2. Good Manufacturing Practices – Part II 3 Specific GMP topics:
Premises, Documentation and Validation
WHO EMRO 1st Workshop on the WHO Prequalification Programme: Priority Essential Medicines,
Cairo, Egypt, 6 and 7 June, 2007
Anton Norder, MSc
Technical Officer
20 Avenue Appia
CH-1211 Geneva 27
Switzerland 2

3. Guidelines and references
Booklet: Quality Assurance of pharmaceuticals. A compendium of guidelines and related materials. Volume 2, second updated edition. Good manufacturing practices and inspection. World Health Organization, Geneva, 2007.
Good Manufacturing Practices for pharmaceutical products: main principles. WHO Technical Report Series, No. 908, 2003, Annex 4.
Good Manufacturing Practices: starting materials. WHO Technical Report Series, No. 823, 1992.
ICH Q7A: Good Manufacturing Practice Guide for Active Pharmaceutical Ingredients, International Conference on Harmonization

4. WHO Guidelines and references (cont'd)
WHO Good Manufacturing Practices: water for pharmaceutical use. WHO Technical Report Series, No. 929, 2005, Annex 3
Supplementary guidelines on good manufacturing practices for heating, ventilation and air-conditioning systems for non-sterile pharmaceutical dosage forms. WHO Technical Report Series, No. 937, 2006, Annex 2
Supplementary guidelines on good manufacturing practices : validation. WHO Technical Report Series, No. 937, 2006, Annex 4

5. WHO Guidelines and references (cont'd)
WHO guidelines for sampling of pharmaceutical products and related materials. WHO Technical Report Series, No. 929, 2005, Annex 4
Good Practices for National Pharmaceutical Control Laboratories. WHO Technical Report Series, No. 902, 2002, Annex 3.
As well as specific GMPs on:
Sterile pharmaceutical products (2002)
Biologicals (1993)
Investigational pharmaceutical products for clinical trials in humans (1996)
Herbal medicinal products (1996/97)
Radiopharmaceutical products (2003)

6. However there's more GMP's:
PIC/S GMP (Pharmaceutical Inspection Co-operation Scheme): ; adopted by many countries, e.g. European Union, or partially (Canada, Australia)
National GMP's in many countries (e.g. USA ( China, India, Brazil, Argentina, etc.)
International Conference on Harmonization (ICH):
Also refer to ISO, e.g in cases of filter types in HVACs, clean room design, risk management, etc.

7. Overview of specific GMP topics to be covered in this presentation:
Part 1: Premises in relation to buildings, design, equipment, etc.
Part 2: Documentation
Part 3: Qualification and validation

8. Part 1: Premises Material Flow
Arrival of goods Visitors entrance Workers entrance 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.

9. Premises: specific areas
Note that specific requirements are given for specific areas:
Ancillary areas (gowning rooms, toilets, refreshment rooms, maintenance areas, animal housing etc)
Storage areas
Weighing areas
Production areas
Quality control areas
Let us now consider other areas that are needed in the factory.
There should be separate areas for the different activities in the company. Normally, separate, areas are designed and include ancillary areas like change rooms, toilet facilities, storage areas, sampling and weighing areas, manufacturing areas and laboratories.
IN the next slides, we will look at these area individually
12.11 – 12.36

10. Premises: ancillary areas
Rest and refreshment rooms separate from manufacturing and quality control areas
Changing, washing and toilet areas accessible and appropriate numbers
Maintenance workshops separated from production - if not possible – tools in reserved areas
Animal houses well isolated – separate air handling and entrance
Let us now consider other areas that are needed in the factory.
Rest and refreshment rooms will be required for the staff. These must be located apart from all other areas involved in manufacturing, packaging, storage or quality control. The type of activity going on will determine the degree of segregation.
Toilet and other wash facilities should not be directly accessible from manufacturing, storage or quality control areas. Hand-washing facilities must be provided and their use encouraged with the provision of toilet paper, soap and towels or other types of hand-drying facilities.
Canteen areas: If all that is to be allowed is consumption of drinks then a separate room will probably be enough. If smoking and eating is to be allowed then the segregation will need to be much more extensive. The smells of cooking and smoking must be kept away from the products. This will require special ventilation systems for the kitchens and the cafeteria.
Maintenance workshops should be separated from production areas. If tools are to be kept in a manufacturing area, then they should be placed in a container or cupboard specific for that purpose.
Animal houses should be isolated from all other areas with separate entry and air-handling facilities to prevent any risk of cross-contamination.
12.11 – 12.14

11. Premises: ancillary areas
Explain the layout of change rooms, washing facilities and toilets.
Explain the importance of hygiene

12. Premises: ancillary areas
Facilities must be provided for operators and all visitors to change their clothes and footwear. Storage will be needed for outdoor clothing and a system provided to assist correct entry to the manufacturing areas.
In some cases, change rooms are designed in such a way that a climb over bench is used to separate areas (before changing clothes, and after).
Some companies have air locks, and some companies are now designing the entry to manufacturing areas as a one-way system with double-sided lockers. This means that all personnel entering a manufacturing area must pass through the change procedure in one direction. People exit the factory and gain access to their outdoor clothes from the other side of the locker. This prevents any possibility of cross-contamination.
Some companies also have air showers where operators go through to remove any dust on their garments.

13. Premises: Receipt and storage of goods
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.

14. Premises: Receipt and storage of goods
Cleaning of incoming containers
Cleaning with a cloth, or duster
Cleaning by using a vacuum cleaner
Use of air curtains and air tunnels
Different means can be used to clean incoming containers. Assess the appropriateness of the manner used by the company and assess whether it is suitable, The procedure should not become a source of contamination of containers. What is the company procedure for cleaning the materials/equipment used fr cleaning? How they handle damaged containers? What happens to the spillages and waste?

