Good Manufacturing Practices (GMP) and Inspections
Training Workshop on Pharmaceutical
Development with a focus on Paediatric
Formulations
15 October 2007
Tallinn, Estonia
Dr A J van Zyl
Technical Officer
HTP/PSM/QSM
World Health Organization (WHO)
Geneva, Switzerland
vanzyla@who.int
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1
Slide 1 of 57
October 2007
Good 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
 Inspections in prequalification
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Slide 2 of 57
October 2007
Good Manufacturing Practices (GMP) and Inspections
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,
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Slide 3 of 57
October 2007
Good Manufacturing Practices (GMP) and Inspections
 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
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Slide 4 of 57
October 2007
Good Manufacturing Practices (GMP) and Inspections
 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
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Slide 5 of 57
October 2007
Good Manufacturing Practices (GMP) and Inspections
Other texts:
 Sterile products
 Herbal medicines
 Radiopharmaceuticals
 HVAC
 Water systems
 Sampling etc
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Slide 6 of 57
October 2007
Good Manufacturing Practices (GMP) and Inspections
Also to consider when necessary:
 PIC/S guidelines
 ISO guidelines
– Sampling
– Risk management
– Clean rooms
 ICH guidelines
– ICH Q9
 USA FDA
– Guidelines and guidance
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Slide 7 of 57
October 2007
Good Manufacturing Practices (GMP) and Inspections
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
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Slide 8 of 57
October 2007
Good Manufacturing Practices (GMP) and Inspections
 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.
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Slide 9 of 57
October 2007
Good Manufacturing Practices (GMP) and Inspections
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
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Slide 10 of 57
October 2007
Good Manufacturing Practices (GMP) and Inspections
Guiding principles:
 Risk based orientation
 Science based policies and standards
 Integrated quality systems
 International standards
 Public interest
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Slide 11 of 57
October 2007
Good Manufacturing Practices (GMP) and Inspections
 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
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Slide 12 of 57
October 2007
Good Manufacturing Practices (GMP) and Inspections
 Where to start?
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Slide 13 of 57
October 2007
Premises
Principle
Important aspects to be kept in mind to ensure the suitability of
the operations to be carried out for different dosage forms and
product range:
 Location




Design
Construction
Adaptation
Maintenance
12.1
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Slide 14 of 57
October 2007
Premises
Principle
 Premises must be
located to minimize
risks of crosscontamination, e.g.
not located next to a
malting factory with
high airborne levels of
yeast
12.4
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Slide 15 of 57
October 2007
Premises
General
The layout and design should aim to:

Minimize risks of errors

Permit effective cleaning

Permit effective maintenance

Avoid cross-contamination, build-up of dirt and dust

Avoid any adverse effect on the quality of products
12.2
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Slide 16 of 57
October 2007
Premises
Design Principles
Keep in mind:

