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Quality by Design Principles Applied to Sterilizing Filtration by Michael Payne
The document discusses the application of Quality by Design (QbD) principles to sterilizing filtration in the biopharmaceutical industry, emphasizing its importance for ensuring drug product quality and patient safety. It outlines concepts, regulatory guidance, and key aspects related to sterilizing filter qualification, as well as iterative workflows and design spaces necessary for efficient filtration processes. The presentation highlights the necessity of integrating QbD throughout the product lifecycle to achieve compliance with evolving regulatory requirements.
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Quality by Design Principles Applied to Sterilizing Filtration by Michael Payne
- 1. The life sciencebusiness of Merck KGaA, Darmstadt, Germany operates as MilliporeSigma in the U.S. and Canada. Quality by Design Principles Applied to Sterilizing Filtration Michael Payne Principal Biosafety Technical Consultant November 2020
- 2. The life sciencebusiness of Merck KGaA, Darmstadt, Germany operates as MilliporeSigma in the U.S. and Canada
- 3. Disclaimer: Views expressed inthis talk constitute my professional opinion. Quality by Design Principles Applied to Sterilizing Filtration | November 2020
- 4. Quality by DesignPrinciples Applied to Sterilizing Filtration | November 2020 Steve Jobs Image via Wikimedia Commons “Design is a funny word. Some people think design means how it looks. But of course, if you dig deeper, it’s really how it works.” 4
- 5. Agenda 1 Concepts, Terminology& Target Focus 2 Regulatory Guidance 3 Example of Critical Aspects & Requirements for Sterilizing Filtration 4 Product Lifecycle Comments
- 6. Quality by Designin the biopharmaceutical industry. RA = risk assessment; PC = process characterisation Presentation Objectives & Scope ✓ Provide generic information ✓ Review Quality by Design (QbD) ✓ Focus on sterilizing filtration for aseptic filling ✓ Discuss current regulatory documents on sterilizing filtration ✓ Show how to gather information for a sterilizing filtration design space ❖Will not focus on Quality Risk Management ❖Will not focus on vendor / supplier product QbD 6
- 7. Poll Question #1 Quality byDesign Principles Applied to Sterilizing Filtration | November 2020
- 8. ✓ Must demonstratethat patient is not at risk from drug product ✓ Must demonstrate drug product quality, safety, identity, purity, & efficacy Requirements for Final Filling Operations Downstream of Purification and Final Filling considered greatest patient risk 8 Quality by Design Principles Applied to Sterilizing Filtration | November 2020
- 9. Sterile Medicinal Productsby Aseptic Processing Drug Product Sterilization Process Closure Sterilization Process Sterile Closure Excipient Sterilization Process Sterile Excipient Aseptic Processing Sterile Drug Product Container Sterilization Process Sterile Container Sterile Final Product Multiple sterilization process conditions each optimized for individual component type Aseptic processing is then the focus of optimizing and troubleshooting9
- 10. Production Formulation /Filling Suite & its Filters Stopper Washer Dryer Autoclave WFI CIP Freeze dryer Formulation Bioburden & Sterile Filtration Sterile Filtration Aseptic Filler Prefilter Bioburden Filter WFI API Excipient Sterile Hold Tank Vial Washing Sterilizing Filter Depyrogenation Clean Room Utility Gas Filters Gassing Filter Blanket / Transfer Gas Filter IT gas inlet filter IT gas inlet filter Vent filter Vent filter Vent filter Vent filter Drying filter Washing filters Vent filter Protection filter Protection filter Circled filters have a critical duty – require full qualification under defined range of conditions Quality by Design Principles Applied to Sterilizing Filtration | November 202010
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- 12. Quality cannot betested into the product - should be built-in by good quality systems & good manufacturing practices Starting Points We should have a systematic approach to • Product specifications and design • Process design & control • Process performance & continuous improvement • Knowledge retention and use • We should have (or have access to) • Drug product/substance and drug manufacturing process knowledge • Scientific understanding of in the establishment of design, specifications and manufacturing • Company mission that patient safety & quality are paramount • Understanding of quality risk management (QRM) & QbD 12
