production All operations should be carried out according to All operations should be carried out according to

pre-established instructionspre-established instructions Process modifications must be validatedProcess modifications must be validated Critical phases of the manufacturing process Critical phases of the manufacturing process

should be regularly re-validatedshould be regularly re-validated Measures must be taken to avoid cross—Measures must be taken to avoid cross—

contamination and mix-upscontamination and mix-ups Adequate and sufficient resources must be made Adequate and sufficient resources must be made

available for in-process controlsavailable for in-process controls

GMP: Quality control

An independent QC department must be set An independent QC department must be set up and placed under the control of a QPup and placed under the control of a QP

At least one, appropriately staffed and At least one, appropriately staffed and equipped lab must be availableequipped lab must be available

Responsibilities of QC personnel

Monitor facilities for cleanlinessMonitor facilities for cleanliness Monitor manufacturing personnel hygieneMonitor manufacturing personnel hygiene Evaluate raw materials, packaging Evaluate raw materials, packaging

materials, intermediates and final product materials, intermediates and final product identityidentity

Perform product safety testing and final Perform product safety testing and final product release proceduresproduct release procedures

GMP: work contracted out Must be subject to a written contract – the contract Must be subject to a written contract – the contract

acceptor must not then pass on work to a further acceptor must not then pass on work to a further party without written authorisationparty without written authorisation

Contract must state all responsibilities and the Contract must state all responsibilities and the manner in which those responsibilities will be metmanner in which those responsibilities will be met

Contract acceptor must follow GMP and be Contract acceptor must follow GMP and be subject to the necessary inspectionssubject to the necessary inspections

GMP: complaints and product recall The manufacturer must have a procedure The manufacturer must have a procedure

for recording and evaluating complaintsfor recording and evaluating complaints

An effective recall system should be in An effective recall system should be in placeplace

The “competent authority” should be The “competent authority” should be informed of any defectsinformed of any defects

GMP: self-inspection

As part of the QA system the manufacture As part of the QA system the manufacture must perform regular self-inspections to must perform regular self-inspections to ensure that all guidelines and GMP ensure that all guidelines and GMP principles are being followedprinciples are being followed

Records should be kept of the results and Records should be kept of the results and subsequent corrective actionssubsequent corrective actions

Validation

Programme designed to identify, prove and Programme designed to identify, prove and document that document that youryour product product consistentlyconsistently meets meets youryour specifications and quality specifications and quality attributesattributes it must be kept as simple as possibleit must be kept as simple as possible it must identify and deal with what is criticalit must identify and deal with what is critical it must not validate what does not matterit must not validate what does not matter

Key Validation Issues

Formal documentation is requiredFormal documentation is required

Consistency of performance factorsConsistency of performance factors

Measured performance should meet pre-Measured performance should meet pre-

set expectationsset expectations

Validation types

ProspectiveProspective new facilities, equipment or productsnew facilities, equipment or products

On-goingOn-going working process which can be used as working process which can be used as

benchmarkbenchmark

RetrospectiveRetrospective historical performance data or observationshistorical performance data or observations

Validation Plan ContentsIntroductionIntroduction

Brief introduction of Brief introduction of plant or processplant or processScope of validationScope of validationOther plans? Other plans? ResponsibilitiesResponsibilities

ObjectiveObjectiveExactly what is to be Exactly what is to be achievedachieved

Process descriptionProcess descriptionComplete but concise Complete but concise description of all inputs, description of all inputs, operations, outputs & limitsoperations, outputs & limits

Validation MatrixValidation Matrix

Extent of validation for each Extent of validation for each

operation, service, item of operation, service, item of

equipment..equipment..

Acceptance CriteriaAcceptance Criteria

Justified limits of acceptanceJustified limits of acceptance

Validation Plan ContentsProceduresProcedures

Standard operating, Standard operating, analytical, cleaning, analytical, cleaning, reporting...reporting...

FormatFormat

Format for all documentationFormat for all documentation

Presentation of resultsPresentation of results

PeoplePeople

Specific training requirements Specific training requirements packagespackages

ResourcesResources

Estimate of manpower & Estimate of manpower &

equipmentequipment

Preliminary schedulePreliminary schedule

Review & ApprovalReview & Approval

Authorised signatures for Authorised signatures for protocol review & approvalprotocol review & approval

Authorised signatures for Authorised signatures for plan review & approvalplan review & approval

Cost of GMP ?

Difficult to quantify:-Difficult to quantify:-

it is not the initial capital costit is not the initial capital cost it is not the running costit is not the running cost it is the loss of business!it is the loss of business!

And finally…. Regulations are constantly developingRegulations are constantly developing

Pharmaceutical companies are increasingly Pharmaceutical companies are increasingly outsourcing more of their manufacturing, outsourcing more of their manufacturing, research and clinical trial operationsresearch and clinical trial operations

Supply companies as well as pharmaceutical Supply companies as well as pharmaceutical companies must embrace GMP to secure companies must embrace GMP to secure future businessfuture business