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

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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 (Not-For-Profit society): PHSS Annex 1 comment platform: Comments from Group 1: Pharmaceutical Industry and GMP consultants. 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. Throughout this document, existing is given in italics where applicable. Where modifications have been made to existing these areas are underlined in the proposed change. Where large changes have been made such that the changes significantly there is no underlining. The most suitable changes considered by the PHSS are given at the start of each paragraph section.

2 1. General comments General comment (1) This draft revision of Annex 1represents an enormous change from the 2008 version, and includes a great deal of updated information, current expectations, and focus on current technologies and practices. However, the Pre Draft issue communication from EU Inspectors Working Group (IWG) indicated that Annex 1 would provide clear guidance to manufacturers with regard to the manufacture of sterile products so Inspectorates and Manufacturers are not held to unclear expectations. This was understood to be of especial importance to less technically mature organisations who currently learn via incidents or adverse regulatory inspections. This document does not meet that expectation nor does it appear to meet current regulatory expectations as experienced by the industry. The draft appears to be somewhat immature with tables repeated, has conflicts in many areas with current practice, and for example doesn t address the EMA non-distillation WFI Q&A paper that it was supposed to replace. The document requires improvement and clarification of technical elements, and should be subject to a further editing process. The use of terminology such as shall, should and must are not used consistently creating uncertainty over where expectations are mandatory. General Comment (2) Note that some companies are concerned that in contrast to enabling manufacturers to take decisions relating to their own processes using Quality Risk Management principles, some elaborated new detail is provided in the draft Annex 1 which state specific requirements in general, rather than enabling using individual risk based requirements based on manufacturing processes. General Comment (3) 1) The draft Annex is very prescriptive in expectations. There is risk of literal interpretations by inspectors and industry that will add cost and complexity to sterile manufacturing operations that are not warranted for sterility assurance. Although QRM principles are included, the statement is such that the controls must meet or surpass the Annex, which is inconsistent with QRM concepts and subject to interpretation/local enforcement. Industry experience has been that examples and recommendations are often interpreted by some authorities as the mandatory requirement. 2) There is an overall emphasis on quality control and testing rather than design, validation and assurance programs. This will add unnecessary cost and operational complexity with associated risk for burdensome activities and risk of errors. Focusing on programs that inherently design robust sterility assurance elements and emphasize risk reduction would provide greater levels of confidence in overall sterility assurance. 3) The draft Annex detailed requirements are based on current technology and the prescriptive methodologies will impede implementation of new scientific, engineering and analytical methods. Although the Annex attempts to promote modern technologies, the detailed prescriptive controls do not enable efficient, effective use of such technology. As a result, manufacturers may be limited in new technology, testing and assurance options for considerable time. 4) The controls outlined are often universal regardless of the technology (e.g. isolator, RABS) and therefore manufacturers are limited in operating to maximal efficiency and assurance. Many of the controls involve taking operations off-line limiting the time available for manufacture of product for supply. In addition, some of the controls are invasive and may have the unintended consequence of adding risk.

3 Specific comments on Line 1-4 Document Map (Index) 1] The order of the whole document should be improved. For example, Section 5 is the first time that the cleanliness Grades A-D are defined, yet Section 4 on personnel makes reference to them. 2] Section 8 has equipment items in it. These should be collected together in Section 6. Proposed change: Change the order of the sections, and rewrite Section 5 to include the equipment/processes in section 8. Reduce the size of section 8 by having a separate section on sterilisation Scope. To aid the clarity of the document, the scope should be re-written. It should be emphasised that there are two routes in the manufacture of sterile product namely terminal sterilisation (TS) and aseptic processing. While the former should be undertaken if feasible, it must be recognised that the growing increase in biopharma products may increasingly preclude the option for a TS approach. This section should also include references to ICH documents for QRM Existing Text The manufacture of sterile medicinal products covers a wide range of product types, (sterile active substance through to finished dosage form), batch sizes (single unit to multiple units), processes (from highly automated systems to manual processes), primary packaging materials and technologies (e.g. biotechnology, classical small molecule manufacturing and closed systems). This Annex provides general guidance that should be used for all sterile medicinal products and sterile active substances, via adaption, using the principles of Quality Risk Management (QRM), to ensure that microbial, particulate and pyrogen contamination associated with microbes is prevented in the final product. Proposed changed : Whenever possible products should be terminally sterilised in their primary containers as this provides the highest level of sterility assurance based on a terminal process of known lethality. Where terminal sterilisation isn t possible due to the product being heat labile, the alternative approach of aseptic processing can be used. See also This guidance considers the manufacture of sterile medicinal products manufactured by both terminal sterilisation and aseptic processing. It covers a wide range of product types, including sterile active ingredients (APIs) and finished dosage forms for both classic small molecule and large molecule biotechnology products. In addition to product types, guidance is also provided on batch sizes (single unit to multiple units); campaign working (single batches to campaigns comprising sequential batches); manual processes to highly automated systems; and primary packaging materials and certain specialised manufacturing technologies. The manufacturing environment is also considered, including cleanrooms, RABS, and isolators, and their relationship with open and closed process systems. This Annex provides general guidance that should be used for all sterile medicinal products and sterile active substances, using the principles of Quality Risk Management (QRM), to ensure that microbial, particulate and pyrogenic contamination associated with microbes is prevented in the final product, and to ensure more broadly that the products consistently meet their quality attributes of potency, purity, sterility, and identity. Extended scope to include primary packaging materials and technologies including biotech and closed systems

