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DRAFT RECOMMENDATION on the VALIDATION OF ASEPTIC PROCESSES Editor: PIC/S Secretariat E-mail gilbert.besson@secrgva.efta.be Table of Contents 1 Introduction...................................................................................... 3 1.1 Purpose............................................................................................. 3 1.2 Scope................................................................................................ 3 1.3 General information............................................................................ 3 2 Definitions........................................................................................ 4 3 Process Simulation Test Procedures............................................ 5 3.1 General Comments............................................................................ 5 3.2 Liquid Products.................................................................................. 6 3.2.1 Vial Products..................................................................................... 6 3.2.2 Sterile Products in Plastic Containers............................................... 6 3.2.3 Ampoule Products.............................................................................. 7 3.3 Injectable Powder Products................................................................ 7 3.4 Suspension Products......................................................................... 7 3.5 Freeze Dried (Lyophilized) Products.................................................. 7 3.6 Semi-Solid Products (e.g. sterile ointments)...................................... 7 3.7 Clinical Trials Materials and Small Batch Size Products.................... 8 3.8 Biological and Biotechnology Products.............................................. 8 3.9 Sterile Bulk Pharmaceuticals............................................................. 8 4 Process Simulation Test Conditions............................................. 8 4.1 Test Performance............................................................................... 8 4.2 Selection of Growth Medium.............................................................. 9 4.3 Incubation Conditions......................................................................... 9 4.4 Reading of the Test.......................................................................... 10 4.5 Test Frequency................................................................................ 10 5 Interpretation of Data.................................................................... 10 6 Environmental and Personnel Monitoring................................... 12 6.1 Air Borne Microbial and Non-Viable Particle Monitoring.................. 12 6.1.1 Non-viable monitoring...................................................................... 12 6.1.2 Microbial Monitoring........................................................................ 13 6.2 Intervention Monitoring..................................................................... 13 7 Staff Training................................................................................. 13 8 Important Factors in Validation of Aseptic Manufacturing........ 14 8.1 Container/Closure Integrity Testing.................................................. 14 8.2 Container/Closure Sterilisation........................................................ 14 8.3 Equipment Cleaning and Sterilisation.............................................. 15 8.3.1 Manual cleaning (see PIC/S Document PR 1/99-1, Cleaning validation) and sterilisation...................................................................................... 15 8.3.2 Clean-in-place/sterilise-in-place (CIP/SIP)...................................... 15 8.4 Disinfection...................................................................................... 15 8.5 Filter Validation............................................................................... 16 8.6 Vent Filters...................................................................................... 16 8.7 Equipment Maintenance and Testing............................................... 16 8.8 Blow Fill Seal/Form Fill Seal............................................................ 16 8.9 Sterility Test..................................................................................... 17
Document History Authors / working group: Hansueli Hofstetter, Switzerland Tobias Gosdschan, Switzerland Lilian Hamilton, Sweden Veronika Subai, Hungary Theo Berg, Netherlands Paul Hargreaves, United Kingdom
1 Introduction1.1 PurposeThe aim of this document is to provide guidance to the current practice in this field by giving recommendations for the validation of aseptic processes. 1.2 ScopeThis document applies to all manufacturers involved in aseptic processing of finished dosage forms (human and veterinary) as well as manufacturers of sterile labelled bulk drug substances (active pharmaceutical ingredients). 1.3 General information The basic principles and application of process validation are described in Validation of aseptic processes relies upon prospective, concurrent and retrospective Prospective studies would include Concurrent validation includes a process validation with the same requirements as for prospective studies, but performed during routine production on qualified equipment. While the r Retrospective validation uses the data of earlier manufactures, but is not a recommended technique for aseptic processes. , process simulation tests include the elements of both prospective and retrospective validation in that results can indicate current and past problems. Concurrent validation Re-validation includes the : · Regular performance of process simulation studies · Monitoring of environment, disinfection procedures, equipment cleaning and sterilisation (including containers and closures) · Routine maintenance and re-qualification of equipment, e.g. autoclaves, ovens, HVAC (heating, ventilation and air conditioning) systems, water systems, etc. · Regular integrity testing of product filters, containers, closures and vent filters · Re-validation after changes It is the sum total of all validation data that provides the necessary level of assurance for aseptically produced products. Validation of aseptic processes includes Process simulation studies (media fills) are simulating simulation of the whole process in order to evaluate the sterility confidence of the