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| 1 | 2 |Who we are and what we do We are pharmaceutical, quality, compliance and technical consultancies based in Europe and the USA. With a combined team of 90 consultants, including former EU and FDA Regulatory Inspectors, we have the infrastructure in place to provide phase-appropriate hands-on compliance advice and guidance across the entire product lifecycle in the areas of product development, technology transfer, regulatory approval, manufacture, distribution, post market (MA Holder) obligations and product discontinuation. |How we do it Our consultants work with our clients at a strategic and tactical level providing solutions, holistic advice and guidance for virtual, operating, and contract manufacturing companies in the biotechnology, pharmaceutical and medical device sectors. Our clients range from emerging enterprises to the top multinational corporations. Our team has the ability and agility to right-size, as appropriate for each client and specific project, to ensure our clients get the right expertise level, personality and maximum value on each project. Whether you need a senior-level strategist to write a roadmap for compliance, or strong mid-level talent to review batch records, close overdue Deviations and CAPAs, or audit your suppliers, we can find the right person for the project. |Why we do it To accelerate and innovate compliant patient care. We hope you enjoy this White Paper and find it informative. We would welcome your feedback. Jonathan Morse Ann McGee Founder and President Managing Director & Principal Consultant Complya Consulting Group McGee Pharma International Following the recent strategic alliance between McGee Pharma International and Complya Consulting Group, we are delighted to present this White Paper entitled Aseptic Processing Key differences between the EU and US FDA. This Paper was born from our desire to add value to you, our colleagues in industry, by imparting practical and holistic advice to assist with your manufacturing processes. | 3 |Authors Ann McGee, Managing Director & Principal Consultant, McGee Pharma International Jilla K. Boulas, Senior Regulatory Affairs Consultant, Complya Consulting Group |Background The need for sterilization has its roots in ancient cultures. Early physicians were aware of small living organisms that affect human body and remain invisible to the eye. Sushruta (Indian physician, 600 B.C.)i advocated sterilization of wounds. The first discovery of the use of alcohol as an antiseptic is contributed to the Iranian physician Al Rhazi (865925)i. The advances in medicine have brought forth the complex set of requirements that currently apply to medical practices and to drug production. Asepsis may be defined as a state of control attained by using an aseptic work area and performing activities in a manner that precludes microbiological contamination of the exposed sterile product.ii In aseptic processing, parts and components of a drug product are sterilized and assembled into the finished form under environmental conditions that maintain the sterility status. There are numerous guidance and regulations addressing different aspects of aseptic processing: 21CFR210, 21CFR211, 21CFR 600s, FDA Aseptic Processing guidance document and EU Directives supported by the EU GMP Guide (Eudralex Vol. 4, Annexes 1 and 2).ii,iii,iv Additional guidance is provided by: International Conference on Harmonization (ICH), World Health Organization (Good Manufacturing for Sterile Pharmaceutical Products), Parenteral Drug Association technical reports (i.e. Number 1, 22, 36, 62), HTM2010 BS EN 285:1997 Sterilization Steam sterilizers Large sterilizers, Pharmaceutical Inspection Convention and Pharmaceutical Inspection Co-operation Scheme (PIC/S) as well as International Organization for Standardization (ISO 13408, 14644). It is pertinent to note that the PIC/S guidelines are expected to be applied in the EU; however some level of interpretation may be applied when properly justified and documented. In the US, the sole responsibility of product approval lies with the FDA. Product approval by the European Medicinal Agency (EMA) can be more complex due to the fact that legislation exists at both an EU level and also at a national level (approximately 30 countries). As one would expect, there are similarities and differences in the requirements for aseptic processing between the two regions. Both regions take a risk-based approach to evaluation of marketing/manufacturing authorization applications as well as inspection of the facilities and processes | 4 associated with the manufacture of a drug product. This paper focuses on some of the differences between Food and Drug Administration (FDA) and EU/ European Medicines Agency (EMA) requirements for aseptic processing. The goal is not to provide a comprehensive list of differences, rather a discussion of four key factors (equipment, process and facility design; air; water and testing/controls); based on the experience of the authors. |Product and Dosage Form The need for sterility is influenced by both the product and route of administration. All injectable products, as