World Health Organization

World Health Organization
15 April, 2017 Basic Principles of GMP Premises Part One This module deals with premises Parts I and 2. It will contain two optional group discussions. The plan* is as follows: Part 1 : Introduction and Principles presentation minutes Part 2 : Detailed area review presentation minutes Group session Option 1 and minutes Test minutes *The exact time will depend on the number, nature and experience of the participants. When talking about premises, we are looking at the buildings in which the processes are to be carried out. We are also looking at the general conditions that exist within them and the area where the factory is located. We have to be sure that the premises promote GMP compliance. The premises must therefore be easy to maintain in a good condition. The word premises means all the buildings where manufacture of the products will take place. 12

Premises World Health Organization 15 April, 2017 Objectives 1. To review general requirements 2. To list key requirements for site choice 3. To consider specific requirements for main areas 4. To list major facilities required in a multifunction site Our objectives for this session are split into 4 main areas: 1. We will review in detail the general requirements that GMP make on the location and design of the premises. We will be looking at the principles supporting all aspects of the design of the factory. 2. Having done that we will have a group session in which we will be asking you to use your knowledge of the general principles and your practical experience in your country to review a concept drawing of a facility “faxed” through to your group. The plan is only on one page, A4 but this is sometimes typical of plans faxed through for comment. 3. We will then examine each key area and review the special requirements for building design. We will also look at the role of the premises in the prevention of cross-contamination. 4. In the second group session we want you to look at a multifunction factory and to define the GMP facilities that you would expect to find there. There is another concept drawing of a sterile facility faxed through to your group for comment.

Premises 15 April, 2017 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 The land and buildings where the manufacturing operations are located must contribute towards the quality of the products. They do this by avoiding the risks of contamination, permitting effective cleaning and maintenance, minimizing the build-up of dirt and dust and preventing quality defects. We will look at each of these areas in more detail in a moment. How do we achieve good conditions in the factory? 12.1

Premises 15 April, 2017 Location Geography, climate, noise and economic factors Neighbouring factories and sites What do they do? What impact can they have on the business? Pollution/effluent control Minimum risk for contamination of products and materials The geography of the chosen location can have a considerable impact upon the design of facilities. Is the location subject to earthquake hazards? Does it experience flooding regularly – during the monsoon season for example? What precautions need to be taken regarding continuity of supply of services? The climate of the area is also important. If the company will be handling, for example, gelatin capsules then humidity is of great concern. If the company has a lot of goods requiring temperature or humidity controls in transport, and the goods have to sit on the dockside for weeks waiting for a boat to arrive, there may be a problem with the quality of the products. The company may need to rent temperature-controlled storage. If it does, how will it check the quality of that storage? The factory may have to seek some expensive design solutions to overcome the problems that arise. Does the process make a lot of noise, for example? If it does and the location is close to neighbours, then the company may be forced into expensive soundproofing. The neighbourhood is also important. If the company is to be located next to a steel mill then the design precautions that it will have to take, and the level of maintenance that it will have to undertake, will be very different than if it is in a rural setting. If the neighbours change, the company will need to take appropriate measures to handle the situation correctly. The company is also required to take measures that prevent the factory polluting the surrounding area with product or by-products from its manufacturing processes. A site inspection is useful before building commences to ensure that the area is suitable for the construction of a pharmaceutical factory (See photo) 12.1, 12.4

Premises 15 April, 2017 Principle Premises must be located, designed, and with a layout to minimize risks of cross-contamination, e.g. not located next to a malting factory with high airborne levels of yeast What should become clear is that the land and buildings where the factory is located will have an effect upon the quality of the products. To illustrate this point let us for a moment consider locating a pharmaceutical factory next to a malting works which uses large amounts of yeast. What are the factors that would need to be taken into account in designing the factory to make tablets or sterile products? In the above photo, a homeopathic company did locate its facility next to a malting company and suffered continuing problems with yeast contamination of its products. 12.4

