Submission of comments on Revision of Annex 1: Manufacture of Sterile Medicinal Products

Transcription

1 Submission of comments on Revision of Annex 1: Manufacture of Sterile Medicinal Products Comments from: Name of organisation or individual Pharmaceutical & Healthcare Sciences Society: PHSS Annex 1 comment platform: Comments from Group 2: Pharmaceutical equipment manufacturers, suppliers, consultants and supporting academics. Acknowledgement: The Pharmaceutical & Healthcare Sciences Society: PHSS Annex 1 comment platform includes contributors from the Pharmaceutical Industry, supporting GMP consultants, Pharmaceutical equipment manufacturers: Barrier Isolator/RABS technology and Filling process machinery, suppliers: Facility monitoring system and gowning plus academics with related research and peer reviewed publications as such provides a broad view of international stake holder interest. The PHSS wish to acknowledge contributions with comments from the following: PHSS Group 1 comments: Pharmaceutical Industry: GSK, AstraZeneca, Pfizer, Merck & Co Inc, Ely Lilly France & Italy, Novartis, Allergan Westport, Fresenius Kabi, Teva-Pliva, Alexion Ireland, Bayer. GMP Consultants: Roland Guinet (France), Gordon Farquharson (UK), Richard Funnel (UK). PHSS Group 2 comments: Pharmaceutical equipment manufacturers: F Ziel GmbH (Barrier Isolator/ RABS Technology), Groninger GmbH & Bausch Stroebel GmbH (Filling process machines), TSI & Pharmagraph (Facility monitoring systems), DuPont (Cleanroom garbing), Sterilisation solutions (Alan Heavey), Rapid Micro Biosystems (David Jones) and Academics working in field of Good manufacturing practice GMP: Professor Bengt Ljungqvist, Associate Professor microbiology Berit Reinmüller, Professor Matts Ramstorp, Dr Bill Whyte.

2 1. General comments General comment (if any) It is accepted Annex 1 cannot be prescriptive for the wide range of applications in sterile/ therapeutic product manufacture. The PHSS Group 2 comments are focused on in Annex 1 related to the technologies and sterile suppliers used in processing pharmaceuticals/ therapeutic products including Barrier separation technologies (Isolators and RABS) and gowning used in environmental control, Filling process machines and environmental facility monitoring systems together with scientific studies that support environmental control and monitoring. For different sterile product types including biological-bio-hazardous products manufactured by aseptic processing, cytotoxic, toxic conjugates and bio-sensitive (hormones) both cross contamination control and containment is increasingly required for operator protection and in multiproduct processing in the same facility. The current Annex 1 scope does not reference cross contamination control or containment so some comments made relate to principle requirements when cross contamination control and containment may apply with points to consider if specified that are not prescriptive to application. The document could benefit from a thorough review to ensure consistency in terminology throughout. There are inconsistencies with respect to the structuring of each paragraph and the terminology used and some of the information is scientifically incorrect. It would be beneficial if the whole document could be reviewed and amended by an independent body with appropriate specialist knowledge in such publications in order to maximise its credibility and authenticity. The recommendation to terminally sterilise finished product, whenever possible should clearly be stated be at the beginning of the document (Section 2) as a clear statement of preference rather than in the later sterilisation section Section 5 (Premises) defines the grades of environmental cleanliness levels required for sterile product manufacture. These grades are referenced in the previous section (4 - Personnel) to define dress standards for each grade and therefore the section on Premises should precede the section on Personnel.

3 Specific comments on Line 2. Principle Comment: Consider adding cross contamination control in principle requirements: The strategy should consider all aspects of contamination control and its life cycle with ongoing and periodic review and update of the strategy as appropriate. Proposed change: Add at line 57: Where sterile products are hazardous in manufacture containment strategies and justified design that does not compromise sterility assurance should be considered as part of a Contamination control strategy. Comment: Add Cross contamination control and Containment to Elements to consider in a Contamination control strategy. Elements to be considered within such a documented contamination control strategy should include (but not be limited to): p) Cross contamination control. q) Containment of APIs or in Aseptic processing e.g. filling of hazardous products where bioburden control and sterility assurance are required in combination with personnel safety and potentially cross contamination control. Line 154 Paragraph(e) Comment: The risk to a patient is dependent on the chance that an aseptically produced product will support microbial growth after production (see Whyte and Eaton (2017). Assessment of degree of risk from sources of microbial contamination in cleanrooms; 3: Overall application. European Journal of Parenteral & Pharmaceutical Sciences, 22(2): pp38-49 ). The risk is much smaller with products such as freeze dried and powders, than aqueous products with nutritional properties that would allow microbial growth. It is important that cleanroom users understand this. Proposed change (if any): Information should be added to Paragraph (e) of Section 3.1 to point out that The risk to a patient is dependent of the chance that an aseptically produced product, which is contaminated during manufacturing, will support microbial growth after production, and that the design of the cleanroom and control of contamination should reflect the degree of risk What is high standard of personal hygiene? It can be interpreted differently. Comment: Sterility of a particular item itself cannot be established by visual inspection. For garments and accessories sterilized by exposure to gamma radiation, radiation indicator dots only indicate that they package has been exposed to radiation, not that they have received a proper sterilizing dose. Garment and accessory labels may contain verbiage to indicate that the enclosed item is sterile. Typically, sterility of items is established by checking the certificates and documents that are provided with the garments and accessories as part of the inbound product receipt process. Sterile items are assumed to remain sterile as long as packaging has not been breached so visual inspection for package integrity prior to use is recommended. Recommended change: Update wording to Garments should be visually checked for cleanliness and integrity prior to entry to the cleanroom. For sterilized garments, particular attention should be taken to ensure garments and eye coverings have been sterilized and that their packaging is integral before use. Since sterility cannot be established by visual inspection, inbound audit of product documentation regarding sterility assurance may be necessary.