well as ophthalmic, and aqueous oral inhalation products are required to be sterile in the US market as per 21CFR200.50 and 21CFR200.51 respectively. Sterility is a state defined where the probability of a single spore surviving (after the sterilization process) is one in a million (10-6). This state may be achieved through filtration, heat (dry or steam), chemical, radiation, etc. Many biologics cannot undergo final sterilization due to the potential for denaturation of the product. Hence the state of sterility must be achieved by control of production activities through the final packaging of the sterile drug product. Terminal sterilization is the preferred method and should be chosen unless the product cannot be terminally sterilized, for example, heat sensitive products (iii). The EMA provides a decision tree for determination of when aseptic processing may be performed where terminal sterilization is not an optionv. Emphasis is placed on packaging not being an acceptable factor in determining the need for aseptic processing. Once the need for sterility has been identified, a decision has to be made regarding terminal sterilization or aseptic processing based on the product formulation and characteristics. According to the EU GMP Guide Annex 1, the manufacture of sterile products is subject to special requirements in order to minimize risks of microbiological contamination, and of particulate and pyrogen contamination. Much depends on the skill, training and attitudes of the personnel involved. Lack of sterility plays a big role in product recalls in the US, Over of the recalls during the years 20042011 involved sterile productsvi many of which were related to failure to maintain state of sterility. Once the product dosage form is identified, a stepwise approach to aseptic design may be taken. The manufacturing process may involve automated systems, the traditional manual process or a combination of both. This in turn will impact the design of facility and equipment followed by specifics regarding clean utilities (air, water, etc.). It is noted that the principles of aseptic processing and core GMP considerations apply equally for the traditional manual processes and the advanced automated processes. The approach to achieving | 5 those requirements may vary with differing levels of technology, reflective of the level of risk that applies for contamination of the manufacturing system and the drug product. |Equipment, Process and Facility Design It is estimated that personnel account for 80% of contamination into a cleanroom environment, equipment for 15% and the environment for 5%vii. Hence, manual operations, by their nature, pose the biggest risk of contamination to the product. Advances towards automation of processes through use of isolators/barriers and blow fill seal systems can reduce risks associated with activities carried out in traditional aseptic processingviii. A well-designed facility allows for maximum control, maintenance of equipment and monitoring of facility, equipment, personnel as well as the process to ensure sterility of the final product. Factors to be taken into account include flow of air, personnel, materials, equipment; appropriate segregation of activities; appropriate dedication of rooms and equipment; alignment of utilities and equipment operational requirements and the level of automation. The system has to be validated and FDA recommends the use of smoke studies for qualification of the critical areas (ii). Smoke studies are not directly referenced in Annex 1; however, visualization studies are expected to be performed per ISO 14644; Part 3ix . To allow for proper segregation, a classification scheme is applied to areas with different levels of cleanliness. Some differences exist between the naming system for area classification used by FDA versus that of EU (see Table 1). While the ultimate intent of both the FDA and EMA/EU regulators is to ensure appropriate conditions for aseptic processing, some GMP requirements are defined specifically by one agency and not the other. This can result in some differences in areas of focus during regulatory inspections and interpretation of minimum requirements by US and EMA/EU Inspectors. For example, in the EU GMP Guide, Annex 1, gowning requirements are specified for each grade of area A to D. In addition, in the EU, it is expected that changing rooms are designed as airlocks and that the final stage of the changing room should, in the at-rest state, be the same grade as the area into which it leads. The design of the process and whether it is manual or automated affects the requirements for classification of the neighboring or background areas. In a traditional aseptic process design, most often the entire aseptic filling room is maintained at Class 100 (ISO 5); however, the background environment for isolators may be Grade C or D classification (or ISO equivalent). The controls required to support aseptic processing in an isolator located in a Grade C versus a Grade D | 6 environment are different and the handling of adverse conditions or events needs to reflect the level of protection offered by the background environment. Equipment used