Challenges using Multiple Single-use Systems: Functionality versus Extractables and Leachables
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The document discusses the regulatory requirements and challenges of using single-use systems (SUS) in biopharmaceutical manufacturing, particularly focusing on extractables and leachables (E&L) testing. It emphasizes the need for a risk-based approach in evaluating these systems, as well as the importance of supplier data in mitigating risks associated with material leachables. The document also outlines industry guidelines and trends related to the adoption of SUS, emphasizing their impact on manufacturing efficiency and product safety.
Challenges using Multiple Single-use Systems: Functionality versus Extractables and Leachables
- 1. The life science business of Merck KGaA, Darmstadt, Germany operates as MilliporeSigma in the U.S. and Canada. Challenges using Multiple Single-use Systems: Functionality versus Extractables and Leachables Jessica Shea April 18, 2019
- 2. The life science business of Merck KGaA, Darmstadt, Germany operates as MilliporeSigma in the U.S. and Canada
- 3. Agenda Regulatory Environment Complexity and Risk with SUS Risk Evaluation: TFF Risk Mitigation 1 2 3 4 5 Risk Evaluation: Application of USP <665> and <1665> draft Conclusion
- 5. Extractables and Leachables Regulatory Requirements FDA EU European Commission, EUDRALEX Volume 4, “Good Manufacturing Practices, Medicinal Products for Human and Veterinary Use”, Chapter 3, “Premise and Equipment”, 2003 “ Production equipment shall not present any hazard to the product. The parts of the production equipment that come into contact with the product must not be reactive, additive or absorptive to such an extent that it will affect the quality of the product and thus present any hazard.” FDA, Code of Federal Regulations, Part 211, “Current Good Manufacturing Practice for Finished Pharmaceuticals”, Part 211.65, “Equipment Construction”, 2005 “Equipment shall be constructed so that surfaces that contact components, in-process materials, or drug products shall not be reactive, additive, or absorptive so as to alter the safety, identity, strength, quality, or purity of the drug product beyond the official or other established requirements.” Challenges Using Multiple Single-Use Systems5
- 6. Regulatory expectation Risk-based approach is recommended by regulators • CBER recommends a risk-based approach to evaluate extractables and leachables. Where you take multiple aspects into account (e.g., indication, safety issues, product characteristics, dosage, formulation, and stability profile). • If there’s no relevant risk associated with the (materials in question), vendor data can be cross referenced and a detailed justification for the application of these data and a justification for no additional testing should be submitted. • Where there is relevant risk, the drug sponsor may have to determine toxicity based on maximum dosage of potential leachables based on extractables data. • If the maximum dosage of potential leachables presents a safety risk, leachable evaluation and testing may be necessary. • Additionally, if product quality could be affected by potential leachable, studies may need to be performed to assess the effect on product quality, including efficacy. Destry M. Sillivan – Senior Regulatory Review Officer, CBER, FDA. IBC’s 7th International Single Use Application for Biopharmaceutical Manufacturing Conference, la Jolla, CA, June 14, 2010 Challenges Using Multiple Single-Use Systems6
- 7. Why Worry?: FDA Warning Letters “Please provide data from an extractables/leachables study conducted on the vessel, tubing and filters used for drug product manufacturing. Please ensure that the studies are conducted taking into account the nature of the non-aqueous vehicle used in your proposed drug product.” “We recommend you to conduct a leachable study for the filtration system with the drug solution to ensure the absence of leachable in the drug product after filtration.” Challenges Using Multiple Single-Use Systems7
