Good Manufacturing Practices

Dr AJ van Zyl for Quality Assurance and Safety: Medicines Medicines Policy and Standards Health Technology and Pharmaceuticals Cluster World Health Organization

Guilin, PRC

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 Incoming goods Corridor Corridor Raw Materials & Packaging Weighing Storage

Offices Gowning

Canteen Shipping

Corridor

Zone: Clean
Processing Filling Packaging Finished Products Storage

Zone: Packaging Zone: Controlled

Washing

Machine Shop Corridor Waste Treatment

Utilities and Services

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 Incoming goods Corridor Corridor Raw Materials & Packaging Weighing Storage

Offices Gowning

Canteen Shipping

Corridor

Red: Supply
Filling Packaging Finished Products Storage

Green: Exhaust

Processing

Washing

Machine Shop Corridor Waste Treatment

Utilities and Services

Problems with components

Filters Fan Flow rate controller

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

Control damper
Humidifier Cooling coil 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 Relative humidity Particulate matter Air movement and pressure differentials Cooling coil Dehumidifier Filters Fan

Re-circulation Air System

A IRHA NDLINGU NIT
SECONDARY FILTER COOLING COIL PRIMARY FILTER SUPPLY AIR FAN

HEPA FILTER

HEPA filters installed?

Production Room

ISPE Baseline Vol. 2 #6.3.3 (d) WHO HVAC Guideline

Typical de-ionizer schematic

from water softener HCl NaOH

6 5 4 3 2 1

6
5 4 3 2 1

Water must be UV light kept circulating

Cationic column

Anionic column

Cartridge filter 5 m

Cartridge filter 1 m Ozone generator

Eluates to neutralization 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