EU GMP Annex 1 – Implications on Filtration and Single Use Technology by Somasudaram and Simone Biel
1 like782 views
The draft EU GMP Annex 1 provides additional guidance on sterile filtration and single-use systems. It emphasizes minimizing contamination risks through engineering controls like preassembled equipment. It recommends considering a second sterile filter immediately before filling due to filtration risks. It also provides more specific recommendations around filter selection, validation, and system design to ensure sterility and product quality.
EU GMP Annex 1 – Implications on Filtration and Single Use Technology by Somasudaram and Simone Biel
- 1. The life science business of Merck KGaA, Darmstadt, Germany operates as MilliporeSigma in the U.S. and Canada. EU GMP Annex 1 Draft Implication on Sterilizing Filtration & Single-Use Systems Somasundaram (Som) Senior Technical Consultant Asia Pacific Dr. Simone Biel Senior Regulatory Consultant
- 2. Agenda 1 2 3 Regulatory Framework PUPSIT (Pre-use Post-sterilization Integrity Testing) 5 Draft Annex 1 - Impact of Proposed Additional Sections & Key Differences - Single-use Systems 4 Conclusions Draft Annex 1 - Impact of Proposed Additional Sections & Key Differences - Filtration
- 4. Boost Covid-19 vaccine production would not be possible without SUT Fast Growing Biopharmaceutical Market Challenges 4 Business driver to implement SUT Speed to Market High flexibility Quick changeover of equipment Ensure patient safety Identity Efficacy Purity
- 5. Sterile Medicinal Product subject to regulatory guidelines compliant filter qualification EU GMP Annex 1 – guidance on sterile medicinal product manufacturing Contamination Risks Throughout the Process Sterile media filtration Not subject to regulatory guidelines BUT should require aspects of sterilizing filter qualification
- 6. Sterilizing-grade designation is a functional definition 6 Sterilizing Grade Filter – Definition EU GMP, Annex 1 draft, Feb 2020 “Sterilizing grade filter – A filter that, when appropriately validated, will remove a defined microbial challenge from a fluid or gas producing a sterile effluent. Usually, such filters have a pore size equal or less than 0.22 μm” PDA TR 26, revised 2008 A filter that reproducibly removes test microorganisms from the process stream, producing a sterile filtrate. FDA cGMP, Guidance for Industry, 2004 “A sterilizing grade filter should be validated to reproducibly remove viable microorganisms from the process stream, producing a sterile effluent. Currently, such filters usually have a rated pore size of 0.2 μm or smaller.” Demonstrate removal of a standard test organism Brevundimonas diminuta At minimum concentrations of 107 cfu/cm2 ASTM F 838-05 is a “Standard Test Method for Determining Bacterial Retention of Membrane Filters Utilized for Liquid Filtration”
- 7. Critical steps are transferred from end-user to supplier Drug Product Manufacturing 7
- 8. Risk assessment (starting point) − Sterility/integrity − Particles − Process fluid interaction with SUS SUS supplier’s data as basic information Additional validation studies if required Supplier management − Audit, audit reports and follow up Incoming control Transport, storage, material flow at end-user’s site Operator training Usage of SUS Documentation … 8 “Do you know what your supplier does?” The GMP Inspector
- 9. Patient safety: identity, efficacy, purity Key regulatory concerns for medicinal products 9 Market authorization Manufacturing authorization
- 10. Ongoing consultation of new draft – global approach 10 EU GMP, Annex 1: Manufacture of Sterile Products 1971 → ensure sterility of medicinal products − Since then several updates 2017 → full review of Annex 1 − 140 companies provided more than 6200 comments 2020 → targeted stakeholder consultation − 16 organisations − WHO and PIC/S to maintain global alignment PIC/S, The Pharmaceutical Inspection Co- operation Scheme non-binding, informal co-operative arrangement between Regulatory Authorities in the field of Good Manufacturing Practice (GMP) of medicinal products 54 participating authorities from Europe, Africa, America, Asia and Australia Mission: lead the international development, implementation and maintenance of harmonised GMP standards and quality systems of inspectorates in the field of medicinal products.
