377218-GMP-TRAINING-STERILE-FACILITY
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This document provides an overview of sterile production requirements including: 1) Different sterile product types and their air classification requirements for different production steps. 2) Key GMP requirements for sterile facilities including air quality grades, environmental monitoring, and personnel requirements. 3) Sterilization methods including heat, filtration, radiation and ethylene oxide gas. Validation and process monitoring requirements are discussed. 4) Quality control testing requirements for sterility, endotoxins and environmental monitoring are summarized.
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377218-GMP-TRAINING-STERILE-FACILITY
- 1. Module 13 Slide 1 of 48 WHO - EDM Part Three Basic Principles of GMP Sterile Production
- 2. Module 13 Slide 2 of 48 WHO - EDM Sterile Production Objectives To review basic GMP requirements in the manufacture of sterile products To review air classifications for activities related to the manufacture of sterile products To review the different types of sterilisation methods To review quality assurance aspects in the manufacture and control of sterile products To consider current issues applicable in your country.
- 3. Module 13 Slide 3 of 48 WHO - EDM Sterile Production Types of sterile products Terminally sterilised prepared, filled and sterilised Sterilised by filtration Aseptic preparation
- 4. Module 13 Slide 4 of 48 WHO - EDM Sterile Production GMP Requirements for Sterile Products Additional rather than replacement Specific points relating to minimizing risks of contamination microbiological particulate matter pyrogen
- 5. Module 13 Slide 5 of 48 WHO - EDM Sterile Production General Requirements Production in clean areas Airlocks for entry personnel goods Separate areas for operations component preparation product preparation filling etc Level of cleanliness Filtered air
- 6. Module 13 Slide 6 of 48 WHO - EDM Sterile Production General Requirements (contd) Air classification: Grade A, B, C and D Laminar air flow: air speed (horizontal versus vertical flow) number of air changes air samples Conformity to standards Work station and environment Barrier technology and automated systems
- 7. Module 13 Slide 7 of 48 WHO - EDM Sterile Production Manufacture of sterile preparations Terminally sterilised preparation: – Grade C: then immediate filtration and sterilisation – Grade D: Closed vessels – Grade A: Filling (Grade C environment) of parenterals – Grade C: Filling of ointments, suspensions etc
- 8. Module 13 Slide 8 of 48 WHO - EDM Part Three 17.5.1 Sterile Production Classifications - I Terminally Sterilized Products Product type Preparation of solution Filling of solution SVP and LVP C A/C SVP and LVP D (c losed container) A/C Others C C
- 9. Module 13 Slide 9 of 48 WHO - EDM Sterile Production Manufacture of sterile preparations Sterilisation by filtration Handling of starting materials – Grade C – Grade D: Closed vessels – Sterile filtration into containers: Class A (in Class B environment) or Class B (in Class C environment)
- 10. Module 13 Slide 10 of 48 WHO - EDM Part Three 17.5.2 Sterile Production Classifications - II Sterile Filtered Products Product type Preparation of solution Filling of solution SVP and LVP C A/B SVP and LVP C B/C SVP and LVP D (closed container) B/C Other products C B/C
- 11. Module 13 Slide 11 of 48 WHO - EDM Part Three 17.5.3 Sterile Production Classifications - III Products produced from Sterile Materials Product type Preparation of solution Filling of solution SVP and LVP A/B A/B SVP and LVP B/C B/C Other products A/B A/B Other products B/C B/C
- 12. Module 13 Slide 12 of 48 WHO - EDM Sterile Production Manufacture of sterile preparations Aseptic preparation Handling of materials All processing Grade A in Grade B environment or Grade B in Grade C environment
- 13. Module 13 Slide 13 of 48 WHO - EDM Part Three 17.16 - 17.21 Sterile Production Premises Design avoid unnecessary entry Clean areas smooth, impervious, unbroken surfaces permit cleaning no uncleanable recesses, ledges, cupboards, equipment no sliding doors ceilings pipes and ducts sinks and drains
- 14. Module 13 Slide 14 of 48 WHO - EDM Part Three 17.22 - 17.23 Sterile Production Premises Changing rooms designed as airlocks flushed with filtered air separate for entry and exit desirable hand washing facilities interlocking system visual and/or audible warning system
- 15. Module 13 Slide 15 of 48 WHO - EDM Part Three 17.34 - 17.37 Sterile Production Sanitation Clean areas frequency SOP Disinfectants periodic alterations monitor microbial contamination dilutions, storage and topping-up Fumigation Monitoring micro and particulate matter
- 16. Module 13 Slide 16 of 48 WHO - EDM Air Classification System Sterile Production Grade at rest in operation maximum permitted number of particles/m3 equal to or above 0.5 µm 5 µm 0.5 µm 5 µ A 3 500 0 3 500 0 B 3 500 0 350 000 2 000 C 350 000 2 000 3 500 000 20 000 D 3 500 000 20 000 not defined not defined
- 17. Module 13 Slide 17 of 48 WHO - EDM Comparison of Various Codes Sterile Production Comparison of different classification systems WHO cGMP US Customary US 209E ISO/TC 209 EEC Annex I GMP A M 3.5 100 ISO 5 A B M 3.5 100 ISO 5 B C M 5.5 10 000 ISO 7 C D M 6.5 100 000 ISO 8 D
- 18. Module 13 Slide 18 of 48 WHO - EDM Part Three 17.10 - 17.15 Sterile Production Personnel Outdoor clothing Appropriate to air grade Grade D – hair, beard and shoes Grade C – hair and beard – suit covering wrists, neck – no fibres Grade B – masks, gloves Laundry and changes
- 19. Module 13 Slide 19 of 48 WHO - EDM Part Three 17.6 - 17.8 Sterile Production Personnel Minimum number in clean areas aseptic processing inspection and control Regular training manufacture hygiene microbiology outside staff Animal tissue and cultures of micro-organisms
- 20. Module 13 Slide 20 of 48 WHO - EDM Part Three 17.9,17.11 - 17.12 Sterile Production Personnel Hygiene and cleanliness contaminants health checks SOPs : Changing and washing Jewellery and cosmetics
- 21. Module 13 Slide 21 of 48 WHO - EDM Part Three 17.24 - 17.33 Sterile Production Equipment Air supply:(HVAC) Generation and supply of filtered air under positive pressure Airflow patterns Failure of air supply Pressure differentials monitored and recorded Conveyer belts Effective sterilisation of equipment Maintenance and repairs Planned maintenance, validation and monitoring Water treatment plants
- 22. Module 13 Slide 22 of 48 WHO - EDM Sterile Production Environmental Monitoring - I Microbiological Air Surfaces Personnel
- 23. Module 13 Slide 23 of 48 WHO - EDM Sterile Production Environmental Monitoring - II Physical Particulates Differential pressures Air changes Filter integrity Temperature/humidity
- 24. Module 13 Slide 24 of 48 WHO - EDM Part Three 17.38-39, 17.42-43 Sterile Production Processing Minimise contamination No unsuitable materials e.g. live microbiological organisms Minimise activities staff movement Temperature and humidity Water sources and systems monitoring records action taken