- 13. What do weknow about Quality by Design (QbD)? x QbD isn’t “new” (first draft 2004) x QbD does not have to be focused on Design of Experiment (DoE) ✓ Quality system manages a product’s lifecycle ✓ Intended to increase process & product understanding, decrease patient risk ✓ Multidisciplinary & Multidepartmental exercise ✓ Applicable to whole manufacturing process OR a unit operation (one process inside another process) ✓ Defines “opportunities for continuous improvement and real-time release” ✓ Expected by regulatory agencies ✓ Defines “'design space' and ‘what is and is not a change’” 13
- 14. Target Target Range Proven AcceptableRange Observation ObservationDiscrepancy Discrepancy Alert Limit Action Limit QbD Concept – Multidimensional Design Space (ICH Q8) Knowledge space (information of the product / process / activity outside our company) Design space (information on the product, process, activity inside our company) • Demonstrated range of all process parameters (CPPs or KPPs) where process meets the product’s Critical Quality Attributes (CQAs) • Moving out of the design space is a change and may require post-approval change Control space (how we control the product, process, activity inside our company) 14 Quality by Design Principles Applied to Sterilizing Filtration | November 2020
- 15. Example of IterativeQbD Workflow & Systemic Approach From Quality by Design I Biopharmaceuticals Anurag S Rathore & Helen Winkle, Nature Biotechnology 27, 26 - 34 (2009) 15 Quality by Design Principles Applied to Sterilizing Filtration | November 2020
- 16. QbD Concepts -Quality Target Product Profile (QTPP) ”prospective summary of the quality characteristics of a drug product that ideally will be achieved to ensure the desired quality, taking into account safety and efficacy.” (ICHQ8) What is the drug and what must it do to be safe, effective, (convenient)? Intended use, dosage form, strengths, closure system (stability), route of administration, delivery systems, mechanism of action Concept brief (clinical, drug metabolism, pharmacokinetics, safety & marketing) to set product specifications Should have a target value or an acceptable range Quality attribute is critical when it has an impact on the patient Strength/Efficacy – Effect of wrong dose? Purity/Safety – Effect of potentially harmful impurities? Quality – degradants 16 Quality by Design Principles Applied to Sterilizing Filtration | November 2020
- 17. Example of QualityTarget Product Profile (QTPP) - Mab 17 Source: CMC Biotech Working Group, (October 2009), A-Mab: A Case Study in Bioprocess Development, V2.1 Provides a metric when reviewing the filtration processes in all clinical phases Quality by Design Principles Applied to Sterilizing Filtration | November 2020
- 18. Raw material andcomponent attributes & process parameters linked to output product CQAs From a Process Viewpoint Courtesy of Engineers Journal July 2014 Source: How QbD and the FDA Process Validation Guidance Affect Product Development and Operations, Part 1, Peter H. Calcott, (November 2011), Bioprocess International (http://www.bioprocessintl.com/analytical/downstream-validation/how-qbd-and-the-fda-process-validation-guidance-affect-product-development-and-operations-part-1-323457/ & Process parameters 18 Quality by Design Principles Applied to Sterilizing Filtration | November 2020
- 19. Poll Question #2 Quality by DesignPrinciples Applied to Sterilizing Filtration | November 2020
- 20. EMA / PICS/ WHO Regulatory Guidance
- 21. ICH Q10 andChange Management: Enabling Quality Improvement Dr. Bernadette Doyle, GlaxoSmithKline US FDA Use ICH Documents as Guidances Focus on Product Lifecycle – Development to Removal from Market Linkage of Q8 -> Q12 Joseph C. Famulare, “Workshop on Implementation of ICH Q8/Q9/Q10 and Other Quality Guidelines” Beijing, China, 3-5 December 2008 Add ICH Q11 (Development and Manufacture of Drug Substances), ICH Q12 Lifecycle Management 21 Quality by Design Principles Applied to Sterilizing Filtration | November 2020
- 22. Traditional style sterilefiltration system with bioburden reduction filter and EMA/PICS/WHO compliant 22 Aseptic Filler Sterile Hold Tank Vent FilterVent Filter Sterilizing Filter Bioburden Reduction Filter Sterilizing Filter Compounding Formulation “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.” (CCS = Contamination Control Strategy) Annex 1 July 2020 Draft Quality by Design Principles Applied to Sterilizing Filtration | November 2020
- 23. EMA Guideline onmanufacture of the finished dosage form – Effective January 2018 EMA/CHMP/QWP/245074/2015 Table of contents 1. Introduction (background) 2. Scope 3. Legal basis 4. Manufacture − 4.1. Manufacturer(s) − 4.2. Batch Formula − 4.3. Description of Manufacturing Process and Process Controls − 4.4. Controls of Critical Steps and Intermediates − 4.5. Process Validation and/or Evaluation Definitions Control Strategy: Critical Process Parameter (CPP): Critical Quality Attribute (CQA): Design Space Hold Time: − Real Time Release Testing: References Annex 23
