1. World Health Organization
Pharmaceutical Development
17 April, 2017
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

2. Pharmaceutical Development
World Health Organization
Pharmaceutical Development
17 April, 2017
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, Geneve, 27 Switzerland

3. Good Manufacturing Practices (GMP) and Inspections
World Health Organization
Good Manufacturing Practices (GMP) and Inspections
17 April, 2017
Outline and Objectives of presentation
Introduce WHO GMP texts
Main principles
Supplements
Others
In the context of Prequalification
Current and future approaches

4. Good Manufacturing Practices (GMP) and Inspections
World Health Organization
Good Manufacturing Practices (GMP) and Inspections
17 April, 2017
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

5. Good Manufacturing Practices (GMP) and Inspections
World Health Organization
Good Manufacturing Practices (GMP) and Inspections
17 April, 2017
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

6. Good Manufacturing Practices (GMP) and Inspections
World Health Organization
Good Manufacturing Practices (GMP) and Inspections
17 April, 2017
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

7. Good Manufacturing Practices (GMP) and Inspections
World Health Organization
Good Manufacturing Practices (GMP) and Inspections
17 April, 2017
Supplements:
Sterile products
Herbal medicines
Radiopharmaceuticals
HVAC
Water systems
Sampling etc

8. Good Manufacturing Practices (GMP) and Inspections
World Health Organization
Good Manufacturing Practices (GMP) and Inspections
17 April, 2017
Others:
PIC/S guidelines
ISO guidelines
Sampling
Risk management
Clean rooms
ICH guidelines
ICH Q9
USA FDA
Guidelines and guidance

9. Good Manufacturing Practices (GMP) and Inspections
World Health Organization
Good Manufacturing Practices (GMP) and Inspections
17 April, 2017
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

10. Good Manufacturing Practices (GMP) and Inspections
World Health Organization
Good Manufacturing Practices (GMP) and Inspections
17 April, 2017
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.

11. Good Manufacturing Practices (GMP) and Inspections
World Health Organization
Good Manufacturing Practices (GMP) and Inspections
17 April, 2017
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

12. Good Manufacturing Practices (GMP) and Inspections
World Health Organization
Good Manufacturing Practices (GMP) and Inspections
17 April, 2017
Guiding principles:
Risk based orientation
Science based policies and standards
Integrated quality systems
International standards
Public interest

13. Good Manufacturing Practices (GMP) and Inspections
World Health Organization
Good Manufacturing Practices (GMP) and Inspections
17 April, 2017
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

14. Good Manufacturing Practices (GMP) and Inspections
World Health Organization
Good Manufacturing Practices (GMP) and Inspections
17 April, 2017
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

15. Good Manufacturing Practices (GMP) and Inspections
World Health Organization
Good Manufacturing Practices (GMP) and Inspections
17 April, 2017
Where to start in the inspection to assess GMP compliance?

16. World Health Organization
Premises
World Health Organization
17 April, 2017
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
This sheet shows the flow of material and personnel.
The green arrows indicate the material flow, and show materials that are brought in each room through the corridor zone. The cubicle between the corridor and the work zone may be an airlock, but in some countries this is required to be an air shower.
The red arrows indicate the people flow and show how people enter each room through the corridor divided by the zones.

17. Premises and personnel entry
World Health Organization
17 April, 2017
Explain the layout of change rooms, washing facilities and toilets.
Explain the importance of hygiene

18. World Health Organization
Material entry
World Health Organization
17 April, 2017
Separate receiving and dispatch bays
Materials and products protected from weather
Area to clean incoming materials provided
Separate receiving and dispatch bays are recommended and materials and products should be protected from weather (rain, sun etc).
An area to clean incoming materials and containers should be provided.

