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