- 11. Prevent any contamination in the final product 11 QRM through entire document Key Changes Introduction of new sections Introduction of Quality Risk Management (QRM) Principles Restructured to give more logical flow Added detail to a number of the previous sections to provide further clarity Annex 1 draft, 2020 https://ec.europa.eu/health/sites/health/files/files/gmp/ 2020_annex1ps_sterile_medicinal_products_en.pdf
- 12. Established ICH Quality Guidelines Manufacturing and Control Strategy ICH Q8 (R2), Pharmaceutical Development − “Quality by Design” – understand the process and its control early in development, based on sound science and quality risk management ICH Q9, Quality Risk Management − Systematic process for assessment, control, communication, and review of risks to protect the patient − Higher risk require higher level of qualification ICH Q10, Pharmaceutical Quality System − Knowledge management – systematic approach to acquiring, analysing, storing, and disseminating information Quality Guidelines of the International Council for Harmonisation (ICH) Overview of a typical quality risk management process (ICH Q9) 12
- 13. Keep it close and sterile 13 CCS = Contamination Control Strategy General considerations “aseptic process should be clearly defined” “identify risks” “control” “describe” “document residual risks” “minimize contamination” Specific guidance Sterile filtration and PUPSIT Closed processing Single-Use Systems
- 14. EU GMP Annex 1 draft (Feb 2020) “specific risks associated with SUS” → contamination control strategy − Interaction with DP and SUS surface − Integrity (“fragile”, “risk of holes and leakage”, “complexity” − Risk of particulate contamination What to do? − Supplier qualification, including sterilization verification − Evaluation of adsorption and reactivity of product − Verification of integrity throughout the process − Establish acceptance criteria and incoming control procedure − Operator training 14 Finally, regulatory expectations are formalized! SUS in Aseptic Processing
- 15. Who is doing what? Regulatory and Industry Expectations Biosafety Seminar | 22 October 2020 Law Country specific drug law Regulatory Agencies Provide regulations and recommendations Market authorization Surveillance Compendia - Reference for quality control of medicines Ph. Eur is legally binding USP standards are legally recognized Harmonization effort Through consensus organizations Industry expectations Interpretation and elaboration on regulatory expectations 15
- 16. Guidelines on primary packaging materials and container 16 Supporting documents – Drag and Drop Ph. Eur. 3.1.x, Materials used for the manufacture of containers USP <661>, Plastic Packaging Systems and Their Materials of Construction (obsolete in 2025) <661.1>, Plastic Materials of Construction <661.2>, Plastic Packaging Systems for Pharmaceutical Use USP <87>, Biological Reactivity Test, In Vitro USP <88>, Biological Reactivity Test, In Vivo ISO 10993-xx, Biological evaluation of medical devices USP <85>, Ph. Eur. 2.6.14 and JP 4.01 , Bacterial endotoxin testing USP <788>, Ph. Eur. 2.9.19, JP 6.07 sub-visible particulate testing <665> Plastic components used in manufacturing, draft 2020 First and only standard approach on SUS component qualification
- 17. Interpretation of regulatory guidance and filling the gap 17 Industry Associations BioPhorum Extractables & Leachables User requirement specification (BPSA) Change notification (BPSA) Sterile filtration (PDA), 2020 Supply partner program BPSA Particles Integrity Cell & Gene Therapy ISPE Good Practice Guide: Single-Use Technology (2019) PDA TR 26, Sterilizing Filtration of Liquids (revised 2008) TR 66, Application of Single-Use Systems in Pharmaceutical Manufacturing (2014) ASTM - Standard test methods Bacterial retention Filter integrity Single-use systems integrity
- 18. PUPSIT (Pre-use Post-sterilization Integrity Testing) Applies to BOTH single and redundant sterilizing filtration systems
- 19. Annex 1 to Volume 4 of EU GMP “The integrity of the sterilised filter should be verified before use and should be confirmed immediately after use by an appropriate method such as a bubble point, diffusive flow or pressure hold” test. 2017 PIC/S guidelines “The integrity of the sterilised filter should be verified before use and should be confirmed immediately after use by an appropriate method such as a bubble point, diffusive flow or pressure hold test.” Draft Annex 1 (Feb 2020) 8.88 The integrity of the sterilised filter assembly should be verified by testing before use, in case of damage and loss of integrity caused by processing, and should be verified by on line testing immediately after use by an appropriate method such as a bubble point, diffusive flow, water intrusion or pressure hold test. Regulatory PUPSIT References