to achieve sterility of parts and components, namely sterilizers/autoclaves play an important role in design considerations. While there are various methods of sterilization, heat sterilization is the preferred method by EMA/EU and considered the most widely used method by the FDA (ii). Sterilization processes must be validated and monitored through a combination of mechanical, chemical, physical and biological techniques. The validation of sterilization processes is looked at in considerable technical detail during EU/EMA regulatory inspections. Two elements require consideration: equipment qualification and process validation. EU regulators inspect against the EN 285 standardx and with reference to the HTM 2010 Sterilization Standardxi for autoclave qualification. Inspectors are likely to review the qualification data in detail, for example, load thermometric testing and autoclave performance tests. In relation to the validation and re-validation of sterilization cycles, expectations are broadly aligned between the agencies. Validation is expected to include heat penetration and load configuration testing with the use of Biological Indicators. Consistent performance of the sterilization process is expected; HTM 2010 defines very specific performance criteria for interpretation of thermometric measurements, including equilibration time. In terms of monitoring in routine use, the expectation for routine monitoring of cold spots reflecting the outcome of the validation studies is also aligned. For routine use of autoclaves, a test is required to be performed each day the equipment is used, to confirm the continued validated status of the autoclave e.g. Bowie Dick test or equivalent. Capping equipment maintenance, operating parameters and the quality of air supply for the capping process are subject to inspection. Capping seals the stoppered vials and protects the stopper from damage. The FDA does not specify the environmental requirements for capping operations but recommends on-line detection of improperly seated stoppers (viii). This is also an expectation of the EU/EMA. The environmental requirements of the capping area have been the subject of much debate in the EU and hence also for companies operating in the USA that export product to the EU. The EU/EMA considers that a vial is not closed until the seal is in place; therefore, the potential for contamination exists until that point. Two options for a capping environment include the capping station within the aseptic core or one outside the core. According to the EU Guide Annex 1 vials should be protected by Grade A conditions up to the point of leaving the aseptic processing area, and thereafter stoppered vials should be protected with a Grade A air supply until | 7 the cap has been crimped. Where vial capping is carried out within the aseptic core, sterile components are required to minimize the risk of contamination of the area. Unfortunately, in reality, significant challenges exist as a result of the interpretation of minimum requirements in the EU. A revision of Annex 1 is expected to be published in Q2 2016 which will hopefully provide additional clarity in relation to this topic. | 8 |Table 1 Differences in Equipment, Process and Facility Design (EU vs. FDA) Factor Topic Differences Comments Design Validation/Qualification EU/EMA Smoke studies not directly mentioned but are expectediii,ix FDA - reference to the use of smoke studiesii EU/EMA Annex 1 defines laminarity for laminar air flow stations; low turbulence unidirectional flow is sometimes accepted FDA requirement is for unidirectional airflow in critical areas; Both agencies expect the air flow pattern not to cause contamination. Room Classification Subtle differences between the classification of areas per Annex 1 and FDA. See Table 2 for Class A requirements for particles of 5 m Area Segregation - Isolator background environment EU/EMA Does not define the allowed level of particulates in Class D areas during operations. FDA Defines the maximum number of microbiological particles in air and plate samples Requirements for the background environment for Isolators is harmonized between the EU and the US. Area Segregation Changing Room EU/EMA the final stage of a change area/room is required to be the same grade as the area into which it leads iii FDA No specific classification for the final gowning stage (see Air section below); inspections are risk based, focusing on those operations that require employees to enter the critical areas of the processing line Equipment Sterilizer/Autoclave EU/EMA Bowie Dick test is spe-cifically referenced for heat pene-tration studies. However, an ap-propriate alternative test is likely to be considered acceptable. Inspections against the detail of the EN 285 & HTM 2010 stand-ards. FDA Expectations are aligned; however, not as specifically de-fined in regulations or guidance documents. Both regulatory bodies will study the Sponsors challenge studies for validation of the sterilizers. USP . Expectations are aligned for monitoring cold spots routinely. | 9 |Air The classification of a clean area is based on the quality of air as determined by the number of particles per