1. 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

2. Program Good Manufacturing Practices
Presentation on GMP (Production focus)
Product specific focus
Group session
Presentation on GMP (QC focus)

3. 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

4. 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

5. 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
Ancillary areas
Storage areas
Weighing areas
Production areas
Quality control areas

6. 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
Documents required

7. 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

8. 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)

9. Good Manufacturing Practices (GMP)
Production
Product focus
Premises
Utilities
Equipment
Dosage form and data verification (development, validation, biobatch, stability, BMR and specification)
Documentation

10. 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

11. Example of Materials and People Flow
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.
Zone: Clean
Zone: Packaging
Zone: Controlled

12. 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

13. Facility layout Flow of personnel and material, activities
In process bulk stores
Packaging areas (primary and secondary packaging)
Finished product

14. 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

15. 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

16. 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

17. Equipment and utilities (2)
HVAC – air supply and extraction
Compressed air – machine operation, drying of equipment and parts
Water – washing, rinsing, manufacture
Steam – cleaning

18. 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

19. Utilities HVAC: GMP and GEP Effective ventilation
Cross-contamination and contamination
Qualification/validation
Design
Installation
Operation
Performance

20. Air supply and extraction
Red: Supply
Green: Exhaust

21. 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 ® 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 insulation
Leaking ducts

22. 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

23. Validation status Validation Master Plan Manufacturing areas Utilities
Equipment
Manufacturing process
Cleaning validation
Computer systems
Others…

24. On site verification From receiving to stores Sampling and weighing
Manufacturing areas
Utilities
Documentation review

25. Sampling and weighing

26. Weighing

27. Granulation

28. Blending

29. Blister line

30. AHU

31. Examples of control measures:
Temperature
Cooling coil
Relative humidity
Dehumidifier
Particulate matter
Filters
Air movement and pressure differentials
Fan

32. Re-circulation Air System
HEPA filters installed?
HEPA filters must be installed!
Note final filtration is in the AHU
ISPE Baseline Vol. 2 #6.3.3 (d)
WHO HVAC Guideline

33. Typical de-ionizer schematic
Cationic column
Anionic column
Hygienic pump
Outlets or storage.
Ozone generator
UV light
HCl
NaOH
Eluates to
neutralization
plant
Air break to sewer
Drain line
from water softener
Water must be kept circulating
Typical de-ionizer schematic 1 2 3 4 5 6
Return to de-ioniser
Cartridge
filter 5 µm
filter 1 µm
This schematic drawing of a typical de-ionizer is given in handout 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.

34. Documentation review
HVAC
DQ, IQ, OQ, PQ
Important aspects including air flow direction, filtration, air changes, pressure differentials
Water
Sampling and testing

35. Documentation review
Equipment and utilities
SOPs (operation, cleaning, calibration)
Records and use logs
Calibration records/certificates
Preventative maintenance and maintenance
Qualification

36. Documentation review
Product related
Batch Manufacturing document as per product dossier
Process Validation protocol and report
Bio-batch records
Stability batches
Batch records

37. Documentation review
Other documents
SOPs including:
Cleaning
Complaints
Recalls
Validation protocols and reports including:
Cleaning validation
Computer validation

38. Documentation review
Inspection of the quality control laboratory…

39. Group session
Group 1
Group 2

40. Documentation review Q

41. Documentation review Q