- 24. Guideline on processvalidation for finished products - information and data to be provided in regulatory submissions – Effective November 2016 - EMA/CHMP/CVMP/QWP/BWP/70278/2012-Rev1,Corr.1 Table of contents 1. Introduction (background) 2. Scope 3. Legal basis 4. General considerations 5. Process validation 5.1. Traditional process validation 5.2. Continuous process verification 5.3. Hybrid approach 5.4. Design space verification 6. Scale-up 7. Post approval change control 8. Standard vs. non-standard methods of manufacture Definitions References Annex I: Process validation scheme Annex II: Standard/non-standard processes 24 Target Target Range Proven Acceptable Range Observation ObservationDiscrepancy Discrepancy Alert Limit Action Limit
- 25. EMA Guideline onthe sterilisation of the medicinal product, active substance, excipient and primary container - Effective 1 October 2019 - EMA/CHMP/CVMP/QWP/850374/2015 Table of contents 1. Introduction (background) 2. Scope 3. Legal basis 4. General requirements − 4.1. Requirements for the manufacture of sterile medicinal products and sterile components − 4.1.1. Steam sterilisation − 4.1.2. Dry heat sterilisation − 4.1.3. Ionization radiation sterilisation − 4.1.4. Gas sterilisation − 4.1.5. Sterile filtration − 4.1.6. Aseptic processing − 4.2. Good manufacturing practice for sterile active substances, sterile excipients and sterile containers − 4.2.1. Active substances − 4.2.2. Excipients − 4.2.3. Containers 4.3. Selection of sterilisation method 5. Decision trees 6. Definitions 7. References 25 Key Document Especially when used with PICS/WHO Annex 1 (Manufacture of Sterile Medicinal Product (currently under 3rd review)
- 26. EMA Guideline onthe sterilisation of the medicinal product, active substance, excipient and primary container 4.1.5. Sterile filtration This table mirrors many aspects of the US FDA Compliance Guide for Inspection of Sterile Drug Product Facilities and ISO 13408-2 A CLOSE alignment across major regulatory agencies and organisations. Regulator highlights both critical (i.e sterilizing) and moderately critical (i.e. bioburden reduction) filter AND shows some of what should be qualified and what fluid should be used 26 Quality by Design Principles Applied to Sterilizing Filtration | November 2020
- 27. DRAFT Annex 1Manufacture of Sterile Medicinal Products (Document Revised July 2020 – 3rd revision in 3 years) Filtration of medicinal products which cannot be sterilized in their final container “8.81 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 products, documented and justified.” “8.87 iii. Filtration process conditions including: • Fluid pre-filtration holding time and effect on bioburden. • Filter conditioning, with fluid if necessary. • Maximum filtration time/total time filter is in contact with fluid. • Maximum operating pressure. • Flow rate. • Maximum filtration volume. • Temperature. • The time taken to filter a known volume of bulk solution and the pressure difference to be used across the filter” 27 Alignment with QbD Approach Note the process parameters referenced Quality by Design Principles Applied to Sterilizing Filtration | November 2020
- 28. Some Key DesignSpace Points in EMEA Documents Design Space Defined ➢ The multidimensional combination and interaction of input variables (e.g., material attributes) and process parameters that have been demonstrated to provide assurance of quality. ➢ Working within the design space is not considered as a change. ➢ A design space will normally be developed at laboratory or pilot scale. ➢ During scale-up the commercial process is generally conducted and validated in a specific area of the design space, defined as the target interval or Normal Operating Range (NOR). ➢ Movement out of the design space is considered to be a change and would normally initiate a regulatory post approval change process. ➢ Design space is proposed by the applicant, supported by data and is subject to regulatory assessment and approval 28
- 29. Poll Question #3 Quality by DesignPrinciples Applied to Sterilizing Filtration | November 2020
- 30. Example of Critical Aspects &Requirements for Sterilizing Filtration
- 31. Objectives of SterilizingFilter Discussion • Identification of characteristics that could affect filter performance and hence patient safety • Review characteristics that should be determined in drug product development • Be a reminder of some characteristics that can be compromised during drug product lifecycle • Not to expand the design space but to define the design space (early stage clinicals have a much smaller design space) 31 Quality by Design Principles Applied to Sterilizing Filtration | November 2020