15. Premises: Receipt and storage of goods
Storage areas of sufficient capacity
Orderly storage of categories of materials and products
Separate and segregated areas: starting materials, packaging materials, intermediates, bulk, finished products, quarantined, released, rejected, returned and recalled products and materials
I will now go through the main areas of the factory and highlight a few key points in each area.
The importance of the warehouse is sometimes under estimated. Incoming goods areas are often the forgotten places at the back of the factory. However, they should be seen as the first point of entry of materials into the factory, and the last point at which the factory still has control of its products before they leave to go to a customer. Warehouses should have sufficient capacity to allow orderly storage of the various categories of materials and products, for example: starting and packaging materials, intermediates, bulk and finished goods, products in quarantine, and released, rejected, returned or recalled goods.
The design must ensure protection against the heat or moisture. It must also provide protection for special deliveries such as tankers. These give rise to special problems. For example, what measures are in place to ensure a clean connection between the tanker and the holding tank? What precautions are taken to ensure that the tanker is using clean transfer pipes before transferring materials into the tank? Is there a static electricity discharge point for safety purposes where necessary?
All the material requirements with regard to temperature and humidity control must be adhered to. This means suitable records have to be maintained and procedures available to describe what to do in the case of failure of cooling equipment or the electricity supply. How long may materials remain exposed to unsatisfactory temperature or humidity conditions? This question must be able to be answered by the responsible staff in the factory. They should have SOPs describing the various storage conditions required and specifying which materials should be stored there. Examples of materials that need special controls are vaccines and gelatin capsules.
Incoming goods containers may be stored outside. They may need to be cleaned before they can be opened for sampling, and before they go into the warehouse. Facilities for this will need to be provided.
These areas must be designed to provide sufficient space to accommodate the deliveries or shipments passing through them. The areas should be operated in accordance with appropriate SOPs.
It is recommended that there should be separate receiving and dispatch bays, and that materials and products be protected from weather during loading and off loading.
There should also be storage areas of sufficient capacity to ensure proper segregation and separation, easy cleaning of areas.
Orderly storage of categories of materials and products
Separate and segregated areas for different materials are recommended including: Starting materials, packaging materials, intermediates, bulk, finished products, quarantined, released, rejected, returned and recalled products and materials
The following slides show examples of storage of materials in different areas.
12.15, 12.16

16. Premises: Receipt and storage of goods
Explain racking, storage of primary and secondary packaging materials (protected from contaminants), different status such as quarantine and released, materials management, bin location systems.

17. Premises: Receipt and storage of goods
Examples of storage of packaging materials and in process bulk

18. Premises: Receipt and storage of goods
Appropriate temperature and relative humidity conditions within defined limits
Provided, controlled, monitored and recorded
Good storage conditions: clean, dry and appropriate lights
I will now go through the main areas of the factory and highlight a few key points in each area.
The importance of the warehouse is sometimes under estimated. Incoming goods areas are often the forgotten places at the back of the factory. However, they should be seen as the first point of entry of materials into the factory, and the last point at which the factory still has control of its products before they leave to go to a customer. Warehouses should have sufficient capacity to allow orderly storage of the various categories of materials and products, for example: starting and packaging materials, intermediates, bulk and finished goods, products in quarantine, and released, rejected, returned or recalled goods.
The design must ensure protection against the heat or moisture. It must also provide protection for special deliveries such as tankers. These give rise to special problems. For example, what measures are in place to ensure a clean connection between the tanker and the holding tank? What precautions are taken to ensure that the tanker is using clean transfer pipes before transferring materials into the tank? Is there a static electricity discharge point for safety purposes where necessary?
All the material requirements with regard to temperature and humidity control must be adhered to. This means suitable records have to be maintained and procedures available to describe what to do in the case of failure of cooling equipment or the electricity supply. How long may materials remain exposed to unsatisfactory temperature or humidity conditions? This question must be able to be answered by the responsible staff in the factory. They should have SOPs describing the various storage conditions required and specifying which materials should be stored there. Examples of materials that need special controls are vaccines and gelatin capsules.
Incoming goods containers may be stored outside. They may need to be cleaned before they can be opened for sampling, and before they go into the warehouse. Facilities for this will need to be provided.
These areas must be designed to provide sufficient space to accommodate the deliveries or shipments passing through them. The areas should be operated in accordance with appropriate SOPs.
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

19. Premises: Receipt and storage of goods
Quarantine area: clearly marked and access restricted
Separate sampling area is the norm: no risk for contamination or cross-contamination
Segregated areas for rejected, recalled and returned materials and products
Safe and secure areas for highly active, radioactive materials, narcotics and other materials (risk of abuse, fire, explosion)
Areas must be clearly marked with status of goods and access to unauhorized visitors enforced. Throughout the stores areas, consideration needs to be given to controlling access of staff and visitors. We have mentioned here a number of times that security is important, particularly around labels and cartons. Systems, such a computer control, that replace physical security should give equivalent security.
A separate sampling area to GMP standard is normally required. Sampling is the first stage in pharmaceutical processing. The conditions must be of pharmaceutical processing quality. Proper procedures need to be in place, defining what samples are required, who takes them, how they are to be taken and the cleaning procedures to be used after each sample has been taken. The sampling procedures used must prevent cross-contamination.
All the stores must provide proper separation between quarantined, approved and rejected materials. This separation can be physical. If another system is used, it must be validated to give at least the same level of security. Whichever method is chosen, it must demonstrate complete control over the status of materials. Any rejected, returned or recalled materials should have a separate storage area with controlled access.
Separate areas have to be provided for any hazardous materials including flammables or narcotics. An additional difficulty is how to conform to the law, regarding safety and security as well as requirements for GMP. For example, the law may require the presence of security personnel during any handling operations. If this is the case, they and their equipment must conform to GMP requirements.
12.18 – 12.20, 12.22

20. Premises: Receipt and storage of goods
Storage of packaging materials should be in closed containers
Rejected materials and containers should be stored separately and marked as such

21. Premises: Receipt and storage of goods
Printed packaging materials
Critical to ensure correct labelling of products
Special attention to sampling of printed packaging materials
Special attention to safe and secure storage
Ensure compliance with specifications, prevent mix-ups
In some countries, more than half of all product failures occur through problems with printed materials. These problems often result in a product recall. Product recalls are very expensive and damage the reputation of the company. Products with defects warranting a recall may have potentially fatal consequences for patients. Security of storage, issue and receipt of printed materials is absolutely essential. Quality control procedures for printed components must be very rigorous. This is particularly important if the factory is dealing with export orders requiring foreign language labelling. More details on this will be included in the documentation module.
12.21

