BPSA Technical Guides For Single-Use Systems used In Bio-Pharmaceutical Manufacturing

1. BPSA Technical Guides For Single-Use Systems used In Bio-Pharmaceutical Manufacturing Roberta Morris Dir. Marketing & Product Development – Charter Medical, Ltd. Director,BioProcess Systems Alliance (BPSA)

2. Overview The Bio-Process Systems Alliance (BPSA) Published Guides and Recommendations Component Quality Tests Extractables and Leachables Irradiation and Sterilization Disposal Guide

4. BPSA Objectives Implementation Encourage and facilitate adoption of single-use systems in biopharmaceutical manufacturing Information Communicate industry best practices to biopharmaceutical manufacturers, regulatory bodies and non-government organizations Quality Establish industry consensus guidelines and standards for the manufacture and use of single-use process components and systems

8. BPSA Component Quality Test Matrices Component Subcommittees Films and containers (bags) Filter capsules Tubing Connectors Quick connects, fittings, clamps Aseptic/sterile connectors

9. Actions: Reviewed current quality tests and methods by system component Compiled consensus Matrix of Quality Tests and References for bioprocess system components BPSA Component Quality Test Matrices

10. Many applied test and performance references are not specific to bioprocess components Drug and biologic GMP regulations and guidances Pharmacopoeial standards and info. chapters Medical device standards (e.g. AAMI, ANSI, ISO) References sourced from related fields Medical Devices Sterile implantables Blood product transfusion systems Pharmaceuticals and Biologicals Final dosage containers Processing equipment, e.g. sterilizing filters Component Quality Test Matrices

11. 21 CFR 177 – Code of Federal Regulations AAMI – Association for the Advancement of Medical Instrumentation ANSI – American National Standards Institute ASME BPE – American Society of Mechanical Engineers, Bioprocessing Equipment ASTM - American Society for Testing and Materials EP – European Pharmacopoeia Component Quality Test Matrices

12. ISO – International Standardization Organization ISTA – International Safe Transit Association FTMS – Federal Test Method Standard NIH – National Institutes of Health JP – Japanese Pharmacopoeia BP – British Pharmacopoeia USP – United States Pharmacopoeia Component Quality Test Matrices

13. Test type and general description Test reference Standard or guidance Test frequency Qualification, intermittent, lot release Summary description Component Quality Test Matrices

14. Qualification Test Methods include: Component Quality Test Matrices

15. Qualification Test Methods include: Component Quality Test Matrices

16. Qualification Test Methods include: Component Quality Test Matrices

17. Qualification Test Methods include: Component Quality Test Matrices

18. Defines consensus quality criteria and methods applied by BPSA members Minimum quality criteria for component selection Reference sources and applicability Component Quality Test Matrices

20. Standards for validation of sterilization by gamma irradiation are established ASTM International ANSI / AAMI / ISO 11137 (2006) AAMI TIR33 Recognized by regulatory agencies Application to biopharma process scale systems can be costly and complex Less burdensome alternate approaches may be application

21. BPSA is in the process of developing supplier guidelines related to leachables and extractablesBPSA is in the process of developing supplier guidelines related to leachables and extractables

22. Goal Educate and enable readers to: Understand meaning of Microbial control and Validated sterility Differentiate where each is applicable Make educated decisions about which will be sufficient or required

23. Basics of Gamma Irradiation Electromagnetic radiation (higher energy than x-rays) Emitted from radionuclides, e.g. Cobalt 60 Breaks DNA = Microbial Lethality Provides benefits in safety, time and cost No residual radioactivity, no quarantine for out-gassing Minimal waste byproducts Well-defined operating parameters Ensures accurate dosing Repeated radiation of single-use systems/components should be avoided

24. Basics of Sterilization by Gamma Sterility Assurance Level (SAL) Probability of a non-sterile unit (not simply 0 cfu / unit) Typically validated to SAL <10-6 (<1 non-sterile unit / million) Dosages (kiloGrey, kGy, = 0.1 megaRad, obsolete) Bioburden (cfu) generally low and non-resistant <8-10 kGy typically adequate to achieve 0 cfu / unit >25-50 kGy generally applied to achieve SAL <10-6 Sterility 0 cfu / sample ? “sterile” Sterility = validated SAL (typically <10-6)

25. Microbial Control vs. Sterilization Validation of sterility of bioprocess systems can be costly and burdensome Consider “microbial control” by irradiation as an alternative to a “sterile” label claim: >25 kGy provides equivalent lethality without quantified sterility assurance level (SAL) required for validated “sterile” claim “Sterile” claim may not be required

26. Single-Use Biopharmaceutical Process

27. Microbial Control and Sterilization >25 kGy dose typically sufficient to: Eliminate viable bioburden (0 cfu / unit) Provide high level of microbial control Single-use systems often used with non-sterile processes Low to 0 cfu / unit adequate Validated sterile claim (SAL=10-6) not required Adequately qualified as “microbially controlled”