Premises 15 April, 2017 General The layout and design should aim to: Avoid any adverse effect on the quality of products Avoid cross-contamination, build-up of dirt and dust Minimize risks of errors Permit effective cleaning Permit effective maintenance The land and buildings where the manufacturing operations are located must contribute towards the quality of the products. They do this by avoiding the risks of contamination, permitting effective cleaning and maintenance, minimizing the build-up of dirt and dust and preventing quality defects. We will look at each of these areas in more detail in a moment. How do we achieve good conditions in the factory? 12.2

Premises 15 April, 2017 Design Principles Ensure logical flow. Keep in mind: Material flow People flow Process flow (Look at the layouts and see how people, materials and products flow) When designing any facility it is most important to set out the principles upon which that design will be based. It is also important to ensure that the flows of process, material and people are brought together without conflict. It sounds easy to say but it is not so easy to do. Let us consider each design principle in turn. Process flow: What we are looking for here is the sequence of events that will take place in a process. For those of us who are familiar with the industry, this may seem simple. However, the company may well be talking with engineers who know nothing of pharmaceutical manufacture. It means describing for the engineers the way in which the process is operated, the equipment that will be used and the services required. It also means describing the environment required by the product. All of this information can be put into a room data sheet. Material flow: Material flow is shown on the plan of the factory as the routing of materials throughout the facility. It is important to show the status of the materials as well. This means indicating whether they are quarantined, approved or rejected, and also the volume, weight or frequency of movement, and the way in which the material is to be moved. Will it be moved by forklift truck, by pipeline or manually by people? Frequently people show all of this with different coloured lines on a factory layout with different thickness of line to show frequency of movement. In this way it is possible to identify areas of high movement frequency and where the floor is going to have to be very strong to resist the high workload that is placed on it. Materials should flow in the direction of manufacturing. There should be no cross-flow of materials. All of this information is placed on the factory layout plan. People flow: A plan of the factory showing the routing taken by people when they enter the factory, when they move around in the factory from one department to another, and when they leave the factory. It should also show how visitors will enter and where they will go. It can show how people will move from the office areas to the warehouse. People should be limited to those areas where they have their activities. Production areas should not be used as passages or corridors for non-essential personnel movement. This is particularly important in the case of purchasing and accounts department staff who will be handling invoices for goods delivered or shipped out. This plan shows how access control is maintained. 12.10

Premises World Health Organization 15 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.

Premises 15 April, 2017 Design Suitable design and construction to facilitate good sanitation Cleaning and disinfecting according to detailed written procedures – records maintained Maximum protection against entry of insects, birds and animals Procedure for rodent and pest control implemented Design The design of the factory is rather important. The company should plan properly right from the beginning when the factory is designed. Consideration should be given for possible expansion in the future. You often see factories where the company has grown over the years. Then expansion took place, and there is no logical flow of personnel or materials. Suitable design and construction to facilitate good sanitation. Cleaning and disinfecting should be done according to detailed written procedures – records should be maintained. (Explain what is needed in terms of SOPs for cleaning of different areas, depending on the design of the area, cleaning records, cleaning frequency). Maximum protection against entry of insects, birds and other animals should be provided. Inspectors should look at the design of the premises to assist in this especially at entrances, receiving and despatch bays, and change rooms. In some cases you see extraction fans in stores areas. On occasion, birds nests were noticed here and doves flying in and out of the stores. There should also be procedures for rodent and pest control. 12.5, 12.7, 12.9

Premises 15 April, 2017 Construction and utilities Suitable construction materials Electrical supply Suitable lighting (especially for visual on-line checks) Temperature and relative humidity Controlled, monitored and recorded Appropriate and effective ventilation These may affect products during manufacture or storage as well as functioning of equipment Construction Construction should be of suitable materials to ensure proper cleaning, no cracks, and that the building can withstand pressures, vibrations and other effects. Electrical supply is required for consistent performance of equipment and instruments. Where there is not a constant supply of electricity, power generators may have to be considered. Suitable lighting (especially for visual on-line checks) Temperature and relative humidity control should be provided where necessary. In many cases, materials and products have to be stored or processed under controlled conditions. The temperature and RH should be controlled, monitored in accordance with an SOP, and the results recorded. Appropriate and effective ventilation should be provided (See supplementary training material on HVAC). These may affect products during manufacture or storage as well as functioning of equipment 12.8, 12.32

Basic Principles of GMP
World Health Organization 15 April, 2017 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 storage requirements for materials and products 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.