4 17-22 Comment (1): A definition for the Contamination Control Strategy would be very beneficial. Existing Text The intent of the Annex is to provide guidance for sterile medicinal products. However some of the principles and guidance, such as contamination control strategy, room qualification, classification, monitoring and gowning, may be used to support the manufacture of other products that are not intended to be sterile (such as certain liquids, creams, ointments and low bioburden biological intermediates) but where the control of microbial, particulate and pyrogen contamination, to reduce it as far as possible, is considered important. Proposed changed : Important GMP principles, such as cross-contamination control, are addressed elsewhere in the GMP guidelines. The intent of this Annex is to provide guidance for sterile medicinal products. However, some of the principles and guidance, such as contamination control strategy, cleanroom classification, qualification, monitoring and gowning, may be used to support the manufacture of other products that are not intended to be sterile. Examples include some liquids, creams, ointments and low bioburden biological intermediates where the control of microbial, particulate and pyrogenic contamination is considered important. Comment (2) Extended scope to include non-sterile products. This statement is too general. It needs to be more specific to eliminate any lack of clarity. Why pyrogen contamination should be a concern for non-sterile products? Is this statement on non-sterile products really needed in this guidance? Proposed change: Suggest delete line 17 to 20. Comment (3) The proposed scope includes non-sterile medicinal products and intermediates. This revision will provide uncertainty as to the specific application of each of the requirements of Annex 1 as they relate to the manufacture of non-sterile products. The governing regulatory guidelines for contamination control for the manufacture of non-sterile products is already provided within the EU Annex 2 regulations. Within that Annex, specific cross reference to Annex 1 is currently included. The scope of the guideline should be unambiguous (i.e., sterile medicinal products). If some of the principles and guidance contained in Annex 1 are to be utilised for non-sterile medicinal products and intermediates, guidelines for those products should cross-reference the applicable requirement in Annex 1. Comment (4): Distinction should be made between contamination - microorganisms, pyrogens and particulates which represent a direct hazard and risk to product quality and microorganisms, pyrogens and particulates which are not hazards to product quality. Proposed change: However some of the principles and guidance, such as microbial and particle control strategy, room qualification, classification, monitoring and gowning, may be used to support the manufacture of other products that are not intended to be sterile (such as certain liquids, creams, ointments and low bioburden biological intermediates) but where the control of microorganisms, particulates and pyrogens is considered important Principle General It is not clearly indicated that the direct intervention of operators in the critical grade A area should be discouraged, as indicated by MHRA in many communications on the revision of EU GMP Annex 1.

5 This should be indicated also for the manufacturing of all open containers since at point 8.17 for the transfer of partially stoppered containers two times the requirement is with physical segregation from operators. Thus, point 8.9 is not sufficiently clear and should be Where possible, the use of RABS, isolators or closed systems, should be considered in order to reduce the need for avoid direct interventions into the grade A environment... Comment (1): Existing Text a) Facility, equipment and process design must be optimized qualified and validated according to Annex 11 and Annex 15 of EU GMP. The use of appropriate current technologies should be implemented to ensure protection and control of the product from potential extraneous sources of particulate and microbial contamination such as personnel, materials and the surrounding environment. Proposed changed : a) Facility, equipment and process design must be optimized qualified and validated according to Annex 11 and Annex 15 of EU GMP. The use of appropriate current technologies according to EU directives 2003/94 Article 5 and 2001/83 Article 23 should be implemented to ensure protection and control of the product from potential extraneous sources of particulate and microbial contamination such as personnel, materials and the surrounding environment Comment (2) Line 26-28: Distinction should be made between contamination - microorganisms, pyrogens and particulates which represent a direct hazard and risk to product quality and microorganisms, pyrogens and particulates which are not hazards to product quality. Alternative proposed : The manufacture of sterile products is subject to special requirements in order to minimize risks of a microbiological (microorganisms and pyrogens), and particulate nature. The following key areas should be considered Comment (3) Line 31-34: Distinction should be made between 'contamination' - microorganisms, pyrogens and particulates which represent a direct hazard and risk to product quality and microorganisms, pyrogens and particulates which are not hazards to product quality. Specifically, in this con unless the transfer of microorganisms, particulates is of a quantity or nature (e.g. pathogenic microorganisms) that exceeds the materials quality attributes at that point (i.e. at a tolerable level) the microorganisms and particulates are not necessarily contamination. Alternative proposed : The use of appropriate current technologies should be implemented to ensure protection and control of the product from potential extraneous sources of particulate and microbial hazards such as personnel, materials and the surrounding environment Comment; As attitude is subjective i.e. cannot be reliably measured or evaluated, it is suggested that this term is omitted. Existing Text Personnel must have appropriate skills, training and attitudes with a specific focus on the principles involved in the protection of sterile product during the manufacturing, packaging and distribution processes. Proposed changed : Personnel must have defined skills and training with a specific focus on the principles to ensure the safety, quality and efficacy of sterile product(s) during the manufacturing, packaging and distribution processes Existing Text