28. BPSA is in the process of developing supplier guidelines related to leachables and extractablesBPSA is in the process of developing supplier guidelines related to leachables and extractables

29. ANSI/AAMI/ISO 11137:2006 (Parts 1 – 3) Method 1 and Method 2 VDmax - Substantiation of two pre-established irradiation sterilization dosages 15 kGy and 25 kGy AAMI TIR33:2005 VDmax - Flexibility of 7 additional dosages 17.5, 20, 22.5, 27.5, 30, 32.5 and 35 kGy Current Standards for Sterile Validation

30. Approaches to Validation Testing Single-use bioprocess systems / components pose technical challenges Size and complexity Relatively high cost/system Small batch sizes Alternate strategies to minimize validation described in ANSI/AAMI/ISO 11137 Master Product Equivalent Product Simulated Product

31. Large articles are difficult to manipulate aseptically Bioprocess systems/components may be expensive Need to balance desire to ensure technical correctness with desire to avoid false results Approaches to Testing Large Systems

32. Approaches to Testing Large Systems Entire system Validate sterility of external system Product packaging as containment device Difficult to validate internal fluid path System portion only Fluid Path Sectioning of a large product

33. Summary - Key Decisions Microbial Control or Sterile Claim? Irradiation only Claim gamma dosage for microbial control Irradiation + Validation of Sterility (SAL <10-6) Bioburden analysis of >30 units Sterility testing of >10 units Quarterly audits of >10 units for bioburden and >10 units for sterility to maintain Sterile claim If sterility validation… Product/packaging or fluid path only? Model / equivalent / simulated product?

35. Regulations FDA Title 21 of the Code of Federal Regulations (CFR) Part 211.65 (1)*: “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.”

36. Regulatory Guidance FDA ICH Q7*: “Equipment should be constructed so that surfaces that contact raw materials, intermediates, or APIs do not alter the quality of the intermediates and APIs beyond the official or other established specifications.”

37. Definitions Extractables – Chemical compounds that migrate from any product contact material, including elastomeric, plastic, glass, stainless steel or coating components when exposed to an appropriate solvent under exaggerated conditions of time and temperature. Leachables - Chemical compounds, typically a subset of extractables, that migrate into the drug formulation from any product contact material, including elastomeric, plastic, glass, stainless steel or coating components as a result of direct contact with the drug formulation under normal process conditions or accelerated storage conditions and are found in the final drug product.

38. Extractables include: Known additives Impurities in additives and polymers Reaction products of material with extraction solvents Relationship

39. Processing Materials Process systems can have many more individual product contact materials/components than container/closures Many of the components are custom packaged: Bag from Vendor A + Tubing from Vendor B + Filter from Vendor C + Connectors from Vendor D Complete E&L assessment for each component can be a daunting task

40. BPSA is in the process of developing supplier guidelines related to leachables and extractablesBPSA is in the process of developing supplier guidelines related to leachables and extractables

41. Learn from what others have done PQRI Study – the science of E&L is universal Learn from earlier single use system Filters Adapt to address the present and future Educate vendors and end-users so that expectations and responsibilities are clear

42. Addit’l Relevant Documents 1999 CDER Container Closure Guidance Not applicable to processing materials Classes of drug formulations Inhalation, Parenterals > Ophthalmics, Topical 2005 EMEA Guideline For Plastic Immediate Packaging Material PDA TR 26 Sterilizing Filtration of Liquids 21 CFR Part 177 – Indirect Food Additives: Polymers (GRAS)

43. Program for Extractables - Overall Goals Keep within the concepts that have been developed by the current science for extractables and leachables Modify, where appropriate, for processing materials Provide a framework to help guide users Understand there may be more than one way to address the issue of extractables and leachables

44. Single-Use Biopharmaceutical Process

45. First, Understand Your Process R&D Studies Process descriptions, Batch records SOPs Technical reports Batch analysis Data trending Create comprehensive list of operating parameters at each step

46. Process System Considerations Materials Filter membrane Filter assembly Prefilters Piping / Tubing Tanks / Bags Connectors Formulation Solvent Composition Preparation Sterilization Pre-flush Process Contact time, temp Mode (batch or fill) Batch size Position Filling or upstream Drug dose, regimen Dilution, frequency

47. Create a List of Product Contact Materials Any material that has the potential to migrate into the final product List begins upstream with the starting buffers List finishes with materials used directly before the final fill of containers Can include: Tubing Bags Filters Connectors O-rings

48. Risk Assessment

49. Perform Risk Assessment Goal is to determine the product contact materials that have the greatest potential for an objectionable level of leachables Must be performed using criteria that are specific to the end user – cannot be generalized between applications Best performed early in the process development when changes are more easily addressed