4 Comment: Both laundering and many sterilization methods can degrade fabric properties such as particle shedding, strength and barrier, these changes cannot be seen visually testing on relevant properties, as determined by QRM principles, may be necessary. The way the current sentence is worded, it may appear that either criteria is acceptable for determining replacement timing: qualification or damage. Visual damage should be additional to change frequency set be qualification. Recommended change: Reusable garments should be replaced based at a set frequency determined by qualification or, additionally, if damage is identified. Damage to garments may not manifest by visual inspection alone, so qualification should consider any necessary garment testing requirements. Section Comment: The general description of cleanroom clothing fails to explain the major influence that clothing has on airborne contamination of products (see Ljungqvist B and Reinmuller B (2006). Cleanroom clothing systems in Practical safety ventilation in pharmaceutical and biotech cleanrooms. Parenteral Drug Association, Bethesda, USA. pp 57 76). Airborne contamination is a major route of product contamination, and information on the effectiveness of cleanroom clothing should be given to minimise this risk. Proposed change (if any): Insert between the two sentences in Section 4.11 information similar to the following: Personnel are the main source of airborne microbial contamination in a cleanroom, and cleanroom clothing reduces dispersion of contamination. How personnel are effectively covered, the filtering efficiency of the fabric, and the design of cleanroom clothing, has a substantial effect on the dispersion rate of airborne contamination into the cleanroom. It is important that cleanroom clothing system are replaced when their validated time of use has passed. The number of washing/sterilization cycles a clothing system has passed could also be important to note in the personnel monitoring program Section Section 4.15 Comment: Reuse timeframe is not well defined. Is reuse qualification meant to cover when garments should be replaced, as the description for reusable garments in section 4.10, or is it meant to cover how many working sessions the garments can be used prior to being laundered? Proposed change: Clarify timeframe for reuse: either per working session, or end-of-life, or both. Update wording to reflect. For instance, if this is meant to establish end-of-life criteria, clarify to: Where clothing is reused, replacement frequency should be considered as part of the qualification. Or, for instance, if this is meant to establish number of working sessions a garment can be used: Where clothing is to be reused for multiple work sessions, the number of reuses should be considered as part of the qualification. Comment: Visual inspection to verify that garments and accessories have no obvious holes, tears or other breaches is important, however, visual inspection alone may not be sufficient to evaluate garment performance. Both laundering and many sterilization methods can degrade fabric properties, such as strength and barrier, these changes cannot be seen visually testing on relevant properties, as determined by QRM principles, may be necessary Proposed change: After washing and before sterilization, garments should be checked for integrity, this may include any testing determined by qualification.