6 Processes and monitoring systems for sterile product manufacture must be designed, commissioned, qualified and monitored by personnel with appropriate process, engineering and microbiological knowledge. Proposed changed : Processes and monitoring systems for sterile product manufacture must be designed, commissioned, qualified and assessed by personnel with defined process, engineering and microbiological knowledge. These systems must be defined within the facility contamination control strategy Will this require evidence of qualifications of personnel who designed and commissioned systems? Existing Processes, equipment, facilities and manufacturing activities should be managed in accordance with QRM principles that provide a proactive means of identifying, scientifically evaluating and controlling potential risks to quality. Risk assessments should be used to justify alternative approaches to those specified in this Annex only if these alternative approaches meet or surpass the intent of this Annex. Proposed changed : Processes, equipment, facilities and manufacturing activities should be managed in accordance with QRM principles that provide a proactive means of identifying, scientifically evaluating and controlling potential risks to quality. Risk and impact assessments should be used to identify and justify alternative approaches to those specified in this Annex only if these alternative approaches meet or surpass the intent of this Annex Existing Comment (1): The basis of quality risk management is to establish controls commensurate with the risk. Requiring that QRM be used, but then stating that it can only be used if the approaches meet or surpass the intent of the annex is contradictory in nature. Furthermore, scientific rationale in addition to risk assessment should be used to justify alternative approaches. Proposed change: Processes, equipment, facilities and manufacturing activities should be managed in accordance with QRM principles that provide a proactive means of identifying, scientifically evaluating and controlling potential risks to quality. Risk assessments and scientific rationale should be used to justify alternative approaches to those specified in this Annex. The draft consistently advocates the use of science based risk assessments to enhance the effectiveness of the contamination control procedures. However, there is no inclusion that the risk to the patient is dependent on the chance that an aseptically manufactured product will support microbial growth during the shelf life following manufacture. For example, a freeze dried product, or one which has a water activity of less than 0.6 will not support microbial growth and so presents a greatly reduced risk to the patient than a product which does support growth 1. The design of the contamination control devices (e.g. Isolators, RABS or open workstations) and the associated cleanrooms utilised should reflect this risk Recommendation: Information should be added that the risk to a patient is dependent of the likelihood that an aseptically manufactured product that is contaminated during manufacturing will support microbial growth during the period following manufacture prior to administration to the patient. The design of the contamination control devices (e.g. Isolators, RABS or open workstations) and the associated cleanrooms utilised during manufacturing should reflect this risk Quality Assurance is particularly important, and manufacture of sterile products must strictly follow carefully established and validated methods of manufacture and control. A contamination control strategy should be implemented across the facility in order to assess the effectiveness of all the control and monitoring measures employed. This assessment should lead to corrective and preventative actions being taken as necessary. Proposed changed :