50. Risk Factor #1 - Material Compatibility Most biopharmaceutical products are aqueous and therefore are compatible with many materials Most biopharmaceutical materials pass USP <87> or <88> Biological Toxicity testing But first, obtain manufacturers’ recommended operating parameters such as pH, temperature, pressure Check to be sure material is being used within the recommended normal operating ranges

51. Risk Factor #2 - Proximity to Final Product Location directly upstream of final fill has direct risk to final product Location upstream in process MAY have a reduced risk This is true if there are steps where contaminants can leave the process Diafiltration – diafiltrate volume can be 100x the process volume Lyophilization – volatiles may be removed Ideally, supporting data should be obtained

52. Risk Factors #3 and #4 Solution Composition Extreme pH Higher organic or alcohol content Surfactants Components with High Surface Area/Volume Ratio Filters – porous structure leads to area much larger than filtration area Smaller process volume usually has higher surface area/volume ratio

53. Risk Factors #5 and #6 Contact time and temperature Pretreatment steps Sterilization (e.g., gamma, ethylene oxide, autoclave, H202 vapor) tends to increase leachables Rinsing prior to product contact tends to lower leachables

54. What to do with the Risk Factors Create priorities for testing If a change is needed, better to find out soon Weigh according to use-specific criteria Example: the presence of surfactants may be considered a high risk for leachables, requiring more testing

55. What to do with the Risk Factors If determine no relevant regulatory or safety risk for a specific product contact / material interaction Submit vendor information for regulatory filings If there is relevant risk Proceed to extractables evaluation

56. Evaluation of Extractables

57. Extractables Data Determine if extractables data is available from vendor or other reference source The most useful extractables data is a comprehensive list of potential leachables Goal of extractables testing is to identify potential leachable compounds Less vendor data does not necessarily mean less extractables or leachables A vendor who performs high quality extractables testing and identifies many extractables should be admired

58. Characteristics of High Quality Data Extraction performed with at least two solvents at extreme conditions* with respect to time, temperature, surface area/volume ratio and pretreatment steps Suggest: water and low MW alcohol Where relevant, also or alternately a low MW organic Solvents or extraction conditions should not chemically or mechanically degrade polymer

60. Analysis with specific analytical methods HPLC-UV-MS GC-MS Other specific methods as appropriate (e.g. ICP, Headspace GC) Non-specific methods such as FTIR, TOC, NVR, pH may also be helpful to estimate total extractables FTIR can detect compounds that are not otherwise found (e.g., oligomers). Characteristics of High Quality Data

61. Extractables Data Evaluation Assess toxicity based on worst-case extractables data Many processing material applications have a high dilution factor Extractables tests are conducted with high surface area to volume ratios Process materials can have surface area to process volume ratios 1000’s of times lower Relatively high concentration of extractables may be acceptable when converted to dosage Must be evaluated case by case

62. What if Vendor Data is Not Available? Convince vendor to provide data Perform extractables tests Could be resource intensive if process has many product contact materials OR Proceed directly to leachables testing

63. Leachables Testing

64. Leachables Testing Should be performed on materials for which extractables data does not eliminate toxicity risk Ideally performed with process formulation Alternatively With Suitable models Analysis methods should be same or based on methods used for extractables testing

65. Proposed Roles and Responsibilities BPSA is in the process of developing supplier guidelines related to leachables and extractablesBPSA is in the process of developing supplier guidelines related to leachables and extractables

67. Typical Single-Use System and Composition 2,500 L bag – 3-7 layers; PE, EVA, polyamide? 3-15 M of tubing Silicone rubber or thermoplastic elastomer, typically 3/8” ID X 5/8” OD Filter capsules Shells: ABS, polysulfone, polypropylene, polyester? Membranes: PES, PVDF, Nylon? Fittings, connectors, clamps ABS, polysulfone, polycarbonate, polypropylene?

68. Current practice with non-process disposables (labware, cleaning supplies, etc.) Local agency requirements, guidelines, and available options Volume and weight Biohazard level Recycle-ability Factors to be considered in selecting a method of disposal

69. Landfill, untreated Landfill, treated Grind, autoclave, and landfill Recycle Incinerate Incineration with generation of steam or electricity Pyrolysis Disposal Options

70. BPSA Guides and Recommendations Component Quality Test Matrices Part 1 - BioProcess Int’l; April, 2007 Part 2 - BioProcess Int’l: May, 2007 Guide to Irradiation and Sterilization Part 1 - BioProcess Int’l; Sept, 2007 Part 2 - BioProcess Int’l: Oct, 2007 Guide to Disposal BioProcess Int’l: Nov, 2007 Recommendations for Extractables and Leachables Part 1 - BioProcess Int’l; Dec, 2007 Part 2 - BioProcess Int’l: Jan, 2008

71. Integrate end-user company members Develop supplemental information with more detailed options and case studies Provide input for development of PDA Technical Reports on Single-Use Manufacturing What’s Next?

73. Questions