process. Process simulation studies including include formulation (compounding), filtration and filling with suitable media in order to evaluate the sterility confidence of the process. Simulations are made to ensure that the regular process for commercial batches repeatedly and reliably produces the finished product of the required quality. However, each process simulation trial is unique and so it is not possible to extrapolate these results directly to actual production contamination rates. The performance of process simulation tests (media fills) and related test data are only a part of the overall validation strategy for an aseptic process. In addition the following aspects (the most important ones) need to be addressed: · Container/Closure Integrity Tests · Container/Closure Sterilisation · Equipment Cleaning and Sterilisation · Disinfection · Filter Validation · Vent Filters · Equipment Maintenance and Testing · Blow Fill Seal/Form Fill Seal · Sterility Test These subjects are covered under chapter 8: Some other important factors in validation of aseptic manufacturing. The methods for simulating an aseptic process vary according to the process used for the various types of products, i.e. liquid, semi-liquid and solid dosage forms. In thisese Recommendations the term „should“ indicates requirements that are expected to apply unless shown to be inapplicable or replaced by an alternative demonstrated to provide at least an equivalent level of quality assurance. 2 DefinitionsA A A A B C E G H HVAC: Heating, v I M Sampling frequency: Established period for collecting samples. S
S Sterilisation: Validated process used to render a product free of viable organisms. Note: In a sterilisation process, the nature of microbiological death of reduction is described by an exponential function. Therefore, the number of microorganisms which survive a sterilisation process can be expressed in terms of probability. While the probability may be reduced to a very low number, it can never be reduced to zero. S S
V 3 Process Simulation Test Procedures3.1 General Comments
Where filling takes place over extended periods, i.e. longer than 24 hours, the process simulation test should extend over the whole of the standard filling period. In order to prevent excessively high numbers of units being filled it is usually acceptable to just run the machine for a reasonable time, if the validity of the simulation is not diminished by this procedure. It should be considered that inert gases will prevent the growth of aerobic microorganisms. Therefore for process simulations sterile filtered air should be used instead of inert gases, also for breaking a vacuum. Where anaerobes are detected in the environmental monitoring or sterility testing, the use of an inert gas should be considered for a process simulation, as inert gas is supporting the growth of anaerobes. Before enumerating the different process simulation test procedures some preliminary explanations are necessary for the preparation of liquid media as it is used for the majority of the process simulation tests. Where a liquid nutrient medium is used it should be prepared in a similar manner to the product. The medium should be dissolved in Water for Injection in a standard manufacturing vessel. If heat is required to dissolve it then only minimal heat should be used. The pH of the medium should be measured and, if necessary, adjusted to bring it into the required range. The medium should be aseptically filtered into an aseptic The following chapter illustrates the test procedures for the various simulation tests for aseptically produced solutions, lyophiles, suspensions, ointments and powders and summarises the considerations to be made. 3.2 Liquid Products3.2.1 Vial ProductsThe liquid growth medium for the simulation test is prepared as above and kept in a sterile holding vessel for the maximum permitted holding time before starting the simulation test. If the bulk solution is stored under refrigerated conditions during the holding time then this should also be performed for the medium. Vials and closures should be prepared as in regular production. 3.2.2 Sterile Products in Plastic ContainersEar and eye drops are typically marketed in plastic containers. Containers, inserts, closures and where applicable overseals are washed and sterilised as in regular production. Instead of sterilisation with heat, irradiation or ethylene oxide are used. Whilst clear plastic containers are frequently used for process simulation trials, the plastic is usually slightly opaque and thus hinders identification of contaminated units that show only a slight haze. In such case examination under natural or room lighting would not suffice. Where opaque containers are used for process simulation trials the whole contents should be removed for examination. 3.2.3 Ampoule ProductsOpen or closed ampoule types may be used. They should be sterilised by dry heat and afterwards used in the simulation test as per the regular production run. Ampoules should be prepared as in regular production. 3.3 Injectable Powder ProductsThere are two possibilities for simulation of this process. Either by filling a sterilised liquid growth medium into the sterile container or adding a powder (inert or growth medium) before or after a sterile diluent (WFI or growth medium). Inert materials commonly used include: polyethylene glycol 8000 and carboxymethyl cellulose. These materials are usually sterilised by irradiation. 3.4 Suspension ProductsThis procedure is comparable to the filling of liquid products, except for the process step of maintaining suspension of the ingredients. The stirring or recirculation should be part of the simulation. If aseptic additions are made to the bulk solution these should be simulated by the use of inert sterile liquids/powders. 3.5 Freeze Dried (Lyophilised) ProductsCrystallisation of the medium should be prevented because it may reduce the likelihood of recovery of organisms. Two simulation methods are commonly used. In the first one a dilute medium is subject to a cycle that removes water until a determined medium strength is obtained, but is not subject to freezing. The second method uses full strength medium and requires only a partial vacuum be drawn whilst the chamber should be kept at ambient temperature. There is a risk that the medium may boil over and contaminate the chamber unless conditions are tightly controlled. The absence of boiling under the defined cycle conditions should be confirmed.