22. Premises: weighing Weighing operations – in separated areas
Appropriate design (see also GMP on HVAC)
Provision for dust control
Smooth, impervious, durable, easy-to-clean finishes
Cleaning procedures and records
Documentation, e.g. SOPs, logs and records
Failure in dispensing right first time may result in a major problem of product quality.
The design, operation, control systems, recording and cleaning of the dispensing department must all be aimed at ensuring that there is no risk of cross-contamination. The procedures, design and operation of the area must ensure that the right material is dispensed in the right quantity for the right product. The segregation, control systems and record-keeping must all be aimed at achieving this result.
The environmental controls for the area must be designed to ensure that the powders are kept within the area. The air handling, pressure differentials, airflow patterns and dust extraction systems need to be designed carefully to provide pharmaceutical quality conditions with good separation from the main warehouse area. As necessary, appropriate microbiological control systems may be required. Weighing should be treated as the second stage in pharmaceutical processing after sampling, with all the requirements being met.
Weighing areas need to be segregated from the main production areas, and from each other to allow flexibility and to permit clean down between materials and products. If segregation is maintained by air handling systems (as is often the case), then there must be control systems available to demonstrate that the systems are working properly.
The surfaces of the weighing area need to be of appropriate quality. They will have rounded corners and coving and be made of smooth impervious materials to enable easy cleaning. This standard of finish applies to the floor and ceiling as well as the walls. Since the changes of product are much more frequent in this area, the ability to clean is essential.
The cleaning methods used will need to be validated for effectiveness. This means that for each material there should be a SOP of the cleaning method to be used. The SOP should also specify the cleaning materials to be used. There should be logbooks.
Since the area is working with many different materials, it is potentially the area with the greatest possibility for a mix-up or cross-contamination. Provision of space for intermediate storage, order collection and order storage should be done whilst maintaining ease of movement and separation between orders.
12.23

23. Premises: weighing

24. Requirements on premises:
Design
Walls, floors, ceilings, ledges, drains, air supply, dust extraction
Prevention of build-up of dirt and dust to avoid unnecessary risks of contamination
Cleaning programme, appropriate cleaning, cleaning records
Effective cleaning and disinfection
Choice of materials and chemicals, validation
Drains – prevent backflow
Protection from insects, birds, vermin and weather
from receipt of raw materials to dispatch of released product
12.2, 12.3, 12.7, 12.9, 12.29

25. Design of premises: Walls, floors, ceilings – smooth and easy to clean
No ledges or areas where dust can accumulate
Prevention of build-up of dirt and dust to avoid unnecessary risks of contamination

26. Premises: production areas
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
In order to minimize the risk of a serious medical hazard due to cross-contamination, dedicated and self-contained facilities must be available for the production of particular pharmaceutical products, such as highly sensitizing materials (e.g., penicillins) or biological preparations (e.g, live microorganisms). The production of certain other products, such as some antibiotics, hormones, cytotoxic substances, highly active pharmaceutical products, and non-pharmaceutical products, should not be conducted in the same facilities. The manufacture of technical poisons, such as pesticides and herbicides, should not normally be allowed in premises used for the manufacture of pharmaceutical products. In exceptional cases, the principle of campaign working in the same facilities can be accepted provided that specific precautions are taken and the necessary validations are made.
Premises should preferably be laid out in such a way as to allow the production to take place in areas connected in a logical order corresponding to the sequence of the operations and to the requisite cleanliness levels.
The adequacy of the working and in-process storage space should permit the orderly and logical positioning of equipment and materials so as to minimize the risk of confusion between different pharmaceutical products or their components, to avoid cross-contamination, and to minimize the risk of omission or wrong application of any of the manufacturing or control steps.
Where starting and primary packaging materials and intermediate or bulk products are exposed to the environment, interior surfaces (walls, floors and ceilings) should be smooth and free from cracks and open joints, should not shed particulate matter, and should permit easy and effective cleaning and, if necessary, disinfection.
Production areas should be suitably designed to minimize risk of cross-contamination. In some cases, dedicated and self-contained facilities for some products such as highly sensitizing materials (e.g. penicillins) or biological preparations (e.g. live micro-organisms) may be required.
Separate facilities for other products such as some antibiotics, hormones, cytotoxic substances are recommended.
Non-pharmaceutical products should normally not be manufactured in the same facility e.g. pesticides, herbicides
12.24

27. Premises: production areas
Layout in accordance with sequence of production
Appropriate cleanliness level
Adequate work and in-process storage space
Orderly and logical positioning of equipment
minimizes risk of contamination, mix-ups and missing production steps
Specially designed areas for packaging
Layout to avoid mix-ups and cross-contamination
In order to minimize the risk of a serious medical hazard due to cross-contamination, dedicated and self-contained facilities must be available for the production of particular pharmaceutical products, such as highly sensitizing materials (e.g., penicillins) or biological preparations (e.g, live microorganisms). The production of certain other products, such as some antibiotics, hormones, cytotoxic substances, highly active pharmaceutical products, and non-pharmaceutical products, should not be conducted in the same facilities. The manufacture of technical poisons, such as pesticides and herbicides, should not normally be allowed in premises used for the manufacture of pharmaceutical products. In exceptional cases, the principle of campaign working in the same facilities can be accepted provided that specific precautions are taken and the necessary validations are made.
Premises should preferably be laid out in such a way as to allow the production to take place in areas connected in a logical order corresponding to the sequence of the operations and to the requisite cleanliness levels.
The adequacy of the working and in-process storage space should permit the orderly and logical positioning of equipment and materials so as to minimize the risk of confusion between different pharmaceutical products or their components, to avoid cross-contamination, and to minimize the risk of omission or wrong application of any of the manufacturing or control steps.
Where starting and primary packaging materials and intermediate or bulk products are exposed to the environment, interior surfaces (walls, floors and ceilings) should be smooth and free from cracks and open joints, should not shed particulate matter, and should permit easy and effective cleaning and, if necessary, disinfection.
The layout of the areas should be in accordance with sequence of production where possible. All areas should be of an appropriate cleanliness level. There should be procedures and records for the cleaning.
There should be adequate work and in-process storage space and orderly and logical positioning of equipment is essential to minimize the risk of contamination, mix-ups and missing production steps.
Specially designed areas for packaging are recommended and care should be taken to prevent contamination and cross-contamination also during packaging (primary packaging – where product and materials are exposed to the environment). The lay out should be such to avoid mix-ups and cross-contamination.
12.32, 12.26, 12.31

28. Premises: production areas
Starting and packaging materials, intermediates and bulk exposed to environment:
Interior surfaces (walls, floors, ceilings) – smooth, free from cracks and open joints
No shedding of particles
Easy and effective cleaning permitted
Disinfection if needed
In order to minimize the risk of a serious medical hazard due to cross-contamination, dedicated and self-contained facilities must be available for the production of particular pharmaceutical products, such as highly sensitizing materials (e.g., penicillins) or biological preparations (e.g, live microorganisms). The production of certain other products, such as some antibiotics, hormones, cytotoxic substances, highly active pharmaceutical products, and non-pharmaceutical products, should not be conducted in the same facilities. The manufacture of technical poisons, such as pesticides and herbicides, should not normally be allowed in premises used for the manufacture of pharmaceutical products. In exceptional cases, the principle of campaign working in the same facilities can be accepted provided that specific precautions are taken and the necessary validations are made.
Premises should preferably be laid out in such a way as to allow the production to take place in areas connected in a logical order corresponding to the sequence of the operations and to the requisite cleanliness levels.
The adequacy of the working and in-process storage space should permit the orderly and logical positioning of equipment and materials so as to minimize the risk of confusion between different pharmaceutical products or their components, to avoid cross-contamination, and to minimize the risk of omission or wrong application of any of the manufacturing or control steps.
Where starting and primary packaging materials and intermediate or bulk products are exposed to the environment, interior surfaces (walls, floors and ceilings) should be smooth and free from cracks and open joints, should not shed particulate matter, and should permit easy and effective cleaning and, if necessary, disinfection.
Production areas - 3
Where starting and packaging materials, intermediates and bulk are exposed to environment, all interior surfaces (walls, floors, ceilings) – should be smooth, free from cracks and open joints. There should be no shedding of particles.
Areas should be easily and effectively cleaned. When necessary, disinfection may be needed
12.27