- 32. 8 Elements ofSterilizing Filter Qualification Should represent “worst case” process conditions, process fluid, & filter characteristics all of which come from the qualified design space Integrity Testing Compatibility Sterilization Extractables & Leachables Duty Binding Retention QS, VMP & Documentation Prove the filter meets all performance & duty requirements within product & process conditions. Prove the sterilization method is effective and does not compromise the filter. Prove the filter does not unacceptably remove stream components. Prove the stream does not adversely impact the filter duty or process stream Identify, quantify, and assess impact of compounds that are added to process product stream. Prove the filter removes bacteria from the stream compliant with ASTM and relevant regulations Prove the filter’s bacterial retention capabilities with a non- destructive test. 32 Quality by Design Principles Applied to Sterilizing Filtration | November 2020
- 33. Assumption is thatdrug product production is under GMP with robust QS Quality System ICH Quality Working Group Training. How ICH Q8, Q9, Q10 guidelines are working together throughout the product lifecycle. Nov 2010. Product Discontinuation Commercial Manufacturing Technology Transfer Pharmaceutical Development Pharmaceutical Quality System Investigational products GMP Management Responsibilities Knowledge Management Quality Risk Management Process Performance & Product Quality Monitoring System Corrective Action / Preventive Action (CA/PA) System Change Management System Management Review Enablers PQS elements Quality by Design Principles Applied to Sterilizing Filtration | November 2020
- 34. Some Considerations inSterilizing Filtration for Early Phase Clinical Trials • Collect data as per xGMP • Design space and control space are similar or same • QbD objective is to collect data and expand design space without affecting QTPP • Critical equipment should be qualified • Process conditions are sometimes based on convenience e.g. available equipment but this may not represent conditions used in later process runs or clinical phases • Sterilization processes are as per compendial requirements • Filtration process parameters should be collected • Time, pressure, flowrate, temperature, etc. (as per Annex 1) • Keep the end in mind – phase 3 & manufacturing • Gain knowledge of larger scale filling operating conditions during phase 2 Quality by Design Principles Applied to Sterilizing Filtration | November 2020 Image https://blogs.biomedcentral.com/on-medicine/2018/05/18/clinical-trials-and-trial-registration/ 34
- 35. Division of theElements of Sterilizing Filter Qualification Part 1 Phase 1-2a – Development or Prior to Small Scale Tech Transfer Integrity Testing Compatibility Sterilization Extractables & Leachables Duty Binding Retention QS, VMP & Documentation 35 Quality by Design Principles Applied to Sterilizing Filtration | November 2020
- 36. Duplicate or Triplicatetrials using small equipment provides; Filter integrity testing (FIT) information − Pre-use water bubble point − Post-use product bubble point − Water volume to flush to get pre-use value Filter loading / capacity (L/m2) determines area − Graph Volume/time vs Time − Filtrate flowrate Adsorption studies (active/excipient/preservative etc.) − Take samples throughout filtration − Graph concentration vs loading − Determine volume for saturation − Mimic filling process – e.g. hold / header tanks / bags Compatibility − Visual inspection / Weight change Using small (~33-50mm) disk filter flow decay equipment. Small Scale Membrane Trials in Process Development 36 Confirmed Outputs ✓ Filter MOC ✓ Filter Area ✓ Likely FIT result ✓ Flush volume ✓ Flowrate/Area (flux) ✓ Time for volume Quality by Design Principles Applied to Sterilizing Filtration | November 2020
- 37. Collected during earlyphase using calculated area, flushing conditions Filter Duty & Compatibility Data Confirmation Scale-up Parameters to Hold Constant ➢ Loading (i.e. V/A), Flux (Q/A) Process Parameters ➢ Feed fluid pretreatment ➢ Temperature, differential pressure, flowrate, volume ➢ Surface area ➢ Exposure time Attributes ➢ Sacrifice volume before first container in batch ➢ Process yield ➢ Visual filter inspection before and after filtration 37 Confirmed Outputs ✓ Product preparation ✓ Filter preparation ✓ Filter area ✓ Flush / Discard volume ✓ Likely FIT result Quality by Design Principles Applied to Sterilizing Filtration | November 2020
