EU GMP Annex 1 Draft - Closed System Design Consideration with Single-Use Systems
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Biopharmaceutical manufacturing capacities have expanded dramatically which has resulted in an increased demand for single-use systems (SUS) as they have their own advantages. Although SUS are well established in the biopharmaceutical industry there is limited guidance on regulatory expectations. Please attend the webinar to learn more!
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EU GMP Annex 1 Draft - Closed System Design Consideration with Single-Use Systems
- 1. The life science business of Merck operates as MilliporeSigma in the U.S. and Canada. Closed System Design Consideration with Single-Use Systems Somasundaram (Som), Senior Technical Consultant, Asia Pacific Dr. Simone Biel, Senior Regulatory Consultant EU GMP Annex 1 Draft
- 2. Agenda 1 2 3 Regulatory Framework Contamination Control Strategy Single-Use System Integrity Approach
- 4. “Closed system. Where a drug substance or product is not exposed to the immediate room environment during manufacture.” (1) “Live organisms and spores are prevented from entering non-related areas or equipment by addressing all potential routes of cross-contamination and utilizing single use components and engineering measures such as closed systems.” (1) “Closed or contained equipment should be used whenever appropriate.” (2) “Concurrent production of two different ATMPs/batches in the same area is not acceptable. However, closed and contained systems may be used to separate activities…” (3) The use of closed systems [i.e. single use systems] can reduce the risk of extraneous contamination such as microbial, particulate and chemical from the adjacent environment (4) (1) EudraLex Vol 4, Annex 2: Manufacture of Biological active substances and Medicinal Products for Human Use (2) EudraLex Vol 4, Part II: Basic Requirements for Active Substances used as Starting Materials (3) EudraLex Vol 4, Part IV: GMP Guiedelines specific to Advanced Therapy Medicinal Products (4) EudraLex Vol 4, Annex 1 draft (2020): Manufacture of Sterile Products Single-Use Systems to Reduce Cross-Contamination Closed System – Some Quotes EU GMP Annex 1 Draft - Closed System Design Consideration with Single-use Systems
- 5. Contamination Risks Throughout the Process Manufacturing process can affect patient outcomes EU GMP Annex 1 Draft - Closed System Design Consideration with Single-use Systems
- 6. Closed Systems – Benefits of Single-Use Technology Compared to stainless-steel manufacturing Benefits of single-use technologies Speed to market Ease of use Increased productivity • Plug and play • Sterile connections • Reduced room classification stringency • Decreased risk of product cross- contamination • Elimination of SIP/CIP and decontamination process steps • Reduced capital investment in facility and equipment • Reduced time to get facility up and running EU GMP Annex 1 Draft - Closed System Design Consideration with Single-use Systems
- 7. Who is doing what? Regulatory and Industry Expectations EU GMP Annex 1 Draft - Closed System Design Consideration with Single-use Systems 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
- 8. Ongoing consultation of new draft – global approach 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. EU GMP Annex 1 Draft - Closed System Design Consideration with Single-use Systems
- 9. Prevent any contamination in the final product EU GMP Annex 1 draft – Scope Scope “…to provide guidance for the manufacture of sterile products. However, some of the principles and guidance, such as contamination control strategy, design of premises, cleanroom classification, qualification, monitoring and personnel 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 and reduction of microbial, particulate and pyrogen contamination is considered important.” Annex 1 draft, 2020 https://ec.europa.eu/health/sites/health/files/files/gmp/2020_annex1ps_sterile_medicinal_products_en.pdf EU GMP Annex 1 Draft - Closed System Design Consideration with Single-use Systems
- 11. • Why & What is Contamination Control Strategy • Understand the impact of bioburden excursions • Recognize the sources of bioburden • Develop strategies to mitigate risk Contamination control strategy (CCS) EU GMP Annex 1 Draft - Closed System Design Consideration with Single-use Systems