29. Premises: production areas
Design of pipework, light fittings, and ventilation points – no recesses that are difficult to clean
Access for maintenance from outside production areas
Drains of adequate size, and equipped to prevent back-flow
Open channels avoided
In order to minimize the risk of a serious medical hazard due to cross-contamination, dedicated and self-contained facilities must be available for the production of particular pharmaceutical products, such as highly sensitizing materials (e.g., penicillins) or biological preparations (e.g, live microorganisms). The production of certain other products, such as some antibiotics, hormones, cytotoxic substances, highly active pharmaceutical products, and non-pharmaceutical products, should not be conducted in the same facilities. The manufacture of technical poisons, such as pesticides and herbicides, should not normally be allowed in premises used for the manufacture of pharmaceutical products. In exceptional cases, the principle of campaign working in the same facilities can be accepted provided that specific precautions are taken and the necessary validations are made.
Premises should preferably be laid out in such a way as to allow the production to take place in areas connected in a logical order corresponding to the sequence of the operations and to the requisite cleanliness levels.
The adequacy of the working and in-process storage space should permit the orderly and logical positioning of equipment and materials so as to minimize the risk of confusion between different pharmaceutical products or their components, to avoid cross-contamination, and to minimize the risk of omission or wrong application of any of the manufacturing or control steps.
Where starting and primary packaging materials and intermediate or bulk products are exposed to the environment, interior surfaces (walls, floors and ceilings) should be smooth and free from cracks and open joints, should not shed particulate matter, and should permit easy and effective cleaning and, if necessary, disinfection.
12.28, 12.29

30. Premises: production areas
Effective ventilation with air control facilities
Including filtration of air to a sufficient level to prevent contamination and cross-contamination – also external environment
Control of temperature and relative humidity where necessary
Regular monitoring of conditions during production and non-production periods
In order to minimize the risk of a serious medical hazard due to cross-contamination, dedicated and self-contained facilities must be available for the production of particular pharmaceutical products, such as highly sensitizing materials (e.g., penicillins) or biological preparations (e.g, live microorganisms). The production of certain other products, such as some antibiotics, hormones, cytotoxic substances, highly active pharmaceutical products, and non-pharmaceutical products, should not be conducted in the same facilities. The manufacture of technical poisons, such as pesticides and herbicides, should not normally be allowed in premises used for the manufacture of pharmaceutical products. In exceptional cases, the principle of campaign working in the same facilities can be accepted provided that specific precautions are taken and the necessary validations are made.
Premises should preferably be laid out in such a way as to allow the production to take place in areas connected in a logical order corresponding to the sequence of the operations and to the requisite cleanliness levels.
The adequacy of the working and in-process storage space should permit the orderly and logical positioning of equipment and materials so as to minimize the risk of confusion between different pharmaceutical products or their components, to avoid cross-contamination, and to minimize the risk of omission or wrong application of any of the manufacturing or control steps.
Where starting and primary packaging materials and intermediate or bulk products are exposed to the environment, interior surfaces (walls, floors and ceilings) should be smooth and free from cracks and open joints, should not shed particulate matter, and should permit easy and effective cleaning and, if necessary, disinfection.
Effective ventilation with air control facilities should be provided, including filtration of air to a sufficient level to prevent contamination and cross-contamination – also external environment
Control of temperature and relative humidity where necessary
Regular monitoring of conditions during production and non-production periods e.g. temperature, relative humidity, particulate matter, and micro
(See HVAC module for more details)
12.30

31. Avoiding cross contamination
Special precautions should be taken to prevent generation and dissemination of dust
Proper air control – supply and extraction, suitable quality
Due to uncontrolled release of:
dust, gas, particles, vapours, sprays, organisms, residue, insects
Dedicated and self-contained areas for:
Live vaccines
Live bacterial preparations
Certain other biological materials
Penicillin products
Special precautions should be taken to prevent generation and dissemination of dust
Proper air control – supply and extraction, suitable quality
Due to uncontrolled release of:
dust, gas, particles, vapours, sprays, organisms, residue, insects, operators
16.12(a)

32. Avoiding cross contamination (cont'd)
Campaign production:
Separation in time
Followed by appropriate cleaning
Validated cleaning procedure
Ventilation systems and airlocks
Appropriately designed ventilation system with air supply and extraction systems
Supply or incoming air should be filtered
Recirculation of air versus 100% fresh air supply
Proper airflow patterns
Pressure differentials
Appropriately designed airlocks
16.12(b)
Campaign production:
Separation in time
Followed by appropriate cleaning
Validated cleaning procedure
See also slide in sanitation and Hygiene
16.12 (c and d)

33. Avoiding cross contamination (cont'd)
Clothing
Protection of operator and product
Fit for its intended use
Highly potent products or those of particular risk - need for special protective clothing
Personnel should not move between areas producing different products
Garments need to be cleaned
Clothing relates to the protection of both the operator and the product. For highly potent products or those that create a particular risk of cross-contamination, special protective clothing needs to be worn. Decontamination processes for these clothes need to be in place. For all manufacturing areas where there is any risk of the product contaminating the clothing, the simple precaution of not moving between areas producing different products should be adopted.
16.12(e)

34. Avoiding cross contamination (cont'd)
Cleaning and decontamination
Procedure for removing soil and dirt
Remove all cleaning chemical residues or disinfectant residues
Remove and/or reduce micro-organisms
Validated (known effectiveness of the procedure)
Use cleanliness status labels
Test for residues
Closed processing systems
For example: totally enclosed water purification systems
Tanks fitted with appropriate filtration - without removable lids
Present special cleaning difficulties, sometimes use
clean-in-place (CIP)
16.12(f, h and i)
Cleaning should be a procedure for removing soil and dirt. It should not add or leave behind anything, including cleaning, chemical or disinfectant residues.
It must remove or reduce micro-organisms.
Cross reference to the module on validation can be mentioned if questions arise on how and what is cleaning validation.
16.12(g)

35. Sanitation in production operations
Work-flow
designed to avoid potential contamination
Access
to production areas restricted to authorized personnel
direct operators, QC staff, warehouse staff, maintenance personnel, cleaners
the more critical the area - fewer number of persons there
Simultaneous operations
not permissible to process different products in different areas with a common ventilation system
permissible to carry out secondary packaging activities for different products within a packing hall with adequate physical separation
The work-flow has to be designed in such a way as to avoid any potential contamination. Access to production areas should be restricted to authorized personnel only. These will include direct operators, QC staff, warehouse staff, maintenance personnel and cleaners. The more critical the area, the fewer the people that should be in there during processing operations.