- 25. Module 13 Slide 25 of 48 WHO - EDM Part Three 17.44-47; 17.50-17.51 Sterile Production Processing Bio-burden determination raw materials in-process materials – LVP : filtered immediately before sterilisation – sealed vessels: pressure-released outlets Components, materials and containers fibre generation no re-contamination after cleaning stage identified sterilised when used in aseptic areas Gas through a sterilising filter
- 26. Module 13 Slide 26 of 48 WHO - EDM Part Three 17.52, 17.40 Sterile Production Processing Validation new processes re-validation: Periodic and after change Aseptic process: Sterile media fill (“broth fills”) simulate actual operation appropriate medium/media sufficient number of units – acceptable limit – investigations revalidation: periodic and after change
- 27. Module 13 Slide 27 of 48 WHO - EDM Part Three 17.47,17.48 Sterile Production Processing Time intervals: Components, containers, equipment washing, drying and sterilisation sterilisation and use – time limit and validated storage conditions Time intervals: Product preparation preparation and sterilisation short as possible maximum time for each product
- 28. Module 13 Slide 28 of 48 WHO - EDM Sterile Production Finishing of products Validated closing process Checks for integrity Maintenance of vacuum (where applicable) checked Parenteral products: Individual inspection illumination and background eyesight checks breaks validation
- 29. Module 13 Slide 29 of 48 WHO - EDM Sterile Production Group session 1 You are asked to visit a factory producing the following product lines: Injections in ampoules and vials, including insulin, vaccines and heat-stable pharmaceuticals. Sterile eye ointment Describe the type of facility you would expect to find. List the typical rooms, their purpose and air classification
- 30. Module 13 Slide 30 of 48 WHO - EDM Sterile Production Possible Issues Poor design of the building Poor design of the systems e.g. water, HVAC Flow of personnel Flow of material No validation or qualification Old facilities not complying with current requirements
- 31. Module 13 Slide 31 of 48 WHO - EDM Sterile Production Possible Issues(contd) Particulate levels/micro-organisms Differential pressures Air changes Temperature/humidity
- 32. Module 13 Slide 32 of 48 WHO - EDM Part Three 17.53 - 17.55 Sterile Production Sterilization Methods of sterilization heat sterilization: Method of choice Validation all processes non-pharmacopoeia non-aqueous or oily solutions Suitability and efficacy part of load type of load repeated: annually and after change
- 33. Module 13 Slide 33 of 48 WHO - EDM Part Three 17.56 - 17.57 Sterile Production Sterilization Biological indicators Differentiation between sterilized and not-sterilized products labelling autoclave tape
- 34. Module 13 Slide 34 of 48 WHO - EDM Part Three 17.58 - 17.60 Sterile Production Sterilization by Heat Recording of each cycle, e.g. time and temperature validated coolest part second independent probe indicators Heating phase each load determined Cooling phase no contamination leaking containers
- 35. Module 13 Slide 35 of 48 WHO - EDM Part Three 17.61- 17.63 Sterile Production Moist Heat Sterilization Water wettable materials Temperature, time and pressure monitored Recorder and controller independent Independent indicator Drain and leak test Removal of air Penetration of steam, quality of steam All parts of the load: Contact, time, temperature
- 36. Module 13 Slide 36 of 48 WHO - EDM Part Three 17.64 Sterile Production Dry Heat Sterilization Air circulation and positive pressure in chamber Filtered air Temperature and time must be recorded Removes pyrogens validation (challenge tests with endotoxins)
- 37. Module 13 Slide 37 of 48 WHO - EDM Part Three 17.65 - 17.67 Sterile Production Sterilization by Radiation Suitable for heat sensitive materials and products confirm suitability of method for material ultraviolet irradiation not acceptable Contracting service Measurement of dose Dosimeters quantitative measurement number, location and calibration Biological indicators Colour discs
- 38. Module 13 Slide 38 of 48 WHO - EDM Part Three 17.67 - 17.70 Sterile Production Sterilization by Radiation Batch record Validation density of packages Mix-ups: Irradiated and non-irradiated materials Dose: Predetermined time span
- 39. Module 13 Slide 39 of 48 WHO - EDM Part Three 17.71 - 17.76 Sterile Production Sterilization by Ethylene Oxide Gas Only when no other method is practicable Effect of gas on the product Degassing (specified limits) Direct contact with microbial cells Nature and quantity of packaging materials Humidity and temperature equilibrium Monitoring of each cycle time, pressure temperature, humidity gas concentration
- 40. Module 13 Slide 40 of 48 WHO - EDM Part Three 17.77 Sterile Production Sterilization by Ethylene Oxide Gas Post-sterilization storage ventilation defined limit of residual gas validated process Safety and toxicity issues
- 41. Module 13 Slide 41 of 48 WHO - EDM Sterile Production Sterilization by Filtration Previously sterilized containers Nominal pore size 0.22 µm or less remove bacteria and moulds not viruses or mycoplasmas Double filter layer or second filtration No fibre shedding or asbestos filters Filter integrity testing Time taken and pressure difference validated
- 42. Module 13 Slide 42 of 48 WHO - EDM Sterile Production Sterilization by Filtration Length of use one working day or validated Filter interaction with product removal of ingredients releasing substances
- 43. Module 13 Slide 43 of 48 WHO - EDM Sterile Production Group session 2 Considering the same factory as in the previous group session, discuss the process of sterilization. List all the items that will need to be sterilized. What are the key features you should find in each sterilization situation? Which aspects would be subject to validation?
- 44. Module 13 Slide 44 of 48 WHO - EDM Sterile Production Possible Issues Autoclave - no pressure gauge Autoclave - no temperature recorder Autoclave - superheated steam Clean room - pressure differentials Exposure for settle plates Interlocks turned off Rusty Laminar airflow cabinets HEPA filters not checked regularly
- 45. Module 13 Slide 45 of 48 WHO - EDM Sterile Production Quality Control Environmental monitoring Sterility testing Endotoxin testing
- 46. Module 13 Slide 46 of 48 WHO - EDM Sterile Production Sterility Testing Samples representative of the batch aseptic fill – beginning, and end of batch, or interruption heat sterilization – coolest part of the load Last of series of control measures Adequate testing facility (e.g. Class A in B environment) Test failure: Second test subject to investigation: – type of organism
- 47. Module 13 Slide 47 of 48 WHO - EDM Sterile Production Pyrogen Testing Rabbit method LAL test (endotoxin monitoring) Injectable products water, intermediate, finished product validated pharmacopoeia method for each type of product always for water and intermediates Test failures cause investigated remedial action
- 48. Module 13 Slide 48 of 48 WHO - EDM Sterile Production Group session 3 Considering the same factory as in the previous group sessions, devise a plan for monitoring of the facility. List the parameters to be tested, tests to be used, acceptance criteria and frequency of testing.