5 Premises Comment: This section is confusing, as it is unclear where to measure the air velocity, and what velocity is desirable. The problems are as follows. (a) Owing to turbulence immediately next to the filter face, the velocity is 20% to 25% higher than the true velocity (see Whyte et al (2011). The measurement of air supply volumes and velocities in cleanrooms. International Journal of Ventilation, 84(4), pp ). A measuring distance of 15cm to 30cm from the filter face is needed to give the correct value (as suggested in ISO : Test methods). (b) The unidirectional airflow from supply air filters cannot pass through solid objects, such as machinery, but passes round the object and create a stagnant area close to the manufacturing machinery. This means that the velocity next to product will approach zero and it is impractical to achieve a velocity in the range of 0.36 to 0.54m/s. (c) It is not clear what working height means. This height should be defined (if information is retained) as the closer to the stagnant area is to the machinery, the lower the velocity. Cleanroom users with insufficient knowledge of the above problems may take what they think is a safe approach and specify a high velocity close to the exposed product. However, the higher the velocity, the more difficult it is to achieve, and the greater the engineering difficulties in providing uniform velocities in the air plenum behind the UDAF air supply filters, higher noise levels, and a substantial waste of energy. Such high velocities are unnecessary to achieve the correct airflow pattern objectives explained in the remaining part of the paragraph. Proposed change (if any): Remove lines 321 to 326 and substitute the following:..unidirectional airflow should be provided in the area where product and other vulnerable components are exposed to airborne contamination. During qualification and requalification, several velocities should be measured across the face of the filters, to demonstrate a uniform velocity, and should be measured 15 to 30cm from the filter face. Each measurement should have a minimum velocity of 0.3m/s. Airflow visualisation should be carried out to demonstrate that air movement provides unidirectional airflow from the filters to product, and other components exposed to airborne contamination Comment: 5.3 Grade A. Unidirectional velocity (vertical) and air velocity at working height is impossible to achieve when small units are on a horizontal surface (such as accumulation tables). Could unidirectional air be interpreted as main airflow direction? What exactly is working height, still 300mm above the working area? 5. Premises Comment: Barrier Technologies. Process interactions can impact respective processes hence compromise the intended purpose so should be mentioned alongside the individual process steps like decontamination, disinfection, and sterilization of product contact surfaces applied in Barrier technologies. Proposed change: Add process interactions in elements to consider in for RABS and Isolator design. The design of the RABS or isolator shall take into account all critical factors associated with these technologies, including the quality of the air inside and the surrounding area, the materials and component transfer, the decontamination, disinfection or sterilization processes and process interactions together with the risk factors associated with the manufacturing operations and materials, and the operations conducted within the critical zone Comment: Current technology can provide containment of sterile hazardous products for personnel protection in Aseptic process filling at positive pressure in Isolator barrier technology together with a series of containment measures applied in design and operation that may include the Isolator as a primary containment the cleanroom as a secondary containment. API powder containment and Aseptic preparation primarily of closed container sterile product transfers may be suitable for processing in negative pressure Isolators with appropriate risk controls. By first intent Aseptic process filling of Hazardous products should consider use of positive pressure Isolators with additional containment control measures for personnel protection. RABS used for closed aseptic processing e.g. Transfer of pre-sterilised containers, capping in direct connection to Isolators may be justified to use the same Grade C background based on a risk assessment.

6 In addition Localized-Unidirectional airflow (L-UDAF) is used for aerodynamic protection within a controlled area to provide airborne contamination protection of materials and controlled area in transfers between different grades of zone, examples include: Autoclave offloads, Freeze dryer load/unload to Transfer carts, over Open RABS doors at interventions, at Mouse hole (Entry and exit) from Isolators. L-UDAF requires independent classification, qualification and monitoring from the surrounding area and requirements need to consider contamination risks on what protection is specified for. Grade A air supply is defined for Capper applications so L-UDAF requires a definition and reference in Annex 1 to prevent Grade A air supply being incorrectly specified for localized airflow protection. Add L-UDAF to glossary. Proposed change in : The critical zone of the RABS or isolator used for aseptic processes should meet grade A with unidirectional air flow. Under certain circumstances turbulent airflow may be justified in a closed isolator when proven to have no negative impact on the product The design of the RABS and open isolators should ensure a positive airflow from the critical zones to the surrounding areas unless containment is required in which case localised air extract is required to prevent contamination transfer to the surrounding room; negative pressure isolators should only be used when containment of the product is considered essential and risk control measures are applied that do not compromise the sterile preparation or product. In Aseptic process filling to maintain the highest level of protection of sterile product by first intent positive pressure in Isolators should be maintained and where hazardous product containment is required other containment attributes and control measures must be applied in combination. Where localized Uni-directional airflow (L-UDAF) is applied within a controlled area for protection against airborne contamination of materials in transfer or areas between different grades the classification, qualification and monitoring of L-UDAF should be defined relative to risk and level of protection required. Comment: Some of the guidance seems appropriate to Hospital Pharmacy/ ATMP Aseptic preparation Isolators and could be confused when trying to apply to Aseptic processing of sterile products particularly in critical filling processes where products are exposed to the Grade A environment. More clarity and differentiation is required. Sometimes the obvious may be worth stating to reinforce the requirement For isolators, the required background environment can vary depending on the design of the isolator, its application and the methods used to achieve bio-decontamination. The decision as to the supporting background environment should be documented in a risk assessment where additional risks are identified and risks mitigated to acceptable levels with appropriate control measures, such as for negative pressure isolators there is added to risk of sterile product contamination by contamination ingress from the background area and may require a higher classification for the surround. Where items are introduced into isolator Grade A conditions with a manual surface disinfection step in combination with a transfer device e.g. transfer hatch, a higher grade of background should be considered to mitigate risks of airborne and surface contamination transfer. For RABS, the required background environment can vary depending on the design of the RABS, its application and risks to sterile product contamination. Where sterile product/ containers are exposed/ openly processed in a Grade A environment the expectation is a Grade B background. Where components are in transfer to an Isolator via a RABS within closed components or containers e.g. pre-sterilised container transfer in primary packaging of stopped vials for capping RABS may be justified with a Grade C background in combination with the Isolator, subject to risk assessment.

