Production and Process validation17 January 2006by...Wiriya charoenkunathum

References:

GMP for pharmaceutical products: main principles; WHO TRS No. 908,2003GMP for biological products; WHO TRS No.822,1992A WHO guide to GMP requirements, part 2:validation; WHO,1997

GMPThe good practices outlined are to be considered general guides and they may be adapted to meet individual needs.

GMPare aimed primarily at diminishing the risks inherent in any pharmaceutical productionCross contamination; unexpected contaminantsMix-ups; confusion (false labels)

Good practices in productionPrinciple: production operations must follow clearly defined procedures in accordance with manufacturing and marketing authorizations, with the objective of obtaining products of the requisite quality.

Production of VaccineMaster seedWorking seedInoculumSingle harvestPool/Concentrated materialPurified/Bulk materialFinal bulkFinal lotMedia/Cell cultureExcipientsValidation - process - methodStability studiesGMP

Good practices in production:GeneralAll handling of materials and products;receiptcleaningquarantinesamplingstoragelabellingdispensingprocessingpackagingdistributionshould be done in accordance with written procedures and recorded.

Good practices in production:GeneralAny deviation from instructions or procedures should be avoid as far as possible.If deviations occur: should be done in accordance with an approved procedure approved in writing by a designated person

Good practices in production:GeneralChecks on yields and reconciliation of quantities to ensure that there are no discrepancies outside acceptable limits.

Good practices in production:GeneralOperation on different products should not be carried out simultaneously or consecutively in the same room or area unless there is no risk of mix-up or cross-contamination.

Good practices in production:GeneralAt all time during processingall materialsbulk containersmajor items of equipmentrooms packaging linesbeing used should be labeled or identified

Good practices in production:GeneralAccess to production premises should be restricted to authorized personnel.Non-medicinal products should not be produced in areas or with equipment destined for the production of pharmaceutical products.

Good practices in production:GeneralIn-process controls are usually performed within the production area.The performance should not have any negative effect on the quality of the product or another product.

Good practices in production: Prevention of cross-contamination during productionWhen dry materials and products are used in production, special precaution should be taken to prevent the generation and dissemination of dust.

proper air control e.g. supply and extraction of air of suitable quality

Good practices in production: Prevention of cross-contamination during productionContamination of a starting material or of a product by another material or product must be avoid.

accidental cross-contamination arises fromuncontrolled release of dust, gases, particles, vapours. sprays or organisms from materials and products in processresidues on equipmentintruding insectsoperators clothing, skin, etc.most hazardous, highly sensitizing materialsliving organisms, hormones, cytotoxic substances, and others

Good practices in production: Prevention of cross-contamination during productionAvoided by taking appropriate technical e.g.

carrying out production in dedicated and self-contained areasconducting campaign production followed by appropriate cleaning in accordance with a validated cleaning procedureproviding appropriately designed airlocks, pressure differentials and air supply and extraction systems

Good practices in production: Prevention of cross-contamination during productionminimizing the risk of contamination caused by recirculation or re-entry of untreated or insufficiently treated airwearing protective clothing using cleaning and decontamination procedures of known effectivenessusing a closed system in productiontesting for residuesusing cleanliness status labels on equipment

Good practices in production: Prevention of cross-contamination during productionMeasures to prevent cross-contamination and their effectiveness should be checked periodically according to SOP

Production areas periodic

environmental monitoring

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Good practices in production: Processing operationsBefore any processing operation work area and equipment

clean and free from any starting materials, products, product residues, labels or documents not required for the current operation

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Good practices in production: Processing operationsAny necessary in-process controls and environmental controls should be carried out and recordedIndicate the failures of equipment or services (e.g. water, gas) to equipmentdefective EQ withdrawnafter use, production EQ

cleaned without delay,stored under clean and dry conditions in separate area

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Good practices in production: Processing operationsTime limits for storage of EQ after cleaning and before useContainers for filling should be cleaned before fillingAny significant deviation from the expected yield recorded and investigated

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Good practices in production: Processing operationsCheckspipelines and other pieces of EQ used for transportation of productsPipe used for conveying distilled or deionized water sanitized and stored according to written procedures (action limits for microbiological contamination and measures

