| slide 1 of 37 april 2007 training workshop on pharmaceutical development with focus on paediatric...

| Slide 1 of 37 April 2007

Training Workshop on Pharmaceutical Development

with focus on Paediatric Formulations

Protea Hotel

Victoria Junction, Waterfront

Cape Town, South Africa

Date: 16 to 20 April 2007

Pharmaceutical DevelopmentPharmaceutical Development


Pharmaceutical DevelopmentPharmaceutical Development

Good Manufacturing Practices (GMP) and Inspections

Presenter: Dr AJ van Zyl

Prequalification Programme: Priority Essential Medicines, HTP/PSM/QSM

World Health Organization, 20 Ave Appia, 1211 Geneve, 27 Switzerland

[email protected]


Good Manufacturing Practices (GMP) and InspectionsGood Manufacturing Practices (GMP) and Inspections

Outline and Objectives of presentation

Introduce WHO GMP texts– Main principles– Supplements– Others

In the context of Prequalification

Current and future approaches



WHO GMP text: Main principles

WHO Technical Report Series, No. 908, 2003– Annex 4

Regularly reviewed and updated

Divided into "chapters" or "quality systems"

Quality assurance



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

8. Self-inspection and quality audits



9. Personnel

10. Training

11. Personal hygiene

12. Premises

13. Equipment

14. Materials

15. Documentation

16. Good practices in production

17. Good practices in quality control



Supplements:

Sterile products

Herbal medicines

Radiopharmaceuticals

HVAC

Water systems

Sampling etc



Others:

PIC/S guidelines

ISO guidelines– Sampling– Risk management– Clean rooms

ICH guidelines– ICH Q9

USA FDA– Guidelines and guidance



Context in Prequalification

Product specific (dosage form) inspections

SOPs followed:– Planning, preparation, conduct, report– Inspection team

Appropriate guidelines used

Report with references to text, and rating – Critical, major, minor



A critical deficiency was defined as a deficiency which had produced, or led to a significant risk of producing, either a product which was harmful to the human patient or a product which could result in a harmful residue in a food producing animal.

A major deficiency was defined as a non-critical deficiency, which had produced or might produce a product which did not comply with its marketing authorisation.

A minor deficiency was defined as a deficiency where an observation made could improve the quality system and quality assurance approach of the manufacturer, but which did not have a major impact on the quality of the product.



Inspection approach

Normally a "routine type" of GMP inspection

Opening meeting, follow the flow, closing meeting

On site inspection (production and quality control) and documentation review

Quality systems approach

Modern challenges including risk assessment



Guiding principles:

Risk based orientation

Science based policies and standards

Integrated quality systems

International standards

Public interest



Product quality and performance ensured through– design (manufacturing processes)

Product and process specifications– Understanding of affect of formulation and process factors

on product quality and performance

Quality by design (build quality into the product)

Interaction between review, compliance and inspection



Quality by design (QbD)

Means designing and developing formulations and manufacturing processes to ensure predefined product quality

Understanding and controlling formulation and manufacturing process variables affecting the quality of a product



Where to start in the inspection to assess GMP compliance?


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

PremisesPremises

Example of Materials and People Flow

Arrival of goods Entrance for visitors Entrance for Workers Shipment of goods

Material Flow

People Flow

Zone: Clean

Zone: Packaging

Zone: Controlled


Premises and personnel entryPremises and personnel entry

TOILETS

AIRLOCK

CANTEEN

FACTORY CHANGEROOM


Material entryMaterial entry

Separate receiving and dispatch bays

Materials and products protected from weather

Area to clean incoming materials provided


Basic Principles of GMPBasic Principles of GMP


EquipmentEquipment

Contents and direction of flow indicated

e.g. water lines, equipment components, air-handling systems


EquipmentEquipment

All aspects including

Design, installation, operation, performance, specifications, logs, maintenance, use, cleaning, qualification, calibration etc…


Qualification and ValidationQualification and Validation


DocumentationDocumentation



Utilities

HVAC

Water

Compressed air

Steam . . .


PrefilterAir flow patterns

AHU

Main filter

Uni-directional TurbulentTurbulent

1 2 3

HVAC


+

Production Room

Exhaust air treatment

Central air handling unit

Terminal air treatmentat production room level

Fresh air treatment (make-up air)

HVAC Main subsystems


Qualification – examples of aspects to consider in qualification (OQ, PQ)

Test

Differential pressure on filters

Turbulent / mixed airflow

Description Uni-directional airflow / LAF

Room differential pressure

Airflow velocity / uniformity

Airflow volume / rate

Parallelism

Air flow pattern

2 2

N/A 2, 3

2, 3 Optional

2 2

2 N/A

2 3

1 := As built (ideally used to perform IQ)

2 = At rest (ideally used to perform OQ)

3 = Operational (ideally used to perform PQ)

HVAC


raw water in

« S” trap to sewer

Water is kept circulating

To water softener & DI plant

Pretreatment – schematic drawing

cartridgefilter

5 micrometers

activatedcarbon

filter

spray ball

break tank

air break to draincentrifugal pump

air filter

floatoperated

valvesand filter

excess water recycledfrom deioniser

Water for Pharmaceutical Use


Separate guideline in addition to basic GMP

Part 1: Management and organization

Part 2: Materials, equipment, instruments and devices

Part 3: Working procedures and documents, and safety in the laboratory

Part 4: Inspecting the laboratory

Quality ControlQuality Control


Dissolution

Testing errors are caused by:

Temperature variations

Rotational speed variations

Vibration

Wobble

Shaft perpendicularity

Tension on the chain or belt

Bubbles

Shaft centering

Quality ControlQuality Control



Quality control (also micro, water, environment…)

Sampling and testing

Reference Standards

Specifications

Stability testing

Source/raw data

Qualification and validation



Other aspects to look at include:

Validation (process, cleaning etc)

CAPA, failure investigation

Change control

Deviations

Complaints

Product quality review



Unlimited resources ?

Inspectors ?

Days ?

Guidelines ?



Planning and conduct of inspection

Type of product(s)

Type of material(s)

Premises

Changes (deviations, additional products, cleaning procedure, campaigns etc)

Utilities and applications


Formal process of risk managementFormal process of risk management

Ref. ICH Q9, Quality Risk Management



Summary

GMP remains important component of ensuring QA and quality

New approaches in quality (including risk management, CAPA, PAT)

Impact on total approach including– Product design, product development, pilot batches,

production batches

Quality systems and quality assurance



Acknowledgements

WHO Training modules – Basic and supplementary

ICH Q9

S Galson and LX Yu (USA FDA presentations)

| slide 1 of 37 april 2007 training workshop on pharmaceutical development with focus on paediatric...

Documents

good practices

minor slide

guidance slide

quality control slide

pharmaceutical products

inspections context

inspections supplements

inspections presenter