3.6 Semi-Solid Products (e.g. sterile ointments) For this simulation test the liquid growth medium is thickened to the appropriate viscosity, used as in the routine production procedure. Suitable thickening agents are agar and carboxymethyl cellulose. Other agents would need to be validated with regard to lack of their bacteriostatic and fungistatic properties. Metal and plastic ointment tubes prevent the examination of the medium in-situ. Usually 3.7 Clinical Trials Materials and Small Batch Size Products
The size of media fills for small batch size products should at least equal the number of containers filled for the commercial product. 3.8 Biological and Biotechnology ProductsThe manufacture of these products vary, such that there is not one single process. It may be more practical to validate the various segments of the process individually. The frequency of the revalidation should relate to the one of regular, commercial production. 3.9 Sterile Bulk PharmaceuticalsWhenever possible a growth medium should be used and the process should be simulated as closely as possible to the normal route of manufacturing the sterile bulk drug substance. The aseptic manufacture of a sterile bulk The validation may include segments, where the use of growth media is not feasible. 4 Process Simulation Test Conditions4.1 Test PerformanceThe process simulation test should follow as closely as possible the routine aseptic manufacturing process and include all critical subsequent manufacturing steps. All equipment should remain the same wherever practicable as for the routine process. Appropriate combinations of container size and opening as well as speed of the processing line should be used (preferably at the extremes). The process simulation test should represent a „worst case“ situation and include all manipulations and interventions likely to be represented during a shift. Worst case conditions are often thought to be the largest container with the widest mouth as it is exposed longer to the environment. However, there are exceptions to this and one of them is small ampoules run at the highest speed as the ampoules may be unstable and cause frequent jams thus necessitating frequent operator intervention.
The fill volume of the containers If batches smaller than 3000 units are produced, the minimum number of containers used for the process simulation should be equal to that of the commercial batch size. Simulation tests should be performed on different days and hours during the week and not only at the beginning of a work day. In order to find the possible source of contamination it may be a good advise to video tape the aseptic fill and also number the individual vials or segregate vials in chronological order during incubation. 4.2 Selection of Growth MediumThe criteria for the selection of growth medium include: low selectivity, clarity, medium concentration and filterability. Ability to support growth of a wide range of microorganisms: The medium should have a low selectivity i.e. be capable of supporting growth of a wide range of microorganisms such as Bacillus subtilis, Staphylococcus aureus, Candida albicans, Aspergillus niger and Clostridium sporogenes (e.g. Soybean Casein Digest). The selection of the medium has to be based also on the in house flora (e.g. isolates from monitoring etc.). Growth promotion tests should demonstrate that the medium supports recovery and growth of low numbers of microorganisms, i.e. 10-100 CFU/unit or less. Growth promotion testing of the media used in simulation studies should be carried out on completion of the incubation period to demonstrate the ability of the media to sustain growth if contamination is present. Growth should be demonstrated within 5 days at the same incubation temperature as used during the simulation test performance. Clarity: The medium should be clear to allow for ease in observing turbidity. Medium Concentration: Recommendations of the supplier should be followed unless alternative concentrations are validated to deliver equal results. Filterability: If a filter is used in the aseptic manufacturing process, the medium should be capable of being filtered through the same grade as used in production. 4.3 Incubation ConditionsIt is generally accepted to incubate at 20-25°C for a minimum of 14 days without having collected data to support this incubation schedule. It is similarly acceptable for firms who prefer a two temperature incubation schedule to incubate at 20-25°C for a minimum of 7 days followed immediately by incubation at a higher temperature range not to exceed 35°C for a total minimum incubation time of 14 days. Other incubation schedules should be based on supporting data. Prior to incubation the containers with the microbiological growth medium should be inverted or otherwise manipulated to ensure that all surfaces, included the internal surface of the closure, are thoroughly wetted by the medium. The containers should not be completely filled with medium in order to provide sufficient oxygen for the growth of obligate aerobes. Similarly, containers should not be overlaid with inert gases even though the product may be (see also general comment in Chapter 3.1). The microorganisms present in the containers of the simulation test should be identified to genus but preferably species level to aid determination of the possible sources of the contamination. 4.4 Reading of the TestWhen inspecting the containers they should be compared to a known sterile container for comparison as some microbial growth shows up as a faint haze which is difficult to detect unless there is a control container to compare against. Personnel should be trained for this task. 4.5 Test Frequency
It should be distinguished between „start-up“ and „on-going“ simulation tests. A „start-up“ simulation test consists of three consecutive satisfactory simulation tests per shift and should be carried out before routine manufacturing can start. “Start–up” simulation tests are performed for example for new processes, new equipment or after critical changes of processes, equipment or environment as for example significant personnel changes (a new shift), modifications in equipment directly in contact with the product or modifications in the HVAC system.