Editor's Notes
- This module deals with the important topic of sterile production. It is a full- day session module divided into four roughly equal parts as follows: General points : Classification systems and how to achieve them Methods of sterilization Quality Control and quality assurance aspects In each case, there will be 15-40 minutes of presentation, 45 minutes discussion in groups and 30 minutes feedback to the whole group. There will be two tests covering the whole module that will be taken at the end of the day (or at the start of the next day as appropriate). All that can be achieved with this module is a very basic introduction to the topic. Separate courses lasting several days are needed to cover properly such issues as moist heat sterilization.
- The first objective of this module is to identify and understand the key issues and GMP requirements relating to sterile product manufacture. This type of manufacturing is one of the most complex in the industry. The critical nature of the products in question make this a very important subject indeed. The second objective is to review air classifications for activities related to the manufacture of sterile products. The third is to review the different types of sterilisation methods and the forth is to review quality assurance aspects in the manufacture and control of sterile products We shall also consider current issues applicable in your country.
- There are three main types of sterile products. The nature of the product determines the manufacturing requirements, as we will see later on. The three types of product are listed on this slide in order of increasing criticality. The first type is terminally sterilized products. These are products that are tolerant to sterilization in their final containers. This usually means they are process tolerant; for example, they are stable when exposed to heat or gamma-irradiation, so they can be manufactured and filled under clean rather than aseptic conditions. The key task here is to reduce the bioburden to a minimum so that the challenge to the sterilization process will be as low as possible. This is the method of choice for sterile manufacture where possible. Sterile filtered products are not tolerant to terminal sterilization. An example of this type is heat-sensitive products. They are manufactured under clean conditions, and then filtered into containers in the filling room where they are filled under aseptic conditions. All components, such as primary containers, must be sterilized before they are introduced into the filling area. Sterile filtered production should only be considered if all methods of terminal sterilization are impossible. Finally, there are products that are produced from sterile starting materials. In this case, manufacture and filling are both carried out under aseptic conditions, with components sterilized before use.
- The first point to be emphasized is that GMP requirements for sterile products are additional to the usual requirements for pharmaceutical manufacture, rather than a replacement for them. The WHO GMP text deals with this subject in part three, and in supporting and supplementary guidelines The emphasis of all the extra requirements for sterile production is to minimize the risks of contamination by particulates, microorganisms or pyrogens. This is because sterile products are administered to particularly sensitive parts of the body, whether intravenously or intramuscularly as an injection, as an eye ointment or as a wound dressing.
- A general requirement for the manufacture of sterile products, is that production must be done in clean areas. Entry to these areas are through airlocks for personnel and/or goods. To achieve the appropriate level of cleanliness in these areas, filtered air should be supplied to the areas. There are different operations to be carried out. This includes component preparation, product preparation and filling. Separate areas for these operations are needed.
- The clean areas are classified according to required characteristics of the air. The air classification is : Grade A, B, C and D Laminar air flow is used to obtain the required characteristics. During inspections you have to verify the compliance with the specifications including air speed (horizontal versus vertical flow), the number of air changes (e.g. a minimum of 20 per hour) and the number of air samples taken to determine the presence of particulate matter in the area. The results should comply with the specifications for acceptable limits for micro and particulate matter at the work station and the environment Some manufacturers also make use of barrier technology and automated systems to minimize human intervention in the manufacturing process.
- During the inspection, you have to verify that the operations for the manufacture of sterile products are carried out in the correct grade or class of air. Products that are terminally sterilised should be prepared in a Grade C environment, and then immediately filtered and sterilized. If closed vessels are used, then preparation can be done in Grade D. Filling of parenterals should be done in Grade A within a Grade C environment. Ointments and suspensions can be filled in Grade C. Starting materials for products sterilised by filtration, should be handled in Grade C. If closed vessels are used, then in Grade D. Sterile filtration into containers must be done in Class A (in Class B environment) or Class B (in Class C environment)
- The next three slides cover the appropriate classifications for activities involved in the manufacture of the various product types that we defined earlier. There is a further sub-division of the products into injection products and others. Injections may be small volume parenterals (SVP) or large volume parenterals (LVP). In both cases, they are the most critical types of product since they are injected or infused into the body. The other sterile products, such as eye ointments, creams, emulsions and suspensions can be filled in a grade C environment. This slide deals with the situation for terminally sterilized products. SVPs and LVPs are generally prepared in a grade C environment, although this can be reduced to a grade D if a closed system is being used. Filling takes place in a grade A zone within a grade C environment. For other products, both manufacture and filling may take place in a grade C environment as a concession.
- During the inspection, you have to verify that the operations for the manufacture of sterile products are carried out in the correct grade or class of air. Products that are terminally sterilised should be prepared in a Grade C environment, and then immediately filtered and sterilized. If closed vessels are used, then preparation can be done in Grade D. Filling of parenterals should be done in Grade A within a Grade C environment. Ointments and suspensions can be filled in Grade C. Starting materials for products sterilised by filtration, should be handled in Grade C. If closed vessels are used, then in Grade D. Sterile filtration into containers must be done in Class A (in Class B environment) or Class B (in Class C environment)
- For sterile filtered product, the regime remains the same for manufacture and preparation, not only for SVPs and LVPs but also for other products. Once again, these activities are carried out in a grade C environment, unless a closed system is used, in which case grade D is acceptable. For filling, there are some changes. For SVPs and LVPs, filling takes place as before in a grade A zone, located within a grade B. For other products, a grade B filling zone is required, located within a grade C zone as a concession.
- The situation for products produced from sterile materials is even more straightforward. For SVPs and LVPs all activities take place in place in a grade A zone within a grade B zone. For other products, a grade B zone is required within a grade C background as a concession.
