World Health Organization 9 September, 2018 Basic Principles of GMP Sanitation and Hygiene In this session, we are going to deal with an area of importance to the good functioning of a pharmaceutical factory, sanitation and hygiene. This will be a quarter-day session with the following approximate timings: Presentation 45 minutes Group session 45 minutes Group feedback 30 minutes Test paper 30 minutes (Timings are approximate and should be adjusted to suit the class and the course structure.) Section 3

Sanitation and Hygiene World Health Organization 9 September, 2018 Objectives Review measures to ensure good sanitation in: Premises and personnel Equipment and apparatus Processes, materials and containers To review measures to ensure good personal hygiene Group session - to discuss the situation in your country and to look at some bad sanitation and hygiene practices There are three main objectives to this session: Firstly, we are going to look at the measures that need to be taken to ensure good sanitation during manufacturing. These relate primarily to the premises, the equipment and the process to prevent any type of contamination. Secondly, we are going to look at the measures that need to be taken to ensure that good levels of hygiene are achieved during manufacturing. These relate primarily to the personnel. Finally, we are going to relate everything back to the issues particularly relevant to your country. During the group session, you will be looking at the key factors that you need to be aware of during your inspections. We will be presenting you with some photographs to list all the sanitation and hygiene problems that you can.

Sanitation and Hygiene World Health Organization Sanitation and Hygiene 9 September, 2018 Scope High level of sanitation and hygiene practised – in every aspect of manufacturing. It covers: Personnel Premises Equipment and apparatus Production materials and containers Products for cleaning and disinfection All potential sources of cross-contamination The WHO GMP refers to sanitation and hygiene in part one, section 4. It makes the point that all aspects of manufacturing are affected by one or both of these factors. Consideration must be given to all personnel, both direct operators and other staff who enter the manufacturing area for whatever purpose. Then there are the premises in which manufacturing takes place. The level of attention to this aspect will vary with the operation that is carried out. All equipment and apparatus used in manufacturing must be controlled, together with production materials and the containers in which they are held. Production materials (if not handled properly) and the containers (if not properly cleaned) can contribute to dirt and contamination in the factory. Secondary materials, such as cleaning agents and disinfectants, must be controlled to ensure that they do the job for which they are designed but do not cause any contamination to the product. Cleaning tools, such as mops and brushes, must also be controlled. To summarize, the aim of sanitation and hygiene measures is to eliminate all potential sources of contamination and cross-contamination from all areas where the product is at risk. 3.1

Sanitation and Hygiene World Health Organization Sanitation and Hygiene 9 September, 2018 Personal Hygiene (1) Health examinations: Before and during employment Periodic eye examinations for those who do visual inspections Training: Practices in personal hygiene Written procedures and instructions Signs in areas Having dealt with sanitation, we now move on to the hygiene of the personnel involved in manufacturing. This is covered in the WHO GMP texts in part one, section 10. The recruitment process for direct operators in particular should include a medical examination. This should be repeated on a regular basis during the employment period. The definition of “regular” will obviously depend on the activities being undertaken and the products being processed. Induction training for new operators should include basic training in personal hygiene and should state the level of hygiene that is required for working in manufacturing areas. There should be written procedures covering the need to wash hands before entering a manufacturing area. In addition, signs should be posted in the changing rooms to reinforce this. 11.1 - 2

Basic Principles of GMP World Health Organization Basic Principles of GMP 9 September, 2018 Written procedures and instructions - to wash hands before entering production areas Some also use disinfectants Explain the use of disinfectants as appropriate, before entering production areas 11.1 - 2

Basic Principles of GMP World Health Organization Basic Principles of GMP 9 September, 2018 Wash hands before entering production areas Signs in areas (e.g. changing rooms) Explain the use of signs in washing areas, toilet facilities - before entering production areas 11.1 - 2