7 5.21 Comment: Glove management strategies should consider the glove life cycle from selection, through integrity testing and in response to detected integrity failure at batch end. The different risk profiles and operations of RABS and Isolators needs to be differentiated between RABS and Isolators barrier glove management. Isolator barrier leak test criteria should follow published references otherwise Isolator manufacturers set limits based on ability to manufacture an Isolator without reference to process or risk and impose such equipment manufacture criteria on user requirement specifications. Leak integrity (defined leakage) is a control state that other combination control attributes are applied in combination to meet environmental control levels but inevitability the less integrity the more risks so published references should apply Recommended change in wording: Glove systems, as well as other parts of an isolator, are constructed of various materials that can be prone to puncture and leakage. The materials used shall be demonstrated to have good mechanical and chemical resistance. Barrier glove management strategies must reflect the glove life cycle including: selection for robustness, change frequency based on life cycle of stresses: physical and chemical, leak integrity testing method and frequency and risk assessment when glove integrity compromise is detected at batch end. Integrity testing of the barrier systems and leak testing of the isolator and the glove system should be performed using a specified combination of in-place and/or out-of-place visual, mechanical and physical methods that mitigate risk of impact from barrier system/ glove integrity loss. They Leak integrity tests should be performed using referenced acceptance criteria at defined periods, at a minimum of the beginning and end of each batch. Barrier glove integrity testing during campaigns following interventions that may affect the integrity of the glove or at interim session end must not compromise the integrity of maintained Grade A conditions over the course of the campaign. Glove management strategies should be defined in the Contamination control strategy Bio-decontamination, as a combination of cleaning and disinfection processes, and chemical Decontamination used for denaturing adverse residues on isolator or RABS and possibly enclosed process machine non product contact surfaces should be validated and controlled in accordance with defined parameters. Evidence must also be available to demonstrate that the qualified agent(s) applied do not affect any process performed in the isolator or RABS, such as having an adverse impact on product or sterility testing. Clean room and clean air device qualification. Comment: Grade A air sample levels set at I cfu presents a conflict with the expectation of (0) cfu. Grade A areas are not sterilized so by default cannot be defined as sterile having 0 cfu. The limitations in growth media monitoring methods and recovery does means a 1 cfu recovery may be a significant event hence an investigation would be required. Recommended change: Rather than state any cfu numbers replace with wording Absence of CFU detection across the three types of sample. Absence of cfu detection aligns with expected result and regulatory expectation and takes into account limitations of cfu monitoring microbiological methods and recovery. Absence of CFU detection

8 5.34 Disinfection Comment: Automated gaseous/ vapor phase Disinfection such as VHP is widely used in the Pharmaceutical industry for Isolators (and some Closed RABS) bio-decontamination and can also be applied (may be useful) in cleanrooms for area disinfection that may include difficult to manually disinfect inaccessible places. Biological indicator challenges can provide more rapid indication surfaces are bio-decontaminated other than waiting for growth media based EM results so areas can be released more quickly back into use after shutdown periods. Dry Fog aerosol methods that may also use hydrogen peroxide can become confused with VHP and they are very different processes: VHP is a dynamic process with small H202 molecule exchange with target surfaces and Dry fog aerosol droplets are delivered for static settlement. VHP requires surface bioburden control/ characterisation so the fragility of the process in terms of inability to biodecontaminate occluded contamination/ multi layers is accommodated and efficacy established as robust. Design integration of gaseous vapor phase disinfection process including mechanical and automation integration into barrier technology and/or cleanrooms can impact effectiveness and robustness of the process so an appropriate level of scientific and process knowledge is required. Clarity is required between fundamentally different processes and suitability of application and requirements for scientific and process knowledge. Comment: A stronger definition between Disinfection (<=2-log reduction), Decontamination (<=4-log reduction), 6- log reduction and Sterilization (6-log reduction / half-cycle approach or Overkill cycle + SAL) should be outlined. This would clarify also the validation targets for individual processes such as e.g. material transfer, surface states and differentiate disinfection and sterilization Proposed changes: Fumigation or vapor phase disinfection of cleanroom areas using sporicidal agents such as Vaporised Hydrogen Peroxide (VHP) may be useful for reducing microbiological contamination in inaccessible places and provide a more automated process to reduce variability that is a function of manual application of disinfectant agents. Bio-decontamination of Barrier separation technology, Isolators and RABS, using gaseous/ vapor phase sporicidal agents such as VHP requires scientific and process knowledge with documented and step wise disinfection cycle development including qualification of efficacy using appropriate biological challenges that demonstrate specified efficacy and cycle robustness with justified overkill. Typically 6log sporicidal efficacy is required to provide necessary assurance of the process. Surface disinfection of materials in transfer to a higher grade of area may use chemical or other physical methods and if bioburden is low a reduced efficacy of the specified disinfection process may be justified. The disinfection process selected must be justified as appropriate for intended use and subjected to risk assessment.