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Good practices in production: Processing operationsEQ and instrumentsserviced and calibrated at prespecified interval records maintainedchecked daily or prior to useclearly indicated the date of calibration and servicing, recalibration (label attached to instrument)Repair and maintenance operations not present any hazard to the quality of the products

GMP for biological products :ProductionSOP for manufacturing operations: available, up dateStarting material: source, origin, method of manufacture, QCMedia and culture shall be added to fermenter and other vessels under carefully controlled conditions, avoid contamination

GMP for biological products :ProductionMedia should be sterilized in situ. In line sterilizing filters for routine addition of gases, media, acids, alkalis, deforming agents, etc. to fermenter should be used where possible.Validation of sterilization.Inactivation process: measures should be taken to avoid risk of cross-contamination between treated and untreated products.

GMP for biological products :ProductionA wide equipment used for chromatographyshould be dedicated to purification of one productshould be sterilized or sanitized between batchesdefine the life span of columns and the sterilization method

In-process controls play a specially important role in ensuring the consistent quality of biological products because certain deficiencies may not be revealed by testing the finished product.Tests that are crucial for quality control but that cannot be carried out on the finished product shall be performed at an appropriate stage of production.

Samples of intermediate and final products shall be retained in sufficient amount and under appropriate storage conditions to allow the repetition or confirmation of a batch control.Certain operations require the continuous monitoring of data during a production process e.g.monitoring and recording of physical parameters during fermentation.

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

Validation studiesanalytical testequipmentfacility systems (air, water, steam, process; manufacturing processes, cleaning, sterilization, sterile filling, lyophilization)

Separate validation for lyophilizer/ lyophilization processcleaning of glassware/ cleaning of facilitysterilization process/ sterility test

Validation studiesverify the system under test under the extremes expected during the process to prove that the system remains in control.Critical equipment and processes are routinely revalidated at appropriate intervals to demonstrate that the process remains in control.

Type of validationProspective

pre-planned protocolConcurrent

base on data collected during actual performance of a process already implemented in a manufacturing facilitysuit manufacturers of long standing, have well-controlled manufacturing processRetrospective

for production for a long time, but has not been validated according to a prospective protocol and concurrent validation is not realistic optionis not generally accepted

Type of validationLaboratory-and pilot-scale validations

some production processes cannot be carried out in production facilityremoval of impurities by individual purification steps in process- not acceptable to bring unacceptable impurities (endotoxin, unwanted protein, contaminating bacteria and virus) spike into process

Facility systems and equipment: Stage of validationDesign qualification (DQ)Installation Qualification (IQ)Operational Qualification (OQ)Performance Qualification (PQ)

Systems and EQ; PQ=validationDepending on the function and operation of some EQ

Facility systems and equipmentDesign qualification (DQ)

necessary when planning and choosing EQ or systems to ensure that components selected will have adequate capacity to function for the intended purpose, and will adequately serve the operations or functions of another piece of EQ or operation.

Facility systems and equipmentInstallation Qualification (IQ)

written for critical processing EQ and systemslist all the identification information, location, utility requirements, and any safety features of EQverify that the item matches the purchase specifications

Facility systems and equipmentOperational Qualification (OQ)

outlines the information required to provide evidence that all component of a system or of a piece of EQ operate as specified.should provide a listing of SOPs for operation, maintenance and calibrationdefine the specification and acceptance criteria include information on EQ or system calibration, pre-operational activities, routine operations and their acceptance criteria

Facility systems and equipmentPerformance Qualification (PQ)

performed after both IQ and OQ have been completed, reviewed and approveddescribes the procedures for demonstrating that a system or piece of EQ can consistently perform and meet required specification under routine operation and, where appropriate, under worst case situationsinclude description of preliminary procedures required, detailed performance tests to be done, acceptance criteriaother supporting EQ used during qualification have been validated.

Facility systems and equipmentpH meter, incubator, centrifuge, freezer; IQ,OQsystem: air (HVAC), compressed air, pure steam, raw steam, purified water, WFI, central vacuum; IQ, OQ, PQEQ: autoclave, oven, lyophilizer, continuous flow centrifuge; IQ, OQ, PQ

Process validationA process is a series of interrelated functions and activities using a variety of specified actions and EQ which is designed to produce a defined result.