Sanitation and Hygiene World Health Organization Sanitation and Hygiene 9 September, 2018 Personal Hygiene (2) Illness or open lesions: May affect the quality of products Should not handle starting materials, intermediates or finished products, etc. Instruction and encouragement to report to supervisors Direct contact between product and operator: Should be avoided Starting materials, primary packaging materials, intermediate and bulk product Staff who have an illness or open lesions that are likely to present a risk to the product, should not be allowed to carry out operations that involve handling of starting materials, intermediates or finished products until the condition has cleared up. Since not all illnesses are going to be obvious, operators must be trained to recognize such risks themselves and be willing to report any illness to the area supervisor. Direct contact between the operator and the product should be avoided wherever possible. If direct handling is unavoidable, then gloves should be worn and, if appropriate, these should be disinfected after being put on. 11.2 - 5

Sanitation and Hygiene World Health Organization Sanitation and Hygiene 9 September, 2018 Personnel Hygiene (3) Protection of product from contamination: Clean clothes appropriate to personnel activities Including hair covering (e.g. caps) Check change rooms/changing facilities Hand washing, signs, drying of hands Used clothing stored in separate closed containers while awaiting cleaning Laundering of clean area clothing according to an SOP and in an appropriate facility Procedure for disinfecting and sterilizing when required Products should be protected from contamination. There should be procedures for cleaning of garments/clothes. Clothes can become a source of contamination and cross-contamination. These should be cleaned regularly according to validated procedures. Where relevant, caps, masks, gloves etc should be worn. Be on the lookout for dedicated shoes. How often are these cleaned, and how? Check change rooms/changing facilities Hand washing, signs, drying of hands Used clothing stored in separate closed containers while awaiting cleaning Laundering of clean area clothing according to an SOP and in an appropriate facility Procedure for disinfecting and sterilizing when required 11.6

Sanitation and Hygiene World Health Organization Sanitation and Hygiene 9 September, 2018 Personnel Hygiene (4) Smoking, eating and drinking not allowed in production areas, laboratories and storage areas No chewing (e.g. gum), or keeping food or drinks allowed No plants kept inside these areas Rest and refreshment areas should be separate from manufacturing and control areas Smoking, eating and drinking should not be allowed in any manufacturing area, including laboratories and storage rooms. Chewing of gum should also be banned. There should be no plants kept inside any factory areas. Rest and refreshment areas should be separate from manufacturing areas. 11.7, 12.11

Basic Principles of GMP World Health Organization Basic Principles of GMP 9 September, 2018 Toilets should not open directly into production or storage areas 12.12 Toilets should not open directly into production or storage areas. However, there should be a reasonable access procedure. This should be taken into consideration when setting up changing procedures for entry to manufacturing areas.

Sanitation and Hygiene World Health Organization Sanitation and Hygiene 9 September, 2018 Personnel Hygiene (5) Personal hygiene procedures including wearing protective clothing apply to all persons entering into production areas: Full-time employees Temporary workers Contractor's employees Visitors Managers Inspectors Personal hygiene procedures including wearing protective clothing apply to all persons entering into production areas Full time employees Temporary workers Contractor's employees Visitors Managers Inspectors 11.8

Sanitation and Hygiene World Health Organization Sanitation and Hygiene 9 September, 2018 Design of 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 Sanitation is covered as part of the general discussion of premises in part one, section 11 of the WHO GMP text. As discussed (or will be discussed) in the module on premises, the design of any area depends on the activities that are going to be performed there. However, in general terms, all areas should be designed in such a way that prevents the build-up of dirt and dust. This includes the absence of ledges and unnecessary surfaces, sealing of all joints in ceilings, coving at floor and ceiling and installation of a ventilation system that provides an appropriate flow of air. There are a number of aspects to be covered in looking at cleaning. An effective programme should be designed that covers both cleaning and disinfection. The frequency of each will vary with the function of each area and the particular activities undertaken there. There must be a written procedure (SOP) covering the programme, who is responsible for carrying it out, the materials to be used and methodology. The procedure should be appropriate to the area being cleaned. For example, the procedure for cleaning the warehouse would not be appropriate for cleaning a sterile area. There should also be a written record of cleaning that has been performed. While drains are inevitable in some manufacturing areas, they should be kept to a minimum and should certainly not be located in sterile areas. Their design must prevent the possibility of back-flow. Open channels should be easy to clean and disinfect. There should be maximum protection against the entry of insects or other animals. In loading bays in particular, there needs to be protection against the weather. 12.2, 12.3, 12.7, 12.9, 12.29