unit volume, the size of the particles and their microbiological properties. Class 100 (US designation, 3520 particles per ft3 of 0.5m size) is analogous to the EU Class A in respect of 0.5m particle limits. In the EU, class A standards are based on monitoring of both 0.5m and 5.0m particulates while the US requirements relate to 0.5m particles only (see Table 2 for details). The EU GMP Guide, Annex 1 defines the requirement for measurement of the number of 0.5m and 5.0m particles for area classification and routine monitoring. The limits defined for 5.0um particles mean that Grade A areas need to meet ISO 4.8 and Grade B ISO 5. US based companies that wish to market their products in the EU need to meet the requirements of Annex 1 in this regard. Both FDA and EU/EMA regulators recommend the use of air handling systems capable of achieving a minimum of 20 air changes per hour, air flow speed of 0.36-0.54m/s (EU Annex 1) or 0.45m/s (20%, FDA) in the critical areas. The air handling units must be equipped with High Efficiency Air Particulate (HEPA) filters of 99.97% efficiency for removal of particulates, as small as 0.3m in diameter. As noted above, design considerations must segregate the air in the critical areas from contamination by the air from the lower classification of the neighboring rooms. Such design factors should include a positive pressure differential whereby typically, the air flows from the critical clean area to area of lower cleanliness classification. Depending on the classification of the adjacent room, a pressure differential of 10-15 Pascals (Pa) is expected for traditional aseptic processing areas. It is noted that pressure differential requirements for isolators may be quite different. Monitoring of the pressure differential is often a component of the building alarm system which must be validated; system alarms must be defined, qualified and any event activating an alarm must be properly investigated and documented while restoring aseptic conditions. | 10 |Table 2 Differences in Air Quality Requirements (EU vs. FDA) Factor Topic Differences Comments Air quality Classification naming system EMA/EU Grade A; FDA Class 100 etc. EMA/EU Class A must meet ISO classification of 4.8 for particles of 5m EMA/EU operates to m3 measurements FDA operates to ft3 measurement; See guidance documents for specifics EN ISO 14644-1 ix provides for intermediate classifications Particulates Type, size, and number/m EU distinction between critical area particulates while at rest and in-operation FDA particulates at dynamic conditions (i.e. in-operation). See Table 4 for more details HEPA filters Air exchange rate not specified by either agency EU HEPA filters are discussed in the context of air that has passed through filters of an appropriate efficiency & the ability to meet clean room classification standards as defined in ISO 14644iii FDA Provides additional guidance on efficacy, leak and challenge testing; FDA HEPA filters are leak-tested twice a year and require periodic monitoring The FDA requirements for filter leak testing and periodic monitoring applies equally in the EU and is defined by the ISO 14644 standard. | 11 |Water Water for injection (WFI) is required for aseptic processing to minimize the risk of contamination. Historically, there have been differences between the two regulatory agencies in relation to acceptable methods of production. The FDA accepts reverse osmosis and distillation (per USP) as methods for production of WFI; WFI produced by ultrafiltration (not listed in USP)xii may also be acceptable. In the EU, it is currently a requirement for WFI to be produced by distillation; reverse osmosis is not considered acceptable. However, it is pertinent to note that a new draft of the European Pharmacopeia monograph allows for non-distillation methods for producing WFI but does not define GMP controls for the generation system; this update is being coordinated and aligned with a revision to EU GMP Guide Annex 1. Constant circulation of the WFI at high temperature is a common expectation; the EU references temperature of >70C (Per EU Annex 1, paragraph 59) while FDA refers to a temperature of 65C 80C is commonly used and is acceptable(xii). Agencies in both jurisdictions expect a risk based approach to defining the sampling points in the water distribution systems; and EU/EMA expects this risk assessment to be formal, documented and reviewed annually for improvement and assessment of potential changes to the sampling program. Inspections by both agencies will include water system sampling frequency as justified by the system validation and performance data and must cover critical areasxiii and the point-of-use (where water is delivered to the process). Action or alert limits must be based upon validation data and must be set low enough to signal significant changes from normal operating conditionsxiv. Meaningful alert and action limits that reflect the capability of the system will ensure detection of a shift or emerging trend in compliance with both agencies expectations. Clean Steam is used in autoclaves or sterilization in place (SIP) cycles for equipment, tanks and surfaces. Steam condensate