9 Consideration should be given when using either manually applied disinfectant agents or aerosol droplet applied agents, which deliver a static surface coverage, to contact time and residual removal. Where an automated gaseous/ vapor phase process is specified that establishes a dynamic exchange of generated agent molecules between the process environment to target surfaces the cycle phases that establish required starting conditions, maintain process lethality to qualified conditions and phase time together with gas/ residual removal to a specified level should be based on science and demonstrated to meet specified requirements with cycle reports that provide evidence of cycle validity. 5.9 Material Airlocks Comment: Further information is required to avoid poorly designed airlocks. The present description fails to explain that the effectiveness of airlocks is dependent on three variables, namely, magnitude of dispersion of contamination in the airlock, the air supply rate, and the time to reduce airborne contamination. For further information on the design of airlocks see Whyte W, Ward S, Whyte WM and Eaton T (2014) The application of the ventilation equations to cleanrooms Part 2: decay of contamination. Clean Air and Containment Review, 20, pp Proposed change(if any): The following should be inserted in line 363 between the two sentences. Airlocks should be designed by consideration of the magnitude of dispersion of airborne contamination in the airlock, the air change rate, and the time delay requirement to reduce airborne contamination before the door to the production cleanroom is opened. Aseptic preparations Comment: To maintain the highest level of protection of Grade A process environments and sterile products processed within Separation Barrier Technology in the form of RABS and Isolators must be considered by first intent in the process design, following Quality by Design and QRM principles. Recommended change in wording: Where possible, By first intent the use of technologies that separate human commensal and other objectionable or harmful contaminants from process environments that process sterile products must be considered in order to reduce the need for interventions into the grade A environment and minimize the risk of contamination to acceptable levels. Separation technologies may include, but not limited to: RABS, isolators or closed systems Automation of processes should also be considered to remove the risk of contamination by interventions (e.g. dry heat tunnel, automated lyophilizer loading, SIP). Section 8 Production and specific technologies Comment: The terminology, Alert Level and Action Level, defined in the glossary is not used in many instances throughout the document where Alert Limit and Action Limit is used instead.

10 , 702, 706, 707, 1625, 1629, 1630, 1633, 1634, 1648, 1651, 1653, 1655, 1659, 1660, 1662, 1669, 1676, 1680, 1715, 1744, 1746, 1750, 1759, 1761, 1763 Section 9 Proposed change (if any): Replace Level with Limit in the lines referenced. Viable and non-viable environment & process monitoring 1580, 1642, 1644, 1652, 2146 Comment: The term Non-viable is used in reference to airborne particles. Optical particle counters do not discriminate between viable and non-viable particles so what is being referenced as non-viable in the document is actually the sum of viable and non-viable particles. Proposed change (if any): Use the term airborne particulate in place of non-viable Comment: Maintaining differential pressure in critical for control of Grade A/B areas so recording regularly is not sufficient for these areas Proposed change (if any): 5.13 A warning system should be provided to indicate failure in the air supply and reduction of pressure differentials below set limits. Indicators of pressure differences should be fitted between areas, based on QRM principles. These pressure differences should be recorded regularly or otherwise documented in Grade C/D areas and continuously monitored in Grade A/B areas. This is also consistent with the verbiage used in the recently released GMPs for ATMPs Comment: This clause appears to have the same intent for selecting locations as ISO does, but the wording is not as clear. Also, it is advantageous to use the ISO locations during the PQ to gather data that is useful for the risk assessment used to determine monitoring locations. Proposed change (if any): 5.26 For initial classification, the minimum number of sampling locations can be found inshould be determined in accordance to ISO Part 1. However, a higher number of samples and sample volume is typically required for the aseptic processing room and the immediately adjacent environment (grade A/B) to include consideration of Aall critical processing locations, such as point of fill or stopper bowls, should be included. With the exception of the aseptic processing room, the sampling locations should be distributed evenly throughout the area of the clean room. For later stages of qualification and classification, such as performance qualification, locations should be based on a documented risk assessment and knowledge of the process and operations to be performed in the area