- 8. Industrial References: PDA Technical Report 66 Application of Single-Use Systems in Pharmaceutical Manufacturing 2014: Implementation of SUS 1 2 Regulatory Environment For Filters And Single Use Equipment Compendial Standard: USP <665> Draft Plastic Components and Systems Used in Pharmaceutical Manufacturing: Focus on defining extractables standards 3 Regulations: EMA/CHMP/BWP/187338/2014 Guideline on process validation for the manufacture of biotechnology-derived active substances and data to be provided in the regulatory submission Defining requirements for single use equipment Challenges Using Multiple Single-Use Systems8
- 9. Evolving Industry Guidance Expectations PDA Technical Report 66, 20141 •“Supplier documentation may be sufficient for certain applications where risk is low (such as, short term exposure, no contact with drug product, or position in the process stream); but more detailed studies may be required where significant risk (such as longer term contact and extreme conditions) exists.” •Extractables is essential step in the accurate prediction of leachables •To check the impact of E&L by risk assessment on process, patient safety and product quality •If high, leachables data may be need How to use supplier’s data Step wise approach Challenges Using Multiple Single-Use Systems9 Source: Parenteral Drug Association
- 10. 2 USP <665> Draft March 2019: Plastic Components and Systems Used in Pharmaceutical Manufacturing Emprove® Program For Filters and Single Use Evolving Industry Guidance Expectations • Addresses the qualification of plastic components used in the manufacture of both pharmaceutical and biopharmaceutical active pharmaceutical ingredients (APIs) and drug products (DPs) • Risk assessment based on dosage form (i.e., oral solid/liquid is low risk) and application • Extraction requirements: Solution Composition Tests Performed Acid/salt buffer, pH 3 Organic extractables Phosphate buffer, pH 10 Organic extractables Ethanol and water (50:50) Organic extractables. Low risk tests Challenges Using Multiple Single-Use Systems10
- 11. EMA/CHMP/BWP/187338/2014 (28 April 2016) Guideline on process validation for the manufacture of biotechnology-derived active substances and data to be provided in the regulatory submission Chapter 6.1.3.: General issues related to single use equipment ▪ “…consideration should be given to leachables* and extractables.” ▪ “Information should be provided on the nature and amount of potential leachables*,…” ▪ “Besides data, this normally includes a risk assessment.” ▪ “Data do not necessarily need to be generated under actual process conditions, for example supplier data or data generated under representative model conditions may be suitable.” ▪ “For verification studies, commercial scale equipment should be used.” ▪ “Various batches of disposable components should be used, as appropriate,…” *leachables can be done only under process conditions, here we offer the Bioreliance services. Emprove® Dossiers: Support Fulfilling Regulatory Requirements 3 Challenges Using Multiple Single-Use Systems11
- 12. Complexity and Risk with SUS
- 13. Biopharma Market Trends Market: $200 B, CAGR 15% 1. Greater focus on manufacturing efficiency and productivity improvements 2. Survey responses stated the use of single-use and disposable devices improved the biomanufacturing performance Top Reasons for Implementing Single-Use 1. Reduce capital investment with facility and equipment 2. Eliminate cleaning requirements with associated validation 3. Reduced time in getting facility up and running 4. Decrease risk of product cross contamination Top Single-Use Product Attributes 1. Reliable lead-time & faster delivery 2. Extractables & leachables data is the top reason for restricting use. 3. Quality of product 4. Cost of product Single-use Adoption Enables Desired Process Efficiency Improvements in Biomanufacturing Source: Bioplan 2016, 13th Annual report of Biopharmaceutical manufacturing capacity and production Challenges Using Multiple Single-Use Systems13
- 14. Product & Process Single-Use Assembly DrawingsTesting for E&L Assembly Train Sequence Flow Path on Drawing Challenges Using Multiple Single-Use Systems Evaluation Process 1 2 5 4 3 14
- 15. Introduction to Single-Use Systems Challenges Using Multiple Single-Use Systems15
