gmp production
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Good Manufacturing PracticesGuilin, PRCDr AJ van Zyl for Quality Assurance and Safety: MedicinesMedicines Policy and StandardsHealth Technology and Pharmaceuticals ClusterWorld Health Organization
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ProgramGood Manufacturing Practices
Presentation on GMP (Production focus)Product specific focusGroup session
Presentation on GMP (QC focus)Product specific focusGroup session
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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
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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
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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
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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
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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
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Good Manufacturing Practices (GMP)ProductionUtilitiesEquipmentDosage form and data verification (development, validation, biobatch, stability, BMR and specification)Quality controlAPI, excipientsPackaging materialData verification (e.g. stability)
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Good Manufacturing Practices (GMP)ProductionProduct focusPremisesUtilitiesEquipmentDosage form and data verification (development, validation, biobatch, stability, BMR and specification)Documentation
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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
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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
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Facility layoutFlow of personnel and material, activities
Sampling (starting materials and packaging materials)WeighingMixingMillingSieving/sifting/screeningGranulationDryingSievingBlendingCompression
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Facility layoutFlow of personnel and material, activities
In process bulk storesPackaging areas (primary and secondary packaging)Finished product
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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
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Facility layoutFlow of personnel and material, activities
Batch Manufacturing DocumentFormula and manufacturing stepsAPI and excipientsProperties and requirements for temperature or RH controlMaterial quantities, batch sizeSub lotsEquipment and utilitiesProduction areas
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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
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Equipment and utilities (2)HVAC air supply and extractionCompressed air machine operation, drying of equipment and partsWater washing, rinsing, manufactureSteam cleaning
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Utilities
The environment may be influenced by: LightTemperatureHumidityAir movementMicrobial contaminationParticulate contamination
Uncontrolled environments can lead to:Product degradationProduct contamination Loss of Product & Profit
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Utilities
HVAC: GMP and GEPEffective ventilationCross-contamination and contaminationQualification/validationDesignInstallationOperationPerformance
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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
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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
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Utilities: Water systemsType of waterIntended useQuality (specification)Design of the systemQualification and validationOngoing monitoring and quality controlSampling, testing, trends
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Validation statusValidation Master Plan
Manufacturing areasUtilitiesEquipmentManufacturing processCleaning validationComputer systemsOthers
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On site verificationFrom receiving to storesSampling and weighingManufacturing areas
UtilitiesDocumentation review
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Sampling and weighing
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Weighing
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Granulation
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Blending
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Blister line
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AHU
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Examples of control measures:
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Re-circulation Air SystemISPE Baseline Vol. 2 #6.3.3 (d)WHO HVAC GuidelineHEPA filters installed?
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Documentation review
HVACDQ, IQ, OQ, PQImportant aspects including air flow direction, filtration, air changes, pressure differentials
WaterDQ, IQ, OQ, PQSampling and testing
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Documentation review
Equipment and utilitiesSOPs (operation, cleaning, calibration)Records and use logsCalibration records/certificatesPreventative maintenance and maintenanceQualification
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Documentation review
Product relatedBatch Manufacturing document as per product dossierProcess Validation protocol and reportBio-batch recordsStability batchesBatch records
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Documentation review
Other documentsSOPs including:CleaningComplaintsRecallsValidation protocols and reports including:Cleaning validationComputer validation
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Documentation review
Inspection of the quality control laboratory
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Group sessionGroup 1
Group 2
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Documentation review
Q
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Documentation review
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.
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