- Aseptic preparation, handling of materials and all processing of such products must be done in: Grade A in Grade B environment or Grade B in Grade C environment
- There are a number of specific requirements for premises that are used for the manufacture of sterile products. Unnecessary entry to all processing areas should be avoided. The design of the premises should support this. It should be possible to observe operations from the outside. Processing takes place in suites of rooms with different classifications, depending on the activities carried out in them. The classifications relate primarily to the supply of air to the rooms. We will be looking at this topic in more detail in the second part of this session. Assess whether the rooms are designed to reduce the accumulation of dust, with all exposed surfaces being smooth, impervious and unbroken. (The trainer may want to show the slides of photographs of suitable and unsuitable premises and finishing). There should also not be excess equipment, cupboards or tools in the area. Doors should also be suitably designed and sliding doors should be avoided in sterile product manufacturing areas, as these cause areas where it is difficult to clean. Ideally there should be false ceilings, which are sealed so that no dirt can fall from the void above. This should also permit access to light fittings from above allowing maintenance without stopping production. Wherever possible, pipes and ductwork should be outside the area, or boxed in. Sinks and drains should be avoided if possible and must not be installed in aseptic areas. Drains should have cleanable traps and air breaks to prevent back flow. Floor channels must be open and easy to clean. Maintenance of clean and sterile areas is very demanding. If work needs to be done, the processing should stop. The area must be decontaminated and disinfected as appropriate before it is started again. There should be a detailed plan and procedure for cleaning and sanitation. We will return to this in a few minutes. Finally, there must be a full programme of monitoring for the area. This will be the topic of the final session in this module .
- Entry to all processing areas should be through airlocks. For personnel, these airlocks generally take the form of changing rooms that have a variable number of interconnecting rooms, depending on the grade of the area. Ideally, separate airlocks should ideally be provided for the entry of materials into the area. Airlocks should be flushed with filtered air. In some facilities, there are different airlocks for entry to and exit from manufacturing areas. This can promote unidirectional flow of personnel and material. Hand washing facilities should only be provided in change rooms, and not in production areas. The doors at either end of an airlock should be interlocked so that they cannot both be opened at the same time. Fire regulations may require alternative solutions. Visual and audible alarms are recommended as an alternative to interlocked doors. (Note: Trainers should explain with the aid of a flip chart and drawings, suitable layout of premises, indicating air supply and return to areas, desired air flow patterns, design and purpose of air locks, and the concept of pressure differentials between different areas).
- As mentioned before, clean and sterile areas must have a documented and planned programme of sanitation. Procedures must include details of who is responsible and the frequency of cleaning in each area. Cleaning and sanitation will vary for different rooms, depending on the activities and the risk to the product. There should also be details of the methodology, including preparation of cleaning materials. The cleaning procedure and cleaning materials should be evaluated and approved by the QC department. A liquid detergent is preferable to a powder-based, one as the latter could leave a powder residue. Where disinfectants are used, more than one type should be employed, with periodic alterations. Monitoring should be regularly undertaken in order to detect the emergence of resistant strains of micro-organisms. In view of its limited effectiveness, ultraviolet light should not be used as a substitute for chemical disinfection. You could review records indicating that disinfectants and detergents are monitored for microbial contamination. Dilutions should be kept in previously cleaned containers and should not be stored for long periods unless sterlized. Try to verify that partly emptied containers are not topped up. (Also look at the label on the containers). Fumigation of an area is an effective method, but requires careful performance and adequate “degassing” afterwards. With effective ventilation systems, it may be possible to eliminate the need to carry out this process or, at least, to reduce its frequency. There must also be a programme to monitor all environmental aspects including micro and particulate matter. This is covered in detail later in the module.
- In this session, we are going to talk about the classification systems that are in use in clean and sterile areas and the air supply that is required in each one. This table is taken from the WHO GMP text and describes four classifications A - D. From the point of view of air supply, there are three grades, B - D. A is the laminar airflow workstation located in a grade B area. The different grades are defined in terms of the maximum permitted number of particles per cubic metre of air (at two different sizes). The WHO text also contains values for microbial contamination of the various grades. They have been included in the text for information and are not intended to represent specifications. We will talk later about how these characteristics are measured. They are attained by means of a ventilation system in which air is passed through a series of filters. The generally accepted design is for two pre-filters and a HEPA (high efficiency particulate air) filter at the outlet into the room. The air inlet is usually located at a high level in the room, whereas the extract is at a low level. The filtered air supply must be maintained at positive pressure to the surrounding areas. Airflow patterns must be designed so that they do not distribute particles into the area where the product is exposed. An alarm system, in the case of air supply failures, should be installed. During the inspection, you have to evaluate records and results from the manufacturer in which it is established and proven, that a claimed grade is achieved.
- There are a number of different systems for describing classification of clean rooms in use around the world. Although this training course relates specifically to the WHO code, it is likely that some of the companies that you have to inspect will be using an alternative terminology, depending on the history of the company and any relationships that it has had with other organizations. For reference purposes, the main systems are listed above. They are roughly equivalent, although the US standard is different with respect to the microbiological standard. There are two classifications listed for the US federal standard. Although the latest system (M3.5 etc) has been issued for a some time, most people are still using the more familiar grade 100 etc - in fact this is the most commonly terminology used in many countries even if they are not working to FDA standards in any way. There are other systems of classification in use in Europe and other countries. Many companies still refer to these systems and it is important to recognise the classification that is being aimed at.
- There should be no outside clothing brought into the clean areas. The WHO GMP text specifies the type of clothing that is appropriate for the different grades of rooms. Arrangements must be in place for the laundering and sterilization of clean-room clothing. This should be carried out in a controlled environment. If fibres are damaged due to inappropriate cleaning or sterilization, an increased risk for contamination may develop as clothing could shed particles. The use of contract laundries for this purpose, requires an audit by the company to ensure that appropriate procedures are in place. It is important to remember that there may be visitors to the sterile manufacturing areas (although these should be kept to an absolute minimum.) Appropriate procedure for clothing and supervising visitors should be in place, up to and including Grade C. Clean, sterilized clothing should be provided to workers in Grade B areas. This should be done at each work session or at least once a day if monitoring results justify it. Gloves should be regularly disinfected during operations. Disposable clothing could also be used. Visitors may need special training before entry to the area of higher Grade is permitted. This special training is necessary to ensure that they can conform to entry procedures.
- During sterile manufacturing, the number of people working in the area should be kept to a minimum, particularly in an aseptic operation. Where possible, inspections and in-process controls should be performed from outside the clean-room. Alternatively, operators should be trained to carry out tests themselves, to reduce the number of indirect personnel who come into the area. There should be regular training for all personnel who routinely enter the sterile areas - both direct operators and service personnel such as cleaners and maintenance staff. This training should cover not only the job itself, but also hygiene and the basics of microbiology. To avoid cross-contamination, personnel who have worked with animal-tissue material or live microorganisms should not enter the sterile area. If this cannot be avoided, then strict decontamination procedures must be followed in all cases.