11 Comment: This clause appears to be requiring recovery testing as part of the qualification. Recovery testing is a more recognized terminology and it is part of the qualification, not the classification Proposed change (if any): The particle limits given in Table 1 above for the at rest state should be achieved after a clean up periodthe area has been allowed to recover after the on completion of operations. The "clean up"recovery period should be determined during the initial classificationqualification of the rooms. Additional Comment: Information about the clean-up test has changed from the previous version of Annex, and the guidance time left out. It now appears that any clean-up time is acceptable. This means that poor ventilation effectiveness is acceptable as long as the poor results are repeatable. A minimum time must be included in the clean up test if the test has any relevance. An alternative approach is to completely remove the requirement for a clean up test. This is sensible, as the clean up test adds little (if anything) to demonstrating that the ventilation system is effective. The correct approach is to measure a ventilation effective index in the cleanroom, such as obtained by means of the ACE index (see Whyte, W, Ward, S., Whyte WM, and Eaton, T (2014). Decay of airborne contamination and ventilation effectiveness of cleanrooms. International Journal of Ventilation, 13(3), pp. 1-10). Proposed change (if any): There are a number of alternatives to improve the. These are as follows, with the ones with least amount of change given first, and the most desirable change given last. a) Add a guidance time similar to the existing annex, b) Remove the requirement for carrying out the clean up test. c) Suggest that the recovery rate test (with a specified recovery time) as described in ISO is used. Suggest that a ventilation effectiveness index is measured at locations where the product and other vulnerable surfaces are exposed Comment: Clause 5.25 already states that the rooms need to be qualified in the at rest state so a room would have to be designed to meet this. This statement adds no value. Proposed change (if any): Remove these lines. 544 Comment: Suggest that the plate diameters are changed to the active media surface area for contact plates, 25cm 2. The plastic dimensions of contact media plates can vary and it is the active area that is important. Proposed change (if any): Change 55mm to 25 cm 2 Comment: For Settle plates there are more media plate diameter options available for use. There is no guidance on changing the size of the settle plate surface area. The standard 90mm plate may be too large to use in some sample sites. Some companies prefer to use 150mm diameter media plates. The Annex 1 allows a shorter sampling time to fit application but not a change in surface capture area, which would be equivalent. The active air sample specifies the volume to take but does not define the capture efficiency of the sampler. Active air sampler efficiency can vary significantly by supplier potentially leading to less microbial detection. The sampler methods capture efficiency are however reproducible over time. The microbial specifications are the same regardless of capture efficiency. The critical parameter for Environmental Monitoring is a change to a trend result over time.

12 Proposed change (if any): The media capture area for settle plates can be selected and validated by the company to suit their local sampling requirements. Current specified action and alert levels will be maintained Comment: The intervals for requalification are not consistent with what is in the most recent version of which states Periodic classification testing shall be undertaken annually in accordance with ISO This frequency can be extended based on risk assessment, the extent of the monitoring system, and data that are consistently in compliance with acceptance limits or levels defined in the monitoring plan. Proposed change (if any): Replace current for 5.29 with: Clean room should be requalified at appropriate intervals. The requirements for reclassification in ISO provide guidelines in this regard. In particular, periodic qualification testing is expected annually but the frequency can be extended based on risk assessment, the extent of the monitoring system and data that are consistently in compliance with acceptance limits or levels defined in the monitoring plan Comment: Particle loss in tubing should be limited during qualification and monitoring, and is effected not only by the length of the tubing, but by the configuration as well. It is also critical to have isokinetic probes pointing into unidirectional airflow. Proposed change (if any): 6.9 Particle counters should be qualified (including sampling tubing). Portable particle counter s with a short length of sample tubing should be limited in length and curvature to prevent particle loss used for qualification purposes. Isokinetic sampling probese heads shall be used in unidirectional airflow systems and positioned pointing into the airflow. 632 Comment: Add an additional clause for active microbial sampling devices. Instruments that do not have the efficiency to sample particles down to 1 µm in size are not sufficient for testing in Grade A/B areas. This aligns with ISO Proposed change (if any): New clause: Active air sampling devices should be capable of detecting viable particles down to 1 µm in size. Steam used for sterilisation Comment: It is recommended to reference guidance documents/standards, e.g. HTM 2010 (HTM 01-01), EN 285, ISO and ISO The following change is recommended: Steam used for sterilization processes should be of suitable quality and should not contain additives at a level which could cause contamination of product or equipment. The quality of steam used for sterilization of porous/hardware loads, fluid loads and for Steam-In-Place (SIP) should be assessed periodically (at least 6-monthly) against validated parameters. These parameters should include consideration of the following examples: non-condensable gases, dryness value (dryness fraction), superheat and steam condensate quality.