is expected to meet WFI standard and it should be tested accordingly in line with a defined program. Factors such as pressure of the steam, contact surface/ material of construction and risks of condensate formation are referenced in the FDA inspection manualxv. The utility system used to generate and deliver WFI or clean steam must be validated/qualified for its intended use. Such studies need to include biological kill at the cold spot(s) and achievement of the required level of sterility assurance. | 12 |Table 3 Differences in Water and Clean Steam Requirements (EU vs. FDA) Factor Topic Differences Comments Water WFI required for parenteral products EU/EMA Per Ph. Eur.; distillation is currently the only acceptable methodxvi FDA Per USP reverse osmosis & distillation are acceptable methods; ultrafiltration may be accepted Ph. Eur. revision recommended by European Directorate for the Quality of Medicines (EDQM) regarding acceptable methods for production of feed water quality WFI must meet compendia specifications. EU/EMA - Constant circulation at a temperature above 70C FDA Constant circulation at a temperature range of 65C 80C. Specific inspection guidance applies. Rinse Water - for parenteral products, final rinse water should meet the specifications of WFI. FDA Critical areas identified during validation must be sampled at the point of use EU Annex 15: Qualification and Validation USP Clean Steam Quality and use EU Discussed in the context of autoclave use FDA Discussed in the context of autoclave and SIP System validation & verification of the quality of the steam is important to both agencies for all relevant uses of clean steam. | 13 |Testing and Controls In addition to the regular environmental monitoring of the classified areas, testing plans must be in place for maintaining aseptic conditions while manufacturing processes are in progress during all shifts. All components of aseptic processing discussed above (equipment, area, air, water, personnel) require proper routine and in-process monitoring. Specific testing requirements are applicable per US Pharmacopeia (USP), European Pharmacopeia (Ph. Eur.). The Pharmacopeial Discussion Group (PDG) has worked diligently to harmonize several pharmacopeia topics, resulting in harmonization of methods such as microbial endotoxin test method (ICH Q4B). However, while test methods may be harmonized, there are some differences in sample collection requirements (see Table 4). When establishing a monitoring program, requirements such as sample size/volume; frequency of sampling; location and time of sampling; appropriateness of sample collection technique and test methods must be taken into account (21 CFR 211.84, 211.160(b)). Both regulatory agencies expect scientifically sound methodology and provide examples of acceptable monitoring methods. These comprise, active air sampling; settle plating; contact plating and personnel finger dabs. The preferred air sampling method in both the US and EU is active air, using active air samplers. In the EU, it is expected that all methodologies are used routinely and it is our experience that settle plating is used more extensively in the EU during routine production than it is by companies in the USA. Samples must be collected from sites that allow the highest potential for detection of contaminants,xvii such as the gown of operators, fingers (5 fingers, iii) or areas where complex manipulations are performed. Samples must represent the entire process (beginning, middle and end) and results are evaluated against appropriate limits. Microbiological samples, limits and method of collection are not harmonized (see Table 4). However, both EU/EMA and FDA require identification of contaminants when positive results are obtained. EU/EMA requires a formal risk assessment to support the EM program (iii). Annual review of the risk assessment, and potential revision of the program is expected with reference to data generated. The agencies in both jurisdictions expect the review of environmental monitoring data to include evaluation of the effectiveness of the cleaning procedures, potential presence of resistant strains of micro-organisms (iii) and/or adverse trends (ii). Simulation/media fill studies are an important element of validation and re-validation of the aseptic manufacturing process. Media fill studies are simulations of the production process using growth medium, instead of the product, known to | 14 promote microbiological growth. They must be conducted per approved protocol and appropriately documented. There is much agreement between the two agencies regarding the frequency of such studies. An apparent difference relates to the recommended microbiological action limits for Grade A; in the EU the action limit is less than 1 whereas in the US, the action limit is listed as 1. However, there is a caveat that samples from Class 100 (ISO 5) environments should normally yield no microbiological contaminants. Therefore, in effect, to meet expectations of both regulatory agencies, there should be no microbial growth. In relation to sterile filtration of products, both agencies have an expectation for Filter Integrity Testing (FIT) of