Selection of Single-Use ComponentsPresenters: Pietro Perrone & Christopher Smalley
ISPE Webinar 21 May 2020
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Thank you for joining us today! A few housekeeping items before we begin:
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• Have a question? Use the Question box on the control panel to the right to submit your question.
Before We Get Started
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POLL – Pre-session
Where are you getting information about Single-Use Technology?(Select all that apply)
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ISPE Good Practice Guide to Single-Use Technology
ISPE Conferences and Training
Other guides to Single Use Technology
Other organizations conferences and training
Other
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Speaker
Pietro P. Perrone, P. E.Automation Process EngineerCytiva (Formerly GE Healthcare Life Sciences)• 20+ years of purification/separation technology experience
• Process development/optimization, equipment scale-up, and project management.• Design, automation and operation of filtration systems, bioreactors, and
chromatography unit operations• Conventional stainless-steel equipment and single-use technology.
• ISPE• Lead author of Good Practice Guide: Single-Use Technology• Past chair of the Disposables Community of Practice • Active in Boston Chapter of ISPE and formerly on its board of directors.• Member of the Pharmaceutical Engineering Committee and Editorial Reviewer for
Pharmaceutical Engineering.
• Certifications• Professional Engineer registered in Massachusetts • ASQ Certified Biomedical Auditor
• Education• Chemical Engineering - Tufts University • Biomedical Engineering & Biotechnology - University of Massachusetts
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AGENDA
-- Introduction of Good Practice Guide: Single-Use Technology
-- Components, Assemblies & Systems
-- Comparison of Stainless Steel and SUT Components
-- Quality Requirements
-- User Requirements Specifications
-- Design Space
-- Critical Quality Attributes
-- Risk assessment
-- In-House Qualification
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ISPE Good Practice Guide:Single-Use Technology
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Released for publication at the 2018 Annual Meeting in Philadelphia.
Provides a road map for “how-to” implement Single-Use Technology (SUT) into manufacturing processes. A practical guide for knowing what to do “now.”
Plan, anticipate, and respond to surprises that can arise when implementing the new technology.
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ISPE Good Practice Guide:Single-Use Technology
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POLL #1
Which of the following are Single Use Components or Systems?(Select all that apply)
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Self contained filter unit
Sample bottles
Disposable 2,000 L bioreactor
Tubing that is disposed of following a campaign
All of the above
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Single-Use Technology
Systems
Assemblies
Components
Ref: ISPE Good Practice Guide: Single-Use Technology, Fig. 1.1, Page 11
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Single-Use Technology
Systems
Assemblies
Components
Ref: ISPE Good Practice Guide: Single-Use Technology, Fig. 1.1, Page 11
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Comparison of SUT and Stainless-Steel components:
• Vessels
• Tubing
• Connectors
Single-Use Technology
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Single-Use Technology: Vessels
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Stainless Steel TechnologyUse – Clean, Sterilize & Validate – and Repeat
Size – Typically up to 20,000 Liters.
Pressure – Typically to 50 psig but can be designed and rated higher.
Sterilization – Done multiple times on-site with steam by end user.
Instrumentation - Large array of instruments are installed on vessel.
Transparency – Generally limited to illuminated sight glasses/view ports that are added to vessel.
Single-Use Technology (SUT) Use Once and Done
Size - Typically up to 2,000 liters with some vessels projected to be up to 6,000 liters.
Pressure - Typically operates under 1 psig.
Sterilization – Done one time with irradiation as part of supplier’s manufacturing process.
Instrumentation – Conventional instruments often added to SUT Assembly at point of use. Some instruments (pH, DO, etc.) for biomanufacturing are available in SUT Style.
Transparency – Generally through or from top/sides of bags. View ports used when bag is placed in containers.