- 20. 20 Since 1998, the EU Guidelines to Good Manufacturing Practice: Medicinal Products for Human and Veterinary Use, Annex 1 (Manufacture of Sterile Medicinal Products) or “Annex 1” has contained the requirement for verifying the integrity of a sterilizing grade filter before use and after its sterilization. The requirement remained in the 2008 revision and in the 2017 and 2020 draft revisions to Annex 1. Concerns by European and other Health Authorities over the risk of filtration failure resulted in an increase in enforcement of this requirement. This enforcement started a discussion within the industry of the of the challenges, benefit, and aseptic process related risk of PUPSIT. The resulting debate has exposed a need for scientific evidence to support and effective risk-based approach to PUPSIT use. To help meet that need, BioPhorum and the PDA formed the Sterile Filtration Quality Risk Management (SFQRM) Consortium, which has been working to provide objective, unbiased, scientific data to help guide informed decisions about sterile filtration control measures. PDA/BioPhorum conducted Series of Webinars in from September 2020 PDA & BioPhorum Task Force
- 21. EMA response was to keep PUPSIT • The EU’s rationale for keeping PUPSIT was offered by Andrew Hopkins, rapporteur for the revision’s drafting group and an expert GMDP inspector with the UK’s Medicines and Healthcare products Regulatory Agency. He said, “PUPSIT is necessary.” • “sterilization is an aggressive process, even the irradiation mode; that filter manufacturing is not always consistent and damaged filters can go undetected through the manufacturing process.” • “the argument against is that manufacturers don’t like it, that it is difficult to do such testing.” It “has been a reality since 2007” to comply with Annex 1 and that “it is not sufficient to say that such testing is unnecessary; rather these arguments need to be supported by scientific rationale.” Rationale is a scientifically and fact based risk assessment document October 2017 PDA Meeting – Proposal to Remove PUPSIT
- 22. Draft Annex 1 - Impact of Proposed Additional Sections & Key Differences - Filtration
- 23. “8.15-16 Aseptic manipulations (including non-intrinsic aseptic connections) should be minimized using engineering solutions such as the use of preassembled and sterilized equipment. Whenever feasible, product contact piping and equipment should be pre-assembled, then cleaned and sterilized in place.” 8.82 “Due to the potential additional risks of a sterile filtration process, as compared with other sterilization processes, a second filtration through a sterile sterilizing grade filter, immediately prior to filling, should be considered as part of an overall CCS.” − Added explanation avoids the question of “How close is close” - result should be focus on connections and risk of loss of sterility − Places major focus on aseptic risk reduction (CCS) including SUS systems Example of Additional Specific Recommendations in Draft Annex 1 Revision – 2nd SGF as close as possible
- 24. 8.81 If the product cannot be sterilized in the final container, solutions or liquids should be sterilized by filtration through a sterile sterilizing grade filter (with a nominal pore size of 0.22 μm (or less) that has been appropriately validated to obtain a sterile filtrate) and subsequently aseptically filled into a previously sterilized container. The selection of the filter used should ensure that it is compatible with the product and as described in the marketing authorization (refer to paragraph 8.125). Shows what should be considered during sterilizing filter qualification but no definition of “compatible” 8.82 “Due to the potential additional risks of a sterile filtration process, as compared with other sterilization processes, a second filtration through a sterile sterilizing grade filter, immediately prior to filling, should be considered as part of an overall CCS.” Replaces term “microorganism retentive” in old annex – now MORE SPECIFIC Example of Additional Specific Recommendations in Draft Annex 1 Revision – Choice of Product Sterilization
- 25. Traditional Style Sterile Filtration System with Bioburden Reduction Filter and EMA/PIC/S Draft Annex 1 Compliant 8.82 “Due to the potential additional risks of a sterile filtration process, as compared with other sterilization processes, a second filtration through a sterile sterilizing grade filter, immediately prior to filling, should be considered as part of an overall CCS.” Aseptic Filler Sterile Hold Tank Vent Filter Vent Filter Sterilizing Filter Bioburden Reduction Filter Sterilizing Filter Prefiltered Formulation NOT Redundant Filtration
- 26. 8.83 The selection of components for the filtration system and their interconnection and arrangement within the filtration system, including pre-filters, should be based on the critical quality attributes of the product, justified and documented. The filtration system should minimize the generation of fibres and particulates, not cause or contribute to unacceptable levels of impurities, or possess characteristics that otherwise alter the quality and efficacy of the product. Similarly, the filter characteristics should be compatible with the fluid and not be adversely affected by the product to be filtered. Adsorption of product components and extraction/leaching of filter components should be evaluated (refer to paragraph 8.125). Component selection is Drug Manufacturer’s responsibility Prefilter needs to be part of the validated system (8 elements) Greater focus on target quality product profile / QbD Reference point is the final sterile medicinal drug product safety and patient protection Example of Additional Specific Recommendations in Draft Annex 1 Revision – Filtration & prefilters
