gmp production

Good Manufacturing PracticesGuilin, PRCDr AJ van Zyl for Quality Assurance and Safety: MedicinesMedicines Policy and StandardsHealth Technology and Pharmaceuticals ClusterWorld Health Organization

ProgramGood Manufacturing Practices

Presentation on GMP (Production focus)Product specific focusGroup session

Presentation on GMP (QC focus)Product specific focusGroup session

Guidelines and referencesGMP: World Health Organization

WHO Technical Report Series, No. 908, 2003, Annex 4. Good Manufacturing Practices for pharmaceutical products: main principles

WHO Technical Report Series, No. Annex 3. Water

WHO Technical Report Series, No. Annex 3. HVAC

Good Manufacturing Practices (GMP)IntroductionGeneral considerationsGlossary

Quality management in the drug industry: philosophy and essentialelements

1. Quality assurance2. Good manufacturing practices for pharmaceutical products (GMP)3. Sanitation and hygiene4. Qualification and validation5. Complaints6. Product recalls7. Contract production and analysisGeneralThe contract giverThe contract accepterThe contract

Good Manufacturing Practices (GMP)8. Self-inspection and quality auditsItems for self-inspectionSelf-inspection teamFrequency of self-inspectionSelf-inspection reportFollow-up actionQuality auditSuppliers audits and approval9. PersonnelGeneralKey personnel10. Training11. Personal hygiene12. PremisesGeneralAncillary areasStorage areasWeighing areasProduction areasQuality control areas

Good Manufacturing Practices (GMP)13. Equipment14. MaterialsGeneralStarting materialsPackaging materialsIntermediate and bulk productsFinished productsRejected, recovered, reprocessed and reworked materialsRecalled productsReturned goodsReagents and culture mediaReference standardsWaste materialsMiscellaneous15. DocumentationGeneralDocuments required

Good Manufacturing Practices (GMP)

16. Good practices in productionGeneralPrevention of cross-contamination and bacterial contamination duringproductionProcessing operationsPackaging operations

17. Good practices in quality controlControl of starting materials and intermediate, bulk and finished productsTest requirementsBatch record reviewStability studies

Good Manufacturing Practices (GMP)ProductionUtilitiesEquipmentDosage form and data verification (development, validation, biobatch, stability, BMR and specification)Quality controlAPI, excipientsPackaging materialData verification (e.g. stability)

Good Manufacturing Practices (GMP)ProductionProduct focusPremisesUtilitiesEquipmentDosage form and data verification (development, validation, biobatch, stability, BMR and specification)Documentation

Good Manufacturing Practices (GMP)Where to start the inspection?Facility layoutFlow of personnel and material, activitiesProduct listType of products, dosage forms, activitiesUtilities (HVAC, water, etc)Validation status

Zone: Clean Zone: Packaging Zone: ControlledExample of Materials and People Flow

Incoming goods

Q C

Offices

Gowning

Canteen

Shipping

Corridor

Corridor

Raw

Materials & Packaging Storage

Corridor

Finished

Products

Storage

Weighing

Processing

Filling

Packaging

Washing

Machine

Shop

Corridor

Utilities and Services

Waste Treatment

Facility layoutFlow of personnel and material, activities

Sampling (starting materials and packaging materials)WeighingMixingMillingSieving/sifting/screeningGranulationDryingSievingBlendingCompression


In process bulk storesPackaging areas (primary and secondary packaging)Finished product

Product listType of products, dosage forms, activities

Multi-productVarious tablets Uncoated artesunate

Risk of cross-contamination and contaminationNon dedicated areas and equipmentBatch to batch consistency


Batch Manufacturing DocumentFormula and manufacturing stepsAPI and excipientsProperties and requirements for temperature or RH controlMaterial quantities, batch sizeSub lotsEquipment and utilitiesProduction areas

Equipment and utilities (1)Sieving/sifting sifter (e.g. vibrosifter)Mixing mixerGranulation - granulatorDrying fluid bed drierBlending octagonal blenderCompression compression machinePackaging - blister machine

Others include Metal detector, sieves, punches and dies

In process quality control instruments and equipment may include hardness tester, disintegration tester, balance, caliper