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Single-Use Technology: Vessels
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ReadyCircuitTM Bags & Tubing Assemblies – Data file 28-9606-44 AF GE Healthcare 2014
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SUT and Sustainability - GE Healthcare -2017
Single-Use Technology: Vessels
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https://cdn.gelifesciences.com/dmm3bwsv3/AssetStream.aspx?mediaformatid=10061&destinationid=10016&assetid=17085
Typical vessel capacities range from 10 liters to 2,000 liters
Single-Use Technology: Vessels
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https://www.gelifesciences.com/en/us/solutions/bioprocessing/products-and-solutions/upstream-bioprocessing/fortem
Single-Use Technology: Vessels/Film
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https://www.gelifesciences.com/en/us/solutions/bioprocessing/products-and-solutions/upstream-bioprocessing/fortem
Single-Use Technology: Vessels/FilmAttributes of film layers
Mechanical robustnessTear & puncture resistance
Low gas permeability
BiocompatibilityLow extractables & leachablesWeldability for seal strength
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Single-Use Technology: Tubing
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Stainless Steel TechnologyUse – Clean, Sterilize & Validate – and Repeat
Size – Up to 4 inch diameter is typically available.
Pressure – Tens or hundreds of psig.
Sterilization – Done multiple times on-site with steam by end user.
Flow Management – Valves of various designsare available to connect with tubing. CIP velocity often defines flow requirement.
Transparency – None – Instruments are needed to determine conditions in tubing.
Single-Use Technology (SUT) Use Once and Done
Size - Up to about one inch internal diameter.
Pressure - Typically operate under 10 psig with reinforced tubing reaching up to 80 psig.
Sterilization – Done one time with irradiation as part of supplier’s manufacturing process.
Flow Management – Pinch valves or clamps provide closure without contact with fluid.
Transparency – Most tubing types are translucent and allow fluids to be seen.
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Silicone, Cflex, Braided
Single-Use Technology: Tubing
ReadyCircuitTM Bags & Tubing Assemblies – Data file 28-9606-44 AF GE Healthcare 2014
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Single-Use Technology: Connectors
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Stainless Steel TechnologyUse – Clean, Sterilize & Validate – and Repeat
Size – Sanitary ferrules up to 4 inch diameter are typically available.
Pressure – Tens to hundreds of psig.
Sterilization – Done multiple times on-site with steam by end user.
Joining Methods – Connectors are welded to tubing, vessels, or other stainless steel components.
Single-Use Technology (SUT) Use Once and Done
Size - Up to about one inch internal diameter.
Pressure - Typically operate under 10 psig.
Sterilization – Done one time with irradiation as part of supplier’s manufacturing process.
Joining Methods – Inserted into tubing and fastened with mechanical strap or clamping device outside of tubing. May result in reduced diameter for flow of liquid.
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Wide variety and sizes:
• Barb connector
• Barb to sanitary connector
• Luer fitting
• Molded connection
• Aseptic connection
Single-Use Technology: Connectors
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Single-Use Technology
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Assemblies Bring It All Together
ReadyCircuitTM Bags & Tubing Assemblies – Data file 28-9606-44 AF GE Healthcare 2014
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Quality Requirements Wetted Non-Wetted
Extractables Profile ABiological and Chemical Compatibility A BIntegrity/Compliance with Function A BCompatibility with Temperature & Pressure A ACompliance with Qualification Criteria A ALimits for Bioburden and Endotoxin ALimits for Particulate Matter A BManufacturing Environment A AInspection A BInventory Control A ANote: A Indicates Required; B Indicates Useful; No Letter Indicates Not Needed
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Single-Use Technology: Quality Requirements
Ref: ISPE Good Practice Guide: Single-Use Technology, Fig. 2.5, Page 40
Table 2.5: Suggested Quality Requirements Based on Classification of Components
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POLL #2
Which order of tasks is most appropriate for Single-Use Technology?
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Leachables, Extractables, Risk Assessment, Qualification, User Requirements
Extractables, User Requirements, Risk Assessment, Leachables, Qualification
User Requirements, Extractables, Risk Assessment, Leachables, Qualification
User Requirements, Risk Assessment, Extractables, Qualification, Leachables
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Speaker
Christopher J. Smalley, PhD, MS, MBACompounding Pharmacist AdvisorValSource
Chris Smalley has recently retired from Merck, where he had responsibility for innovative implementation and validation, including Single Use Systems, globally. Previously, he had been Director of Quality Operations for Wyeth Pharmaceuticals for 12 years with responsibility for setting validation standards and validation activities globally. His research experience includes responsibility for Quality in the U.S. operations of the Sanofi Research Division, and earlier he had worked for the Johnson & Johnson family of companies, where he was a Plant Manager.