An „on-going“ simulation test consists of one satisfactory simulation test per shift and is mainly performed for the periodic monitoring of aseptic conditions during routine manufacturing but also for example after less critical changes of processes, equipment or environment or if processing lines stand idle for more than 6 months. “On-going“ simulation tests should be performed with
5 Interpretation of DataAfter the incubation period of the media-filled containers they are visually examined for microbial growth. Contaminated containers should be examined for evidence of container/closure damage which might compromise the integrity of the packaging system. Damaged containers should not be included as failures (positives) when evaluating results. Different approaches may be used to determine limits and acceptance criteria. One method (Method 1) is to determine a contamination rate as an absolute value (e.g. 0.1 %) with guidance on the minimum number of units filled and the other method (Method 2) is to use a statistical method based on the Poisson distribution of contaminated filled units. However the application of the Ideally the contamination rate should be zero. However currently the accepted contamination rate should be less than 0.1 % with a 95 % confidence In order to calculate the „worst case“ contamination rate for an observed frequency of failures the following table can be used. The number indicated as the upper 95% confidence limit describes the maximum number of failures that can be expected with a 95% certainty in the true population Table: Relation between observed number of failures and upper 95 % confidence limit
The maximum contamination rate that can be expected with a 95 % certainty for an observed frequency of failures can be calculated according to the following formula: Contamination rate = Upper 95 % confidence limit / Number of filled units x 100 % Example 1: If 3'000 units were filled and two contaminated units observed, the upper 95% confidence limit for the contamination rate would be not more than 6.3/3'000 x 100 % = 0.21 %. This rate would Example 2: If 3'000 units were filled and no contaminated unit observed, the upper 95% confidence limit for the contamination rate would be not more than 3/3'000 x 100 % = 0.1 %. Since 3 is a rounded value and the true value is slightly smaller than 3 this rate would be smaller than the required value (less than 0.1 %) and therefore be acceptable. This means on one side that the minimum number of containers to be filled during a process simulation test performed after Method 2 is 3’000 units and on the other side that there should be no contaminated container in case of filling of the minimal number of 3'000 units. It is the responsibility of every manufacturer to ensure that a statistically valid number of containers is filled during a process simulation test. To achieve an adequate confidence level of reliable processing conditions it requires repeated satisfactory simulation tests. Corrective actions: The manufacturer should act according to predetermined action and alert limits for the different batch sizes of the simulation tests. Contamination rates for simulation tests above the 0.1 % level should be investigated and repeated tests are required. Exceeding an alert level twice should be considered as exceeding the action limit. The manufacturer should indicate in an SOP what has to be done in such cases. All contaminating microorganisms whether or not an alert or action limit has been exceeded should be identified to at least genus and preferably species where practicable to determine the possible source of contamination. If a process simulation test fails then due account should be taken of products filled between the last successful test and the test failure. Recording of any deviations during the simulation test is important to trace later on the exact cause and to evaluate the consequences. The investigation should identify batches that could be affected during this time period and 6 Environmental and Personnel MonitoringAnnex I of the EU/PIC-PIC/S Guide to GMP provides the basis for environmental and personnel monitoring requirements and recommendations. Some specific additional guidance is given below on air borne microbial and non-viable particle monitoring, intervention monitoring and staff training. 6.1 Air Borne Microbial and Non-Viable Particle MonitoringIt is important to state that the monitoring activity itself should not compromise the product quality. Worst case scenarios of simulations tests should also include monitoring activities. 