36. Sanitation in production operations (cont'd)
Area clearance checks:
Process of checking
all materials and documentation from the previous batch removed
all plant and equipment thoroughly cleaned and appropriate status labelling
checklist useful
The area clearance check should be carried out by two persons
between batches of same product, acceptable for both checks to be carried out by production personnel
for product changeover, second check carried out by QC staff
all checks carried out in accordance with written SOP and results recorded on the batch documentation.
The first step in any batch processing operation is the area clearance check. This is the process of checking that all materials and documentation from the previous batch have been removed, and that all plant and equipment has been thoroughly cleaned.
A useful group exercise is to use a flipchart to get the trainees to list all the requirements for a cleaning status label. Items can include: name of the equipemnt, cleaned or not clean, date cleaned, who cleaned, who passed, how long will the cleaned equipment remain clean before rrequiring recleaning, etc.,

37. E.g. line clearance in packaging
Absence of all materials from previous run, including printing masters
Includes checks on materials and components
Batch number
Expiry date
Printed packaging material including cartons, leaflets, foil . . .
Explain the process of line opening, documents to be checked, quantities, correct documents and materials, signatures and relevant procedure and checklists.

38. Sanitation in production operations (cont'd)
Cleaning and cleaning validation
degree of cleaning depends on whether consecutive batches are of same or different product
Check cleaning agent is fully removed
If possible hot water alone used for cleaning
all cleaning and disinfecting solutions carefully prepared and expiry dated
For sterile products: Final rinse with purified water, or water for injection
Full records kept
We have already talked about cleaning of premises. Another important point is the cleaning of the equipment in which products are manufactured. The degree of cleaning will depend on whether consecutive batches are of the same product or of different products. It is important that any cleaning agent introduced is also fully removed so that it does not contaminate the product. Wherever possible, hot water alone should be used for cleaning. The final rinse should be with purified water or water for injection in the case of equipment used for processing sterile products.
A validation programme should be based on the worst case situation, e.g. a relatively insoluble material that is active at low levels of concentration. Additionally, full records should be kept of cleaning and sanitation.

39. Sanitation in production operations (cont'd)
Maintenance and repair
activities inevitable in manufacturing area
Should present no risk to product
Whenever possible, all planned maintenance outside normal operating hours
Emergency work in working area followed by thorough clean down and disinfection before manufacturing recommences
Area clearance by QC
Repair and maintenance activities are inevitable in a manufacturing area. However, they should be carried out in a way that does not present any risk to the product. Therefore, whenever possible, all planned maintenance should be done outside of normal operating hours. Any emergency work in a working area should be followed by a thorough clean down and disinfection of the area before manufacturing recommences, AND area clearance by QC

40. Basic Principles on premises in GMP
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
Explain also examples such as Hard Gelatine Capsules, temperature and relative humidity limits. In some cases, companies have limits for temperature and relative humidity, but these are outside the required storage conditions of the materials.

41. Premises: maintenance
Careful maintenance done
Repairs and maintenance should not present any hazard to the quality of the products
Maintenance workshops should be separated from production areas. If tools are to be kept in a manufacturing area, then they should be placed in a container or cupboard specific for that purpose.
Animal houses should be isolated from all other areas with separate entry and air-handling facilities to prevent any risk of cross-contamination.
12.6

42. Premises of Quality Control Labs
QC laboratories should be separate from production areas
Separate areas for biological, microbiological and radioisotope methods
Suitable design with sufficient space to avoid mix-ups and cross-contamination
Suitable space for storage samples, reference standards, solvents, reagents and records
In order to minimize the risk of a serious medical hazard due to cross-contamination, dedicated and self-contained facilities must be available for the production of particular pharmaceutical products, such as highly sensitizing materials (e.g., penicillins) or biological preparations (e.g, live microorganisms). The production of certain other products, such as some antibiotics, hormones, cytotoxic substances, highly active pharmaceutical products, and non-pharmaceutical products, should not be conducted in the same facilities. The manufacture of technical poisons, such as pesticides and herbicides, should not normally be allowed in premises used for the manufacture of pharmaceutical products. In exceptional cases, the principle of campaign working in the same facilities can be accepted provided that specific precautions are taken and the necessary validations are made.
Premises should preferably be laid out in such a way as to allow the production to take place in areas connected in a logical order corresponding to the sequence of the operations and to the requisite cleanliness levels.
The adequacy of the working and in-process storage space should permit the orderly and logical positioning of equipment and materials so as to minimize the risk of confusion between different pharmaceutical products or their components, to avoid cross-contamination, and to minimize the risk of omission or wrong application of any of the manufacturing or control steps.
Where starting and primary packaging materials and intermediate or bulk products are exposed to the environment, interior surfaces (walls, floors and ceilings) should be smooth and free from cracks and open joints, should not shed particulate matter, and should permit easy and effective cleaning and, if necessary, disinfection.
See the separate module on QC labs.
QC laboratories should be separate from production areas, and there should be separate areas for biological, microbiological and radioisotope methods
The laboratory should be of suitable design with sufficient space to avoid mix-ups and cross-contamination.
12.33, 12.34

43. Premises of Quality Control Labs
There should also be enough space for storage of samples, reference standards, solvents, reagents and records.
Retention samples of finished products (left) and APIs and excipients (right) should be kept.

44. Part 2: Documentation Objectives
1. To review general requirements for documents
2. To review specific requirements for each document
3. To consider current issues applicable to your countries
There are three objectives for this session:
1. We are going to start by looking at the general requirements for all documents and to review the types of documents listed in the WHO GMP text.
2. Then we will look at the specific requirements for each type of document.
3. Finally, we will look at the specific issues that are likely to arise during your inspection visits and the sort of solutions that you will need to be able to offer.