- 38. Applies to devices/ elements used once OR complete single-use assemblies What Single-use System is Specified 38 Ensure design is right – iterative process Confirm effect of SUS on product Experience with SUS process and handling Key Scaling Parameters - Keep the same ✓ MOC ✓ Sterilization method ✓ Product contact time ✓ Temperature – holding, storage, processing ✓ Volume / Contact Area Complete Systems – example has 31 different components – need vendor discussion on extractables data, compatibility, etc. Quality by Design Principles Applied to Sterilizing Filtration | November 2020 Single-use devices
- 39. -Use physical measurementsand biological indicators where appropriate Filter / System Sterilization Parameters - Use validated system sterilization (autoclave / SIP / gamma) - Use sterilizing filter documentation (e.g. CoQ, Validation Guide) - Establish filter / system preparation (dry or wet) - Conduct environmental monitoring Attributes Passed filter integrity test result Visual filter inspection post SIP /Autoclave SIP or Autoclave chart Required F0 Quarterly gamma dose audit report from vendor 39 C C B C R B R R C RT L FLT FC TC FB R Quality by Design Principles Applied to Sterilizing Filtration | November 2020 User History Time Temperature / Pressure Normal Operating Space Moist heat sterilization Gamma sterilization
- 40. Division of theElements of Sterilizing Filter Qualification Part 2 – Phase 2b / Phase 3 or Part of Production Tech Transfer Discussion / Confirmation Integrity Testing Compatibility Sterilization Extractables & Leachables Duty Binding Retention QS, VMP & Documentation 40 Quality by Design Principles Applied to Sterilizing Filtration | November 2020 All circled items need to be done using confirmed process conditions and process fluids
- 41. Trending pre- andpost-use results and deviations Process Filter Integrity Confirmation Parameters - wetting fluid (water, buffer, product, excipient, etc.) - wetting conditions (temperature, flowrate, volume, time, inlet/differential pressure) - test gas (type, temperature) - Post-use flushing volume Attributes Values before and/or after filtration Test result incl. trending Number of attempts to pass 41 Quality by Design Principles Applied to Sterilizing Filtration | November 2020
- 42. -Use physical measurementsand biological indicators where appropriate -Checking batch records and SOPs Process Filter Sterilization Parameters - sterilization conditions (autoclave / SIP / gamma) - Filter preparation (dry or wet) - Sterilization conditions; temperature, time, inlet/differential pressure - Whole cycle data is vital Attributes Passed pre & post-use integrity test result Visual filter inspection after SIP SIP or Autoclave chart Required F0 Quarterly gamma dose audit report from vendor User History Time Temperature / Pressure Normal Operating Space 42
- 43. Definitions from PDATechnical Report #26 Extractables & Leachables (E&L) Fluid Contact Surface “Any chemical component that is removed from a material by the application of an artificial or exaggerated force (e.g., solvent, temperature or time).” Determined under “worst-case” conditions following a Model Stream approach (e.g. BPOG) Extractables “A chemical component that migrates from a contact surface into a drug product or process fluid during storage or normal use conditions.” Determined with product under normal processing/storage conditions. • Solvent stream approach to identify the plastic compounds. • Product testing (Interference between product and analytical method has to be evaluated). Leachables Extractables will have a higher mass than leachables and are used in first part of risk assessment for potential patient impact e.g. during early clinical stages 43 Quality by Design Principles Applied to Sterilizing Filtration | November 2020
- 44. e.g. Tubing, connectors,fittings, containers, bags, filters, etc. Examples of Polymeric Extractables & Leachables Oligomers PVDF, PP, PE Etc. Additives and Degradants Antioxidants, UV stabilizers, Slip agents, etc. Residual Manufacturing Solvents Material of Construction Contact Fluid Process Conditions Quantity and Type 44 Key Leachables Parameters Contact fluid (media, buffer, process intermediates, DS/ bulk, DP, etc.) Contact material Sterilization / Pre-treatment Temperature Contact time Dilution ratio (V/A) All process fluid interactions DON’T forget the prefilter . . . . . And formulation container if single-use Quality by Design Principles Applied to Sterilizing Filtration | November 2020