7 Quality Assurance is particularly important, and manufacture of sterile products must strictly follow carefully established and validated methods of manufacture and control because sterility of the final product cannot be definitively measured. A contamination control strategy should be defined and implemented across the facility in order to assess the effectiveness of all the control and monitoring measures employed. This assessment should lead to corrective and preventative actions being taken as necessary. Comment (1): Line 51: New requirement. The site is required to implement and periodically update a documented holistic contamination control strategy. The control strategy defined in 8.7 should be crossed referred here. Comment (2) Line 51-53: A single control strategy, and an appropriate strategy term is needed which includes and distinguishes between the different approaches to controlling microorganisms, pyrogens and particulates which represent direct hazards to product quality and microorganisms, pyrogens and particulates which do not represent a hazard to product quality. The control strategy is required to be implemented across the facility, however controls are necessary in systems and subsystems which may be specific to product (e.g. tests supporting assessment of controls are qualified to ensure suitability with specific products). Clarification is suggested by changing the and to include a description of the term in the glossary. Alternative proposed changed : A microbial and particulate control strategy should be implemented across the facility in order to assess the effectiveness of all the facility s control and monitoring measures employed and specific to each product Existing 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 changed : The strategy should consider all aspects of contamination control throughout the life cycle of the facility with ongoing and periodic review and update of the strategy as appropriate. Distinction should be made between 'contamination control' of microorganisms, pyrogens and particulates which are potential hazards to product quality (contaminants) and the control of microorganisms, pyrogens and particulates which are not hazards to product quality. Specifically tolerable levels of microorganisms in facility areas such as Grade D or C cleanrooms are not contaminants or contamination as long as they are a quantity and nature which is not adverse to control or product quality. Alternative proposed changed The strategy should consider all aspects of microbiological (microorganisms and pyrogens), and particulate control and its life cycle with ongoing and periodic review and update of the strategy as appropriate Existing Contamination control and steps taken to minimise the risk of contamination from microbial and particulate sources are a series of successively linked events or measures. These are typically assessed, controlled and monitored individually but these many sources should be considered holistically. Proposed changed : Contamination control and the proactive steps taken to minimise the risk of contamination from microbial and particulate sources and any other extraneous material which may adulterate the product, are a series of linked events or measures including viable and non-viable particulates counts, airflows, pressure differentials, temperature and humidity, adherence to procedures etc. These are typically assessed, controlled and monitored individually but these multiple sources should be considered holistically.

8 Distinction should be made between 'contamination control' of microorganisms, pyrogens and particulates which are potential hazards to product quality (contaminants) and the control of microorganisms, pyrogens and particulates which are not hazards to product quality. Alternative proposed changed Microbial and particulate control and steps taken to minimise the risks from microbial and particulate sources are a series of successively linked events or measures. These are typically assessed, controlled and monitored individually but these many sources should be considered holistically Existing The development of such strategies requires thorough technical and process knowledge. Potential sources of contamination are attributable to microbiological and cellular debris (e.g. pyrogens/endotoxins) as well as particulate matter (glass and other visible and sub-visible particles). Proposed changed : The development of such contamination and control strategies requires thorough technical and process knowledge. Potential sources of contamination are attributable to microbiological and cellular debris (e.g. pyrogens/endotoxins) as well as particulate matter (glass and other visible and sub-visible particles). Distinction should be made between "contamination' - microorganisms, pyrogens and particulates which represent a direct hazard and risk to product quality and microorganisms, pyrogens and particulates which are not hazards to product quality. Alternative proposed changed The development of such strategies requires thorough technical and process knowledge. Potential sources of hazards are attributable to microbiological and cellular debris (e.g. pyrogens/endotoxins) as well as particulate matter (glass and other visible and sub-visible particles) Comment (1): The list does not include training and qualification program. Suggest add section on training. A single control strategy, and an appropriate strategy term is needed which includes and distinguishes between the different approaches to controlling microorganisms, pyrogens and particulates which represent direct hazards to product quality and microorganisms, pyrogens and particulates which do not represent a hazard to product quality. Alternative proposed changed Elements to be considered within such a documented microbial and particulate control strategy should include (but not be limited to): Distinction should be made between 'contamination' - microorganisms, pyrogens and particulates which represent a direct hazard and risk to product quality and microorganisms, pyrogens and particulates which are not hazards to product quality. Proposed changed Preventative maintenance - maintaining equipment and premises (planned and unplanned maintenance) to a standard that will not add significant microbial or particulate risk Distinction should be made between 'contamination' - microorganisms, pyrogens and particulates which represent a direct hazard and risk to product quality and microorganisms, pyrogens and particulates which are not hazards to product quality. Specifically, cleanrooms and environments are expected to and normally contain a micro flora; the

