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 duringproduction
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 Shipping
Corridor
Corridor
Cor r idor
Raw
Zone: Clean
Materials F inished
P ackaging
& Filling P r oduct s
Packaging Weighing P r ocessing
St or a ge Packaging
Storage

Washing Machine
Shop Controlled
Cor r idor
Ut ilit ies and Ser vices Wast e Tr eat m ent
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 Shipping
Corridor
Corridor
Cor r idor
Red: Supply
Raw
Materials F inished
P ackaging
& Filling P r oduct s
Packaging Weighing P r ocessing Green: Exhaust
St or age
Storage

Washing Machine
Shop

Cor r idor
Ut ilit ies a nd Ser vices Wast e Tr ea t m ent
Problems with components
 Filters Incorrect retention rate/leaking/badly
installed
 Fan Low air flow ® loss of pressure cascade

 Flow rate controller Blocked ® poor pressure cascade ® cross-

contamination
 Control damper Poorly adjusted, bad pressure differential
system
 Humidifier Bad water/steam quality/poor drainage/

 Cooling coil No elimination of condensed water/poor

drainage/stagnating water

 Ducts 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

P o w d e r F lo o r S c a le
C o n t a in e r
Weighing
Granulation
Blending
Blister line
AHU
Examples of control measures:

Temperature Cooling coil

Relative humidity Dehumidifier

Particulate matter Filters

Air movement and Fan

pressure
differentials
Re-circulation Air System
A IR H A N D LIN G U N IT

S E C O N D A R Y
C O O L IN G C O IL
P R IM A R Y

A IR F A N
S U P P LY

F IL T E R

F IL T E R
H E P A
F IL T E R
F
S

HEPA filters
installed?
P r o d u c tio n
R oom

ISPE Baseline Vol. 2 #6.3.3 (d)

WHO HVAC Guideline
Typical de-ionizer schematic
from water softener
HCl NaOH

6 6
5 5
4 4
3 3
2 2
1 1

Water
must be Cationic column Anionic column Cartridge Cartridge
filter 5 µm filter 1 µm
kept UV light

circulating Eluates to
neutralization
Ozone generator

plant
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