19. Basic Principles of GMP
World Health Organization
17 April, 2017
Discuss the:
issuing of materials,
reconciliation,
storage and transport in closed containers to prevent mix-ups

20. Equipment Contents and direction of flow indicated
e.g. water lines, equipment components, air-handling systems

21. World Health Organization
Equipment
World Health Organization
17 April, 2017
All aspects including
Design, installation, operation, performance, specifications, logs, maintenance, use, cleaning, qualification, calibration etc…
Discuss the aspects of the fluid bed dryer such as:
Procedures and records for qualification,
Quality of inlet air and air out to the atmosphere, filtration levels,
Controllers and recorders e.g. temperature (inlet and outlet),
Calibration,
PLC,
FBD bag (dedicated or not,
Cleaning of the FBD and the bag, including drying after cleaning,
FBD bowl and integrity checks,
Air volume, pressure .

22. Qualification and Validation
World Health Organization
17 April, 2017
Discuss dispensing of materials

23. World Health Organization
17 April, 2017
Documentation
During inspections, you can also verify the documents against actual instruments, equipment, premises etc. You have to verify that the documents are accurate, and current. Check the drawings against the qualification reports and proof of components. If any changes were made, did these go through a change control procedure? Was requalification required and done?

24. Good Manufacturing Practices (GMP) and Inspections
World Health Organization
Good Manufacturing Practices (GMP) and Inspections
17 April, 2017
Utilities
HVAC
Water
Compressed air
Steam . . .

25. World Health Organization
17 April, 2017
HVAC
Prefilter
Air flow patterns
AHU
Main filter
Uni-directional
Turbulent 1 2 3
This slide shows an HVAC installation feeding 3 rooms, each one with terminal filters, all terminal filters protected by a remote pre-filter.
Room 1 has a turbulent air flow, with low level exhaust.
Room 2 has a uni-directional air flow, over the largest part of the surface, hence the large number of filters, with low level air returns.
Due to the high cost of the ventilation in class A areas, the tendency is to keep these areas as small as possible.
Room 3 has a turbulent air flow, with ceiling exhaust.
Good design practices recommend that cleanrooms A, B and C (ISO Class 5, 6 & 7) should have low level air returns.

26. World Health Organization
17 April, 2017
HVAC Main subsystems +
Production Room
Exhaust air treatment
Central air handling unit
Terminal air treatment
at production room level
Fresh air treatment
(make-up air)
To understand the air handling systems, it is necessary to know what their components are.
A conventional Air Handling System has 4 sub-systems:
1. Air handling of the incoming (fresh) air: elimination of coarse contaminants and protection from frost if necessary. In the case of air re-circulation, the fresh air is also called make-up air.
2. Central air handling unit (AHU), where the air will be conditioned (heated, cooled, humidified or de-humidified and filtered), and where fresh air and re-circulated air, if any, (indicated here by the dotted line) will be mixed.
3. Air handling in the rooms under consideration (pressure differential system, additional filtration, air distribution).
4. Air exhaust system (filtration).

27. World Health Organization
17 April, 2017
HVAC
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
N/A
2, 3
Optional 3
1 := As built (ideally used to perform IQ)
2 = At rest (ideally used to perform OQ)
3 = Operational (ideally used to perform PQ)
This slide shows a series of tests to be carried out during qualification.
There are different tests for the turbulent and for the uni-directional air flows.
The differential pressure on filters is an indication of the clogging of the filters: with the charging of dust on the filters, the differential pressure will increase.
In order to keep the volume of air constant, the fan speed may increase, with the following consequences:
Damage to filters, and passage of unfiltered air
Particles and micro-organismes will be “pushed” through the filter units.
(Inspectors should check whether pressure differential manometers are installed on the AHUs. Without this means of monitoring the filters, the system could go out of control causing contamination problems.)
Airflow patterns are interesting to visualize (smoke tests), as zones without proper flushing can be easily identified.
It is also important to monitor air flow velocities for each HEPA filter according to a program of established intervals because significant reductions in velocity can increase the possibility of contamination, and changes in velocity can affect the laminarity of the airflow.
Airflow patterns should be tested for turbulence, as these can interfere with the flushing action of the air.