- High standards of personal hygiene are important for all aspects of pharmaceutical manufacturing (as discussed in the module on sanitation and hygiene). They are even more important in the case of sterile product manufacture. Periodic health checks and monitoring by swabbing are important in the identification of conditions that can cause contamination. In addition, operators should be trained to report such conditions themselves. Clothing should not be the cause of any possible contamination of the product or containers. There should be a written procedure for changing and washing. However, when it comes to the detail of that procedure, there are a variety of approaches that may be taken. In particular, the order in which different pieces of clothing are taken off or put on and the point at which hands are washed will vary between companies. There is no single correct answer to this question and the important point is the logic of the approach and the consistency with which it is applied. Watches and jewellery should not be worn, nor should cosmetics that will shed particles.
- The supply of suitable quality air to sterile manufacturing areas, is very important. Filtered air under positive pressure should be supplied to production areas of sterile products. Verify whether the manufacturer has validation data of aspects relating to airflow patterns, and warning systems indicating failure of air supply (e.g. manometers measuring pressure differentials, or an audible alarm).Check the configuration and maintenance of HVAC and filters. The pressure differentials between areas should be monitored and recorded in accordance with written SOPs. You should also check whether the manufacturer uses conveyer belts that pass through a clean and dirty area, to convey components or products. This can only be allowed if the conveyer belt is sterilised before moving into the clean area. Equipment for use in the sterile area should be designed so that it can be operated with the minimum of personnel interference, thus reducing the possibility of contaminating the product. It should also be easily sterilized by moist or dry heat sterilization. Sterilizers should be designed with a door at each end (known as double door autoclaves or double- ended autoclaves) to eliminate the possibility of mixing up sterile and non-sterile materials. This is particularly important for sterilizing components that are going into the filling room. They are loaded in the preparation area and unloaded in the sterile area, although preferably in a buffer room rather than directly in the filling room. It is important that the zone in which the product is to be exposed is protected to the maximum extent possible. This requires the installation of laminar airflow cabinets over the piece of equipment, to ensure a supply of filtered air flowing with positive pressure towards the surrounding areas. It is also necessary to ensure that the locations of the equipment and the operator do not cause a risk to the product by interrupting the flow of filtered air. Where possible, maintenance and repairs of equipment should take place outside the area. However, if this is impossible, it should be done when there is no work going on and should be followed by a complete clean down and disinfection. Tools for such work should be sterilized before being taken into the area. It is even better if a full set of sterilized tools can be stored in the area specifically for this purpose. After maintenance has been completed, there should be a documented procedure for obtaining approval to resume operations in the area. It is permissible to have transport systems to take product from the filling room to the sterilization/finishing area, but there must be a physical barrier across the actual interface between the two areas. Water of appropriate qulaity should be supplied by a water treatment plant that is suitably designed, constructed and maintained. You should evaluate the water treatment plant in terms of maintenance and qualification, as well as the monitoring of the quality of the water. The production, storage and distribution of water should be done in such a way that microbial growth is prevented. Evaluate the SOP for water sampling and review the results of the water testing. You should also check the deign of the water treatment plant, the distribution and storage of water. If water is stored in a tank, then the temperature should be kept at about 70 degrees Celsius.
- The first aspect of microbiological monitoring of the environment relates to the air supplied to the rooms. There are a number of methods for taking samples, but the simplest and most widely used is to place open settle plates of growth medium on the floor for around 2 - 4 hours. (The exact time period has to be developed to suit local conditions.) The exposure time should not be too short as non-representative results will be obtained. If the exposure time is too long, then the plates can dry out. The number of plates required depends on the classification and use of the room, and can be determined from international standards. The location of the plates will have been determined during validation and will be based on the risk to the product and the level of activity in the area. It is not necessary to obtain zero-growth results from these plates, but a validated pattern of likely contamination will be established and significant deviations need to be investigated. If zero growth is observed, then low levels of bacteria are inoculated onto the plate to demonstrate that it will support growth. Monitoring of surfaces is generally carried out using swabs. Emphasis should be placed on the areas that come into contact with the product. In these areas, zero-growth results are expected. This method of monitoring, carried out before and after cleaning and disinfecting can be used to validate the methods being used. Finally, it is necessary to monitor the micro-organisms that could be shed from the personnel in the clean rooms. Personnel can be the greatest source of contamination. Samples are generally taken by swabs from clothing and by “finger-dabs” onto plates. Sampling should be representative of the situation during operations. So, if the operator normally wears gloves and disinfects them before use, the samples should be taken afterwards. Review the SOP and records of results during your inspection.
- The ventilation systems used to supply air to clean rooms have already been discussed. We shall now look at the physical monitoring that is carried out on these systems. Particulate matter counts are carried out with a particle counter that measures the number of particles in a given quantity of air. They should be carried out during validation and at regular intervals thereafter. The differential pressures between rooms are measured by means of manometers. The manometers should be calibrated and should provide continuous monitoring. Values should be recorded regularly. The number of air changes within a room is calculated from the air volumes supplied to the room. The calculation should be made during validation and regularly thereafter. The HEPA filter integrity is tested by a number of means. An aerosol generator can be used to send an aerosol across the filter and a photometer used to view it. This will show whether there is any damage to the filter. Additionally, a manometer can be used to measure the pressure differential across the filter. These tests should be carried out when filters are installed and repeated at regular intervals (at least annually). Again, you should verify compliance with this by reviewing the SOP and records to assess complaince with the SOP. The temperature and humidity can be measured by a variety of instruments from the very simple to the very complex. Several of the above parameters can be monitored automatically, and new factories often have sophisticated building management systems (BMS) that not only monitor, but also make adjustments if required. If you are inspecting a factory with such a system, it is worth spending some time checking on the understanding of the personnel regarding this system. It can be all too easy to assume that everything is under control and not notice when something goes wrong. Establish whether any validation had been done to ensure that all the controls and monitors are working as intended?