- 12. CCS – Definition & Regulatory Drivers “A planned set of controls for microorganisms, pyrogens and particulates, derived from current product and process understanding that assures process performance and product quality”. The controls can include parameters and attributes related to active substance, excipient and drug product materials and components, facility and equipment operating conditions, in-process controls, finished product specifications, and the associated methods and frequency of monitoring and control. EU GMP Annex 1 Draft 2020: ‘A contamination control strategy should be implemented across the facility in order to assess the effectiveness of all the control and monitoring measures employed’ CCS is mentioned 44 times in the update PIC/S GMP Part I, 2021: ‘Cross-contamination should be prevented for all products by appropriate design and operation of manufacturing facilities. The measures to prevent cross contamination should be commensurate with the risks. Quality Risk Management principles should be used to assess and control the risks’ ‘5.10 At every stage of processing, materials and products should be protected from microbial and other contamination’ EU GMP Annex 1 Draft - Closed System Design Consideration with Single-use Systems
- 13. Contamination Control Strategy: Holistic program that encompasses concepts within the context of the entire manufacturing facility and process Facility Design: Designed according to GMP Regulations / Guidelines, Best practice and process requirements Personnel: Gowning regime with personnel monitoring program, suitable limits and action plan, training and culture Cleaning and Disinfection/Sterilisation: Consistent removal of soiling and microbial load deactivation Environmental Monitoring: Monitor viable and non- viable, suitable limits and action plan Process Simulation: End to end testing including intervention assessment and worse case stressing Process Design: Process controls including GMP and GEP to ensure product is microbial/pyrogen, chemical, non-viable and cross-contamination free. What is a Contamination Control Strategy Process Design Process Simulation Environmental Monitoring Cleaning & Disinfection/Sterlisation Personnel Facility Design Contamination Control Strategy EU GMP Annex 1 Draft - Closed System Design Consideration with Single-use Systems
- 15. 30 Percent 1- 6 Months 1-14 Million Euro Percent of process deviations caused by contamination* Length of time to complete an investigation Operations cost *Sources Langer 2013, Wiebe 2014 Biologics in-process contamination EU GMP Annex 1 Draft - Closed System Design Consideration with Single-use Systems
- 16. 30 Percent 1- 6 Months 1-14 Million Euro *Sources Langer 2013, Wiebe 2014 Biologics in-process contamination Impact Productivity losses Material replacement costs Batch loss Interruption of product supply Delay in clinical development EU GMP Annex 1 Draft - Closed System Design Consideration with Single-use Systems
- 17. Microbial Byproducts Endotoxin Exotoxin Lipopeptides Flagellin DNA Extracellular proteases Bioburden Bacteria Fungi Mycoplasma Virus TSE Agents Why : Bioburden and their byproducts Scope EU GMP Annex 1 Draft - Closed System Design Consideration with Single-use Systems
- 18. Facility & Environment Equipment Processes Materials Utilities Personnel Each source contributes to the process bioburden profile Sources of bioburden Staphylococcus Bacillus Non-fermenting Gram Negative rods Aspergillus Source: Public domain CDC/ Robert Simmons EU GMP Annex 1 Draft - Closed System Design Consideration with Single-use Systems
- 19. • Many routes for microbial ingress • Bioburden excursions are often the result of − Improper cleaning, storage, or sanitization − Suboptimal system design − Aseptic connections − Sampling − Lapses in aseptic technique Intensive risk assessments can prevent many of these contaminations or excursions Key Points Sources of bioburden EU GMP Annex 1 Draft - Closed System Design Consideration with Single-use Systems
- 20. Downstream Risk profile & control strategies differ throughout the process Secondary Clarification Chromatography Protein A Final Filling Final Sterile Filtration Concentration & Formulation Bulk Storage and Transport Viral Inactivation Chromatography CEX Virus Filtration Clearance Ultrafiltration / Diafiltration Bioreactor Primary Clarification MCB WCB Seed Train Raw Materials Filtration Bioburden Reduction Bioburden Reduction Chromatography AEX Bioburden Reduction Bioburden Reduction Final Fill Risk Areas Upstream Downstream EU GMP Annex 1 Draft - Closed System Design Consideration with Single-use Systems
