Transcript
Good Manufacturing Practices
Guilin, PRCDr AJ van Zyl
for Quality Assurance and Safety: Medicines
Medicines Policy and StandardsHealth Technology and Pharmaceuticals Cluster
World Health Organization
ProgramProgramGood Manufacturing Practices
• Presentation on GMP (Production
focus)• Product specific focus• Group session
• Presentation on GMP (QC focus)• Product specific focus• Group session
Guidelines and referencesGuidelines and references
GMP: 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 Good Manufacturing Practices (GMP)Practices (GMP)
IntroductionGeneral considerationsGlossary
Quality management in the drug industry: philosophy and essential
elements
1. Quality assurance2. Good manufacturing practices for pharmaceutical products
(GMP)3. Sanitation and hygiene4. Qualification and validation5. Complaints6. Product recalls7. Contract production and analysis
GeneralThe contract giverThe contract accepterThe contract
Good Manufacturing Good Manufacturing Practices (GMP)Practices (GMP)
8. Self-inspection and quality auditsItems for self-inspectionSelf-inspection teamFrequency of self-inspectionSelf-inspection reportFollow-up actionQuality auditSuppliers’ audits and approval
9. PersonnelGeneralKey personnel
10. Training11. Personal hygiene12. Premises
GeneralAncillary areasStorage areasWeighing areasProduction areasQuality control areas
Good Manufacturing Good Manufacturing Practices (GMP)Practices (GMP)
13. Equipment14. Materials
GeneralStarting materialsPackaging materialsIntermediate and bulk productsFinished productsRejected, recovered, reprocessed and reworked materialsRecalled productsReturned goodsReagents and culture mediaReference standardsWaste materialsMiscellaneous
15. DocumentationGeneralDocuments required
Good Manufacturing Good Manufacturing Practices (GMP)Practices (GMP)
16. Good practices in productionGeneralPrevention of cross-contamination and bacterial contamination during productionProcessing operationsPackaging operations
17. Good practices in quality controlControl of starting materials and intermediate, bulk and finished productsTest requirementsBatch record reviewStability studies
Good Manufacturing Good Manufacturing Practices (GMP)Practices (GMP)
Production
•Utilities
•Equipment
•Dosage form and data
verification (development,
validation, biobatch, stability,
BMR and specification)
Quality control
•API, excipients
•Packaging material
•Data verification (e.g. stability)
Good Manufacturing Good Manufacturing Practices (GMP)Practices (GMP)
Production
•Product focus
•Premises
•Utilities
•Equipment
•Dosage form and data
verification (development,
validation, biobatch, stability,
BMR and specification)
•Documentation
Good Manufacturing Good Manufacturing Practices (GMP)Practices (GMP)
Where to start the inspection?
• Facility layout
•Flow of personnel and
material, activities
• Product list
•Type of products, dosage
forms, activities
• Utilities (HVAC, water, etc)
• Validation status
Q C
Offices Gowning
Canteen
Incoming goods
Corridor
Corridor
Shipping
Corridor
Packaging
Weighing Processing
Filling
Raw Materials
& Packaging Storage
Washing
Machine
Shop
Finished Products Storage
Corridor Utilities and Services Waste Treatment
Zone: Clean Zone: Packaging Zone: Controlled
Example of Materials and People Flow
Facility layoutFlow of personnel and material,
activities• Sampling (starting materials and
packaging materials)• Weighing• Mixing• Milling• Sieving/sifting/screening• Granulation• Drying• Sieving• Blending• Compression
Facility layoutFlow of personnel and material,
activities
• In process bulk stores• Packaging areas (primary and
secondary packaging)• Finished product
Product listType of products, dosage forms,
activities
• Multi-product
• Various tablets
• Uncoated artesunate
• Risk of cross-contamination and
contamination
• Non dedicated areas and
equipment
• Batch to batch consistency
Facility layoutFlow of personnel and material,
activities
Batch Manufacturing Document
• Formula and manufacturing steps