- At all times during processing, there should be measures to ensure that contamination of product, material and components, is minimized. No unsuitable materials should be used in the areas. All furniture and fittings should be of metal or plastic rather than wood. Paper may need to be used in the area, e.g. for batch documentation, but this should be kept to a minimum. Bonded paper or lint-free paper is available. Paper should not be used in a grade A area at all. Alternatives include plastic sheets and permanent markers. It goes without saying that extras such as calendars and notices should be excluded. The processing of preparations containing live micro-organisms is not allowed in the same facility as other pharmaceuticals. Products with dead organisms can be processed in the same facility providing validated procedures for inactivation and cleaning are used. During processing in sterile areas, it is important that the amount of activity is kept to a minimum. This is one area where you will have to spend time to observe the activities of the personnel.The greatest source of contamination in a sterile area is the personnel. Validated automization of processes with fewer people in the area, could minimise the risk of contamination. Processing areas should be built with plenty of inspection (glass) windows to limit the number of persons who need to go into the room during processing. The temperature and humidity in the areas should be controlled to ensure that the integrity of materials is mainteianed, and the operators are also comfortable (considering the nature of the garmetns they should wear in the areas). Treated water and the equipment used to produce it should be monitored regularly for biological and chemical contamination and for the presence of endotoxins. Evaluate the SOP and recorded results of monitoring the water. Determine whether there is provision made for any corrective action should the results indicate problems with the quality of the water. No unsuitable materials should be used in the areas. All furniture and fittings should be of metal or plastic rather than wood. Paper may need to be used in the area, e.g. for batch documentation, but this should be kept to a minimum. Bonded paper or lint-free paper is available. Paper should not be used in a grade A area at all. Alternatives include plastic sheets and permanent markers. It goes without saying that extras such as calendars and notices should be excluded. The microbiological contamination load or bioburden for starting materials prior to sterilization should be kept to a minimum. There should be limits when monitoring has shown that they are needed. Extreme care must be taken with materials that have been sterilized in the area for use in aseptic production, such as primary containers and filling machine parts. After removal from the sterilizer, they should be stored in a way which maintains their sterility (examples: in laminair airflow, triple wrapping etc.). All packs should be marked with the date of sterilization and there should be a procedure setting out how long an item can remain in the area before it needs to be resterilized. There must also be a validated maximum storage period between the preparation of a bulk solution and its sterilization or filtration through a bacteria-retaining filter.
- The microbiological contamination load or bioburden for starting materials prior to sterilization should be determined and kept to a minimum. There should be limits specified in specifications and evidence of testing. The microbiological contamination of products should be kept to a minimum. Large volume parenterals should be passed through a micro-organism retaining filter immediately before sterilisation. Where solutions are stored in sealed vessels, make sure that the pressure release outlets are protected with hydrophobic air filters. There should be a minimum or no containers or other materials in the area, liable to generate fibres due to the risk of contamination. Extreme care must be taken with materials that have been sterilized in the area for use in aseptic production, such as primary containers and filling machine parts. After removal from the sterilizer, they should be stored in a way which maintains their sterility (examples: in laminar airflow, triple wrapping etc.). All packs should be marked with the date of sterilization and there should be a procedure setting out how long an item can remain in the area before it needs to be re-sterilized. The stage of processing should thus be identified (e.g. proper labelling). Components, equipment and bulk-product containers to be used in clean areas, should be sterilised before being taken into the clean area. Any gas used to purge a solution or blanket a product, should be passed through a sterilizing filter. You could verify this by reviewing records for the replacement of such filters.
- Validation is an essential part of GMP. Validation is a very important part of sterile product manufacture. Validation is required for new processes, equipment, premises and personnel. Re-validation is also required, periodically and after change of processes, equipment or maintenance. Let’s look at some GMP and validation requirements specifically for aseptic processing. Sterile media fill (“broth fills”) with nutrient media supporting microbial growth is a valuable part of the validation process. It simulates the actual operation. During the inspection of the micro laboratory, you should establish whether appropriate media are used. When reviewing the records and results of the broth fill, establish whether a sufficient number of units e.g. at least 3000 had been filled, whether acceptable limits had been set (not more than 0,1% contaminated units) and whether any investigations are performed when there is contamination. Revalidation should be performed at periodic intervals, and after any significant change to equipment, processes or materials.
- When reviewing the batch manufacturing documents and other relevant documentation, establish whether the manufacturer has validated the time intervals between washing, drying and sterilisation for components, containers, and equipment. The time interval between sterilisation and use as well as the storage conditions must have been validated. AS far as production is concerned, the time intervals between preparation and sterilisation should be as short as possible and a maximum time for each product must be set by the manufacturer. You could verify this for each individual product, by requesting the validation report for the product. The batch manufacturing document should reflect this time limit, based on the validation data.
- The closing and sealing of containers of sterile products, should be done in accordance with validated methods. Review the validation protocols and reports for the sealing of the containers such as ampoules and vials. You should further evaluate how the manufacturer takes samples of products to check the integrity of the seals. Evaluate the SOP and compliance with the SOP for this process. When containers are sealed under vacuum – samples should be taken and tested at regular intervals as specified in the SOP or batch document. Parenteral products should be individually inspected for foreign particles, pieces of glass, cracks and other contaminants. You should inspect the area where the inspection is performed to assess whether the inspection is done visually or by using automated equipment. When visual inspection is done, assess whether this is done under illumination and background, whether operators have regular eyesight checks, regular breaks are given to rest their eyes, and whether their performance had been validated. (Trainer can elaborate). If automated equipment is used, then the equipment should have been subjected to validation/qualification.
- There are a number of areas where you might expect to find problems: Equipment design - for example sterilizers without the correct instrumentation. Inadequately controlled services - for example, superheated steam or unfiltered compressed air. Inadequate ventilation systems - for example, insufficient pressure differentials between rooms. Badly planned monitoring programmes - for example, settle plates exposed for too long or poorly designed media fills. Bad practices - for example, interlocks not operational on airlocks. Poorly maintained facilities - for example, performance of filters not monitored
- As we have just seen, the classification systems relate to specific levels of particulates and viable micro-organisms. However, there are also a number of other factors that must be defined in order to describe the area fully. There should be a set pattern of pressure differentials between different grades. There may also be a pressure differential between rooms in the same grade. Pressure differentials are set by adjusting the levels of inflow and extract of air to provide a given absolute pressure in a room. Where two rooms have different absolute pressures, a differential is set up which dictates the direction of airflow between the two. (Use a flip chart to demonstrate the principle in more detail, if appropriate). Between two areas of different grades, the cleaner grade area will always have higher pressure than the lower grade, such that the flow of air is outwards and there is no chance of “dirty” air passing into the clean-rooms. A pressure differential of >10-15 Pa is preferable. Within changing rooms, differentials are set such that the airflow sweeps outwards from the clean to the dirty side. Between rooms of the same grade, the pressure differential will depend on the activities that are taking place. There should also be a specification for the number of air changes that take place within a room i.e. the number of times that the volume of air in the room is replaced per hour. This should be more than 20 times according to the WHO GMP text. Temperature and humidity are generally controlled in clean and sterile rooms, both for the protection of the operators and the protection of the product. The levels set may vary depending on the nature of the product, but it should be remembered that the clothing worn by personnel in these areas can be uncomfortable, and a lower than normal temperature may be required for ease of working.