- 16. 16 Compatibility: Choosing the right material for the application Compatibility • Understand the materials of construction and its compatibility with the process stream • Minimize temperature and duration with more difficult process streams. • Minimize the risk for patient safety and potential leachables USP <665> draft • Components are characterized depending on the level of risk associated with their application in a particular manufacturing operation Quantity and Type Material of Construction Process Stream Process Conditions Temp and duration Challenges Using Multiple Single-Use Systems16
- 17. Grouping SU components for Extractables Studies. Components Extractables Test Strategy Can we group components? What type of MOC? Which Resin is used? Any process- ing aids? How are they manufac -tured? Who are the vendors? Resin Group 2 Resin Group n Resin Group 1 Challenges Using Multiple Single-Use Systems 17
- 18. ConnectorsBags Challenges Using Multiple Single-Use Systems Pureflex® Film Pureflex Plus® Film Pharma® 50, 60, 80 Tubing APT® Tubing Braided Tubing C-Flex® Tubing All other tubing Lynx S2S® Connectors Lynx ST® Connectors Kleenpak® Connectors Readymate® Connectors Aseptiquik® Connectors Steam Connectors Needles with Polycarbonate Over- Mold Tubing Needle Components to Validate 18
- 19. Challenges Using Multiple Single-Use Systems Examples: Flow Path & Components to Validate 19
- 20. Classes of E&L from Single-Use Systems Stabilizer Irgafos® 168 Slip agents Erucamide Lubricants Plasticizer DEHP Pigment Degradation Products BHT OH O O OH O O OH O O OH O O Irganox® 1010 Antioxidants Monomers Styrene Extractables and Leachables Challenges Using Multiple Single-Use Systems20
- 22. Most Unit Operations Consist of Polymeric Components Monoclonal Antibody Typical monoclonal antibody processes can be multi-use or single-use. High Risk ClearanceChallenges Using Multiple Single-Use Systems22
- 23. Cleaning Validation of the UF/DF Device First Use and Re-use Qualification Prior to implementation of a UF/DF step, the process must be validated, including validation of two cleaning procedures. The first cleaning procedure is to remove the preservative solution from the device. The Re-use cleaning process between runs to restore the membrane that was stored in sanitizing solution Removal during TFF Processing Step Diafiltration is a conventional method used to achieve high purification of macrosolutes In the diafiltration mode the permeate is sent to waste and a makeup buffer is added to the reservoir to maintain the volume. This process also reduced leachables that are present from previous processing steps Challenges Using Multiple Single-Use Systems Risk Reduction – 2 Ways Tangential Flow Filtration 23
- 24. Challenges Using Multiple Single-Use Systems Removal during TFF Processing Step Tangential Flow Filtration Ultrafiltration/ Diafiltration: Testing was performed in the diafiltration modes and recycle mode. The study demonstrate a >3x log reduction of Bisphenol-A (BPA) Removal of Leachables by Ultrafiltration and Diafiltration (2018). MilliporeSigma Technical Brief TB4663EN00 24
- 25. Conclusion Studies demonstrated the ability of an TFF membrane to remove leachables generated upstream of the product stream. The risk is reduced for steps prior to the UF/DF step. Basic information of the materials are sufficient for steps prior to the UF/DF step due to the low risk level. Challenges Using Multiple Single-Use Systems Removal during TFF Processing Step Tangential Flow Filtration Diafiltration Mode An example of typical clearance for the seven potential E/L from single-use technologies in Protein 4 and its associated buffer control run. Magarian, N., Lee, K., Nagpal, K., Skidmore, K., & Mahajan, E. (2016). Clearance of Extractables and Leachables from Single-Use Technologies via Ultrafiltration/Diafiltration Operations. Biotechnol. Prog., 32:718–724 25