45. Documentation Essential part of the QA system, for all aspects of GMP
Purpose of documentation
Defines specifications and procedures for all materials and methods of manufacture and control
Ensures all personnel know what to do and when to do it
Ensure that authorized persons have all information necessary for release of product
Ensures documented evidence, traceability, provide records and audit trail for investigation
Ensures availability of data for validation, review and statistical analysis
Design and use
Depends upon manufacturer
Some documents combined into one, sometimes separate
Documentation is an essential part of QA and relates to all aspects of GMP. The pharmaceutical industry must have a good document framework (infrastructure). It is important for a manufacturer to get the documentation right in order to get the product right.
There are a number of purposes for documents:
They are used to define specifications for materials and for methods of manufacture and control.
They ensure that everyone concerned with manufacture and QC knows what to do, how and when to do it.
They allow decisions to be taken on batch release.
They provide an audit trail, which is particularly important in the case of suspect batches.
15.1

46. 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?

47. Documentation Why are documents so important? Communication Cost
Audit trail
Communication - "How can I know what I think until I see what I say:
" E M Forster. Communicate ideas to a remote audience. Documentation fixes in time physical expressions to vaguely formed concepts, structured far more rigorously then when they are going around in someone’s head.
Cost - the cost of poor quality documentation is hard to measure. But think of the time wasted through misinterpretation, recovering from errors, resubmitting to regulatory authorities, failing regulatory audits, etc
Audit trail - footprints in the snow. Write what you do, do what you write and if you didn't write what you did...you didn't do it!!

48. Documentation: general principles
Documents should be
Designed, prepared, reviewed, distributed with care
Approved by appropriate responsible persons
Comply with marketing authorization
Design of documentation important
Look at the “Style” of the document
Instructions in the imperative
Short sentences preferred to long sentences
Documents should be designed, prepared, reviewed and distributed with care.
In terms of design, there is no single right answer – the one thing you can be sure about is that every company will come up with a different design. However, it is better for the operators if a consistent approach is taken. It is possible for some of the documents to be combined, but generally they should be separate. They must comply with the relevant part of the manufacturing and marketing authorizations. All documents should be unambiguous with a title and a clear statement of purpose. They should contain clear, numbered references to each activity. They should have sufficient space to record relevant data. They should be easy to check and all relevant activities should be recorded on them.
15.2

49. Documentation: general principles (cont'd)
Contents of documents should be clear (easy to understand) and include, e.g.
Title, nature, objective or purpose
Layout in orderly fashion
Easy to be filled in and checked
Clear and readable – including copies made
No errors if master documents are copied for working documents
The contents of documents should be clear (easy to understand) and include e.g.:
Title, nature, objective or purpose
The layout should be in orderly fashion and allow easy to be filled in and checked
Documents should be clear and readable – including copies made
There should be no errors if master documents are copied for working documents
15.4

50. Documentation: general principles (cont'd)
Documentation control
Regular review of documents
Kept up to date (current) - amended
Superseded documents removed and not used
Distribution and retrieval of documentation
Retention time for superseded documents
Distribution of documents needs to be carefully controlled in order to ensure that the most up-to-date version is always being used. There should be a distribution list, if appropriate, attached to the document. Unauthorized photocopying of original documents should be actively discouraged. Some companies manage this by having part of the front page printed in colour, or by using an official stamp or other means of identification.
There should be an SOP for distribution, retrieval and preparation of documentation. A document register is required. This ensures that change control over all documents is properly managed.
15.5

51. Data entry in documents:
Clear, readable and indelible
Design to allow for sufficient space for entries
Changes to entries:
signed, dated and reason given
original entry still readable
Entries at the time of action
All significant actions recorded – traceable
Operators and staff should make clear, readable and indelible entries in documents.
The design of the document should allow for sufficient space for entries
Once an entry is made, changes should only be made if really necessary. All changes to entries should be
signed, dated and a reason given for the change. The original entry should still be readable
Entries should be made at the time of action. Entries should not be made prospectively or retrospectively.
All significant actions should be recorded and traceable (time, operator, equipment used etc).
15.6 – 15.8

52. Data entry in e-documents:
Electronic data processing systems, photographic systems or other reliable means:
Systems require SOPs and records
Accuracy of records checked
Authorized persons - access and changes
Password controlled
Entries checked
Batch records stored electronically:
Protected
Back-up transfer, e.g. magnetic tape, microfilm, paper print-outs
Records kept 1 year after expiry date of product
Data readily available during retention period
Validation of
computer system
15.9

53. Different types of documents
Labels
Specifications and testing procedures
Master formulae and instructions
Batch processing and batch packaging records
Standard Operating Procedures (SOPs)
Records
Stock control and distribution records
Log books
Other documents …
This slide summarizes all the types of documents that are listed in the WHO GMP text, plus three additional ones. We will review each one in detail later in the session, but at this point, we will run through the list to make sure we are aware of all the requirements (Note for the trainer: that makes a good group session for audience participation rather than just reading the list to the seminar. One can also ask what must go on the e.g. Release label, or cleaning label, etc......)
Labels are required for all containers, equipment and premises.
Specifications and testing procedures are required for all starting materials, packaging materials, intermediates, bulk and finished products.
There must be a master formulation for all manufacturing processes and a packaging instruction for each stock-keeping unit that is produced.
Batch processing documents and records are required for all manufacturing processes.
Batch packaging documents and records are required for packaging operations.
Standard operating procedures (SOPs) are required for all operations that are not product-specific, whether related directly to manufacturing or to operation of the facility.
The following are three examples of other documents that are useful and frequently found:
Stock control records are usually used for all materials that are stored in the warehouse.
Distribution records are usually used for all batches of material that are dispatched from the warehouse.
A water quality manual describes all aspects of the water system design, operation, maintenance and water quality testing.

54. Labels
What must be labelled?
Containers, equipment, premises
Label information?
Clear, unambiguous, company format
Intermediates and bulk products
Colours can be used, e.g. green (accepted), red (rejected)
Different types of labels, e.g. cleaning status, production stage, status of materials
Other types of labels?
There are different types of documents. Let's look at "labels" as one set of documents.
What must be labelled in the factory? (Let the participants name items to be labelled and then expand on why labels are needed, what should be reflected on the labels and so on. These include labels on containers, equipment, rooms (including the product processed, stage of production, cleanliness status, "under maintenance" or "out of order").
The information appearing on labels should be clear, easily readable, and not leave any confusion. Labels should be in the company's format. Often companies prefer to have the name of the company on the label, the use of colour codes for some status, dates, signatures and other relevant information depending on what the label indicates.
15.10

55. Specifications Authorized, approved, signed and dated
Starting, packaging materials and finished products: include tests on identity, content, purity, quality
Intermediates and bulk
Water, solvents and reagents
QC, QA or documentation centre
Periodic review
Compliance with current pharmacopoeia
Pharmacopoeia, reference standards and spectra available
Besides labels, there are also other types of documents. One specific type of document that is important to ensure quality and compliance with a quality standard, is a "specification". Different materials, components and other items may have specifications that indicate the standard to which it should comply. Think of equipment components such as filter bags, sieves, punches and dies.
Materials including starting materials, packaging materials, intermediates and bulk should also have specifications. These materials should eb tested for compliance against the specifications. All specifications should be authorized (that means approved by responsible persons, signed and dated) before use.
Specifications are normally prepared and kept, maintained (reviewed and updated) by QC or QA and are stored in the documentation centre.