9 monitoring systems need to measure this to ensure routine control and also to measure events where genuine contamination events occur in that levels and nature of the permissible microflora are exceeded. Proposed changed Monitoring systems - including an assessment of the feasibility of the introduction of scientifically sound, modern methods that optimize the detection of environmental microbial or particulate risk The control strategy is suggested to include a number of listed elements. These elements are a mixture of important and critical items within various systems and subsystems. The wording does not indicate which if any are absolutely necessary and which are beneficially advantageous but not absolutely necessary. It is recommended that the wording is amended to reflect systems and subsystems, specific elements therein and if these are mandatory. Proposed changed Quality systems and respective elements that must he considered within the control strategy are tabulated below Oualitv System Facility Manulaclurina Process Personnel Procedures Product System Content (includes but not limited to) Desinn. traffic flows, utilities, maintenance nrcventative and repair, cleanine. disinfection, monitorina systems Desicn. ccniipment. in-nrocess controls, in-process tcsls Trainina, certification, garbina. Vendor annroval. out sourcinc. risk assessments. trendina. analysis, investiealional tools. CAPA. continuous improvement Raw materials, in-nrocess tests, end product tests. containers, closures 3 Pharmaceutical Quality System (PQS) General Comments: - line 131 : in chapter 1 of the EU GMP,... should be in chapter 1 of EU GMP Part I,... - line 135 : microbial contamination... should be microbial and other contamination Comment (1): No clarity regarding the definition of sterility assurance. Suggest include a definition of sterility assurance in the glossary Existing Text Distinction should be made between 'contamination' - microorganisms, pyrogens and particulates which represent a direct hazard and risk to product quality and microorganisms, pyrogens and particulates which are not hazards to product quality. Proposed changed : There is an effective risk management system integrated into the product life cycle to minimize microbial and particulate risks to ensure the safety, quality and efficacy of sterile manufactured product, including assurance of sterility. The manufacturer has sufficient knowledge and expertise in relation to the products manufactured and the manufacturing methods employed. Proposed changed : The manufacturer has defined knowledge and expertise in relation to the products manufactured and the manufacturing methods employed and the equipment and engineering systems that have a direct impact on product quality.

10 145 New requirement. The site is required to implement and periodically update a documented risk assessment. Should this risk assessment be incorporated into the contamination control strategy described at line 51? Proposed change (if any): Eliminate lack of clarity about the difference between the contamination control strategy document described at line 51 and the risk assessment document described at line 145. There is no guidance regarding the approach to be taken to complete an effective risk assessment that can accurately quantify the level of product microbial contamination. This requires an understanding of the fundamental risk factors that are responsible for microbial contamination, associated with airborne deposition, surface contact or liquid transfer, and how these factors should be combined to provide an accurate assessment of risk Recommendation: 152 Include further guidance on the requirement to provide an accurate assessment of risk based upon the fundamental mechanisms of product contamination by airborne deposition, surface contact or liquid transfer. The guidance should reference the fundamental risk factors that relate to product (or product contacting surfaces) contamination such as exposure area and time and the number of contacts with contaminated surfaces Chapter 1 of EU GMP vol 4-PQR section 1.10 does not include requirement for QRM. Suggest both documents are aligned Reference to transport of sterile products should be part of GDP. Suggest that this reference is removed. If it remains then see proposed below. Is this more of a GDP requirement and is this Annex the right place for this requirement ( i.e. transport)? Existing Text Processes associated with the finishing and transport of sterile products should not compromise the finished sterile product in terms of container integrity or pose a risk of contamination and ensure that medicinal products are stored and maintained in accordance with registered storage conditions. Proposed changed : Processes associated with the finishing and transport of sterile products should not compromise the finished sterile product. Aspects that should be considered include:- container integrity, risks of contamination, and avoidance of degradation by ensuring that medicinal products are stored and maintained in accordance with their registered storage conditions Existing Text Persons responsible the quality release of sterile medicines should have appropriate access to manufacturing and quality information and possess adequate knowledge and experience in the manufacture of sterile dosage forms and their critical quality attributes in order to be able to ascertain that the medicines have been manufactured in accordance with the registered specification and are of the required safety, quality and efficacy. Proposed changed : Persons responsible for the certification and quality release of sterile medicines should have appropriate access to manufacturing and quality information and possess defined knowledge and experience in the manufacture of sterile dosage forms and their critical quality attributes in order to be able to ascertain that the medicines have been manufactured in accordance with the registered specification and are of the required safety, quality and efficacy Existing Text