- 26. Validation of the cleaning procedure includes: Determine the flush volume necessary to remove the preserving solution. The flush volume is typically determined using a Total Organic Carbon (TOC) endpoint. Fill the device with a sanitizer (e.g. alkali solution) and determine how much contact time is needed to reduce the bioburden. (Typically, companies have established minimal hold times) Determine the volume required to remove the sanitizer. Sanitize the TFF device with an alkaline solution. This second flush volume is usually determined using conductivity. Result TFF unit operation is low risk and need not be subjected to extractables studies when it can be restored to water for injection (WFI) like conditions with specifications of < 500 ppb TOC. Challenges Using Multiple Single-Use Systems Cleaning Validation of the UF/DF Device Tangential Flow Filtration 26 Agalloco,James, (1992). Points to Consider in the Validation of Equipment Cleaning Procedures. J. Parent. Sci. and Technol., 46(5), 163-168 Bader, FG, A Bum, BD Garfinkle, D MacFarland, T Massa, and TL Copmann, (1992). Multiuse Manufacturing Facilities for Biologicals. Biopharmaceuticals, 5(7), 34-42 FDA, Guide to Inspection of Validation of Cleaning Processes, US GPO, Wash. DC, July 1993
- 27. Challenges Using Multiple Single-Use Systems Mitigating Factors - USP <1665> Draft Post-contact processing step that clears extracted substances Reduce the concentration of extractables by diluting them via the process stream mitigating factor = 1 Tangential Flow Filtration 27 Understood by Regulations Risk Assessment
- 28. Risk Evaluation: Application of USP <665> and <1665> draft
- 29. Risk Dimensions for Consideration USP <1665> Draft Plastic component Chemical nature of process stream Duration of contact Temperature of contact Material of construction The risk evaluation matrix considers four dimensions that address the risk that a polymeric component will be leached to such an extent that its extractables may be impactful. These dimensions include: 29 Challenges Using Multiple Single-Use Systems
- 30. Challenges Using Multiple Single-Use Systems Clinical Use Mitigating Factors - USP <1665> Draft 1 The dosage form is a solid or liquid oral 2 The duration of clinical use is <7 days 3 The daily dose volume is <10 mL Lowering the Risk Level 30
- 31. Challenges Using Multiple Single-Use Systems Other Mitigating factors Clearance (TFF) Significant Dilution (pH adjustment) Material Consideration: Flushing 31
- 32. Challenges Using Multiple Single-Use Systems USP <665> Draft Risk Level Biological Reactivity Chemical Assessment Extraction Solution Component Testing Low None Partial 50% Ethanol NVR, pH Differential, UV absorbance Medium USP <87>, Biological reactivity in vitro Limited 50% Ethanol 1. Low-risk tests 2. Organic extractables profiling High 1. USP <87> Cytotoxicity tests 2.USP <88> Systemic Injection Test, Intracutaneous Test Full 1. 0.2M KCl, pH 3 2. 0.1M Phosphate buffer, pH 10 3. 50% EtOH 1. Low risk tests 2. Standard extractables protocol 3. Extractable elements (as necessary and appropriate) 32
- 33. Case Study
- 34. Challenges Using Multiple Single-Use Systems Final Filling – Single-use Risk Assessment – Example 5’’ Express PES Filter 10L Pureflex plus Bag 34
- 35. • Water, 2% API, 0.02% PS80, 2% dextrose, pH 5 Drug Product • 8 hours Filter Contact Time • 25 °C Filtration Temperature Typical Injectable Application Challenges Using Multiple Single-Use Systems35
- 36. Challenges Using Multiple Single-Use Systems Risk Matrix - USP <1665> Draft If the process streams contain multiple solubilizers, e.g. protein and surfactant, the risk is compounded. organic solvents (by volume) surfactants (by weight) blood/blood-derived substances (by weight) lipids and proteins (by weight) pH Aqueous Level 1 <5% <0.1% blood-derived <1% <1% ≥ 3 and ≤ 9 Somewhat organic Level 2 5-40% 0.1-0.5% blood-derived 1-25% 1-5% Highly organic Level 3 >40% >0.5% blood or blood- derived >25% >5% <3 or >9 Process stream 36
- 37. Challenges Using Multiple Single-Use Systems Risk Matrix - USP <1665> Draft Additives (by weight) Treatment for sterilization Processing Inert Level 1 <0.1% Intermediate Level 2 0.1-1% chemical adhesives/bonding of component's materials Reactive Level 3 >1% irradiation/chemi cal treatment chemical adhesives/bonding of component's materials Material Flushing/rinsing can be used to reduce the material reactivity terms by one level, 37