- 45. - User andvendor partnership Typical E & L Test Study Information & Interpretation 45 Quality by Design Principles Applied to Sterilizing Filtration | November 2020 BPOG GUIDE FOR EVALUATING LEACHABLES RISK FROM POLYMERIC SINGLE-USE SYSTEMS USED IN BIOPHARMACEUTICAL MANUFACTURING Example of information required for E or L testing https://bioprocessintl.com/upstream-processing/upstream-single-use- technologies/recommendations-for-extractables-and-leachables-testing-182173/
- 46. Process Considerations ofFilter Preparation & Filter Location on Leachables – Key Process Understanding Filtration system flushed before use • Testing conditions (fluid, flowrate, volume, preparation, etc.) • Acceptable levels of process residue (measurement, sampling, etc.) • Risk to product (stability, toxicity, patient safety) Filtration system not flushed before use • Dilution calculation (use downstream volume) • Risk to product (stability, toxicity, patient safety) If Filter used for tank-to-tank transfer • Dilution calculation (use total downstream volume) If Filter used at true point-of-use (no header tank or bag) • All leachables are in final container – need product sacrifice 46 Quality by Design Principles Applied to Sterilizing Filtration | November 2020
- 47. 4 Interrelated factorscan influence filter retention –> product sterility -> patient safety Filter Retention Validation is a Combination of Parameters Process Size Shape pH Osmolarity Ionic strength Surfactants Differential Pressure Flow rate Microporous structure (pore morphology) Temperature Pore size distribution & membrane thickness Membrane Surface chemistry Contact Time Number Organism Product Viscosity Aggregation Type Concentration 47 1. Need to collect these for all products 2. Prioritize high risk products 3. Collaborate with contract laboratory to; • Determine grouping • Establish design space parameters Often called Bacterial Challenge Test Bacterial Retention Test Filter Integrity test value
- 48. Bacterial Retention TestRisk Factors Conducted by qualified laboratories – user and vendor partnership From PDA TR26 What to look for in 3rd party (mostly vendor) laboratory test report This information is used to confirm the filter retention design space Filter area information sterilization method Required before retention test can be done 48 Quality by Design Principles Applied to Sterilizing Filtration | November 2020
- 49. Examples of FilterProcess Parameters Checked During Changes or when Grouping Need to qualify all sterilising filters – example has 2 operations – sterile hold tank fill, then product filling Example - Looking for worst case process conditions from previous runs ✓ 1st Sterilising filter – high flowrate, shortest time, highest pressure, higher area ✓ 2nd Sterilising filter – low flowrate, longest time, lowest pressure, lower area ✓ Assumes sterilising filters MOC are the same Should be explained in bacterial retention test protocol and report Formulation Aseptic FillerSterile Hold Tank Vent Filter Vent Filter Sterilizing Filter Bioburden Reduction Filter Sterilizing Filter 49
- 50. Summarizing the SterilizingFilter Design Space Process Parameters Times, pressure, temperature, flowrate (flux), volume (loading), sterilization method and conditions, pretreatment, integrity test results, product yield Product Attributes Product pH / ionic strength / osmolarity, product concentrations (active, excipient, preservative etc.), acceptable impurity levels, Microbiological Attributes Species / Identity, concentration This data should already be available from quality, production, validation, regulatory affairs documentation 50 Quality by Design Principles Applied to Sterilizing Filtration | November 2020
- 51. Poll Question #4 Quality by DesignPrinciples Applied to Sterilizing Filtration | November 2020
- 52. Product Lifecycle Approach Quality by design(QbD) concept as presented by U.S. Food and Drug Administration (FDA)
- 53. Quality by DesignPrinciples Applied to Sterilizing Filtration | November 2020 Product Life Cycle Considerations Phase 1 Environmental monitoring , filter sterilization method, batch size, filter area, operating pressure, product stability, pre-flush? Phase 2 • Process condition data collection, CAPA responses, change control activities Phase 3 Sterilization, Integrity testing, capacity Product Grouping for Retention Testing if Product becomes a Family Use of parameter and attribute spreadsheets Focus on products where DS concentration is the only formulation difference Review all process parameters Ensure process parameters are the same or inside the design space 53