11 3.2 Investigations should be performed into non-conformities, such as sterility test failures or environmental monitoring excursions or deviations from established procedures, with a specific focus regarding the potential impact to sterility, to not only the specific batch concerned but also any other potentially impacted batch. The reasons for including or excluding product from the scope of the investigation should be clearly recorded and justified within the investigation. Proposed changed : 3.2 Investigations must be performed into non-conformities, such as sterility test failures or environmental monitoring excursions or deviations from established procedures, with a specific focus regarding the potential impact upon sterility. Investigations must consider not only the specific batch concerned but also any other potentially impacted batch. The reasons for including or excluding product from the scope of the investigation should be clearly recorded and justified within the investigation. 4. Personnel Before this section is introduced it would be better to describe the Premises (currently the following section) to define Grades A-D and the concept of CNC areas. This section also requires revision to clarify and recognise best practise. The term grade A/B cleanroom is not defined. It may be interpreted by some readers to suggest that it is acceptable for personnel to fully enter/occupy Grade A zones, which of course is not acceptable Existing : 4.1 The manufacturer should ensure that there are sufficient appropriate personnel, suitably qualified and experienced in the manufacture and testing of sterile medicines and any of the specific manufacturing technologies used in the site's manufacturing operations, to ensure compliance with Good Manufacturing Practice applicable to the manufacture of sterile medicinal products. Proposed change: Removal of the word appropriate Existing 4.2 Only the minimum number of personnel required should be present in cleanrooms. The maximum number of operators in critical areas should be determined based on QRM principles, documented in the contamination control strategy, and validated during activities such as initial qualification and aseptic process simulations, so as not to compromise sterility assurance. This is particularly important during aseptic processing. Inspections and controls should be conducted outside the clean areas as far as possible. Does this paragraph indicate that staff from the quality function should only conduct audits and inspections from outside of the aseptic area or is it referring to the inspection of filled containers etc? Proposed change: Include the abbreviation (APS) after the aseptic process simulations. The document recommends that the maximum number of operators in critical areas should be determined based upon QRM principles. By the definition of critical areas (see Glossary, line 2104), personnel are unlikely to be within these areas and it is more appropriate to state that the maximum number of operators in the aseptic processing room would be a more appropriate term. Recommendation: Change critical area to aseptic processing room Existing :

12 4.3 All personnel (including those performing cleaning and maintenance) employed in such areas should receive regular training, qualification (including sampling of the operators bioburden, using methods such as contact plates, at key locations e.g. hands arms and chest) and assessment in disciplines relevant to the correct manufacture of sterile products. This training should include reference to hygiene, cleanroom practices, contamination control, aseptic techniques, and potential safety implications to the patient of a loss of product sterility and in the basic elements of microbiology. Monitoring requirements should be described in the monitoring section. Proposed changed : 4.3 All personnel, including those performing cleaning and maintenance employed in such areas should receive regular training, qualification and assessment in disciplines relevant to the correct manufacture of sterile products. This training should include reference to hygiene, cleanroom practices, contamination control, aseptic techniques, and potential safety implications to the patient of a loss of product sterility and in the basic elements of microbiology. Personnel should be monitored for microbial contamination as described in section Existing : 4.4 The personnel working in a grade A/B cleanroom should be trained for aseptic gowning and aseptic practices. Compliance with aseptic gowning procedures should be assessed and confirmed and this should be periodically reassessed at least annually and should involve both visual and microbiological assessment (using additional locations such as arms and chest). Only trained personnel who have passed the gowning assessment and have participated in a successful aseptic process simulation (APS) test, during which they performed their normal duties, should be authorized to enter any grade A/B area, in which aseptic operations will be conducted, or are being conducted, whilst unsupervised. The microbial monitoring of personnel in the grade A/B area should be performed to assess their aseptic behaviour. This monitoring should take place immediately after completion of a critical intervention and upon each exit from the cleanroom. It should be noted that there should also be an ongoing continuous monitoring program for personnel including some consideration of periodic monitoring under the supervision of the quality unit. Use of grade A/B again. There seems to be an expectation that cleaning staff who will not be directly involved in aseptic processing need to participate in a successful APS. This requirement has been omitted in the proposed below. Proposed changed : 4.4 As far as possible personnel should be excluded from entering Grade A zones. The personnel working in a Grade B cleanroom and especially those supporting Grade A zones, must be trained for aseptic gowning and aseptic practices. Compliance with aseptic gowning procedures should be assessed and confirmed and this should be periodically reassessed at least annually and should involve both visual and microbiological assessment. Only trained personnel who have passed the gowning assessment should be authorized to enter any grade B area, in which aseptic operations will be conducted, or are being conducted, whilst unsupervised. Only trained personnel who have participated in a successful aseptic process simulation (APS) test, during which they performed their normal duties, should be authorized to undertake aseptic processing. The microbial monitoring of personnel in the grade B area should be performed to assess their aseptic behaviour. This monitoring should take place immediately after completion of a critical intervention and upon each exit from the cleanroom. It should be noted that there should also be an ongoing monitoring program for personnel which will include periodic monitoring under the supervision of the quality unit.