- 21. The risk profile varies from upstream to final fill Risk Hammock Upstream Downstream Finish and Fill Operations Risk High Low Aseptic Aseptic Bioburden Controlled “The level of effort, formality and documentation of the quality risk management process should align with the level of risk” (ICH Q9A) Shifting “the QRM focus from reactive to proactive will enable continual improvement to become a key aspect of the PQS. Revision of ICH Q9 is of strategic importance. ICH Q(R1) Concept Paper, 2020 EU GMP Annex 1 Draft - Closed System Design Consideration with Single-use Systems
- 22. Assess Mitigate Monitor Risk Mitigation Strategies EU GMP Annex 1 Draft - Closed System Design Consideration with Single-use Systems
- 23. Assess Risks Key Points ▪ Characterize the microbial profile of the process ▪ Utilize a combination of assessment tools ▪ A cross-functional team is crucial to the process ▪ Your Bioburden risk mitigation strategy should address ▪ Patient safety ▪ Drug supply ▪ Business risk 0 EU GMP Annex 1 Draft - Closed System Design Consideration with Single-use Systems
- 24. Prevent Contamination by Containment (Risk Mitigation) Implement Single Use Systems and Closed Sampling Eliminate bioburden contribution Prevent microbial ingress Minimize process validation Mitigate EU GMP Annex 1 Draft - Closed System Design Consideration with Single-use Systems
- 25. Downstream Monitoring What do I test for? Where? Why? Chromatography Protein A Bulk Storage and Transport Viral Inactivation Chromatography CEX Virus Filtration Clearance Ultrafiltration / Diafiltration Bioburden Reduction Bioburden Reduction Chromatography AEX Bioburden Reduction Bioburden Reduction Bioburden Virus Mycoplasma Endotoxin V M B E B E B E B E V E V E B E B E M Monitor EU GMP Annex 1 Draft - Closed System Design Consideration with Single-use Systems
- 26. Case studies
- 27. Case Study Bioburden/Endotoxin excursions in the Protein A Pool Chrom Protein A Bulk Storage and Transport Viral Inactivation Chrom CEX Virus Filtration Clearance Ultrafiltration Diafiltration Bioburden Reduction Bioburden Reduction Chrom AEX Bioburden Reduction Bioburden Reduction Situation • Spore-forming bioburden alert-level excursions in the Protein A pool over several campaigns Root Cause • Failure to recognize a trend in the pattern of excursions • Sanitization solution was not sporicidal • Sub-optimal sanitization process Corrective and Preventative Actions • Scale down studies with a new sanitizer and optimization of sanitization conditions • Process scale verification EU GMP Annex 1 Draft - Closed System Design Consideration with Single-use Systems
- 28. Case Study Bioburden action-level excursions of in the UF/DF step Chrom Protein A Bulk Storage and Transport Viral Inactivation Chrom CEX Virus Filtration Clearance Ultrafiltration Diafiltration Bioburden Reduction Bioburden Reduction Chrom AEX Bioburden Reduction Bioburden Reduction Situation • Bioburden and endotoxin exceeded action levels in multiple batches • Intensive investigation of the process and support areas Root Cause • Bioburden formation in the TFF cassettes due to inadequate cleaning and storage processes Corrective and Preventative Actions • Improve cleaning and storage processes • Sterilization or sanitization of buffer tanks • Assessment of the water for injection (WFI) system and transfer lines • Introduction of bioburden reducing filters • Validation of hold times and storage conditions • Revision of bioburden limits based on process capability Buffer, Sanitizer, and Storage Solutions Operations WFI Operation Suvarna K. et. al. “Case Studies of Microbial Contamination in Biologic Product”, American Pharmaceutical Review 14(1) January/February 2011. EU GMP Annex 1 Draft - Closed System Design Consideration with Single-use Systems
- 29. Case Study Sporadic bioburden action-level excursions Chrom Protein A Bulk Storage and Transport Viral Inactivation Chrom CEX Virus Filtration Clearance Ultrafiltration Diafiltration Bioburden Reduction Bioburden Reduction Chrom AEX Bioburden Reduction Bioburden Reduction Situation • Sporadic mixed bioburden excursions at multiple points in the downstream process Root Cause • Aseptic connections of equipment and sampling devices Corrective and Preventative Actions • Short term: • Retrained operators in aseptic techniques • Long term: • Reduced the number of aseptic connections • Implemented sterile to sterile connectors and steam to sterile connectors. • Introduced a facility-wide sterile sampling system EU GMP Annex 1 Draft - Closed System Design Consideration with Single-use Systems