Chris is a graduate of the Philadelphia College of Pharmacy of the University of the Sciences in Philadelphia. His graduate education includes a MBA from Temple University Fox School of Business, a Masters of Science in Pharmaceutical Chemistry from Temple University School of Pharmacy, and a Ph.D. in Healthcare Administration from LaSalle University. Chris is currently a member of the ISPE Disposables CoP and serves on the Pharmaceutical Engineering Committee (PEC).
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• Determine what is needed
• Design Space is one method to define those needs
• A checklist of Critical Qualification Attributes will help quantify those needs
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Single-Use Technology
DEFINE USER REQUIREMENTS
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• Case Study
− Six Suppliers Were Reviewed
− The Example Company Has Used These Suppliers at its Plants Worldwide
− Suppliers A, B, C, D, E, F
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Single-Use Technology
DESIGN SPACE
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From Chapter 8 (Appendix 4) of the SUT Guide5
• Attribute 1: Biocompatibility Testing
• Attribute 2: Mechanical Properties
• Attribute 3: Gas Transmission Properties
• Attribute 4: Compendial Physicochemical Testing
• Attribute 5: Animal Origin Control
• Attribute 6: Total Organic Carbon (TOC) Analysis
• Attribute 7: pH and Conductivity
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Single-Use Technology
CRITICAL QUALITY ATTRIBUTES
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Continued:• Attribute 8: Extractables and Leachables (E&L)
• Attribute 9: Chemical Compatibility
• Attribute 10: Protein Adsorption Studies
• Attribute 11: Endotoxin Testing
• Attribute 12: Sterilization (Irradiation)
• Attribute 13: Container Closure Integrity
• Attribute 14: Particulate Testing
• Attribute 15: Calibration of Embedded Instrumentation
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Single-Use Technology
CRITICAL QUALITY ATTRIBUTES
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Supplier BSE/TSE Risk BiocompatibilityA BSE/TSE Free USP <88> Class VI
B BSE/TSE Free USP <88> Class VI
C BSE/TSE Free EP 3.1.7
D BSE/TSE Free USP <88> Class VI
E BSE/TSE Free USP <88> Class VI
F BSE/TSE Free USP <88> Class VI
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Single-Use TechnologyDESIGN SPACE
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Supplier Other “Basic” QualificationsA USP <87>, EP 3.1.9B USP <87>, EP 3.1.9CD EP 3.1.9 Japanese Pharmacopeia
Section 51EF
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Single-Use TechnologyDESIGN SPACE
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Supplier Operational Temperature
Operational Pressure
Contact Time
Solvents/pH
A -45°C to 135°C Ambient 72 hrs.
B -45°C to 135°C Ambient 72 hrs.
C -45°C to 135°C Ambient 72 hrs.
D -45°C to 135°C Ambient 72 hrs.
E -50°C to 175°C Ambient 72 hrs.
F -45°C to 135°C Ambient 72 hrs.32
Single-Use TechnologyDESIGN SPACE
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• Solvent/pH Data?− Most Biological Processes Are Water Based
− Information Can be Obtained From Other Qualification Tests:
→ USP <381>→ USP <661>→ ISO 10993-3→ ISO 10993-4→ ISO 10993-6→ ISO 10993-10→ ISO 10993 -11
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Single-Use TechnologyDESIGN SPACE
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• Supplier A provides USP <661> and ISO 10993-6, -10 and -11
• Supplier B provides USP <381>, <661> and ISO 10993-3, -4, -10 and -11
• Supplier D provides USP <381> and USP <661>
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Single-Use TechnologyDESIGN SPACE
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• USP <661> Physicochemical Test for Plastics essentially performs a water extraction at 70 °C for 24 hours
− Extraction is then tested for non-volatile residue, residue on ignition, heavy metals and buffering capacity
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Single-Use TechnologyDESIGN SPACE
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• Once a Design Space (URS) has been identified, some of the components under consideration will have been eliminated
• To make the choice that will have the greatest success in qualification and use, perform a Risk Assessment against the applicable Critical Qualification Attributes
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Single-Use TechnologyDESIGN SPACE TO RISK ASSESSMENT
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• Purpose of the Risk Assessment is to Determine the Extent of In-House Qualification Required According to the Calculated Risk Score of each PCM
• The Risk Model Takes into Account the Potential Risk to Product Quality and Patient Safety
• Certain Risks Will Have Been Mitigated by Supplier Quality Systems and Up-Front Evaluation
• E.g., Chemical Compatibility and Class VI Certification • Supplier Quality Systems Must Include Supplier Audits to
Ensure Full Traceability of the PCM to its Raw Materials
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Single-Use TechnologyRISK ASSESSMENT APPROACH
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A risk assessment model was formulated to calculate the risk score as follows:
Risk Score = A x B x C x DWhere: A = Route of AdministrationB = Proximity to Final ProductC = Contact TimeD = Surface Area/Volume Ratio