• API and excipients
• Properties and requirements for
temperature or RH control
• Material quantities, batch size
• Sub lots
• Equipment and utilities
• Production 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 extraction
• Compressed air – machine
operation, drying of equipment and
parts
• Water – washing, rinsing,
manufacture
• Steam – cleaning
UtilitiesUtilities
The environment may be influenced by: • Light• Temperature• Humidity• Air movement• Microbial contamination• Particulate contamination
• Uncontrolled environments can lead to:• Product degradation• Product contamination • Loss of Product & Profit
UtilitiesUtilities
HVAC: GMP and GEP
• Effective ventilation
• Cross-contamination and
contamination
• Qualification/validation
• Design
• Installation
• Operation
• Performance
Q C
Offices Gowning
Canteen
Incoming goods
Corridor
Corridor
Shipping
Corridor
Packaging
Weighing Processing
Filling
Raw Materials
& Packaging Storage
Washing
Machine
Shop
Finished Products Storage
Corridor Utilities and Services Waste Treatment
Red: Supply Green: Exhaust
Air supply and extraction
Problems with componentsProblems with components
FiltersFilters
FanFan
Flow rate controllerFlow rate controller
Control damperControl damper
HumidifierHumidifier
Cooling Cooling coilcoil
DuctsDucts
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 systemsUtilities: Water systems
• Type of water
• Intended use
• Quality (specification)
• Design of the system
• Qualification and validation
• Ongoing monitoring and quality
control
• Sampling, testing, trends
Validation statusValidation status
• Validation Master Plan
• Manufacturing areas
• Utilities
• Equipment
• Manufacturing process
• Cleaning validation
• Computer systems
• Others…
On site verificationOn site verification
• From receiving to stores
• Sampling and weighing
• Manufacturing areas
• Utilities
• Documentation review
Sampling and weighingSampling and weighing
P ow derC ontainer
F loor S cale
WeighingWeighing
GranulationGranulation
BlendingBlending
Blister lineBlister line
AHUAHU
Examples of control measures:Examples of control measures:
TemperatureTemperature Cooling coilCooling coil
Relative humidityRelative humidity DehumidifierDehumidifier
Particulate matterParticulate matter FiltersFilters
Air movement and Air movement and pressure pressure differentialsdifferentials
FanFan
Re-circulation Air SystemRe-circulation Air System
ISPE Baseline Vol. 2 #6.3.3 (d)
WHO HVAC Guideline
ProductionR oom
F
HEP
AFI
LTER
SEC
ON
DAR
YFI
LTER
CO
OLI
NG
CO
IL
PRIM
ARY
FILT
ER
SUPP
LYAI
R F
AN
AIR HANDLING UNIT
R
S
HEPA filters installed?
Cationic column Anionic column
Hygienic pump
Outlets or storage.
Ozone generator
UV light
HCl NaOH
Eluates toneutralization
plant
Air break to sewer
Drain line
from water softener
Water must be kept circulating
Typical de-ionizer schematic
12345
6
12345
6
Return to de-ioniser
Cartridgefilter 5 µm
Cartridgefilter 1 µm
Documentation reviewDocumentation review
HVAC
• DQ, IQ, OQ, PQ
• Important aspects including air
flow direction, filtration, air
changes, pressure differentials
Water
• DQ, IQ, OQ, PQ
• Sampling and testing
Documentation reviewDocumentation review
Equipment and utilities
• SOPs (operation, cleaning,
calibration)
• Records and use logs
• Calibration records/certificates
• Preventative maintenance and
maintenance
• Qualification
Documentation reviewDocumentation review
Product related
• Batch Manufacturing document as
per product dossier
• Process Validation protocol and
report
• Bio-batch records
• Stability batches
• Batch records
Documentation reviewDocumentation review
Other documents
• SOPs including:
•Cleaning
•Complaints
•Recalls
• Validation protocols and reports
including:
•Cleaning validation
•Computer validation
Documentation reviewDocumentation review
• Inspection of the quality control
laboratory…
Group sessionGroup session
• Group 1
• Group 2
Documentation reviewDocumentation review
• Q
Documentation reviewDocumentation review
• Q
top related