- 30. Case study Bulk solution contamination with Bacillus species Chrom Protein A Bulk Storage and Transport Viral Inactivation Chrom CEX Virus Filtration Clearance Ultrafiltration Diafiltration Bioburden Reduction Bioburden Reduction Chrom AEX Bioburden Reduction Bioburden Reduction Situation • Prefiltration bioburden load was 20 x the specification • Bacillus species suggested a steam-in-place issue Root Cause • Equipment design: improper pipe slope resulted in cold spots that were insufficiently sterilized Corrective and Preventative Actions • Discard (scrap) the batch • Redesign piping • Requalify SIP (steam-in-place) cycle • New processes will use single-use storage systems EU GMP Annex 1 Draft - Closed System Design Consideration with Single-use Systems
- 32. Formulation Filtration Filling Connect Connect Closed processing (maintaining sterility) Entire process can be designed with single-use assemblies Focus: Sterile Production EU GMP Annex 1 Draft - Closed System Design Consideration with Single-use Systems
- 33. Lots of components, connections, assemblies Your Single-Use System Process EU GMP Annex 1 Draft - Closed System Design Consideration with Single-use Systems
- 34. Critical steps are transferred from end-user to supplier SUT in Manufacturing – Considerations 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 Some guidance − 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 EU GMP Annex 1 Draft - Closed System Design Consideration with Single-use Systems
- 35. A Collaboration between Supplier and End User Integrity Assurance Components Bag and assembly manufacture Packaging and shipping Receipt and unpacking Pre-use stage Post-use stage Tear resistant and superior bond strength bag film Sterile connector integrity test Quality by design Automated bag bonding Visual inspection Integrity/leak test Define packaging instructions Shelf life validation Shipping validation Best handling practices Visual inspection to confirm the design Best practices for installation Point of use integrity/leak test Visual verification Supplier End-user EU GMP Annex 1 Draft - Closed System Design Consideration with Single-use Systems
- 36. Do you know what your supplier does? Manufacturing and Control Bag manufacturing Automation Validated process In-process leak test Assembly Standard operating procedures Operator training In-process controls Release testing Visual inspection Final product leak testing Fluid path water extract testing (particles, endotoxin) Leak/integrity testing Various methods depending on application and sensitivity EU GMP Annex 1 Draft - Closed System Design Consideration with Single-use Systems
- 37. Leak Test Integrity Test Helium Integrity Test Leak Test vs Integrity Test Release Test EU GMP Annex 1 Draft - Closed System Design Consideration with Single-use Systems Detects defects of a known size that have a correlation to a known parameter using a specific test methodology such as aerosolized or liquid bacterial ingress. Detects gross leaks in a system Decreasing Defect Detection Size Limit Increasing Level of Risk-Reduction System Volume Approximate Detection Limit Tubing Assemblies 50 µm 1 – 9 L 150 µm 10 – 999 L 1000 µm >1,000 L 2000 µm System Volume Validated Detection Limit Tubing Assemblies 20 µm Up to 50 L 20 µm System Volume Validated Detection Limit Tubing Assemblies 2 µm Up to 50L 2 µm
- 38. Aerosol Challenge Test Bags with known defect sizes (filled with TSB) Microbial aerosol concentration 106 cfu/ml 60 mins Correlation between leak size and bacterial ingress Single-Use System Integrity Test Incubation 30-35 °C 14 days Result Growth present in bags with defects 12.65 µm or greater BPSA Technical Guide, Design, Control, and Monitoring of Single-use Systems for Integrity Assurance, 2017 EU GMP Annex 1 Draft - Closed System Design Consideration with Single-use Systems