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Single-Use TechnologyRISK ASSESSMENT APPROACH
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Risk Factor A: Route of Administration:
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Single-Use TechnologyRISK ASSESSMENT APPROACH
Risk Factor (A) Route of Administration
High =10Inhalation/ Nasal
Injection (> 10 exposures per life)Ophthalmic (> 10 exposures per life)
Medium = 5Injection (≤ 10 exposures per life)Ophthalmic (≤ 10 exposures per life)Internal application
Low = 1
TransdermalInternal irrigation
Topical
Oral
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Risk Factor B: Proximity of Final Product
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Single-Use TechnologyRISK ASSESSMENT APPROACH
Risk Factor (B) Proximity of Final Product Comment / Justification
High = 10Manufacture of dosage form without dilution or purification step and filling into the final container closure system.
Any contaminations will be filled in the container and consumed by patients.
Medium = 5
Compounding of drug product involving dilution or purification step before filling.
Production of active which will be >50% concentration in the final drug product.
All steps including diafiltration, purification, filtration and/or dilution >50% will provide synergistic effect in reducing contaminates in the final products.
Low = 1 Production of final Active including all media, buffer preparation.
All steps before compounding will inherently has lower risk due to the fact that all the downstream processes steps will reduce/dilute contaminates as the process progress.
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Risk Factor C: Contact Time
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Single-Use TechnologyRISK ASSESSMENT APPROACH
Risk Factor (C) Contact Time Comment / Justification
High = 10 > 7 Days of exposure time
SUS will be treated as intermediate/shipping storage vehicle if materials will be stored beyond 7 days
Medium = 5 between 48 Hours and 7 Days of exposure time
Intermediate or bulk may be stored in bags up to 7 days for further processing.
Low = 1 < 48 Hours of exposure time Production campaigns can be filled within 36-48 hours.
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Risk Factor D: Surface Area (SA) / Volume Ratio
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Single-Use TechnologyRISK ASSESSMENT APPROACH
Risk Factor (D) Surface Area (SA) / Volume Ratio Comment / Justification
High = 10 Surface Area (SA) / Volume > 0.01 cm2/ml
A safety factor of >15 fold relative to extraction condition per Class VI testing
Medium = 5 Surface Area (SA) / Volume Ratio 0.01 - 0.001 cm2/ml
A safety factor of between 15 to 150 fold relative to extraction condition per Class VI testing
Low = 1 Surface Area (SA) / Volume < 0.001 cm2/ml
A safety factor of >150 fold relative to extraction condition per Class VI testing
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• Use of Supplier Documentation• Definitive for Film Design/Manufacturing• Starting Point for Extractables and Leachables
• Assess for Relevance• Sufficient for Low Risk/Impact Applications
• Short Term Exposure• No Drug Product Contact• Upstream Step
Critical Review is Required When Comparing Suppliers
Remember – We Have Not ‘Scored’ the Quality of Vendor Documents
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Single-Use TechnologyRISK IDENTIFICATION
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• Collect, Organize and Evaluate all the Available Information From All Vendors
• Do Not be Afraid of Asking the Vendors Detailed Questions –• Often There is More Information Available Than That Published
in Validation Guides; e.g., Get the Original CRO (e.g.Toxicon) Data
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Single-Use TechnologyRISK IDENTIFICATION
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What are Our Absolute No-Nos?We Cannot Accept Any Risk Regarding:• Natural Rubber/Latex• Special Case Compounds – PAH/PNA, MBT, N-Nitrosamines• BSE/TSE• Asbestos
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Single-Use TechnologyRISK IDENTIFICATION
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Proximity to Final ProductHigh Risk = 10
Final Dosage Form – No Dilution/PurificationIntermediate Contributing 25% or More to the Final Drug Product
Medium Risk = 5Upstream of a Dilution or Purification StepIntermediate Contributing More 5% Up to 25% to the Final Drug Product
Low Risk = 1Contribution to the Final Drug Product is Less Than 5%
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Single-Use TechnologyRISK IDENTIFICATION
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Contact Time with Product or ProcessHigh Risk = 10
Static hold (no flow) greater than 7 days
Medium Risk = 5Static hold for 48 hours up to 7 days
Low Risk = 1Static hold for up to 48 hours
Recirculation would be considered the same as Static Hold
Single-Use TechnologyRISK IDENTIFICATION
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Surface Area to Volume RatioHigh Risk = 10
SA/Volume > 0.01 sq.cm./mL
Medium Risk = 5SA/Volume > 0.001 sq.cm./mL
Low Risk = 1SA/Volume < 0.001 sq.cm./mL
Rule of Thumb – If There is At Least 1 L for Every Gasket in the Process, the Gaskets Would be Low Risk
Single-Use TechnologyRISK IDENTIFICATION
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What Does the Formula Look Like for an Upstream Process such as Buffer Preparation?