Equipment and utilities (2)HVAC air supply and extractionCompressed air machine operation, drying of equipment and partsWater washing, rinsing, manufactureSteam cleaning

Utilities

The environment may be influenced by: LightTemperatureHumidityAir movementMicrobial contaminationParticulate contamination

Uncontrolled environments can lead to:Product degradationProduct contamination Loss of Product & Profit

Utilities

HVAC: GMP and GEPEffective ventilationCross-contamination and contaminationQualification/validationDesignInstallationOperationPerformance

Red: Supply Green: Exhaust Air supply and extraction

Incoming goods

Q C

Offices

Gowning

Canteen

Shipping

Corridor

Corridor

Raw

Materials & Packaging Storage

Corridor

Finished

Products

Storage

Weighing

Processing

Filling

Packaging

Washing

Machine

Shop

Corridor

Utilities and Services

Waste Treatment

Problems with componentsFilters

Fan

Flow rate controller Control damper Humidifier Cooling coil

Ducts

Incorrect retention rate/leaking/badly installed Low air flow loss of pressure cascade

Blocked poor pressure cascade cross-contamination Poorly adjusted, bad pressure differential system Bad water/steam quality/poor drainage/ No elimination of condensed water/poor drainage/stagnating water Inappropriate material/internal insulationLeaking ducts

Utilities: Water systemsType of waterIntended useQuality (specification)Design of the systemQualification and validationOngoing monitoring and quality controlSampling, testing, trends

Validation statusValidation Master Plan

Manufacturing areasUtilitiesEquipmentManufacturing processCleaning validationComputer systemsOthers

On site verificationFrom receiving to storesSampling and weighingManufacturing areas

UtilitiesDocumentation review

Sampling and weighing

Weighing

Granulation

Blending

Blister line

Examples of control measures:

Re-circulation Air SystemISPE Baseline Vol. 2 #6.3.3 (d)WHO HVAC GuidelineHEPA filters installed?

Documentation review

HVACDQ, IQ, OQ, PQImportant aspects including air flow direction, filtration, air changes, pressure differentials

WaterDQ, IQ, OQ, PQSampling and testing


Equipment and utilitiesSOPs (operation, cleaning, calibration)Records and use logsCalibration records/certificatesPreventative maintenance and maintenanceQualification


Product relatedBatch Manufacturing document as per product dossierProcess Validation protocol and reportBio-batch recordsStability batchesBatch records


Other documentsSOPs including:CleaningComplaintsRecallsValidation protocols and reports including:Cleaning validationComputer validation


Inspection of the quality control laboratory

Group sessionGroup 1

Group 2


Q


Q

This sheet shows the flow of material and personnel. The green arrows indicate the material flow, and show materials that are brought in each room through the corridor zone. The cubicle between the corridor and the work zone may be an airlock, but in some countries this is required to be an air shower.The red arrows indicate the people flow and show how people enter each room through the corridor divided by the zones. HEPA filters must be installed!Note final filtration is in the AHUThis schematic drawing of a typical de-ionizer is given in handout 2-2-8. Use it to explain the pathway of water through a twin bed de-ionizer.

Softened water enters at the top right into the twin bed de-ionizer. Cation and anion exchange agents are resins with large surface areas. Cations are exchanged for H+, anions for OH-, the combination is H-OH, or water! After Cation and anion exchange, the water is filtered (to remove resin particles and sometimes bacteria) before being re-circulated through the distribution system and returned to the de-ionizer, usually via a buffer tank. The Cation and anion resins are regenerated using hydrochloric acid and sodium hydroxide respectively. There should be specifications available for these two materials for the inspector to check.

Mixed bed de-ionizers are also common. They may be more prone to bacterial contamination and so the inspector should check them carefully.They should be disinfected at regular intervals.

Heat is not a option, because of the resin material. Furthermore, many of the de-ionizers are made of plastic materials. However, the regenerating chemicals are very effective biocides and so the system should be regenerated frequently, at least once a week, regardless of the conductivity readings. Inspectors should ask for the sanitation records so that these can be checked.

Disinfection of the circulating water is necessary; this can be achieved by inline UV irradiation and or ozonization.