- 39. ISO 11137, Sterilization of Health Care Products — Radiation Sterilization Validation Irradiation Process − Development, validation, and routine control of sterilization process (VDmax) − Establishing sterilization dose with SAL <10-6 − Guidance on dosimetric measurement of radiation Quarterly dose audits to substantiate the sterilization dose on an on-going basis. − Demonstrate clean environment by testing bioburden of reference assemblies pre-gamma − Sterility test after low irradiation dose Review of historical data over the last decade − verifies robustness of sterility validation EU GMP Annex 1 Draft - Closed System Design Consideration with Single-use Systems
- 40. Ensure integrity during shipment Packaging Design Protect rigid components Qualified packaging material (shelf life, low particle load, outgassing) Ensure that easy unpacking is possible Vacuum in packaging bags to avoid movement of components EU GMP Annex 1 Draft - Closed System Design Consideration with Single-use Systems
- 41. Ensure Integrity during shipment Transport Validation Manufacturing Visual inspection Leak test (assembly) assembly packaged and boxed per packaging SOP Gamma irradiation (25-40kGy) ISTA 2A treatment 1st Vibration Test Impact Test (drop Test) 2nd Vibration Test Bubble Emission testing of vacuum sealed packaging bags Visual inspection Leak test (assembly) ISTA 2A Reference Assembly Irradiation Testing EU GMP Annex 1 Draft - Closed System Design Consideration with Single-use Systems
- 42. Proper installation of SUS is key to keep integrity New Handling Procedures for End-User Outside Isolator Inside Isolator EU GMP Annex 1 Draft - Closed System Design Consideration with Single-use Systems
- 43. Combined filtration and filling set Dosing pump inside isolator Dosing pump outside isolator Sterile connection device required There is no common or standard approach Final Filling Single-Use Set - Examples Grade C Grade A Bulk Product Peristaltic Pump Sterile Filter Header Bag Peristaltic Pump Filling Needle Grade C Grade A Bulk Product Peristaltic Pump Sterile Filter Header Bag Peristaltic Pump Filling Needle Sterile filtration inside isolator Transfer of entire SUS via Getinge DPTE® Beta Bag EU GMP Annex 1 Draft - Closed System Design Consideration with Single-use Systems
- 44. 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). 8.119 Appropriate measures should be in place to ensure the integrity of components used in aseptic connections. The means by which this is achieved should be determined and captured in the CCS. Appropriate system integrity tests should be considered when there is a risk of compromising product sterility. Supplier assessment should include the collation of data in relation to potential failure modes that may lead to a loss of system sterility. 8.120 The background in which closed systems are located should be based on their design and the processes undertaken. For aseptic processing and where there are any risks that system integrity may be compromised, the system should be located in a Grade A zone. If the system can be shown to remain integral at every usage (e.g. via pressure testing and/or monitoring) then a lower classified area may be used. EU GMP Annex 1 Draft - Closed System Design Consideration with Single-use Systems “Determined and captured in the Cross-Contamination Strategy” Annex 1 Draft and Closed Systems
- 45. Reduce complexity and keep flexibility of the SUS Sterile Connection Device Handling Quick and easy Avoid operator mistakes Design Robust and consistent performance 100% air-integrity tested in manufacturing Validation Aerosolized microbial challenge test Media fill Brevundimonas diminuta aerosol EU GMP Annex 1 Draft - Closed System Design Consideration with Single-use Systems
- 46. SUS enable your process closed! Microbial & Particulate contamination present a real & underappreciated risk Testing is just one aspect of integrity assurance Include your SUS supplier in your cross-contamination/contamination control strategy EU GMP Annex 1 Draft - Closed System Design Consideration with Single-use Systems Reduce complexity with the right SUS design to enable easy operator handling Impact of Microbial contamination/excursions can be highly significant
- 47. Dr. Simone Biel © 2022 Merck KGaA, Darmstadt, Germany and/or its affiliates. All Rights Reserved. Merck, the vibrant M, and Millipore 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. Senior Regulatory Consultant Germany simone.biel@merckgroup.com Somasundaram (Som) G, Senior Technical Consultant Singapore somasundaram.g@merckgroup.com