Basic Principles of GMP Protection from insects, birds, vermin and weather from receipt of raw materials to dispatch of released product 12.9

Sanitation and Hygiene World Health Organization Sanitation and Hygiene 9 September, 2018 Avoidance of Cross-Contamination (1) 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 In part two of the WHO GMP, section 15 covers the measures that need to be taken to avoid cross-contamination. Proper air control – supply and extraction, of suitable quality should be provided. Filtration is often needed. Contaminants can be due to uncontrolled release of dust, gas, particles, vapours, sprays, organisms, residue, insects, operators, 16.10 - 11

Basic Principles of GMP World Health Organization 9 September, 2018 Measures that can be taken to prevent cross-contamination also include: Segregated areas Ventilation systems Airlocks Clothing Closed processing systems Cleaning and decontamination Explain the concept of air locks, and how these other measures can prevent contamination and cross-contamination

Sanitation and Hygiene World Health Organization Sanitation and Hygiene 9 September, 2018 Avoidance of Cross-Contamination (2) Dedicated and self-contained areas for: Live vaccines Live bacterial preparations Certain other biological materials Penicillin products Certain products, such as live vaccines and other biological materials need to be produced in separated areas. In particular, penicillin should be produced in a separate facility. 16.12(a)

Sanitation and Hygiene World Health Organization Sanitation and Hygiene 9 September, 2018 Avoidance of Cross-Contamination (3) Campaign production: Separation in time Followed by appropriate cleaning Validated cleaning procedure The trainer should also give emphasis to the use of campaign processing. Explain what it means, the number of batches in a campaign, and what level and method of cleaning is appropriate. Refer also to the need for cleaning validation where relevant. 16.12(b)

Sanitation and Hygiene World Health Organization Sanitation and Hygiene 9 September, 2018 Avoidance of Cross-Contamination (4) 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 An important measure against cross-contamination is the design of the ventilation system. All incoming air should be filtered to an appropriate standard to achieve the grades of cleanliness specified for the room being supplied. The use of appropriate pressure differentials and air extraction, together with airlocks, is one of the main ways of achieving control over cross-contamination. (Airflow patterns and equipment design are other considerations.) Additionally, the recirculation of air must be examined carefully. If a ventilation system supplies 100% fresh air, then different rooms can be used for different products at the same time. However, if a system includes recirculation, then all rooms supplied by that system must be processing the same product, or the air must be filtered to an appropriate standard. If no filters are installed, then all ductwork will have to be cleaned during product changeover. 16.12 (c and d)

Basic Principles of GMP World Health Organization 9 September, 2018 Appropriately designed ventilation system with air supply and extraction systems Supply or incoming air should be filtered Detailed modules in the supplementary training deal with recommendations for HVAC systems Refer here only to the HVAC system and the supplementary training material on HVAC

Sanitation and Hygiene World Health Organization Sanitation and Hygiene 9 September, 2018 Avoidance of Cross-Contamination (5) Clothing Protection of operator and product 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)

Sanitation and Hygiene World Health Organization Sanitation and Hygiene 9 September, 2018 Avoidance of Cross-Contamination (6) 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 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(f, h and i)

Sanitation and Hygiene World Health Organization Sanitation and Hygiene 9 September, 2018 Avoidance of Cross-Contamination (7) 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) Increasingly, facilities are being designed with closed processing systems. This trend is obviously one that should be encouraged, as it is a major element in the avoidance of cross-contamination. 16.12(g)

Sanitation and Hygiene World Health Organization 9 September, 2018 Production Operations – Sanitation (1) 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 Final rinse with purified water, or water for injection (for sterile products) 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.