- 27. 8.84 The filtration system should be designed to: i. Allow operation within validated process parameters. ii. Maintain the sterility of the filtrate. iii. Minimize the number of aseptic connections required between the sterilizing filter and the final filling of the product. iv. Allow cleaning procedures to be conducted as necessary. v. Allow sterilization procedures, including sterilization in place, to be conducted as necessary. vi. Permit in-place integrity testing, of the 0.22 μm sterilizing filter, preferably as a closed system, prior to filtration as necessary. In-place integrity testing methods should be selected to avoid any adverse impact on the quality of the product. Open for interpretation – “in-place” Example of Additional Specific Recommendations in Draft Annex 1 Revision – Filtration System Design
- 28. 8.85 Sterile filtration of liquids should be validated in accordance with European (or other relevant) Pharmacopeia requirements. Validation can be grouped by different strengths or variations of a product but should be done under worst case conditions. The rationale for grouping should be justified and documented. The filter vendor can and should provide this – but the user must understand this 8.86 During filter validation, wherever possible, the product to be filtered should be used for bacterial retention testing of the sterilizing filter. Where the product to be filtered is not suitable for use in bacterial retention testing, a suitable surrogate product should be justified for use in the test. The challenge organism used in the bacterial retention test should be justified. Environmental monitoring and bioburden studies are vital Example of Additional Specific Recommendations in Draft Annex 1 Revision – Sterilizing Filter Validation
- 29. 8.87 Filtration parameters that should be considered in validation and routine processing should include but are not limited to: a) If the system is flushed or integrity tested in- situ with a fluid other than the product, then flushing with the product should be part of the process. b) The wetting fluid used for filter integrity testing based on filter manufacturer’s recommendation or the fluid to be filtered. For the latter, the appropriate integrity test value specification should be established. 29 Example of Additional Specific Recommendations in Draft Annex 1 Revision – Filter Validation (FIT) Regulators want to see water flushing study information and product based integrity testing studies and filter integrity test result trending
- 30. 30 Example of Additional Specific Recommendations in Draft Annex 1 Revision – Filtration Process Condition 8.87 c) Filtration process conditions including: i. Fluid prefiltration holding time and effect on bioburden. ii. Filter conditioning, with fluid if necessary. iii. Maximum filtration time/total time filter is in contact with fluid. iv. Flow rate. v. Filtration volume. vi. Temperature. vii. The time taken to filter a known volume of bulk solution and the pressure difference to be used across the filter. Note: Results of these checks should be included in the batch record. Any significant difference in parameters from those validated to those observed during routine manufacturing should be noted and investigated. So much of this is the basis of QbD and of user requirement specifications
- 31. 31 Examples of Key Differences in Draft Annex 1 Revision – Filter Integrity Testing 8.88 The integrity of the sterilized filter assembly should be verified by integrity testing before use, to check for damage and loss of integrity caused by the filter preparation prior to use. A sterilizing grade filter that is used to sterilize a fluid should be subject to a non-destructive integrity test post-use prior to removal of the filter from its housing. “assembly” is stated rather than “system” – may implication for SUS assemblies “on-line” testing may immediately require risk assessment due to lack of liquid at POU It is recognized that pre-use post sterilization integrity testing (PUPSIT) may not always be possible after sterilization due to process constraints (e.g. the filtration of very small volumes of solution). In these cases, an alternative approach may be taken providing that a thorough risk assessment has been performed and compliance is achieved by the implementation of appropriate controls to mitigate any risk of non-sterility. Points to consider in such a risk assessment should include but are not be limited to: i. In depth knowledge and control of the sterilization process to ensure that the potential for damage to the filter is minimized. ii. In depth knowledge and control of the supply chain – sterilization facility, transportation & packaging validation iii. In depth process knowledge such as – product type, particle content that could mask/plug the filter First time have mentioned on risk assessment for PUPSIT