product sterilizing filters pre and post use. The requirement is for the pre-use FIT to be performed on the sterilized filter (iii). This is presenting challenges to some manufacturers where the design of their manufacturing lines may not enable this to be done in a manner that minimizes the potential for contamination of the sterilized filter while performing the test. Where the PUPS (pre-use, post sterilization) FIT expectation cannot be met, we would recommend that manufacturers perform a formal risk assessment on their FIT arrangements and engage with their regulators to agree an acceptable approach. Both regulatory agencies require the use of all materials within their validated shelf lives. This extends also to the use of equipment. While the core requirements are similar, in our experience, there is a particular focus in EU/EMA inspections on the following: 1) Paragraphs 7780 of the EU GMP Guide, Annex 1 define specific ex-pectations for acceptable time inter-vals between washing and drying; between drying and the sterilization of components, containers and equipment and between steriliza-tion and use. Typically, compliance with these requirements is reviewed and it is expected that appropriate records are available to demon-strate actual time intervals for rou-tine processing. 2) Paragraph 80 of Annex 1, EU GMP Guide, defines a requirement to minimize the time between the start of preparation of a solution and its sterilization or filtration through a micro-organism retaining filter. Typ-ically, this is also inspected quite rigorously by EU/EMA Inspectors. It is expected that actual times are documented on a batch basis and that compliance with the process validation in relation to time and also critical filtration parameters (e.g. pressure) is evaluated as part of the batch review process. 3) Paragraph 80 of Annex 1, EU GMP Guide, requires bioburden monitor-ing of the bulk solution before steri-| 15 lization. Once again, EU/EMA reg-ulators require this to be performed for every batch and for the results to be considered as part of the batch review process. 4) Paragraph 62 of Annex 1, EU GMP Guide states that disinfectants and detergents should be monitored for microbial contamination. The ex-pectation for solutions of this nature to have appropriate shelf lives is common across the agencies and most companies will perform valida-tion studies to support shelf lives. However, this is a topic of discus-sion for some companies with their EMA/EU Inspectors who also ex-pect that these solutions should be monitored routinely for microbial contamination. | 16 |Table 4 Differences in Tests and Controls (EU vs. FDA) Factor Topic Differences Comments Air Samples -Routine Monitoring Frequency EU/EMA Particles are monitored for the duration of critical activities FDA Must be representative of the entire lot and processing conditions Requirements across the agencies are essentially similar. Type and Size EU/EMA Sample size & frequency for Grade A & B areas should be sufficient to ensure that all interventions, transient events and any system deterioration will be captured and alarms triggered if alert limits are exceeded FDA Sample volume should be sufficient to optimize detection of contaminants Requirements for monitoring across the agencies are essentially similar. Air, surface and personnel (contact plates/swabs) samples are expected by both agencies. For classification of Grade A, EU requires a minimum sample volume of 1m3. Location EU/EMA Locations identified through a formal risk analysis FDAii Not more than 1 ft. from the work site for classification purposes. Must include samples from sites with the highest potential for contamination. Requirements across the agencies are essentially similar. Some critical areas (such as fill line) may be sampled upon completion of the processing. Method EU/EMA All methods to be used routinely (active air, settle plates, contact plates, personnel monitoring) as part of a risk based approach. FDA Methods to reflect a scientific approach by the manufacturer In our experience, the extent of settle plating is greater in EU monitoring programs; approach to using other methods is similar across the two jurisdictions. EU provides additional testing option: contact plates (diameter 55 mm) cfu/plate. In-process EM samples Location EU/EMA specify that 5-finger touch plates are expected. Expectation that the face (typically for forehead), chest and both arms are sampled. Both jurisdictions have expectation that several locations are routinely sampledii,iii. Sampling has to be representative of each production session | 17 Factor Topic Differences Comments FDA several sampling locations include fingers, facemask, etc. reflecting the movement of people Specification EU/EMA | 18 |Conclusion The complexity of aseptic processing justifies the number of guidance documents written to make the interpretation of regulatory rules and expectations clearer. There are several dimensions to aseptic processing all of which are important. Therefore the focus of this paper was limited to address only 4 factors, namely, equipment, process and facility design; air; water and testing/ controls. The dosage form