Process validation studiesexamine a process under normal operating conditions to prove that the process is in controlre-validationmodification to the processproblems occurEQ or systems are changed

Process validationTo validate the reproducibility and consistency of a processfull defined process is carried out using validated EQat least 3 times, under established procedure process must successfully and consistently meet all acceptance criteria at all steps throughout the procedure at least 3 times consecutively

Validated processWorst case: to ensure that process is acceptable in the extreme case

Process validationExamplecleaningsanitizationfumigationdepyrogenation sterilizationsterile fillingfermentationbulk productionpurificationinactivationfilling, capping, sealinglyophilization

Process validationspecific process clearly described in Master formula or in SOPall EQ; identity, code number, construction, operation capacity, actual operating range processing parameter; sufficiently detailed to permit complete reproducibility (time period, pH, volume, temp.etc.)specification at each step

Process validationVery importantspecifications for a process undergoing validation be pre-determinedall critical processing parameters for which specifications have been set, there must be equipment to measure all of those parameters during the validation study

Typical content requirements for process validationsCleaning, Fumigation, Sanitization Processcollecting liquid and swab samples for testing of residual productresidual proteinendotoxin testsmicrobial tests (bioburden)chemical tests (chlorine and phosphoric acid)residual cleaning agentsconductivity testspH

As relevant to the cleaning processAll analytical tests must be validated before

Typical content requirements for process validationsSterilizationsterilization filtration of solutionsmicrobial challenge filter integrity tests performance tests

Typical content requirements for process validationsDepyrogenation process (dry heat, column chromatography, other)endotoxin content reduction of 3 logs

Typical content requirements for process validationsSterile fillingtest filling processperform filling process with nutrient media run at full scale for at least one fill sizeworst case; large volume and number of vialsfilled vials incubated, observed and test for contamination by validated sterility testmust be sterile for 3 consecutive runs media fill performed twice a yearsize of run must be large enough to detect low levels of contamination e.g. contamination rate of 1/1000, 3000 units are needed to provide 95% confidence

Typical content requirements for process validationsMock fermentationfull scale fermentation of a representative fermentation process to validate the parts of process involving connections, sampling, and additions of nutrients etc.fermentor prepared and operated in simulated process with uninoculated nutrient mediaprocess follow the full fermentation process3 consecutive runs at each stage

Typical content requirements for process validationsProduction processes(fermentation, bulk production, purification, filling, lyophilization)run according to approved Master formula including all raw material, personnel, equipment, and facility preparations, in-process tests, processing, through to final testing of the batch lot.all facility systems must be monitored3 consecutive lots must be produced and all facility, EQ, support systems, product spec, and process being validated must pass at all steps

Validation: Type of DocumentationValidation master plan (VMP)Validation protocol (VP)Validation reports (VR)Standard operating procedures (SOPs)

Master validation plan (MVP)is a document pertaining to the whole facility that describes which EQ, systems, methods and processes will be validated and when they will be validated.provide the format required for each particular validation document (IQ, OQ, PQ for EQ and systems; process validation, analytical assay validation)

Master validation plan (MVP)indicate what information is to be contained within each documentindicate why and when revalidations will be performedwho will decide what validations will be performedorder in which each part of the facility is validated

Master validation plan (MVP)indicate how to deal with any deviationsstate the time interval permitted between each validation

Validation: VMPEnables overview of entire validation projectList items to be validated with planning schedule as its heartlike a map

Validation: In summary, VMP should contain at leastValidation policyOrganizational structureSummary of facilities, systems, equipment, processes to be validatedDocumentation format for protocols and reports Planning and schedulingChange controlTraining requirements

Validation: ProtocolObjectives of the validation and qualification studySite of the studyResponsible personnelDescription of the equipmentSOPsStandardsCriteria for the relevant products and processes

Validation: ReportTitleobjective of the studyRefer to the protocolDetails of materialEquipmentProgrammes and cycles useDetails of procedures and test methods

Validation: changes that require revalidationSoftware changes; controllersSite changes; operational changesChange of source of materialChange in the processSignificant equipment changesProduction area changesSupport system changes