- We are now going to talk about sterilization in more detail, with particular reference to the different methods of sterilization. There are a number of available methods, each of which has advantages and disadvantages. Heat sterilization should always be the preferred method if it can be used. Validation of all processes and the method of sterilization is essential, particularly as sterility testing is always a destructive test and can only be carried out on a sample of the batch. You should look very carefully at validation results for any methods that are not in accordance with national standards or pharmacopoeia, or for materials and products that are not solutions. If there are changes in the sterilization method, they must be validated. The manufacturer must have data to support its decision for the sterilisation process. The suitability and efficacy in achieving the desired sterilising conditions in each part of load, and each type of load must have been validated. This validation is done initially and repeated at least annually and after change.
- Biological indicators can be considered as part of the monitoring of the sterilization process. Their use should always be controlled to prevent contamination of the facility and product with live micro-organisms. It is very important that a company has effective methods for separation of sterilized and unsterilized materials. Ideally, sterilizers should be double-ended, so that there is no cross-flow of products or materials. Containers should be clearly labelled and indicators such as autoclave tape or irradiation discs can be used. However, it is important to remember that these indicators only show that a load of material has passed through the sterilizer. They are not in themselves proof of sterility. I am sure that some of have have seen examples where sterilized and not-sterilized products were stored next to each other where there had been a possibility of a mix-up, or where batch documentation had been completed and signed in advance, indicating that products had been sterilised (but in fact, had not yet been through the sterilising process). Always verify the stage in the production process against the batch documentation. Biological indicators Differentiation between sterilized and not-sterilized products labelling autoclave tape
- It is not possible to deal with all the aspects and requirements for sterilisation in the basic module. The information provided here is only a brief introduction. It is recommended that the novice inspector should have an experienced inspector with him/her or an expert, when performing an inspection of sterile product manufacture. An expert adviser should be considered for an in-depth assessment. Let us now look at the different methods of sterilisation. We will first look at the basic principles of heat sterilisation, and then review the different methods. Verify that all sterilization cycles are monitored using appropriate recording equipment. The accuracy and precision of the equipment should have been validated. This is applicable to at least monitors for temperature and time. This must provide a record of all the cycle parameters. The probes for determining temperature must be situated at the coolest part of the loaded chamber so that they are recording the worst case situation. A second independent probe should also be placed in the same position. The charts from these recorders must form part of the batch processing records. For any given cycle and load, there is a period when the sterilizer is heating up, before the sterilization temperature is reached. The recording of the cycle time should not commence until this heating period has been completed. Similarly, there is a cooling down period at the end of the cycle. If a liquid or gas is used to cool the load it must be sterile so that it cannot cause recontamination. Where possible, the manufacturer should also show that any leaking container would not be approved for release or use.
- Moist heat sterilization is suitable only for water wettable materials, and takes place in an autoclave. The critical parameters are temperature, time and pressure. All of these must be recorded and shown to achieve minimum conditions. This method is generally used for sterilizing components such as filling machine parts and clothing, or for aqueous finished products in sealed containers such as ampoules. Aspects that you should verify during the inspection, is whether the recorder and controller are independent form each other. The temperature indicator should be independent. If the sterilizer is fitted with a drain at the bottom of the chamber, then it is recommended that the temperature be monitored in this position as well – throughout the sterilisation period. If a vacuum phase is part of the cycle, then regular leak tests should be performed. Te removal of air is quite important as residual air may affect the process of sterilization. Hot air (even at 121 degrees Celsius will not sterilize products, containers or materials, but may act as a “thermal insulator). (Trainers could explain to the participants what the affect of residual air can be by referring to the so-called “Davenport disaster” of the 1970’s. (See attached documentation in this regard)). In the case of components, these must be wrapped in material that allows removal of air and entry of steam, but does not allow recontamination afterwards. It is critical that all parts of the load are in contact with water or water vapour throughout the cycle. The quality of the steam is also important; the use of a clean steam generator is to be encouraged. The validation data should prove that all parts of the load are in direct contact with water or saturated steam, for the required time period, at the required temperature. Remember to review the charts from the sterilizer for specific batches of product. (Trainer should explain what is meant by this). (The trainer should also refer the participants to other reference documents regarding the sterilization of products, materials and components).
- Dry heat can be used to remove pyrogens and as a sterilization method. It takes place in an oven or sterilizing tunnel and the effectiveness is dependent on a combination of temperature and time. The temperature used is much higher than for moist heat sterilization. This method can be used for dry components such as empty ampoules and vials. There should be air circulation within the chamber and the maintenance of positive pressure should prevent ingress of non-sterile air. The air should be supplied through micro-organism retaining filters (e.g. HEPA (High-efficiency particulate air) filters). Records should indicate that temperature and time were controlled and monitored for the sterilization cycle. When dry heat sterilization is used to remove pyrogens, then the manufacturer is required to have validation data to prove the efficacy of the de-pyrogenation process (e.g. challenge tests with endotoxins)
- There are a number of different types of ionizing radiation sterilization. This method of sterilisation is normally done in a stand-alone, dedicated facility. If you were inspecting such a facility, the assistance of a technical expert would be very helpful. Radiation sterilization is used primarily for heat-sensitive materials and for products, such as ointments, and for plastic components prior to filling. However, care must be taken to ensure that the materials are compatible and not radiation-sensitive. This would form part of the original validation work. Ultraviolet radiation is not an acceptable method for terminal sterilization, although it can be useful in maintaining a low level of microorganisms once obtained, for example in purified water systems. Its use requires careful validation. It remains the responsibility of the manufacturer - even if the manufacturer makes use of a contract accepter to provide the sterilisation service – to ensure that the sterilization process is validated. As with heat sterilization, it is important to monitor the effectiveness of the sterilization cycle. Dosimeters (that are independent of dose rate) should be used which provide a quantitative measure of the dose received. These should be inserted within the load in sufficient number to ensure that there is always one in the chamber. Some companies also make use of biological indicators. Radiation sensitive (colour) discs on the outside of packs can be used to prove that the load has passed through the chamber. Like autoclave tape, they do not prove sterility.
- Documented proof of maintaining the parameters for the sterilisation cycle, should form part of the batch record. When you evaluate the validation protocols and reports, make sure that the company has considered the density of packages when cycles were validated. The total radiation dose should be administered within a predetermined (validated) time span. As with other methods of sterilisation, there should be procedures and controls in place to prevent any possible mix-ups between irradiated and non-irradiated materials, components or products.