Premises 15 April, 2017 Construction Dust generating operations e.g. sampling, weighing, mixing, packing of powders, etc. Measures should be taken to prevent cross- contamination Measures to facilitate cleaning E.g. Materials of construction; ledges and edges; smooth surfaces Where dust is generated (e.g. during sampling, weighing, mixing and processing operations, packaging of powder), measures should be taken to avoid cross-contamination and facilitate cleaning. 12.3

World Health Organization Basic Principles of GMP 15 April, 2017 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

Premises 15 April, 2017 Maintenance Procedure for maintenance of the premises Records maintained Damage repaired Repairs and maintenance should not present any hazard to the quality of the products What should be done if there is any damage while a product is being processed? Premises should be carefully maintained, and it should be ensured that repair and maintenance operations do not present any hazard to the quality of products. 12.6

World Health Organization Basic Principles of GMP 15 April, 2017 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

Premises 15 April, 2017 Specific areas In Part 2 – we will review some recommendations for specific areas such as: Ancillary areas 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

15 April, 2017 Basic Principles of GMP Premises Part two This module deals with premises Parts 2. It will contain two optional group discussions. The plan* is as follows: Part 2 : Detailed area review presentation minutes Group session Option 1 and minutes Test minutes *The exact time will depend on the number, nature and experience of the participants. 12

Premises 15 April, 2017 Ancillary Areas Rest and refreshment rooms: Separate from production and quality control areas Changing, washing and toilet areas accessible and appropriate numbers Animal houses well isolated – separate air handling and entrance Maintenance workshops: Separated from production - if not possible – tools in reserved areas 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

World Health Organization 15 April, 2017 Explain the layout of change rooms, washing facilities and toilets. Explain the importance of hygiene

World Health Organization 15 April, 2017 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.

World Health Organization Basic Principles of GMP 15 April, 2017 Separate receiving and dispatch bay Protect materials and products 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. 12.17

World Health Organization 15 April, 2017 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?

Premises World Health Organization 15 April, 2017 Storage areas - 1 Sufficient capacity, orderly storage of categories of materials and products Storage conditions 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

World Health Organization 15 April, 2017 Explain racking, storage of primary and secondary packaging materials (protected from contaminants), different status such as quarantine and released, materials management, bin location systems.

World Health Organization 15 April, 2017 Examples of storage of packaging materials and in process bulk

Premises World Health Organization 15 April, 2017 Storage areas - 2 Good storage conditions Clean Dry Temperatrure Lights Within defined limits Provided, controlled, Monitored and recorded 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

15 April, 2017 Premises Storage areas - 3 Separated areas recommended - clearly marked and access restricted e.g.: Quarantine area Segregate areas: Rejected, recalled and returned materials and products Separate sampling area recommended to prevent risk for contamination or cross-contamination 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

World Health Organization 15 April, 2017 Storage of packaging materials should be in closed containers Rejected materials and containers should be stored separately and marked as such

Premises 15 April, 2017 Storage areas – 4 Printed packaging materials Correct materials are critical to ensure compliance with correct labelling of products Ensure compliance with specifications, prevent mix-ups Special attention to: Sampling safe and secure storage 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

Premises 15 April, 2017 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 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

World Health Organization 15 April, 2017

Premises World Health Organization 15 April, 2017 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 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 highly active products, such as some antibiotics, hormones, cytotoxic substances and certain non-pharmaceutical products, should not be conducted in the same facilities. 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 (including cleaning validation) are made. The manufacture of technical poisons, such as pesticides and herbicides, should not be allowed in premises used for the manufacture of pharmaceutical products. 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. 12.24

Premises World Health Organization 15 April, 2017 Production areas -2 Layout in accordance with sequence of production (flow) Layout to avoid mix-ups and cross-contamination Orderly and logical positioning of equipment minimizes risk of contamination, mix-ups and missing production steps Appropriate cleanliness level, and lights Adequate work and in-process storage space 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. 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. 12.32, 12.26, 12.31