• A- Final Product is a Vaccine = 5
• B- Buffer Prep occurs before Compounding = 1• C- Contact Time may be up to 7 days being held for
the compounding step = 5• D- Surface Area/Volume Ratio for Buffer Prep = 1
• 5 X 1 X 5 X 1 = 25
Single-Use TechnologySUMMARY OF RISK IDENTIFICATION
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What does the Formula Look Like for Downstream Process like Filling Needle Tubing?
• A- Final Product is a Vaccine = 5• B- Filling Needle Tubing Last Stage = 10• C- Contact Time May Be up to 8 Hours Filling Operation = 1• D- Surface Area/Volume Ratio for Tubing = 1
• 5 X 10 X 1 X 1 = 50
Single-Use TechnologySUMMARY OF RISK IDENTIFICATION
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Risk Score Levels:
Low: < 1001Medium: 1001 – 4099High: 5000 or greater
Both Examples Came in at Low Risk – Extractables Information Will be Examined, But Leachables Studies Are Not Required.
Single-Use TechnologySUMMARY OF RISK IDENTIFICATION
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• Know When to do a Risk Assessment of Your Process
–Flowchart Your Process
• Identify Different Risk Tools and When to Use Each
• Identify Risks Associated with Single Use Systems
• Calculate and Evaluate Risk
Single-Use TechnologySUMMARY OF RISK IDENTIFICATION
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• An Example for Extractables:
• BPOG Standardized Extractables Protocol Described in Nov/Dec 2014 Pharmaceutical Engineering (Vol 34, No 6)
• Tubing is tested with 0.1M Phosphoric Acid, 0.5N NaOH, over 70 days
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Single-Use TechnologyDESIGN PROTOCOLS
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• Saying ‘IN HOUSE’ Does Not Preclude Contracting Out
• In House Qualification Requirements Will Always Include, Regardless of Risk Score:
• Leak/Pressure/Crack Verification• Tear Evaluation (for Bags)• Sterility Evaluation (for Sterile Supplied PCM)• Endotoxin Evaluation (for Sterile Supplied PC)• Integrity Test (for 0.2 Micron Filters, Whether Sterilizing or
Bioburden Reduction)
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Single-Use Technology
EXECUTE IN-HOUSE QUALIFICATION
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POLL #3
Where are you in the Single-Use Technology space?
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Beginning to assess the utility of single-use technology in your processes
Determining if it’s the right choice for you in specific processes
Implementing Single-Use technology in operations
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Q&A
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Q&A
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For more information
Pietro Perrone, [email protected]
Christopher Smalley, Valsource [email protected]
Dharti Pancholi, ADVENT Engineering Services, [email protected]
Upcoming Webinars• Thursday, 11 June 2020 1100 – 1200 EDT
Topic: Risk Based Approach to mitigate SARS –COV -2 challenge to the Virus Control framework in Industrial GMP manufacturing facilities
• Week of 15 June 1100 – 1200 EDTTopic: Creating a Vision of the Future – An Evolution or Revolution of the Pharmaceutical Supply Chain
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