- Fumigants and gases such as ethylene oxide gas (ETO) can be used for sterilization. ETO should only be used as a sterilizing agent and sterilising method, if no other method is available. Validation data should be available as proof that the gas does not have a damaging effect on the product. The data should also specify limits of residual gas after degassing. This method is used for plastic items such as medical devices that are both heat and radiation-sensitive. Direct contact with microbial cells is essential to achieve sterilization. The nature and quantity of packaging materials must be considered during validation of the process. Hence the packaging must be permeable to moisture and gas. Before exposure to the gas, materials must be brought into equilibrium with the humidity and temperature of the process. Verify this in the documentation. The cycle is a combination of time, temperature, humidity and gas concentration. The first three parameters are generally recorded directly, while the last is recorded indirectly. The volume of gas used is also calculated by weighing the cylinders before and after the cycle to cross-check that the amount used is as expected. Biological indicators are often used to measure the effectiveness of the cycle. Their use should be controlled and positive controls should be employed to ensure that they are still viable. If you are going to inspect a facility using ETO gas, then specialist support should be considered.
- As mentioned earlier, one of the problems with ETO is the residues that are left behind at the end of the cycle. The processing cycle must include a validated degassing period, where the load must be stored in a suitably ventilated room under quarantine. The gas is explosive in air at relatively low concentrations and results in significant residues in the product that need to be removed before the batch can be passed. The load should be stored in a ventilated area after sterilization. The product should not be released until the residual gas has fallen to the defined level. There should be validation data for this process. Ethylene oxide gas (ETO) should only be used as a sterilant if no other method is available. The gas is explosive in air at relatively low concentrations resulting in significant residues in the product that need to be removed before the batch can be passed. This method is used for plastic items such as medical devices that are both heat and radiation-sensitive. The cycle is a combination of time, temperature, humidity and gas concentration. The first three parameters are generally recorded directly, while the last is recorded indirectly. The volume of gas used is also calculated by weighing the cylinders before and after the cycle to cross-check that the amount used is as expected. Before exposure to the gas, materials must be brought into equilibrium with the humidity and temperature of the process. It is important that direct contact between the gas and any micro-organisms on the product takes place. Hence the packaging must be permeable to moisture and gas. Biological indicators are used to routinely measure the effectiveness of the cycle. Their use should be controlled and positive controls should be employed to ensure that they are still viable. As mentioned earlier, one of the problems with ETO is the residues that are left behind at the end of the cycle. The processing cycle must include a validated degassing period, where the load must be stored in a suitably ventilated room under quarantine. Remember to keep in mind the issues related to safety and toxicity associated with the use of ETO. Special care needs to be taken when ETO is used for sterilization of products. If you are going to inspect a facility using ETO gas, then specialist support should be considered
- This module gives only a superficial overview of filtration. We have already discussed the fact that terminal sterilization of product is preferable as it reduces the risk of recontamination. However, for some types of products, such as vaccines and insulin, this is not possible,. In this case, sterilization by filtration into a previously sterilized container can be used. The filter should have a nominal pore size of no more than 0.22µm. However, it should be remembered that although these filters can remove bacteria and moulds, viruses and mycoplasmas might not be removed by this method. In order to reduce the risks associated with the filtration method, double filtration may be advisable. There is usually a pre-filter before the main one anyway, but in addition, a final filter, just prior to filling, should also be used where possible. Fibre shedding filters and asbestos filters may not be used. There should be documented evidence of filters integrity tests having been performed after use and in some cases also before use. This requires the use of equipment such as a bubble-point tester. In addition, validation of the method will have produced standard times and pressure differentials for a given volume of liquid. Any variations from this should be noted and investigated.
- Filters should not be used for more than one working day, unless longer use has been validated. Filters should further not interact with the products, including removal of ingredients or releasing of substances into the product.
- We are now going to move into our third group session. Using the hypothetical factory described in the previous group session, you are going to think about sterilization. Start by listing all the items that need to be sterilized - and think in the widest sense, not just about the finished product. Then for each item, review the options that are available for sterilization and decide on the most appropriate. List the key issues to be considered in each case. (Refer to the supplementary notes giving an outline of the sort of responses that may be expected).
- There are a number of areas where you might expect to find problems: Equipment design - for example sterilizers without the correct instrumentation. Inadequately controlled services - for example, superheated steam or unfiltered compressed air. Inadequate ventilation systems - for example, insufficient pressure differentials between rooms. Badly planned monitoring programmes - for example, settle plates exposed for too long or poorly designed media fills. Bad practices - for example, interlocks not operational on airlocks. Poorly maintained facilities - for example, performance of filters not monitored
- In this final part of the module, we are also going to look at the quality control and quality assurance aspects in more detail. In a factory that is producing sterile products, the level of compliance with quality control and quality assurance requirements should be high. (Incidentally, this is something to bear in mind when reviewing the level of support personnel available in QA and QC departments). There are three aspects to QC/QA that we are going to talk about. Firstly, we will look at the requirements for environmental monitoring and control (including microbiological and particulate matter). Secondly, we are going to talk about sterility testing, an important part of monitoring the process itself. Finally, we will look at endotoxin testing.
- Sterility testing is required as part of the process for batch release for all sterile products. It is important that representative samples are taken from the batch. For aseptic production, this means that samples should be taken from the start and finish of the batch and after any major breaks in work. For terminally sterilized products, samples should be taken from the coolest part of the load. Verify compliance with this requirement, and find out how the manufacturer ensures that this is done. If a batch is sterilized in more than one load, then samples should be tested from each load. As discussed previously, sterility testing will only be part of the quality assurance for the batch, and results should be considered in the context of all the other tests and monitoring carried out during production. If a sterility test fails, it could be the reason of various problems including production error, or laboratory error. A test can only be repeated if a proper investigation had been done, and allowed by the national drug regulatory authority. The investigation should include identification of the type of organism and an evaluation of the batch records and environmental monitoring records. The re-testing should be conducted in strict conformance to the pharmacopoeia method in force. Batches that fail the initial sterility test, but pass a second one, should only be released for sale if a full evaluation prove that the original test was invalid.
- The manufacturer should do endotoxin monitoring of injectable products. This includes water, intermediate and finished products. Verify compliance with this requirement and establish whether the manufacturer uses a validated pharmacopoeia method for each type of product. Such monitoring should always be done for water and intermediates For large-volume infusions. Review records of the endotoxin testing. Causes for test failures should have been investigated and remedial action taken and documented.
- We now move into the final group session. Using the same hypothetical factory as before, review all the monitoring that will be required. List the parameters that need to be tested, the tests that should be used and the acceptance criteria. Finally, propose a programme for the monitoring that covers the frequency for each different test. (Refer to the supplementary notes giving an outline of the sort of responses that may be expected)