determines the need for sterility, product characteristics must rule out the possibility of terminal sterilization. It is only then that aseptic processing can be justified. Manufacturing process and facility design must suit the product quality requirements. Automated processes are ideal as they reduce human interventions, the main source of microbiological contamination. The building design is a complex body made of parts such as air, water/steam, gas, temperature and humidity, equipment, direction of flow/movement, etc., all of which must be synchronized to achieve one goal: appropriate environmental classification. This is one area where there is lack of harmonization. Once the building and its utilities are validated to provide aseptic conditions, the operations may begin and evidence of asepsis is collected through continuous environmental and operational monitoring plans. Details of sampling, frequency, location, and test methods may be documented in a formal risk assessment and justified based on validation activities and data. In order to ensure a state of control and also for the purposes of identifying improvement opportunities, evidence of aseptic status is reviewed ensuring compliance with quality standards and/or early identification of a potential adverse trend. This article aimed at pointing out some of the differences between the FDA and the EU/EMA with respect to requirements of aseptic processing. Risk assessment is an expectation shared by both agencies which should be the first step in the development of a product and design of the process to ensure the product is safe and effective. Consideration of aseptic processing step is a critical part of a well-documented risk management plan. It must be scientifically robust, and continuously improving based on meaningful interpretation of product-specific data. While there are significant areas of harmonization of requirements, continued compliance with the multitude of complex aseptic processing requirements across the regulatory jurisdictions worldwide still remains a significant challenge for the industry. The array of aseptic processing requirements necessitates analysis and interpretation of the regulatory requirements and guidelines by relevant Subject Matter Experts (SMEs), and a level | 19 of interpretative variability is somewhat inevitable. The regulators and the industry have a common goal: patient care. The regulatory agencies are actively engaging with one another with a view to optimizing the regulatory environment in the interests of accelerating product development for the benefit of the patient. It is likely that harmonization initiatives through, for example, the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH), will continue. These initiatives are complex and multi-faceted and as a result, take time to achieve. In parallel, regulatory requirements continue to grow and change reflecting developments in technology and experiences in providing patient care. The agencies, through their current co-operation initiatives are building trust and working relationships that undoubtedly will be beneficial to the ongoing harmonization of guidance for the industry. This industry can play its part through engagement with the regulatory process to support the continued development of harmonized guidance and through consistent implementation of appropriate standards to ensure patient care. | 20 |References i History of Clinical Research A merging of Diverse Cultures, John L Gallin M.D, October 2014; Accessed November 2015: https://ippcr.nihtraining.com/handouts/2014/Gallin_John-10-14-14-Slides_with_Notes-Color.pdf ii Guidance for Industry Sterile Drug Products Produced by Aseptic Processing Current Good Man-ufacturing Practice, FDA September, 2004 iii EU GMP Guide, Annex 1 Manufacture of Sterile Medicinal Products, 2008 iv EU GMP Guide, Annex 2 Biological Manufacture of Biological Active Substances and Medicinal Products for Human use, 2012 v Decision Trees for The Selection of Sterilization Methods (CPMP/QWP/054/98) Annex to Note for Guidance On Development Pharmaceutics (CPMP/QWP/155/96) vi A Review of Reported Recalls Involving Microbiological Control 2004-2011 with Emphasis on FDA Considerations of Objectionable Organisms Scott Sutton and Luis Jimenez , American Pharmaceuti-cal Review, January/February 2012 Volume 15, Accessed November 2015: http://www.americanpharmaceuticalreview.com/Featured-Articles/38382-A-Review-of-Reported-Re-calls-Involving-Microbiological-Control-2004-2011-with-Emphasis-on-FDA-Considerations-of-Objec-tionable-Organisms/ vii Prevention or Cure. What are the Risks, Alan Fisher, Contamination Control Specialist, 23 April 2013 http://www.interphex.com/RNA/RNA_Interphex_V2/documents/2013/speaker-presenta-tions/Manufacturing-Alan-Fisher.pdf?v=635012077524560891 viii STERILE DRUG PROCESS INSPECTIONS, FOOD AND DRUG ADMINISTRATION COMPLIANCE PROGRAM GUIDANCE MANUAL, 7356.002A, September 11, 2015 ix ISO 14644-1:2015en - Cleanrooms and associated controlled environment x BS EN 285:2015 Sterilisation Steam Sterilisers Large Sterilisers xi Health Technical Memorandum 2010, Part 3 (Including Amendment 1): Validation and