- 32. 32 Example of Additional Specific Recommendations in Draft Annex 1 Revision – Old vs Revised – Compressed Gas “7.19 Compressed gases that come in direct contact with the product/container primary surfaces should be of appropriate chemical, particulate and microbiological purity . . . Compressed gases must be filtered through a sterilizing filter (with a nominal pore size of a maximum of 0.22μm) at the point of use. Where used for aseptic manufacturing, confirmation of the integrity of the final sterilization gas filter should be considered as part of the batch release process.” “8.89-91 The integrity of critical sterile gas and air vent filters in the filter assembly should be verified by testing after use. The integrity of non-critical air or gas vent filters should be confirmed and recorded at appropriate intervals. For gas filtration, attention should be paid to avoiding unintended moistening or wetting of the filter or filter equipment. This can be achieved by the use of hydrophobic filters.” Post-use testing requirement has not changed HOWEVER 7.19 is specific as to the more specific requirements for critical gas filtration
- 33. 8.92 If the sterilizing filtration process has been validated as a system consisting of multiple filters to achieve the sterility for a given fluid, the filtration system is considered to be a single sterilizing unit and all filters within the system should satisfactorily pass integrity testing after use. 8.93 In a redundant filtration system (where a second filter is present as a backup but the sterilizing process is validated as only requiring one filter), post-use integrity test of the primary sterilizing filter should be performed and if demonstrated to be integral, then a post-use integrity test of the secondary filter is not necessary. However, in the event of a failure of the post-use integrity test on the primary filter, a risk assessment should be carried out to determine the acceptability of performing a post-use integrity test on the secondary (redundant) filter. 33 Examples of Key Differences in Draft Annex 1 Revision - Serial and Redundant Filtration First time serial and redundant filtration mentioned in EU GMP guidelines BUT no guidance as to when to use redundant filtration. Potential conflict with PDA redundant FIT recommendations Bioburden sampling risk
- 34. Aseptic Filler Sterile Hold Tank Vent Filter Vent Filter Bioburden Reduction Filter Sterilizing Filter Sterilizing Filter Formulation Aseptic Filler Sterile Hold Tank Vent Filter Vent Filter Bioburden Reduction Filter Sterilizing Filter Sterilizing Filter Vent Filter Sterilizing Filter Formulation Sampling point Potential Sampling Influence on Sterility in Current and in Redundant Filtration Systems 8.94 Bioburden samples should be taken from the bulk product and immediately prior to the final sterile filtration. Systems for taking samples should be designed so as not to introduce contamination.
- 35. Draft Annex 1 - Impact of Proposed Additional Sections & Key Differences Single-use Systems
- 36. “A Process that ensures that biological material does not come into contact with external environment. Closed processing enables grey space or Controlled Not Classified (CNC) processing and is sometimes referred to as being conducted in a “ballroom”.” According to ISPE: “A Process condition when the product, materials, critical components or container/closure surfaces are contained and separated from the immediate process equipment within closed/sealed process equipment. A process step (or system) in which the product and product contact surfaces are not exposed to the immediate room environment.” BioPhorum: “The key factor for industry acceptance was the Pharmaceutical Inspection Cooperation Scheme (PIC/S) determination that clean room requirements for Biomanufacturing can be relaxed/eliminated if your process is closed” ISPE Baseline Guide: “The strategy of using uncontrolled or unclassified spaces for closed piping system has always been accepted by the regulatory agencies as an acceptable risk.” 36 What is Closed Processing about? Isolating a product from the environment and vice versa
- 37. 8.116 Closed systems can be single use systems (i.e. disposable systems) and fixed systems (such as vessels with fixed pipework). Guidance in this section is equally applicable to both systems. 8.117 The use of closed systems can reduce the risk of extraneous contamination such as microbial, particulate and chemical from the adjacent environment. Closed systems should always be designed to reduce the need for, and complexity of manual interventions. 8.118 It is critical to ensure the sterility of all product contact surfaces of closed systems used for aseptic processing. The design and selection of any closed system used for aseptic processing should ensure maintenance of sterility. Connection of sterile equipment (e.g. tubing / pipework) to the sterilized product pathway after the final sterilizing filter should be designed to be connected aseptically (e.g. by intrinsic aseptic connectors or fusion systems). 37 Key References to Single-use Systems in Draft Annex 1 Revision – Closed Systems 1) Aseptic connections qualified on regular basis as part of routine sterility assurance policy 2) Supplier assessment should include the collation of data in relation to potential failure modes that may lead to a loss of system sterility.
