Good Manufacturing
Practices
Guilin, PRC
Dr AJ van Zyl
for
Quality Assurance and Safety: Medicines
Medicines Policy and Standards
Health Technology and Pharmaceuticals Cluster
World Health Organization
Program
Good Manufacturing Practices
• Presentation on GMP (Production
focus)
• Product specific focus
• Group session
• Presentation on GMP (QC focus)
• Product specific focus
• Group session
Guidelines 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
Practices (GMP)
Introduction
General considerations
Glossary
Quality management in the drug industry: philosophy and
essential
elements
1. Quality assurance
2. Good manufacturing practices for pharmaceutical products
(GMP)
3. Sanitation and hygiene
4. Qualification and validation
5. Complaints
6. Product recalls
7. Contract production and analysis
General
The contract giver
The contract accepter
The contract
Good Manufacturing
Practices (GMP)
8. Self-inspection and quality audits
Items for self-inspection
Self-inspection team
Frequency of self-inspection
Self-inspection report
Follow-up action
Quality audit
Suppliers’ audits and approval
9. Personnel
General
Key personnel
10. Training
11. Personal hygiene
12. Premises
General
Ancillary areas
Storage areas
Weighing areas
Production areas
Quality control areas
Good Manufacturing
Practices (GMP)
13. Equipment
14. Materials
General
Starting materials
Packaging materials
Intermediate and bulk products
Finished products
Rejected, recovered, reprocessed and reworked
materials
Recalled products
Returned goods
Reagents and culture media
Reference standards
Waste materials
Miscellaneous
15. Documentation
General
Documents required
Good Manufacturing
Practices (GMP)
16. Good practices in production
General
Prevention of cross-contamination and
bacterial contamination during production
Processing operations
Packaging operations
17. Good practices in quality control
Control of starting materials and intermediate,
bulk and finished products
Test requirements
Batch record review
Stability studies
Good Manufacturing
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
Practices (GMP)
Production
•Product focus
•Premises
•Utilities
•Equipment
•Dosage form and data
verification (development,
validation, biobatch, stability,
BMR and specification)
•Documentation
Good Manufacturing
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
Example of Materials and People Flow
QC
Offices
Canteen
Gowning
Incoming
goods
Corridor
Shipping
Corridor
Corridor
Raw
Materials
&
Packaging Weighing
Storage
Zone: Clean
Processing
Filling
Packaging Finished
Products
Storage
Zone: Packaging
Zone: Controlled
Washing
Machine
Shop
Utilities and Services
Corridor
Waste Treatment
Facility layout
Flow of personnel and material,
activities
• Sampling (starting materials and
packaging materials)
• Weighing
• Mixing
• Milling
• Sieving/sifting/screening
• Granulation
• Drying
• Sieving
• Blending
• Compression
Facility layout
Flow of personnel and material,
activities
• In process bulk stores
• Packaging areas (primary and
secondary packaging)
• Finished product
Product list
Type 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 layout
Flow 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 – mixer
Granulation - granulator
Drying – fluid bed drier
Blending – octagonal blender
Compression – compression machine
Packaging - 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
Utilities
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
Utilities
HVAC: GMP and GEP
• Effective ventilation
• Cross-contamination and
contamination
• Qualification/validation
• Design
• Installation
• Operation
• Performance
Air supply and extraction
QC
Offices
Canteen
Gowning
Incoming
goods
Corridor
Shipping
Corridor
Corridor
Raw
Materials
&
Packaging Weighing
Storage
Red: Supply
Processing
Washing
Filling
Packaging Finished
Products
Storage
Machine
Shop
Utilities and Services
Corridor
Waste Treatment
Green: Exhaust
Problems with components

Filters

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 ® crosscontamination
Poorly adjusted, bad pressure differential
system
Bad water/steam quality/poor drainage/
No elimination of condensed water/poor
drainage/stagnating water
Inappropriate material/internal insulation
Leaking ducts
Utilities: 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 status
• Validation Master Plan
• Manufacturing areas
• Utilities
• Equipment
• Manufacturing process
• Cleaning validation
• Computer systems
• Others…
On site verification
• From receiving to stores
• Sampling and weighing
• Manufacturing areas
• Utilities
• Documentation review
Sampling and weighing
Powder
Container
Floor Scale
Weighing
Granulation
Blending
Blister line
AHU
Examples of control measures:
Temperature
Cooling coil
Relative humidity
Dehumidifier
Particulate matter
Filters
Air movement and
pressure
differentials
Fan
Re-circulation Air System
F
HEPA
FILTER
SECONDARY
FILTER
SUPPLY
AIR FAN
COOLING COIL
PRIMARY
FILTER
AIRHANDLINGUNIT
S
R
HEPA filters
installed?
Production
Room
ISPE Baseline Vol. 2 #6.3.3 (d)
WHO HVAC Guideline
Typical de-ionizer schematic
from water softener
Water
must be
UV light
kept
circulating
HCl
NaOH
6
6
5
4
3
2
1
5
4
3
2
1
Cationic column
Anionic column
Cartridge
filter 5 µm
Eluates to
neutralization
plant
Cartridge
filter 1 µm
Ozone generator
Hygienic pump
Return to de-ioniser
Outlets or storage.
Drain line
Air break to sewer
Documentation 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 review
Equipment and utilities
• SOPs (operation, cleaning,
calibration)
• Records and use logs
• Calibration records/certificates
• Preventative maintenance and
maintenance
• Qualification
Documentation review
Product related
• Batch Manufacturing document as
per product dossier
• Process Validation protocol and
report
• Bio-batch records
• Stability batches
• Batch records
Documentation review
Other documents
• SOPs including:
•Cleaning
•Complaints
•Recalls
• Validation protocols and reports
including:
•Cleaning validation
•Computer validation
Documentation review
• Inspection of the quality control
laboratory…
Group session
• Group 1
• Group 2
Documentation review
• Q
Documentation review
• Q