6.1.1 Non-viable monitoring The location chosen for monitoring should be checked to ensure that the positions reflect the worst case. For room monitoring, the counts should be performed in locations where there is most operator activity. For the filling environment the counts should be performed adjacent to the filling zone and where components are exposed in such way as to detect operator activity within these areas. Monitoring with sampling probes located in such a way that they monitor the air from the HEPA filter rather than the air immediately surrounding the critical zones should be avoided. However the location of the sample device should not compromise the laminarity of the air flow in the critical zone. Initial validation should be checked to confirm that worst case positions have been adequately identified. These may be reconfirmed during 6.1.2 Microbial MonitoringIt is usually expected that a combination of the methods identified in the Annex 1 of the EU/PIC-PIC/S GMP guide for monitoring microbial levels is used in environmental monitoring programmes where appropriate. Microbial monitoring should be performed in and around areas of high operator activity. It is not unusual to see settle plates and air sample locations well away from such areas. A typical example is where settle plates are located well to the rear of the filling machine where there is little or no operator activity. The same may be true for air sampling. It is important, therefore, to observe operator activity over a period of time and ensure that the monitoring sites are so located as to monitor operator activity. The A useful monitoring technique is to monitor Additional monitoring around the affected area prior to disinfection may provide useful information as to the cause. 6.2 Intervention MonitoringIt is essential to include in a simulation test the various interventions that are known to occur during normal production runs, e.g. repair or replacement of needles/tubes, replacement of on-line filters, microbial sampling by monitoring personnel and sampling device, duration of stops on the line, filling and handling of stoppers etc. The process simulation test should last long enough to accommodate all possible interventions and a „worst case scenario“, which may include several unfavourable conditions which are 7 Staff TrainingThe routine training of personnel who work in a controlled environment needs special emphasis as people are potentially one of the main sources of micro-organisms in the environment. Included are not only operators but also other personnel working in a controlled environment
A formal personnel training programme is needed for all activities in each clean room. This means the programme has to be planned, documented and repeated at adequate intervals to ensure that the once trained individual meets the ongoing requirements for This training encompasses subjects like basic microbiology, good manufacturing practice principles, hygiene (disinfection and sanitisation), aseptic connections, alert and action limits, and gowning procedures. Environmental monitoring personnel need a thorough understanding of the sources of contamination risks (e.g. inadequately disinfected/sterilised sampling equipment) that are involved with the sampling methods. Periodic process simulation tests ( The competence of an individual should be formally assessed after attending the training courses and active participation of a process simulation test. The evaluation of filled containers of a simulation test should be done by personnel who are especially trained. They should have routine eye sight tests. This training should include the inspection of
8 Important Factors in Validation of Aseptic Manufacturing8.1 Container/Closure Integrity TestingThe integrity of Validation of the closure system by filling the container with sterile growth medium and inserting the container in a broth containing approx. 106 cfu/ml of a suitable micro-organism. The container is removed after submersion for a
8.2 Container/Closure SterilisationProblems are rarely encountered with sterilisation of containers. However sterilisation of stoppers might cause problems: Lack of air removal and adequate steam penetration: stoppers should not be packed too densely into trays or bags since this may prevent adequate air removal during the vacuum phase of the autoclave cycle. During the vacuum phases of the autoclave cycle stoppers may clump together to form a tightly bound mass. Pairs of stoppers may become attached to each other with the base of one stopper becoming attached to the top of the other stopper. 8.3 Equipment Cleaning and Sterilisation8.3.1 Manual cleaning (see
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US Pharmacopeial Convention, „1116“ Microbiological evaluation of clean rooms and other controlled environments, IN-PROCESS REVISION, 1995
ISO TC 196 Committee Draft 13408.2 (Aseptic Processing of Health Care Products), 1995
The Use of Simulation Tests in the Evaluation of Processes for the Manufacture of Sterile Products, Parenteral Society UK, 1993
Draft: Sterile Product Pre-Approval/Post-Approval Inspections, FDA, 1993
Annex I to EU/PIC-PIC/S Guide: Manufacture of sterile medicinal products, EU 1997
PDA Technical Report No.22, Process Simulation Testing for Aseptically Filled Products, September 1996
PIC-PIC/S Document PH 1/96 (January 1996), Recommendations on Validation Master Plan, Installation and Operational Qualification, Non-Sterile Process Validation, Cleaning Validation.
PIC-PIC/S Recommendations on Sterility Testing, Draft; PS/W 6/97 (Rev.), 20 February 1997
PIC-PIC/S Recommendations on the Inspection of Isolator Technology, PS/W 3/97 (Rev.), 20 February 1997
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