- 38. 8.121 SUS are those technologies used in manufacture of sterile products which are used as an alternative to reusable equipment. SUS can be individual components or made up of multiple components such as bags, filters, tubing, connectors, valves, storage bottles and sensors. 8.123 Sterilization processes for SUS should be validated and shown to have no adverse impact on system performance. 8.124 Assessment of suppliers of disposable systems including sterilization is critical to the selection and use of these systems. For sterile SUS, verification of sterility should be performed as part of the supplier qualification and on receipt and use of each unit. 38 Key References to Single-use Systems in Draft Annex 1 Revision – SUS Relevance
- 39. 8.122 There are some specific risks associated with SUS which should be assessed as part of the CCS. These risks include but are not limited to: i) The interaction between the product and product contact surface (such as adsorption, or the formation of leachables and extractables). ii) The fragile nature of the system compared to fixed reusable systems. iii) The increase in the number and complexity of manual operations (including inspection and handling of the system) and connections made. iv) The complexity of the assembly. v) The performance of the pre-use integrity test for sterilizing grade filters (refer to paragraph 8.88). vi) The risk of holes and leakage. vii) The potential for compromising the system at the point of opening the outer packaging. viii. The risk of particulate contamination. 39 Key References to Single-use Systems in Draft Annex 1 Revision – SUS Relevance
- 40. 8.125 The adsorption and reactivity of the product with product contact surfaces should be evaluated under process conditions. 8.126 The extractable and leachable profile of the SUS and any impact on the quality of the product especially where the system is made from polymer-based materials should be evaluated. An assessment should be carried out for each component to evaluate the applicability of the extractable profile data. For components considered to be at high risk from leachables, including those that may absorb processed materials or those with extended material contact times, an assessment of leachable profile studies, including safety concerns, should be taken into consideration. If applying simulated processing conditions, these should accurately reflect the actual processing conditions and be based on a scientific rationale. Consider USP 665 draft guidance & BioPhorum E&L protocol. Vendors should be able to provide critical help Key References to Single-use Systems in Draft Annex 1 Revision – SUS Interaction with Product
- 41. Prerequisite to Patient Safety Evaluation Extractables & Leachables Evaluation 41
- 42. 42 8.127 SUS should be designed to maintain integrity throughout processing under the intended operational conditions. Attention to the structural integrity of the single use components is necessary where these may be exposed to more extreme conditions (e.g. freezing and thawing processes) either during routine processing or transportation. This should include certification that intrinsic aseptic connections (both heat sealed and mechanically sealed) remain integral under these conditions. 8.129 Critical manual handling operations of SUS such as assembly and connections should be subject to appropriate controls and verified during the APS. Key References to Single- use Systems in Draft Annex 1 Revision – SUS Relevance Transport studies should be included in the OQ studies Media fills are still required following same rules as used for fixed SS equipment
- 43. 43 8.128 Acceptance criteria should be established and implemented for SUS corresponding to the risks or criticality of the products and its processes. On receipt, each piece of SUS should be checked to ensure that they have been manufactured, supplied and delivered in accordance with the approved specification. A visual inspection of the outer packaging (e.g. appearance of exterior carton, product pouches), label printing, and review of attached documents (e.g. certificate of conformance and proof of sterilization) should be carried out and documented prior to use. Key References to Single-use Systems in Draft Annex 1 Revision – SUS Acceptance Criteria 1) Vendor’s sterilisation validation should be included in audit requirements and on-going performance and consistency should be confirmed regularly (e.g. quarterly dose audit reports 2) Vendor’s change notification process should be included in vendor quality agreements 3) Training is vital across all departments and should be conducted by SMEs
- 44. Regulatory framework – understand the risk and manage it Industry associations facilitate implementation of regulatory guidelines Contamination Control Strategy (CCS) is key PUPSIT is still emphasized – exceptions through risk assessment For the first time, redundant sterilizing filtration has been mentioned in EU guideline Single-use systems enable closed processing 44 Conclusion
- 45. © 2021 Merck KGaA, Darmstadt, Germany and/or its affiliates. All Rights Reserved. The vibrant M, Millipak, Durapore and Emprove are trademarks of Merck KGaA, Darmstadt, Germany or its affiliates. All other trademarks are the property of their respective owners. Detailed information on trademarks is available via publicly accessible resources. Dr. Simone Biel Senior Regulatory Consultant simone.biel@emdgroup.com Somasundaram (Som) Senior Consultant, APAC somasundaram.g@emdgroup.com Thank you for the kind attention