- 54. Suggestions for checkingbefore transferring filling operations Product Life Cycle Considerations Contract Filling or Site Transfer Validation status of aseptic filling suite and services Bacterial retention test done (if not then by whom) Filling area environmental monitoring data review Volume/Area, Flowrate/Area, time confirmed to be within established conditions Sterilization conditions Formulation preparation tank / container check (type, MOC), hold times Process controls within established conditions Change Control & Annual Product Review Excursions / deviations checked Change or Implement Single-use Systems In-depth discussion required with change control team & vendor 54 Quality by Design Principles Applied to Sterilizing Filtration | November 2020
- 55. Examples of FilterProcess Parameters to Check when Changing or Transferring a Process Quality by Design Principles Applied to Sterilizing Filtration | November 2020 Has the process been validated? If so; • Review older validations against the current process conditions. • Have there been filtration process changes? • Has the product formulation changed since the validation? These changes should be part of change control checks for sterilising filtration operations
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- 57. ✓ Regulatory agencieslook for product quality built into the process not tested into the process ✓ Quality by Design (QbD) is a scientific approach to build-in & ensure quality in drug products by emphasising process understanding, relationship between CPPs, CQAs, QTPPs using a methodical approach including risk assessment ✓ Process control strategies help ensure that process parameters are maintained within the desired range to ensure product quality and reliable process operation. ✓ QbD relatively “simple” in processes like sterilising filtration ✓ Developing a design space can be done using information already available from previous batches (e.g. clinicals), previous testing especially bacterial retention testing questionnaires ✓ Vendor support is valuable at many times during initial studies, tech transfer, scale-up and process confirmation Conclusion 57 Quality by Design Principles Applied to Sterilizing Filtration | November 2020
- 58. “Everything should bemade as simple as possible. But not simpler.” Thank YOu Albert Einstein Image via Creative Commons
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- 60. Some Reference Materials ICHQ8(R2). Pharmaceutical Development. https://www.fda.gov/regulatory-information/search-fda-guidance-documents/q8r2- pharmaceutical-development ICH Q9 Quality Risk Management https://www.fda.gov/media/71543/download ICH Q10 Pharmaceutical Quality System https://www.fda.gov/regulatory-information/search-fda-guidance-documents/q10-pharmaceutical- quality-system ICH Q11 Development and Manufacture of Drug Substances https://www.fda.gov/regulatory-information/search-fda-guidance- documents/q11-development-and-manufacture-drug-substances ICH Q12 Technical and Regulatory Considerations for Pharmaceutical Product Lifecycle Management Core Guideline Guidance for Industry https://www.fda.gov/regulatory-information/search-fda-guidance-documents/q12-technical-and-regulatory-considerations-pharmaceutical- product-lifecycle-management-core Guideline on manufacture of the finished dosage form – Effective January 2018 - EMA/CHMP/QWP/245074/2015 Guideline on the sterilisation of the medicinal product, active substance, excipient and primary container - Effective 1 October 2019 - EMA/CHMP/CVMP/QWP/850374/2015 Guideline on process validation for finished products - information and data to be provided in regulatory submissions – Effective November 2016 - EMA/CHMP/CVMP/QWP/BWP/70278/2012-Rev1,Corr.1 DRAFT Annex 1 Manufacture of Sterile Medicinal Products https://ec.europa.eu/health/sites/health/files/files/gmp/2017_12_pc_annex1_consultation_document.pdf PDA Technical Report No. 26, Revised 2008, Sterilizing Filtration of Liquids PDA Technical Report No. 66 Application of Single-Use Systems in Pharmaceutical Manufacturing BPOG www.biophorum.com/download/extractables-testing-of-polymeric-single-use-components-used-in-biopharmaceutical-manufacturing/ BPSA Recommendations for Extractables and Leachables Testing CMC Biotech Working Group, (October 2009), A-Mab: A Case Study in Bioprocess Development, V2.1 Quality by Design I Biopharmaceuticals, Anurag S Rathore & Helen Winkle, Nature Biotechnology 27, 26 - 34 (2009) When do you need to consider revalidating the performance of your sterilizing-grade filter? Merck Millipore AN32450000 60 Quality by Design Principles Applied to Sterilizing Filtration | November 2020
- 61. © 2020 MerckKGaA, Darmstadt, Germany and/or its affiliates. All Rights Reserved. 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. Author contact: michael.payne@external.merckgroup.com (other regions) Michael.payne@emdgroup.com (US/Canada)