13 Comment: Clarify that the appropriate particulate and microbiological quality is equal to or better than the grade of the area into which it is introduced Proposed change (if any): 7.19 Compressed gases should have microbiological and particle quality equal to or better than that of the air in the environment into which the gas is introduced, be of appropriate chemical purity, free from oil with the correct dew point specification, and, where applicable, comply with appropriate pharmacopoeial monographs. Compressed gases that come in direct contact with the product/container primary surfaces should be of appropriate chemical, particulate and microbiological purity, free from oil with the correct dew point specification and, where applicable, comply with appropriate pharmacopoeial monographs. Compressed gases must be filtered through a sterilizing filter (with a nominal pore size of a maximum of 0.22μm) at the point of use. Where used for aseptic manufacturing, confirmation of the integrity of the final sterilization gas filter should be considered as part of the batch release process. Section 8 Comment: Clauses 8.14 and 8.17 seem to cover the same material. One should be removed seems to contradict earlier clauses that state isolators only need a minimum of a Grade D background and Proposed change (if any): 8.17 Partially stoppered vials or prefilled syringesclosed containers should be maintained under grade A conditions (e.g. use of isolator technology, grade A with B background, with physical segregation from operators) or grade A LAF carts (with suitable grade B background environment and physical segregation from operators) at all times until the stopper is fully insertedcontainer is fully closed Moist heat sterilization proposed change: The validity of the process should be verified at scheduled intervals, with a minimum of at least annually. Revalidation of the sterilization process should be conducted whenever significant modifications have been made to the sterilization medium, product, product packaging, and sterilization load configuration, sterilizing equipment or sterilization process parameters. Proposed change: There should be a clear means of differentiating products, equipment and components, which have not been sterilized from those which have. Each basket, tray or other carrier of products, items of equipment or components should be clearly labelled with the material name, its batch number and an indication of whether or not it has been sterilized. Indicators such as autoclave tape, or irradiation indicators may be used, where appropriate, to indicate whether or not a batch (or sub-batch) has passed through a sterilization process. However, these indicators show only that the sterilization process has occurred; they do not necessarily indicate product sterility or achievement of the required sterility assurance level Proposed change: Moist heat sterilization utilises clean Pure steam (WFI quality when condensed), typically at lower temperatures and shorter duration than dry heat processes, in order to sterilize a product or article. Moist heat sterilization is primarily effected by latent heat of condensation and the quality of steam is therefore important to provide consistent results. The reduced level of moisture in dry heat sterilization process reduces heat penetration which is primarily effected by conduction. Dry heat processes may be utilized to sterilize or control bioburden of thermally stable materials and articles. Dry heat sterilization is of particular use in the removal of thermally robust contaminants such as pyrogens and is often utilized in the preparation of aseptic filling components. Moist heat sterilization processes may be utilized to sterilize or control bioburden (for non-sterile applications) of thermally stable materials, articles or products and is the preferred method of sterilization, where possible.

14 Proposed change: Each heat sterilization cycle should be recorded on a time, /, temperature and pressure chart with a sufficiently large scale or by other appropriate equipment with suitable accuracy and precision. Monitoring and recording systems should be independent of the controlling system Proposed change: The position of the temperature probes used for controlling and/or recording should have been determined during the validation (which should include heat distribution and penetration studies), and, where applicable, also checked against a second independent temperature probe located at the same position (this can be a duplex probe). Proposed change: Chemical or biological indicators may also be used, but should not take the place of physical temperature and pressure measurements. Proposed change: After the high temperature phase of a heat sterilization cycle, precautions should be taken against contamination of a sterilized load during cooling. Any cooling fluid or gas in contact with the product should be sterilized unless it can be shown that any leaking container would not be approved for use Moist Heat sterilization Proposed change: Time, temperature and pressure should be used to monitor and record the process. Each item sterilized should be inspected for damage, seal and packaging material integrity and moisture on removal from the autoclave. Seal and packaging integrity should also be inspected immediately prior to use. Any items found not to be fit for purpose should be removed from the manufacturing area and an investigation performed. For sterilizers fitted with a drain at the bottom of the chamber, it may also be is necessary to record the temperature at this position throughout the sterilization period. For Steam-In- Place (SIP) systems, it may also be is necessary to record the temperature at condensate drain locations throughout the sterilization period. Proposed change: Validation should include a consideration calculation of equilibration time, exposure time, correlation of pressure and temperature and maximum/minimum temperature range during exposure for porous/hardware cycles and temperature, time and Fo for fluid cycles. These critical control parameters (CCP's) should be subject to defined limits (including appropriate tolerances) and be confirmed as part of sterilization validation and routine cycle acceptance criteria. Revalidation should be performed at least annually Proposed change: When the sterilization process includes air purging (e.g. porous autoclave loads, lyophilizer chambers) there should be adequate assurance of air removal prior to and during sterilization, e.g. Bowie and Dick air removal test. Loads to be sterilized should be designed to support effective air removal and be free draining where possible to prevent the build-up of condensate. Loads should be dry on completion of the cycle Care should be taken to ensure that materials or equipment are not contaminated after the sterilization exposure phase of the cycle due to the introduction of non-sterile air into the chamber during subsequent phases; typically only sterile filtered air would be introduced into the chamber during these phases