Premises World Health Organization 15 April, 2017 Production areas -2 Specially designed areas for packaging Layout Space No mix-ups 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. 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. 12.32, 12.26, 12.31

Premises World Health Organization 15 April, 2017 Production areas - 3 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 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 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. 12.27

Premises 15 April, 2017 Production areas - 4 Design of pipework, light fittings, and ventilation points no recesses that are difficult to clean Access for maintenance from outside production areas Drains adequate size 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

World Health Organization 15 April, 2017 Design of light fittings and ventilation points should be such that there are no recesses that are difficult to clean

Premises World Health Organization 15 April, 2017 Production areas - 5 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 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) 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. 12.30

Premises World Health Organization 15 April, 2017 Windows should not open to the outside Windows must not open to the outside unless they form an emergency escape route. All emergency escape routes must be sealed to prevent access from the outside, whilst not affecting their use as an escape route.

Premises World Health Organization 15 April, 2017 Finishing of floors, walls and ceilings Should be smooth, impervious, hard- wearing, easy to clean. No bricks, tiles, wood or sliding doors where residue can collect! Unacceptable premises: Trainer to point out: The top left hand side photograph : Unacceptable use of wood for the shelves, bricks which cannot be cleaned, unlabelled drum, unlabelled trays sliding doors, bricks, etc. The top right hand side : Wooden cupboard, unlabelled containers, unacceptable tiles on the bench top, crowded and cluttered conditions.

Premises World Health Organization 15 April, 2017 Finishing of floors, walls and ceilings Much better These pictures illustrate a much better approach to achieving smooth, impervious durable surfaces for floors, walls and ceilings. The light fixtures fit flush with the ceiling, the floor uses welded vinyl which is covered to the wall, the surface are very smooth and easy to clean and there are no gaps or crevices which are difficult to clean properly.

Premises World Health Organization 15 April, 2017 Quality Control areas - 1 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 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. 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. 12.33, 12.34

World Health Organization 15 April, 2017 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.

Premises World Health Organization 15 April, 2017 Quality Control areas - 2 Suitable construction materials Prevention of fumes Ventilation Separate air supply (production and QC) Separate rooms for some instruments to protect them from interference (e.g. electrical, vibration, moisture, etc.) See supplementary training on QC laboratories The laboratory should be constructed with suitable construction materials. Measures should be taken for the prevention of fumes The laboratory should be provided with effective ventilation and separate air supply from production is recommended. Separate rooms for some instruments to protect them from interference (e.g. electrical, vibration, moisture etc) may be required. See supplementary training on QC laboratories 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. 12.35, 12.36

Premises World Health Organization 15 April, 2017 Group Session - Option 1 A company wishes to manufacture simple, non-sterile medicines. It has engaged a consultant to draw up some building plans Comment on the building plans “faxed” through to your group Comment on the people flow, the process flow and the material flow Let us now go into our groups. We want you to consider the creation of a new pharmaceutical factory. What are the key features that should be looked for in the environment in which this factory is built? What are the key features in the general design of the buildings? We do not want you to go into details about specific areas for specific processes at this stage. you to use your knowledge of the general principles and your practical experience in your country to review a concept drawing of a facility “faxed” through to your group. The plan is only on one page, A4 but this is sometimes typical of plans faxed through for comment. Consider the people flow, the process flow and the material flow. Please be prepared to present your answers in a 10-minutes presentation to the plenary session which will start at … (Insert appropriate time).

Premises World Health Organization 15 April, 2017 Group Session - Option 2 Consider a multifunction factory producing sterile and non- sterile products: What GMP facilities would you expect to find in this factory? What would you look for in the quality of those facilities and what weaknesses might you find? How can companies overcome those weaknesses? For this group session we want you to consider a multifunction factory that is producing different types of products. What sort of GMP facilities would you expect to find at such a factory? When thinking about this, please look at all the areas that will be needed. It may be helpful to work logically through the factory, starting at the warehouse. You have 60 minutes for this discussion with a 10-minute report back for each group at the plenary session. This is your opportunity to raise those issues where you have a problem. It is likely that someone here has already experienced your problem. You should plan to be back here by _______ (insert appropriate time).

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