13 Comment (1): Note some companies believe that the personnel monitoring frequency should be based upon the activity that personnel are engaged in and should not necessarily be required on each exit. Comment (2) Line 199: Requalification should include visual and microbiological assessment Proposed change (if any): suggest adding visual and microbiological assessment Comment (3): Line : EM on each exit of the cleanroom may be excessive. One company monitors at the end of a shift or at the end of a campaign, at least once on each operator. Proposed change (if any): recommend EM at each end of shift or campaign - Define critical intervention in the glossary Comment (4): Line : What is the difference between critical and significant intervention? The term continuous monitoring for personnel is confusing. Routine should be used. -Is also gown monitoring required after a critical intervention? To be clarified. Only glove monitoring should be required after a critical intervention, supported by risk assessment Proposed change (if any): -Routine should be used. Clarify if only glove monitoring is acceptable after completion of a critical intervention, supported by risk assessment Comment (5): The Grade A/B cleanroom is a part of the aseptic manufacturing area in which there may be separate rooms which are only Grade B status (contain no Grade A zones). Aseptic processing room (definition included in the Glossary) would be a more appropriate term Recommendation: Change Grade A/B cleanroom to aseptic processing room throughout the document. Comment (6): Line 200: Personnel who are validated and authorised to enter into the aseptic processing room may not perform direct manufacturing activities e.g. to perform peripheral cleaning and disinfectant or supervisory activities, and consequently would have no requirement to participate in a successful aseptic process simulation test. Recommendation: Remove the requirement for all personnel who enter into the aseptic processing room to have participated in a successful aseptic process simulation test and specify that the requirement is specific to those personnel who have direct manufacturing activities. Comment (7) Line 205: Critical intervention is defined in the Glossary section ( line 2154) as Intervention (an aseptic manipulation or activity that occurs at the critical area) so the term critical is not required There are interventions that will have been assessed to be aseptically secure, included in aseptic process simulations and are an inherent part of the process in order for the operation to continue (e.g. replenishment of the container closures). In these cases, it would not be appropriate to perform personnel microbial monitoring. Any such monitoring needs to be considered for, and specific to, corrective interventions that are not included in aseptic process simulations Recommendation: Change critical area to aseptic processing area Change after completion of a critical intervention to after completion of a non validated intervention. (8) Line 206: Personnel may leave the cleanroom in which the manufacturing activities are located to retrieve consumables or related items for use during the manufacturing operation. For these activities, personnel microbial monitoring would not be expected as personnel are returning to the cleanroom. However, when the personnel

14 subsequently leave the aseptic processing area/aseptic manufacturing area, and discard their cleanroom attire, monitoring would be appropriate Recommendation Change upon each exit from the cleanroom to upon each exit from the aseptic manufacturing area Comment (9): Line : Does this refer to finger sample only monitoring or gown monitoring. Gown monitoring would be unachievable as operators would have to leave the area to re-gown mid process to avoid agar contamination from their sterile suit. Proposed change: Finger sample monitoring should take place Existing 4.5 There should be systems in place for disqualification of personnel from entry into cleanrooms, based on aspects including ongoing assessment and/or the identification of an adverse trend from the personnel monitoring program. Once disqualified, retraining and requalification is required before permitting the operator to have any further involvement in aseptic practices. This should include consideration of participation in a successful Aseptic Process Simulation (APS). Proposed changed : 4.5 There should be systems in place for disqualification of personnel from entry into cleanrooms, based on aspects including ongoing assessment and/or the identification of an adverse trend from the personnel monitoring program. Once disqualified, retraining and requalification is required before permitting the operator to have any further involvement in aseptic practices. This should include participation in a successful Aseptic Process Simulation (APS) depending upon the reasons for disqualification and its impact Existing 4.6 Manufacturers should establish written procedures outlining the process by which outside staff who have not received such training (e.g. building or maintenance contractors) need to be brought into grade A/B areas. Access by these persons should only be given in exceptional circumstances, evaluated and recorded in accordance with the PQS. Proposed changed : 4.6 Manufacturers should establish written procedures outlining the process by which outside staff who have not received such training (e.g. building or maintenance contractors) need to be brought into Grade B areas or access Grade A zones. Access by these persons should only be given in exceptional circumstances, evaluated and recorded in accordance with the PQS periodic health checks for such conditions should be performed. This sentence is not clear. Who should perform the check? Is self-assessment acceptable? Proposed change (if any): Clarify the meaning of periodic Existing Actions to be taken with regard to personnel who could be introducing an undue microbiological hazard should be described in procedures decided by a designated competent person. What actions can be taken/how to avoid a breach in confidentiality of personnel medical information. 227