- 38. Challenges Using Multiple Single-Use Systems Risk Matrix - USP <1665> Draft Temperature (°C) Duration Level 1 Frozen (<-10) < 24 hrs Level 2 refrigerated (2-8) Ambient (15-25) 1-7 days Level 3 Elevated (>30) > 7 days Temperature duration 38
- 39. Challenges Using Multiple Single-Use Systems Table A-2. Linking the Numerical Risk Sequence with a Level of Characterization Risk Matrix - USP <1665> Draft If... And... Then the Characterization Level is... Four dimension scores are Level 3 There is no additional qualifier (3333) Level C (High Risk) Three dimension scores are Level 3 The other dimension score is Level 2 (3332) Level C The other dimension score is Level 1 (3331) Level C Two dimension scores are Level 3 The other two dimension scores are both Level 2 (3322) Level C One dimension score of Level 2 (3321) Level B (Moderate Risk) or C (High Risk)a,b The other two dimension scores are Level 1 (3311) Level A or Bb,c One dimension score is Level 3 All of the other dimension scores are Level 2 (3222) Level B One of the other dimension scores is Level 1 (3221)Level B Two of the other dimension scores are Level 1 (3211) Level A or Bb,c All of the other dimension scores are Level 1 (3111) Level A No dimension score is Level 3 All of the dimension scores are Level 2 (2222) Level B Not all of the dimension scores are Level 2 Level A a If the Level 2 score is in temperature, solvent, or duration dimensions, then Level C; otherwise, Level B. b In these cases the temperature, solvent, or duration dimensions have a greater influence on risk than do material considerations. c If one of the Level 1 scores is in the material considerations dimension, then Level A; otherwise, Level B. Flushing 39
- 40. Case Study
- 41. Increased Contact Time and Formulation Change Challenges Using Multiple Single-Use Systems41 • Water, 2% API, 0.1% PS80, 2% dextrose, pH 5 Drug Product • 30 Days Filter Contact Time • 25 °C Filtration Temperature
- 42. Challenges Using Multiple Single-Use Systems Risk Matrix - USP <1665> Draft If the process streams contain multiple solubilizers, e.g. protein and surfactant, the risk is compounded. organic solvents (by volume) surfactants (by weight) blood/blood-derived substances (by weight) lipids and proteins (by weight) pH Aqueous Level 1 <5% <0.1% blood-derived <1% <1% ≥ 3 and ≤ 9 Somewhat organic Level 2 5-40% 0.1-0.5% blood-derived 1-25% 1-5% Highly organic Level 3 >40% >0.5% blood or blood- derived >25% >5% <3 or >9 Process stream 42
- 43. Challenges Using Multiple Single-Use Systems Risk Matrix - USP <1665> Draft Additives (by weight) Treatment for sterilization Processing Inert Level 1 <0.1% Intermediate Level 2 0.1-1% chemical adhesives/bonding of component's materials Reactive Level 3 >1% irradiation/chemi cal treatment chemical adhesives/bonding of component's materials Material Flushing/rinsing can be used to reduce the material reactivity terms by one level, 43
- 44. Challenges Using Multiple Single-Use Systems Risk Matrix - USP <1665> Draft Temperature (°C) Duration Level 1 Frozen (<-10) < 24 hrs Level 2 refrigerated (2-8) Ambient (15-25) 1-7 days Level 3 Elevated (>30) > 7 days Temperature duration 44
- 45. Challenges Using Multiple Single-Use Systems Table A-2. Linking the Numerical Risk Sequence with a Level of Characterization Risk Matrix - USP <1665> Draft If... And... Then the Characterization Level is... Four dimension scores are Level 3 There is no additional qualifier (3333) Level C (High Risk) Three dimension scores are Level 3 The other dimension score is Level 2 (3332) Level C The other dimension score is Level 1 (3331) Level C Two dimension scores are Level 3 The other two dimension scores are both Level 2 (3322) Level C One dimension score of Level 2 (3321) Level B (Moderate Risk) or C (High Risk)a,b The other two dimension scores are Level 1 (3311) Level A or Bb,c One dimension score is Level 3 All of the other dimension scores are Level 2 (3222) Level B One of the other dimension scores is Level 1 (3221)Level B Two of the other dimension scores are Level 1 (3211) Level A or Bb,c All of the other dimension scores are Level 1 (3111) Level A No dimension score is Level 3 All of the dimension scores are Level 2 (2222) Level B Not all of the dimension scores are Level 2 Level A a If the Level 2 score is in temperature, solvent, or duration dimensions, then Level C; otherwise, Level B. b In these cases the temperature, solvent, or duration dimensions have a greater influence on risk than do material considerations. c If one of the Level 1 scores is in the material considerations dimension, then Level A; otherwise, Level B. 45