28. World Health Organization
17 April, 2017
Water for Pharmaceutical Use
raw water in
« S” trap to sewer
Water is kept circulating
To water softener & DI plant
Pretreatment – schematic drawing
cartridge
filter
5 micrometers
activated
carbon
spray ball
break tank
air break to drain
centrifugal pump
air filter
float
operated
valve
sand filter
excess water recycled
from deioniser
This schematic drawing is shown in handout and illustrates a typical storage and preliminary treatment system for water. Raw water arrives into a buffer or break tank via a level controlled valve. If there are further stages of treatment (such as DI or RO), the tank does not, generally, have to have sophisticated spray balls or air filters.
The water is pumped through a sand filter to remove large particles. This filter must be fitted with a back-flush facility, not shown here. The water then enters an activated carbon (AC) filter which removes organic impurities and chlorine. The AC filter can become heavily contaminated with bacteria. There should be some means of sanitizing it, such as a steam supply. Chemicals are generally not used to disinfect activated carbon filters. The water is then “polished” through a 5 micron filter before it enters the next treatment step. If there is no demand for the water it must be re-circulated to the buffer tank.
Water that is kept constantly circulating is less likely to grow bacteria, because they cannot settle and form a “biofilm”. All equipment such as pumps, pipes and tanks should be stainless steel wherever possible. Plastic should be avoided. Plasticizers may leach and this can result in out-of-specification Total Organic Carbon (TOC) levels. Adhesives used for welding plastic pipes may also leach into the water and cause problems.

29. World Health Organization
Quality Control
17 April, 2017
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

30. World Health Organization
Quality Control
World Health Organization
17 April, 2017
Dissolution
Testing errors are caused by:
Temperature variations
Rotational speed variations
Vibration
Wobble
Shaft perpendicularity
Tension on the chain or belt
Bubbles
Shaft centering
Dissolution (contd):
Testing errors will all make the product appear to perform better than it is. They include factors such as:
Influence of temperature: The thermal distribution profile of the water bath should be checked. Note that turbidity in the water could indicate growth of bacteria
Rotational speed: Check calibration with a tachometer.
Sources of vibration: Vibration causes turbulence. Sometimes a shock absorbing rubber mat is used under the apparatus and the drive unit may have good vibration-limiting shock absorbers.
Shaft wobble will mean turbulence.
Shaft Perpendicularity: Check with a spirit level and a builder’s square.
Tension on the chain or belt. Looseness will mean speeding up and slowing down leading to turbulence.
Bubbles: Can create turbulence. Acid on unprotected steel (even stainless steel) can lead to bubbles of hydrogen gas.
Shafts must be centered with respect to the vessels.

31. Good Manufacturing Practices (GMP) and Inspections
World Health Organization
Good Manufacturing Practices (GMP) and Inspections
17 April, 2017
Quality control (also micro, water, environment…)
Sampling and testing
Reference Standards
Specifications
Stability testing
Source/raw data
Qualification and validation

32. Good Manufacturing Practices (GMP) and Inspections
World Health Organization
Good Manufacturing Practices (GMP) and Inspections
17 April, 2017
Other aspects to look at include:
Validation (process, cleaning etc)
CAPA, failure investigation
Change control
Deviations
Complaints
Product quality review

33. Good Manufacturing Practices (GMP) and Inspections
World Health Organization
Good Manufacturing Practices (GMP) and Inspections
17 April, 2017
Unlimited resources ?
Inspectors ?
Days ?
Guidelines ?

34. Good Manufacturing Practices (GMP) and Inspections
World Health Organization
Good Manufacturing Practices (GMP) and Inspections
17 April, 2017
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

35. Formal process of risk management
Ref. ICH Q9, Quality Risk Management

36. Good Manufacturing Practices (GMP) and Inspections
World Health Organization
Good Manufacturing Practices (GMP) and Inspections
17 April, 2017
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

37. Good Manufacturing Practices (GMP) and Inspections
World Health Organization
Good Manufacturing Practices (GMP) and Inspections
17 April, 2017
Acknowledgements
WHO Training modules
Basic and supplementary
ICH Q9
S Galson and LX Yu (USA FDA presentations)