15 Definition required for Undue microbiological hazards Is it problematic for Biological Quality personnel who work in the core to also work in the lab without a rigorous, clearly defined and effective entry procedures have been followed? Not clear how far you need to go to investigate this. You cannot check personal activities? What about part time butchers, farmers? Concern? Our gowning and Cleaning and disinfection SOPs should be effective? Proposed change (if any): More clarification of what entails a rigorous, clearly defined entry procedure is The term sterile product areas is not defined and is a new term, not used throughout the document Proposed change: Existing : Change sterile product areas to aseptic processing area/aseptic manufacturing area 4.9 Wristwatches, make-up and jewellery and other personal items such as mobile phones should not be allowed in clean areas. Comment (1): Is this referring to classified clean areas only OR CNC areas also? The definition of clean areas is not included in the glossary The requirement to not use mobile phones in all Grades of clean rooms is too stringent. Proposed change (if any): Include a definition of clean areas in the glossary. Reword as follows: Wristwatches, make-up and jewelry should not be allowed in clean areas. Other personal items and electronic devices (e.g. mobile phones) should be allowed in clean areas, where needed, only if adequately decontaminated and fit for purpose. Comment (3): More guidance on make-up is needed to suit modern culture. Make-up can now be semi-permanent, for example lip staining. Recommendation: Existing : Change make up to non-permanent make-up 4.10 Changing and hand washing should follow a written procedure designed to minimize contamination of clean area clothing or carry-through of contaminants to the clean areas. Garments should be visually checked for cleanliness and integrity prior to entry to the clean room. For sterilized garments, particular attention should be taken to ensure that garments and eye coverings have been sterilized and that their packaging is integral before use. Re usable garments should be replaced based at a set frequency determined by qualification or if damage is identified. Proposed change: 4.10 Garment changing and hand washing should follow a written procedure designed to minimize contamination of cleanroom clothing or transfer of contaminants to the cleanrooms. 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 that garments and eye coverings have been sterilized and that their packaging is integral before use. Re usable garments should be replaced based upon a set frequency determined by qualification or when damage is identified. Line : The gowning components include the garments and all other items required to complete full personnel enclosure (e.g. garment, hood, overboots, gloves, masks, eye coverings) and all components should be confirmed to have been sterilised with integral packaging prior to use.

16 Recommendation: Change particular attention should be taken to ensure that garments and eye coverings have been sterilised and that their packaging is integral before use to particular attention should be taken to ensure that all garment components have been sterilised and that their packaging is integral before use 253 Disinfected Shoes this should not be a requirement but the type of microbial /particulate control for shoes in Grade D should be based on the risk of contamination entering into the next stage of cleanroom Disinfection of dedicated Grade D shoes should not be required. Suggest to use either overshoes or dedicated shoes Proposed change (if any): re-word as follows: A general protective suit and either area dedicated shoes or overshoes should be worn The objective is to ensure appropriate measures in order not to bring contamination inside clean areas. Entry into Grade C areas with facility dedicated shoes does not pose a risk of undue contamination. Furthermore, the requirement for non -particle shedding garments in Grade C areas is not consistent with the non-viable particulate limits (Grade C level classification) present in those areas. It is also not consistent with QRM principles since in those areas there is no direct exposure of product or sterile product contact surfaces Proposed change: b) Grade C: Hair, beards and moustaches should be covered. A single or two-piece trouser suit gathered at the wrists and with high neck and appropriately disinfected or facility dedicated shoes or overshoes should be worn Existing : c) Grade A/B: Sterile headgear should totally enclose hair and facial hair; it should be tucked into the neck of the sterile suit; a sterile face mask and sterile eye coverings should be worn to cover all facial skin and prevent the shedding of droplets and particles. Appropriate sterilized, non-powdered rubber or plastic gloves and sterilized footwear should be worn. Trouser-legs should be tucked inside the footwear and garment sleeves into the gloves. The protective clothing should shed virtually no fibres or particulate matter and retain particles shed by the body. Garments should be packed and folded in such a way as to allow operators to change into the garments with contact to the outer surfaces of the garment reduced to a minimum. There is no mention of the use of gowning gloves nor under-suits which are essential in contamination control and are used fairly ubiquitously. Proposed change: b) Grade B: A dedicated single or two-piece under-suit should be worn. Sterilised outer garments (nonshedding) must be donned for the manufacture of aseptically processed products. The single trouser suit, gathered at the wrists and with a high neck, must provide total body coverage, such that the headgear must fully enclose the hair and be tucked into the neck of the suit. Full face cover and eye protection must be used to prevent the shedding of droplets. Eye protection equipment e.g. goggles, integral helmets and glasses must be sterilised by suitable procedures. Sterilised non-powdered rubber gloves and sterilised footwear must be worn with trouser legs tucked inside the footwear and garment sleeves into the outer gloves (see below). The garments must be handled and donned, using a pair of sterilised gowning gloves, such that they do not gather additional contamination and must shed virtually no fibres or particulate matter, retaining particles shed from the body. Following gowning an additional pair of sterilised (outer) gloves must be worn over the gowning gloves. Garments should be packed and folded in such a way as to allow operators to change into the garments without contact to the outer surfaces of the garment and to help prevent the garment touching the floor or other surfaces. Comment (2)