- 46. • Total quantity below the AET (Analytical Evaluation Threshold) • Individual quantitation • Scale data to surface area • Sum the quantitation if present in more than one component Extractables Identification • Manufacturing process • Posology Exposure Assessment • Evaluate based on the TTC (Threshold of toxicological concern)? • Establish a PDE (Permitted daily exposure)? Safety Evaluation Single-Use Component Evaluation Assessing the Risk 46 Challenges Using Multiple Single-Use Systems
- 47. Patient Safety Evaluation of Organic Extractables No Yes Quantity above the TTC/PDE? Risk Mitigation Leachables? Dilution? Material/ Process Change? Risk is acceptableQuantity of Each Extractable Challenges Using Multiple Single-Use Systems47
- 48. Conclusion
- 49. More than Extractables Data Emprove® Program and BioReliance® Validation Services 49 Emprove® program offers… • Support on material qualification, risk assessment & process optimization efforts through three well- organized Emprove® Dossiers: − Material Qualification Dossier − Quality Management Dossier − Operational Excellence Dossier • The Operational Excellence dossier aligns with the BPOG standardized extractables testing protocol & the USP 665 (draft chapter) • Complete profile of extractables over a wide scope of the filtration, chromatography and single use portfolio • Provides seamless access to most updated documents anytime anywhere saving valuable customer resources Online 24/7 access through Emprove® suite Certificates & custom extractables reports Customer extractables and leachables studies Patient safety evaluation (risk assessment) Consultancy and risk mitigation 1 3 4 5 6 2 Operational Excellence dossier (standard extractables report aligned with BPOG & USP 665) Challenges Using Multiple Single-Use Systems49
- 50. More than Extractables Data Emprove® Program and BioReliance® Validation Services 50 BioReliance® Validation Services offers… Assistance in: Analyzing data of the Operational Excellence dossier and conducting risk assessment Preparing product- and process-specific extractables reports Designing and executing custom extractables and leachables studies Determining if the resulting drug product presents any toxicological risks Recommending mitigation steps if necessary Other services: complete Validation of sterilizing filters & Mobius® Single use technology used in critical process steps Online 24/7 access through Emprove® suite Certificates & custom extractables reports Customer extractables and leachables studies Patient safety evaluation (risk assessment) Consultancy and risk mitigation 1 3 4 5 6 2 Operational Excellence dossier (standard extractables report aligned with BPOG & USP 665) Challenges Using Multiple Single-Use Systems50
- 51. Challenges Using Multiple Single-Use Systems Component Selection Choose the appropriate materials for the process Ensure functionality and compatibility. TFF processing Step UF/DF provides clearance of extractables and leachables from the previous step Reduces risk to the patient 51
- 52. Clinical Use Short term use and low volume dosages lower the risk. Downstream Processing Highest risk to the patient No dilution of potential leachables Consider flushing to reduce risk Leachables and Patient Safety Ensuring the quantity of leachables is below the concern levels Challenges Using Multiple Single-Use Systems Risk Assessment 52
- 53. jessica.shea@milliporesigma.com https://www.linkedin.com/feed/upd ate/urn:li:activity:65170940416943 26785 Jessica Shea Thank You © 2019 Merck KGaA, Darmstadt, Germany and/or its affiliates. All Rights Reserved. Merck, the vibrant M, and BioReliance 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.