56. Specifications: Starting and packaging materials
Include:
Name (e.g. INN) and internal code
Pharmacopoeia (if applicable)
Qualitative and quantitative requirements and limits
Other data may include:
Supplier
Sampling procedure or reference
Storage conditions, precautions
Retest date
There are specific recommendations in GMP as to what should be included in specifications. In general, the documents should be properly designed to contain the relevant information. Starting and packaging material specifications should include information such as:
Name (e.g. INN) and internal code
Pharmacopoeia (if applicable) reference
Qualitative and quantitative requirements and limits
Other data may include:
Supplier name and address
Sampling procedure or reference e.g. to the SOP
Storage conditions,
Precautions (e.g. to be observed during storage or sampling)
A Re-test date

57. Specifications: Finished products
Include:
Name and code reference
Names of actives (e.g. INN)
Formula
Dosage form, package details
Reference to sampling
Qualitative and quantitative requirements and limits
Storage conditions and precautions
Shelf life
Specifications for finished products should include:
Name and code reference for the product
Names of actives (e.g. INN)
Formula
Dosage form, package details
Reference to sampling
Qualitative and quantitative requirements and limits
Storage conditions and precautions
Shelf life
15.21

58. Production documentation
Bulk manufacturing:
Master formulae
Batch Processing Records
Packaging:
Packaging instructions
Batch Packaging Records
The Master formulae and the Packaging instructions are the connection document between Marketing Authorization, Specifications and the actual records
15.22 – 15.30
There must be a formally approved master formula for each product that is manufactured, in each batch size. The information that it should contain includes the following:
Name of the product with product reference code
Dosage form, strength and batch size
A full list of materials including quantities and unique reference code for each
Expected final yield with acceptable limits (plus intermediate yields)
Processing location and principle equipment

59. Documentation This is an example of a batch record.
The elements to look for here are easy reading, by careful setting out blocks of information so that the reader is able to go through the complicated information easily, and a systematic approach to the sequence of information.

60. Documentation Batch packaging document and line clearance
Discuss the SOP, checklist, checks for the correct batch number and expiry date, correct printed packaging material, correct primary and secondary packaging material

61. Standard Operating procedures (SOPs)
Describe one particular process in detail
Required for a lot of activities mentioned in WHO chapter 15
Many other activities outlined elsewhere in GMPs also require SOPs
SOPs are non-batch related
Authorization
Periodic review
Version management
Clear instruction, no ambiguities
15.31 – 15.48

62. Standard Operating procedures (SOPs)
This is an example of an SOP sheet.
Elements to look for are the set out (all upper case can be difficult to read), accountability of the document, traceability, purpose, scope and instructions in the imperative.

63. Part 3: Qualification and Validation
Definitions:
Validation
Action of proving, in accordance with the principles of GMP, that any procedure, process, equipment, material, activity or system actually leads to the expected results
Qualification
Action of proving that any premises, systems and items of equipment work correctly and actually lead to the expected results
(Validation usually incorporates the concept of qualification)
There are three objectives to this module:
Firstly, we are going to start by looking at the definition of validation and the different types that are used.
Secondly, we will discuss documents associated with validation, and review the key stages of the validation process.
Thirdly, we shall look at a model approach for process validation in the context of the WHO documentation.
Finally, we are going to look at where validation has got to in your country and talk about the barriers that need to be overcome.
This module will deal with the very fundamentals of validation but it will only provide an overview. It will not be an in-depth review of the subject. The subject is very important and requires a lot of careful thought. It will be a major topic of discussion with companies that you inspect and also within the inspectorate.
It is important to remember that validation does not improve bad processes.
Glossary

64. Validation System life cycle: Recommendation Retirement
Maturity
Aging
Development
Project Initiation
Release
for Use
Conceptualization
Early Operational
Life O P E R A T I N L F
Validation

65. Qualification and Validation
Design Qualification (DQ): documentary evidence that a premises, equipment or process has been designed in accordance with GMP requirements
Installation Qualification (IQ): documentary evidence that a premises, equipment or process has been built and installed in accordance with GMP requirements
Operational Qualification (OQ): documentary evidence that a premises, equipment or process operate in accordance with GMP requirements
Performance Qualification (PQ): documentary evidence that a specific process will consistently produce a product meeting its pre-determined specifications and quality attributes
Documented evidence should be provided that prove that e.g.
Premises
Supporting utilities such as water systems, air handling systems, gas supply, compressed air (where these are relevant)
Equipment
have been designed in accordance with GMP and meet their user requirements/design specification needs.
Also referred to as Design Qualification (DQ) where appropriate.
4.3

66. Qualification and Validation
Principle
Qualification and validation should be done in accordance with an ongoing programme
Initial qualification and validation
Annual review
Maintain continued validation status
Policy described in relevant documentation, e.g. quality manual, or Validation Master Plan
Qualification and validation should be done in accordance with an ongoing programme
Initial qualification and validation is normally required (DQ, IQ, OQ and PQ). Then there should be an evaluation or review e.g. annually, to determine whether validation or qualification is required again (Requalification and revalidation).
This is to ensure that the company maintains a continued validation status
The company policy on validation should be described in relevant documentation e.g. quality manual, or Validation Master Plan
4.5, 4.6

67. Types of validation documentation
Validation Master Plan (VMP): policy, responsibilities, management of validation process etc.
Validation protocols
Validation reports
Standard Operating Procedures (SOPs)
There are different types of documents related to validation:
Master plans, protocols, reports and SOPs.
Each manufacturer should have a validation master plan (VMP). It describes the overall philosophy, intention and approach to establishing performance adequacy (validation policy).
It also identifies which items are subject to qualification and validation and the nature and extent of such validation. It defines the applicable validation and qualification protocols and procedures.
During the inspection, you should evaluate the VMP to assess whether it covers the overall policy that defines validation and what should be subjected to validation. It should cover the responsible persons, what should be validated, where should the validation be done, when validation should be performed, why and how the validation should be performed. It should include a breakdown of the process, plant or equipment into separate parts. It should also determine which are critical to the quality of the product and therefore require validation, and at which stages. For example, in a project to commission a sterile manufacturing suite, the operation of the sterilizers is critical and will require IQ, OQ and PQ; and the operation of the ventilation system is critical and will require IQ, OQ and PQ.
The VMP should be a concise and easy-to-read document which will serve as a guide to the validation committee and personnel who are responsible for performing validation. The VMP is also a source document for use by regulatory inspectors.

