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Overview. The Bio-Process Systems Alliance (BPSA)Published Guides and RecommendationsComponent Quality TestsExtractables and LeachablesIrradiation and SterilizationDisposal Guide. What is BPSA? Bio-Process Systems Alliance. An organization representing suppliers of:Disposable process compone
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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