Sanitation and Hygiene World Health Organization 9 September, 2018 Production Operations – Sanitation (2) Full records kept Water systems Water - major constituent of most products SOP for cleaning and sanitization of the water purification system should include distribution line Validation and removal of disinfectant before reuse The sanitation of water systems is particularly important, as water is such a major constituent of most products. Water heated >75oC and recirculated is a good sanitising agent. Water for Injection is usually stored at much higher temperatures. There should be a written standard procedure for cleaning and prevention of contamination, which should include not just the purification system but also the distribution pipework. The procedure should be validated, especially the removal of disinfectant before the system is put back into use. This is important because formaldehyde and peracetic acid are often used to disinfect water systems

Sanitation and Hygiene World Health Organization 9 September, 2018 Production Operations – Sanitation (3) 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

Basic Principles of GMP World Health Organization 9 September, 2018 Clean tools should be used.

Sanitation and Hygiene World Health Organization 9 September, 2018 Group Session - Option 1 Look at the photographs in the handout and record as many sanitation and hygiene issues as you can We are now going to move into the group session. In your groups, you should discuss the subjects of sanitation and hygiene as they relate to the pharmaceutical industry in your country. Use your experience from inspections that you have made and give concrete examples wherever possible to illustrate the key issues that you are to check in a new manufacturing facility.

Sanitation and Hygiene World Health Organization 9 September, 2018 Group Session - Option 2 You are inspecting a new factory. What are the key issues for sanitation and the key issues for personnel hygiene that the company should have in place? We are now going to move into the group session. In your groups, you should discuss the subjects of sanitation and hygiene as they relate to the pharmaceutical industry in your country. Use your experience from inspections that you have made and give concrete examples wherever possible to illustrate the key issues that you are to check in a new manufacturing facility.

Sanitation and Hygiene World Health Organization 9 September, 2018 Possible Issues – I Sanitation Mixed production Penicillins Product versus batch changeovers Water systems How long should a “cleaned” status last for? What should happen if a clearance check is required when no QC personnel are on duty? Procedures and records If production demand is high, there may be resistance from the managers of the factory to spending time carrying out effective cleaning. Production of different products in the same area can cause serious cross-contamination. The issue of decontamination of a factory that has been used for the manufacture of penicillins needs to be addressed carefully. In an older building, the design may not be suitable for effective cleaning. For example, there may not be false ceilings, walls may be covered in tiles, etc. The design of the ventilation system needs to be reviewed, particularly with respect to standards of filters and recirculation. Cleaning of ductwork should also be discussed. Procedures for a changeover from one product to another should be more stringent than the procedure between batches. There should be written procedures for regular cleaning and prevention of contamination of the water system. The procedure for cleaning and prevention of contamination should include details of who is responsible, what they have to do and where it is recorded.

Sanitation and Hygiene World Health Organization 9 September, 2018 Possible Issues – II Hygiene Personal hygiene Health checks Dealing with health problems Personal responsibility Training records Frequency of handwashing Personal hygiene is always a sensitive matter. However, the company must be able to ensure that operators not only understand hygiene requirements, but also fulfil them. Health checks should be carried out on all new operators and periodically on all staff during employment. This could be a problem if the managers are reluctant to carry the expense. There should be trained staff who can deal with issues relating to health problems. The operators must feel that they can report these problems in confidence without risking their jobs. As with any aspect of pharmaceutical manufacture, the final quality of the product depends, to a large extent, on the willingness of the operators to take personal responsibility for such issues as hygiene. Training should include references to procedures for cleaning and hygiene requirements, which should be included in written training records.