68. Validation Master Plan (VMP)
Approval page and table of contents
Introduction and objectives
Facility and process description
Personnel, planning and scheduling
Responsibilities of validation team members
Process control aspects
Equipment, apparatus, processes and systems qualified, validated – and to be qualified or validated
Acceptance criteria
Documentation, e.g.validation protocols and reports
SOPs
Training requirements and other elements…
The VMP should typically include at least the following sections:
Approval page and table of contents.
Introduction and objectives.
Facility and process description.
Personnel, planning and scheduling.
Responsibilities of committee members.
Process control aspects.
Equipment, apparatus, processes and systems to be validated.
Acceptance criteria.
Documentation e.g. validation protocols and reports.
SOPs.
Training requirements.

69. Requirements to Validation documentation
Clearly defines responsibility of performing validation
Conducted in accordance with predefined, approved validation protocols
Conducted in accordance with predefined, approved acceptance criteria
Recorded results and conclusions presented in written validation reports – prepared and stored
Processes and procedures should be established on the basis of these results
Premises, utilities, equipment and processes
Critical importance and particular attention paid to validation of:
Analytical test methods
Automated systems
Cleaning procedures
The documents should clearly define who is responsible for performing validation.
Qualification and validation should be conducted in accordance with predefined, approved validation protocols, and the results and conclusions presented in written validation reports. These should be in a recommended format, ensure a proper audit trail, traceability –and stored for a defined period of time.
Processes and procedures should be established on the basis of these results
4.7 – 4.11

70. Qualification and Validation
WHO References
Good manufacturing practices (GMP): guidelines on the validation of manufacturing processes
Validation of analytical procedures used in the examination of pharmaceutical materials
The main reference text that the WHO has produced relating to validation is published as Annex 6 of the thirty-fourth report of the WHO Expert Committee on Specifications for Pharmaceutical Preparations, published in 1996 (WHO Technical Report Series NO. 863). The Annex is titled “Good Manufacturing Practices: Guidelines on the validation of manufacturing processes”.
This document covers the subject in some detail. It provides a glossary of terms, discussions of the topic in general, types of validation, the different approaches that can be taken and recommendations on how to organize a validation program. It also presents an outline for a validation protocol and report.
The focus is mainly on the validation of manufacturing processes, but many of the points also relate to other operations, such as cleaning.
However, for guidance on the validation of analytical techniques, you should refer to Annex 5 of the WHO Expert Committee’s thirty-second report entitled “Validation of analytical procedures used in the examination of pharmaceutical materials” (WHO Technical Report Series No 863 and Quality assurance of pharmaceutical, A compendium of guidelines and related materials, volume I, pp WHO, Geneva, 1997).
Annex 6

71. Example of priorities for process validation
Type of process Requirement
New Every new process before approval for routine
Existing:
Sterile products All processes affecting the sterility, and
manufacturing environment including
sterilization stage
Non-sterile Low dose tablets and capsules: mixing and
granulation; content uniformity (and other
parameters)
Other tablets and capsules: uniformity of mass
(and other parameters)
These are examples of requirements for process validation.
(See Quality Assurance of Pharmaceuticals, A compendium of guidelines and related materials (Volume 2), Good Manufacturing Practices and inspection, WHO, 1999)

72. Qualification and Validation
A qualification or validation protocol may contain:
Objectives of the validation and qualification study
Site of the study
Responsible personnel
Description of the equipment
SOPs
Standards
Criteria for the relevant products and processes
A validation protocol is a detailed document relating to a specific part of the validation process e.g. the OQ for a manufacturing vessel. It outlines the tests that are to be carried out, the acceptance criteria and the information that must be recorded. It also defines the approval process for the validation.
The protocol should clearly describe the procedure to be followed for performing validation. It should include at least the objectives of the validation and qualification study, the site of the study, the responsible personnel, a description of the equipment to be used (including calibration before and after validation), SOPs to be followed (e.g. the operation and cleaning of the equipment) and the standards and criteria for the relevant products and processes.
The type of validation and time/frequency should also be stipulated. The processes and/or parameters to be validated (e.g. mixing times, drying temperatures, particle size, drying times, physical characteristics, content uniformity, etc.) should be clearly identified.

73. Qualification and Validation
A qualification or validation report should reflect the elements of the protocol, and may contain elements such as:
Title
Objective of the study
Reference to the protocol
Details of materials, equipment, instruments, personnel
Programmes and cycles used
Details of procedure and test methods
… etc.
The results obtained during the performance of the validation, must be recorded.
The validation report reflects the final test results and other documents such as instrument calibration certificates. It is on the basis of this report that the decision is taken on whether a particular process is judged to be validated. During the inspection, you must assess whether there is a written report reflecting the results after completion of the validation. The results should have been evaluated, analyzed and compared with acceptance criteria by the responsible personnel. All results should meet the criteria of acceptance and satisfy the stated objective. If necessary, further studies should have been performed. If the results were found to be acceptable, the report should been approved and authorized (signed and dated).
The report should include the title and objective of the study, and refer to the protocol, details of material, equipment, programs and cycles used, together with details of procedures and test methods. It should provide a comparison of the results with the acceptance criteria.
In addition, it should include recommendations on the limits and criteria to be applied to all future production batches. It is common practice in many companies for the protocol and the report to be combined into a single set of documents. The protocol is approved as a form on which the test results are recorded as they become available. This reduces the amount of paperwork that needs to be stored and makes an overall assessment of the validation results easier to carry out.

74. Possible problems in Qualification and Validation
Lack of time
Lack of personnel
Lack of experience and knowledge
Changes to the process
Prospective versus retrospective validation
Lack of documentation infrastructure
Lack of implementation of validation
Poorly designed documents
Possible Issues
Lack of time
Lack of personnel
Lack of experience and knowledge
Changes to the process
Prospective versus retrospective validation
Lack of documentation infrastructure
Lack of implementation of validation
Poorly designed documents

75. Some GMP topics not covered today:
Vendor evaluation
Personnel
Training
Recall
QC laboratories
Stability
Etc.