Material flow

People flow

Process flow
Ensure logical flow
12.10
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Slide 17 of 57
October 2007
Premises
Example of Materials and People Flow
Arrival of goods
Entrance for visitors
QC
Offices
Corridor
Flow
Shipping
Material
Corridor
Corridor
People Flow
Weighing
Processing
Finished
Products
Storage
Machine
Shop
Utilities and Services
Slide 18 of 57
Filling
Packaging
Zone: Clean
Zone: Packaging
Washing
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Canteen
Gowning
Incoming
goods
Raw
Materials
&
Packaging
Storage
Entrance for Workers Shipment of goods
October 2007
Zone: Controlled
Corridor
Waste Treatment
Premises
Construction
 Suitable materials
 Electrical supply
 Suitable lighting (especially for visual on-line checks)
 Temperature and relative humidity control
 Appropriate and effective ventilation
These may affect products during manufacture or storage as well
as functioning of equipment
12.8, 12.32
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Slide 19 of 57
October 2007
Premises
 The temperature and relative
humidity should be
controlled, monitored in
accordance with an SOP, and
the results recorded. The
limits should be appropriate
according to the materials
stored and product
processed
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Slide 20 of 57
October 2007
Premises
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Slide 21 of 57
October 2007
Premises
Specific areas
Review some recommendations for specific areas in the following
slides (Part 2):
 Ancillary areas
 Storage areas
 Weighing areas
 Production areas
 Quality control areas
12.11 – 12.36
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Slide 22 of 57
October 2007
Premises
FACTORY
CHANGE
ROOM
AIR
LOCK
CANTEEN
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Slide 23 of 57
October 2007
TOILETS
Premises
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Slide 24 of 57
October 2007
Premises
 Separate receiving and
dispatch bays
 Materials and
products protected
from weather
 Area to clean incoming
materials provided
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Slide 25 of 57
October 2007
Premises
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Slide 26 of 57
October 2007
Premises
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Slide 27 of 57
October 2007
Premises
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Slide 28 of 57
October 2007
Premises
Storage areas - 2
 Appropriate temperature and relative humidity conditions within
defined limits
 Provided, controlled, monitored and recorded
 Good storage conditions: clean, dry and appropriate lights
12.16, 12.17
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Slide 29 of 57
October 2007
Premises
Storage areas – 4
Printed packaging materials
 Critical to ensure compliance with correct labelling of products
 Special attention to sampling
 Special attention to safe and secure storage
 Ensure compliance with specifications, prevent mix-ups
12.21
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Slide 30 of 57
October 2007
Premises
Weighing areas
 Weighing operations – in separated areas
 Appropriate design (see also training material on HVAC)
 Provision for dust control
 Smooth, impervious, durable, easy-to-clean finishes
 Cleaning procedures and records
 Documentation, e.g. SOPs, logs and records
12.23
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Slide 31 of 57
October 2007
Premises
Design of areas for weighing of
materials
 Proper air supply
 Dust control measures
(including extraction of dust
and air)
 Easily cleanable surfaces
 No areas for dust
accumulation
 Protection of material,
product and operator
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Slide 32 of 57
October 2007
Premises
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Slide 33 of 57
October 2007
Premises
Production areas - 1
Minimize risk of cross-contamination:
 Dedicated and self-contained facilities for some products such
as highly sensitizing materials (e.g. penicillins) or biological
preparations (e.g. live microorganisms)
 Separate facilities for other products such as some antibiotics,
hormones, cytotoxic substances
 Non-pharmaceuticals normally not in the same facility, e.g.
pesticides, herbicides
12.24
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Slide 34 of 57
October 2007
Equipment
All aspects including
 Design, installation,
operation, performance,
specifications, logs,
maintenance, use,
cleaning, qualification,
calibration etc…
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Slide 36 of 57
October 2007
Equipment
Contents and direction of flow
indicated
 e.g. water lines, equipment
components, air-handling
systems
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Slide 37 of 57
October 2007
Materials
Starting Materials – I
 Purchasing – important operation
 From approved suppliers – if possible, direct from the
manufacturer
 Specifications for materials
 Consignment checks
 Integrity of package
 Seal intact
 Corresponds with the purchase order
 Delivery note
 Supplier’s labels
 Cleaned and labelled with information
14.7 – 14.10
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Slide 38 of 57
October 2007
Materials
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Slide 39 of 57
October 2007
Documentation
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Slide 40 of 57
October 2007
Validation
Scope
 WHO guideline focuses mainly on the overall concept of
validation
 It serves as general guidance only
 Principles may be useful:
– in production and control of active pharmaceutical
ingredients (APIs) and finished pharmaceutical products
 Validation of specific processes and products (e.g. sterile
product manufacture) requires much more consideration and a
detailed approach beyond the scope of the guideline
2.1
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Slide 41 of 57
October 2007
Validation
Scope
 Many factors affecting the different types of validation
 Manufacturers should plan validation to ensure
– regulatory compliance and
– product quality, safety and consistency
 The general text in the guideline (part 1 of presentation) may be
applied to validation and qualification of:
– premises, equipment, utilities and systems
– processes and procedures
 More specific principles addressed in the appendices (parts 2 to
7)
 Semi-automatic or fully automatic clean-in-place (CIP) systems
2.2 – 2.4
and other special cases should be treated separately.
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Slide 42 of 57
October 2007
Qualification and Validation
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Slide 43 of 57
October 2007
Good Manufacturing Practices (GMP) and Inspections
Utilities
 HVAC
 Water
 Compressed air
 Steam . . .
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Slide 44 of 57
October 2007
HVAC
Prefilter
Air flow patterns
AHU
Main filter
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1
2
Turbulent
Uni-directional
Slide 45 of 57
October 2007
3
Turbulent
HVAC Main subsystems
Exhaust air treatment
Fresh air treatment
(make-up air)
+
Terminal air treatment
at production room level
Production Room
Central air handling unit
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Slide 46 of 57
October 2007
HVAC
Qualification – examples of aspects to consider in
qualification (OQ, PQ)
Uni-directional
airflow / LAF
Test
Turbulent / mixed
airflow
Differential pressure on filters
2
2
Room differential pressure
N/A
2, 3
Airflow velocity / uniformity
2, 3
Optional
Description
1 := As built (ideally used to perform IQ)
2 = At rest (ideally used to perform OQ)
3 = Operational (ideally used to perform PQ)
Airflow volume / rate
2
2
Parallelism
2
N/A
Air flow pattern
2
3
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Slide 47 of 57
October 2007
Water for Pharmaceutical Use
Pretreatment –
schematic drawing
float
operated
valve
excess water recycled
from deioniser
air filter
sand filter
spray ball
Water is kept
circulating
raw water in
centrifugal pump
« S” trap to sewer
Slide 48 of 57
October 2007
To water
softener &
DI plant
break tank
air break to drain
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activated
carbon
filter
cartridge
filter
5 micrometers
Quality Control
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
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Slide 49 of 57
October 2007
Good Manufacturing Practices (GMP) and Inspections
Quality control (also micro, water, environment…)
 Sampling and testing
 Reference Standards
 Specifications
 Stability testing
 Source/raw data
 Qualification and validation
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Slide 50 of 57
October 2007
Good Manufacturing Practices (GMP) and Inspections
Other aspects to look at include:
 Validation (process, cleaning etc)
 CAPA, failure investigation
 Change control
 Deviations
 Complaints
 Product quality review
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Slide 51 of 57
October 2007
Good Manufacturing Practices (GMP) and Inspections
Unlimited resources ?
 Inspectors ?
 Days ?
 Guidelines ?
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Slide 52 of 57
October 2007
Quality Risk Management Process
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Slide 53 of 57
October 2007
Good Manufacturing Practices (GMP) and Inspections
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
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Slide 54 of 57
October 2007
Good Manufacturing Practices (GMP) and Inspections
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
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Slide 55 of 57
October 2007
Good Manufacturing Practices (GMP) and Inspections
Acknowledgements
 WHO Training modules
– Basic and supplementary
 ICH Q9
 S Galson and LX Yu
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Slide 56 of 57
October 2007
Good Manufacturing Practices (GMP) and Inspections
Thank you
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Slide 57 of 57
October 2007