ALL RIGHTS RESERVED - Homepage | ISPE · 2020. 6. 22. · Connecting Pharmaceutical Knowledge ispe.org ISPE Good Practice Guide: Single-Use Technology . 6. Released for publication

Selection of Single-Use ComponentsPresenters: Pietro Perrone & Christopher Smalley

ISPE Webinar 21 May 2020

©2020 ISPE - ALL RIGHTS RESERVED

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Before We Get Started


Connecting Pharmaceutical Knowledge ISPE.org

POLL – Pre-session

Where are you getting information about Single-Use Technology?(Select all that apply)

3

ISPE Good Practice Guide to Single-Use Technology

ISPE Conferences and Training

Other guides to Single Use Technology

Other organizations conferences and training

Other



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


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


ispe.orgConnecting Pharmaceutical Knowledge

ISPE Good Practice Guide:Single-Use Technology

6

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.


ispe.orgConnecting Pharmaceutical Knowledge 7

ISPE Good Practice Guide:Single-Use Technology



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



Single-Use Technology

Systems

Assemblies

Components

Ref: ISPE Good Practice Guide: Single-Use Technology, Fig. 1.1, Page 11




Systems

Assemblies

Components




Comparison of SUT and Stainless-Steel components:

• Vessels

• Tubing

• Connectors




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.




13

ReadyCircuitTM Bags & Tubing Assemblies – Data file 28-9606-44 AF GE Healthcare 2014



SUT and Sustainability - GE Healthcare -2017




https://cdn.gelifesciences.com/dmm3bwsv3/AssetStream.aspx?mediaformatid=10061&destinationid=10016&assetid=17085

Typical vessel capacities range from 10 liters to 2,000 liters



https://cdn.gelifesciences.com/dmm3bwsv3/AssetStream.aspx?mediaformatid=10061&destinationid=10016&assetid=17085


https://www.gelifesciences.com/en/us/solutions/bioprocessing/products-and-solutions/upstream-bioprocessing/fortem

Single-Use Technology: Vessels/Film





Single-Use Technology: Vessels/FilmAttributes of film layers

Mechanical robustnessTear & puncture resistance

Low gas permeability

BiocompatibilityLow extractables & leachablesWeldability for seal strength




Single-Use Technology: Tubing

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Size – Up to 4 inch diameter is typically available.

Pressure – Tens or hundreds of psig.


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.


Size - Up to about one inch internal diameter.

Pressure - Typically operate under 10 psig with reinforced tubing reaching up to 80 psig.


Flow Management – Pinch valves or clamps provide closure without contact with fluid.

Transparency – Most tubing types are translucent and allow fluids to be seen.



Silicone, Cflex, Braided

Single-Use Technology: Tubing




Single-Use Technology: Connectors

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Size – Sanitary ferrules up to 4 inch diameter are typically available.

Pressure – Tens to hundreds of psig.


Joining Methods – Connectors are welded to tubing, vessels, or other stainless steel components.


Size - Up to about one inch internal diameter.

Pressure - Typically operate under 10 psig.


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.



Wide variety and sizes:

• Barb connector

• Barb to sanitary connector

• Luer fitting

• Molded connection

• Aseptic connection

Single-Use Technology: Connectors




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Assemblies Bring It All Together




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


Table 2.5: Suggested Quality Requirements Based on Classification of Components



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



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).



• Determine what is needed

• Design Space is one method to define those needs

• A checklist of Critical Qualification Attributes will help quantify those needs

26


DEFINE USER REQUIREMENTS



• 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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DESIGN SPACE



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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CRITICAL QUALITY ATTRIBUTES



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

29


CRITICAL QUALITY ATTRIBUTES



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



Supplier Other “Basic” QualificationsA USP <87>, EP 3.1.9B USP <87>, EP 3.1.9CD EP 3.1.9 Japanese Pharmacopeia

Section 51EF

31




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




• 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

33




• 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>

34




• 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

35




• 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

36

Single-Use TechnologyDESIGN SPACE TO RISK ASSESSMENT



• 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

37

Single-Use TechnologyRISK ASSESSMENT APPROACH



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

38




Risk Factor A: Route of Administration:

39


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



Risk Factor B: Proximity of Final Product

40


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.



Risk Factor C: Contact Time

41


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.



Risk Factor D: Surface Area (SA) / Volume Ratio

42


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



• 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

43

Single-Use TechnologyRISK IDENTIFICATION



• 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

44




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

45




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%

46




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




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




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



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




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.




• 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




• 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



• 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)

54


EXECUTE IN-HOUSE QUALIFICATION



POLL #3

Where are you in the Single-Use Technology space?

55

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


Q&A



Q&A

57

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

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