15 Comment: The requirement to perform the risk assessment is repeated numerous times over these clauses. These can be re-written to be less repetitive and make the intent clearer. Proposed change (if any): 9.4 In order to establish a robust environmental monitoring program, i.e. locations, frequency of monitoring and incubation conditions (e.g. time, temperature(s) and aerobic and or anaerobic), appropriate risk assessments should be conducted based on detailed knowledge of the process inputs, the facility, equipment, specific processes, operations involved and knowledge of the typical microbial flora found, consideration of other aspects such as air visualization studies should also be included. These risk assessments should be re-evaluated at defined intervals in order to confirm the effectiveness of the site s environmental monitoring program, and they should be considered in the overall con of the trend analysis and the contamination control strategy for the site. 9.5 For grade A monitoring, it is important that sampling should be performed at locations posing the highest risk of contamination to the sterile equipment surfaces, container-closures and product in order to evaluate maintenance of aseptic conditions during critical operations. 9.6 Routine monitoring for clean rooms, clean air devices and personnel should be performed in operation throughout all critical stages of operation, including aseptic operations, equipment set up,. The locations, frequency, volume and duration of monitoring should be determined based on the risk assessment and the results obtained during the qualification. 9.6 Monitoring should also be performed outside of operations within the area, e.g. pre disinfection, post disinfection, prior to start of manufacturing, and after a shutdown period, etc., in order to detect potential incidents of contamination which may affect the controls within the areas. The number of samples and frequency of monitoring should be considered in the con of the risk assessments and contamination control strategy. 9.7 For grade A monitoring, it is important that sampling should be performed at locations posing the highest risk of contamination to the sterile equipment surfaces, container-closures and product in order to evaluate maintenance of aseptic conditions during critical operations Comment: Alert levels must be lower than action levels for them to be meaningful Proposed change (if any): 9.9 The alert limits levels for grade B, Cc and D should be set based on the area performance, with the aim to have limits lower than those specified as and be significantly lower than the action limitslevels such that, in order to minimise risks associated and identify potential changes that may be detrimental to the process can be detected to raise awareness of a possible increased risk. Frequent alert level excursions should trigger an investigation Comment: Update recommended 5 µm particle levels for Grades B, C, and D to align with those that appear in ISO Update the notes to match the formatting of the other tables in the document. Most continuous monitoring systems are configured to take one minute samples to allow for a timely response to satisfy clause At a flow rate of 28.3 lpm, the detection of 1 particle would produce a result of 35/m 3 rendering the 5 µm action levels of 20 and 29 meaningless. The second sentence of Note 2 is not applicable here, should be added to clause 9.9.

16 Proposed change (if any): Table 5: Recommended limits action levels for airborne particle concentration for the monitoring of nonviable contamination Grade Recommended maximumaction limitslevels for particles 0.5 μm/m 3 Recommended maximumaction limits levels for particles 5 μm/m 3 in operation at rest (a) in operation at rest (a) A (b) 2035 (b) B (b) C D Set a limit level based on the risk assessment Set a limit level based on the risk assessment (a) Note 1: The particle limits levels given in the table for the at rest state should be achieved after a short clean up period defined during qualification in an unmanned state after the completion of operations (see 5.26e). (b) Note 2: With regards to the monitoring of 5.0 μm, the limit of 20 is selected due to the limitations of monitoring equipment. It should be noted that alert limits should also be set based on historical and qualification data, such that frequent sustained recoveries below the action limit should also trigger an investigation.the level of 35 is based on a particle counter configured to take a one minute sample with a flow rate of 28 litres per minute which would report the detection of a single particle as 35 per cubic meter. If a particle counter is operating with a higher flow rate or longer sample time, a level based on historical and qualification data may be appropriate Comment: It says sample size, but then references a flow rate, although the critical parameter for detecting the phenomena mentioned would be the sample time. Proposed change (if any): 9.15 The grade A zone should be monitored continuously and with a suitable sample size time (at least 28 litres (a cubic foot) per minute) so that all interventions, transient events and any system deterioration would be captured and alarms triggered if alert limits are exceeded Comment: Action levels in Table 6 are only applicable for culture based test methods. Proposed change (if any): 9.31 Recommended action limitslevels for microbial contamination are shown in Table 6. If using a microbiological method that is not culture based, these levels may not be appropriate. Appropriate levels should be determined following validation of the method. Table 6: Recommended maximum limitsaction levels for microbial contamination