Verification, Sterilization McGee Pharma International McGee Pharma International (MPI) provides the pharmaceutical, biopharmaceutical, medical device and healthcare sectors with expert EU Regulatory Affairs, Quality and Compliance advice, across all stages of the product lifecycle. Our team of over 30 consultants and technical specialists, with extensive expertise across all GxPs, includes a numbf former EU Regulatory Inspectors. This ensures that the service we provide our clients is in line with current international regulatory requirements. Services McGee Pharma Internationals Quality, Compliance, Regulatory Affairs and Technical services include: Quality Management System (QMS) Design Process Mapping System Development SOP writing Inspection readiness / mock regulatory audits and remediation support Quality Risk Management, in compliance with ICH Q9 Marketing Authorisation support MAH compliance, ensuring all activities are conducted in accordance with the holders obligations Pharmacovigilance services including EU QPPV Virtual Quality Assurance (VQA), including developments and updates of Technical / Quality agreements Qualified Person (QP) services Responsible Person (RP) services Technical support services Tailored training https://ippcr.nihtraining.com/handouts/2014/Gallin_John-10-14-14-Slides_with_Notes-Color.pdfhttp://www.americanpharmaceuticalreview.com/Featured-Articles/38382-A-Review-of-Reported-Recalls-Involving-Microbiological-Control-2004-2011-with-Emphasis-on-FDA-Considerations-of-Objectionable-Organisms/http://www.americanpharmaceuticalreview.com/Featured-Articles/38382-A-Review-of-Reported-Recalls-Involving-Microbiological-Control-2004-2011-with-Emphasis-on-FDA-Considerations-of-Objectionable-Organisms/http://www.americanpharmaceuticalreview.com/Featured-Articles/38382-A-Review-of-Reported-Recalls-Involving-Microbiological-Control-2004-2011-with-Emphasis-on-FDA-Considerations-of-Objectionable-Organisms/http://www.interphex.com/RNA/RNA_Interphex_V2/documents/2013/speaker-presentations/Manufacturing-Alan-Fisher.pdf?v=635012077524560891http://www.interphex.com/RNA/RNA_Interphex_V2/documents/2013/speaker-presentations/Manufacturing-Alan-Fisher.pdf?v=635012077524560891| 21 xii FDA GUIDE TO INSPECTIONS OF HIGH PURITY WATER SYSTEMS 7/93 Accessed November 2015: http://www.fda.gov/ICECI/Inspections/InspectionGuides/ucm074905.htm xiii USP Water for Pharmaceutical Purposes xiv : FDA WATER FOR PHARMACEUTICAL USE 12/31/86 Number: 46 Accessed November 2015: http://www.fda.gov/ICECI/Inspections/InspectionGuides/InspectionTech-nicalGuides/ucm072925.htm xv : FDA GUIDE TO INSPECTIONS OF STERILE DRUG SUBSTANCE MANUFACTURERS, Sterile Drug Substance Manufacturers (7/94) Accessed November 2015 http://www.fda.gov/ICECI/Inspections/InspectionGuides/ucm074930.htm xvi EMA Note for Guidance on quality of water used for pharmaceutical use, May 2002 Accessed November 2015: http://www.ema.europa.eu/docs/en_GB/document_library/Scien-tific_guideline/2009/09/WC500003394.pdf xvii Eudralex Volume 4 EU Guidelines for Good Manufacturing Practice for Medicinal Products for Hu-man and Veterinary Use Part 1/ Chapter 6: Quality Control Brussels, 28 March 2014 your partner in compliance http://www.fda.gov/ICECI/Inspections/InspectionGuides/InspectionTechnicalGuides/ucm072925.htmhttp://www.fda.gov/ICECI/Inspections/InspectionGuides/InspectionTechnicalGuides/ucm072925.htmhttp://www.fda.gov/ICECI/Inspections/InspectionGuides/ucm074930.htmhttp://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500003394.pdfhttp://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500003394.pdf| 22 McGee Pharma International McGee Pharma International (MPI) provides the pharmaceutical, biopharmaceutical, medical device and healthcare sectors with expert EU Regulatory Affairs, Quality and Compliance advice, across all stages of the product lifecycle. Our team of over 30 consultants and technical specialists, with extensive expertise across all GxPs, includes a number of former EU Regulators. This ensure that the service we provide our clients is in line with current international regulatory requirements. Complya Consulting Complya Consulting is a global Quality As-surance and Regulatory Affairs consulting firm. Complya works closely with compa-nies in the pharmaceutical, medical device and biotechnology industries that require consulting support for GxP compliance, FDA filings and submissions, audits, warn-ing letter remediation and clinical trial oversight. Complyas PEARL Matching process for matching individual consultants with spe-cific project needs differentiates Complya as a go-to company for a broad spectrum of complex strategic and day to day tactical consulting services. McGee Pharma International Suite 2, Stafford House Strand Road Portmarnock, Co. Dublin, Ireland Website: www.mcgeepharma.com Email: info@mcgeepharma.com Telephone: +353 (0)1 846 4742 Fax: +353 (0)1 846 4898 Complya Consulting Group, LLC One Presidential Way Suite 109 Woburn, MA 01801, USA Website: www.complya.com Email: info@complya.com Telephone 001 (617) 475-3470 Fax: 001 (877) 308-8261 http://www.mcgeepharma.com/mailto:info@mcgeepharma.comhttp://www.complya.com/mailto:info@complya.com