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Bringing Legacy Combination Products into
Compliance with 21 CFR Part 4
Tracy TreDenick, July 19, 2016
CASSS CMC Strategy ...
Overview
• Short History of Medical Devices and
Combination Products
• Legacy Combination Products: 21 CFR Part 4
Complian...
• Final rule issued in Federal Register for Medical Device GMPs on
July 21, 1978 and made effective on December 18, 1978.
...
Legacy Combination Products: 21 CFR Part 4
Compliance and Exemptions
• Scope:
– Products no longer under development but n...
Legacy Combination Products: 21 CFR Part 4
Compliance and Exemptions
Possibly Exempt  Phase 1 Investigational Drugs
– Dep...
Key Concepts for Bringing a Legacy Product
into Compliance with 21 CFR Part 4
• Risk Management
– Risk Identification and ...
Key Concept: Risk Management
• A Repetitive Process which includes Risk
Assessment, Risk Control, Risk
Communication and R...
Key Concept: Design Verification
Verification Concept is Consistent with FDA’s
Approach for Legacy Products and Process
Va...
Key Concept: Central Repository for Design
“Verification” Documentation
• Design History File, per 21 CFR 820.30(j)
– Docu...
Slide 10
Company Confidential
Now for a deeper dive into
bringing your combination
product(s) into compliance with
21 CFR ...
Major Initiatives – Deeper Dive
1. Quality System Gap Assessment
2. CAPA
3. Form Cross Functional Team
4. Develop “Device ...
Major Initiatives – Deeper Dive, continued
1.Quality System Gap Assessment
– Assessment Against 21 CFR 3.2(e), 21 CFR Part...
Major Initiatives – Deeper Dive, continued
3. Form Cross Functional Team
– Project Lead
– Include Independent Reviewer “fo...
Major Initiatives – Deeper Dive, continued
6. Prepare Design and Development Plan and
Define High Level Milestones
– Syste...
Major Initiatives – Deeper Dive, continued
7. Create Design History File and Index
– A compilation of documents/records ne...
Major Initiatives – Deeper Dive, continued
9. Compile and Conduct Risk Analyses
– Quality Risk Assessment per 21 CFR 820.3...
Major Initiatives – Deeper Dive, continued
9. Compile and Conduct Risk Analyses, cont’d
– Use-Error Risk Analysis per ISO ...
Major Initiatives – Deeper Dive, continued
9. Compile and Conduct Risk Analyses, cont’d
– Biocompatibility Risk Assessment...
Major Initiatives – Deeper Dive, continued
10. Prepare Design Input and Output Documents
– Design Input Document
• Ensures...
Major Initiatives – Deeper Dive, continued
10. Prepare Design Input and Output
Documents, cont’d
Slide 20
Company Confiden...
Major Initiatives – Deeper Dive, continued
11. Compile Historical Design Control
Verifications
– Collect previously perfor...
Major Initiatives – Deeper Dive, continued
14. Conduct Design Review/Verification
Meetings per 820.30(e)
– Discrepancy Res...
Major Initiatives – Deeper Dive, continued
16. Prepare Design Verification Traceability Matrix
(DVTM), cont’d
– Example of...
Major Initiatives – Deeper Dive, continued
17. Finalize the Design and Development Plan
and Close the Design History File
...
Benchmark: Placement of Design Control
Information in an NDA or BLA
• 3.2.P.2.4: Container Closure System
– Description of...
Thank you
Slide 26
Company Confidential
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Bringing Legacy Combination Products into Compliance with 21 CFR Part 4

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Presentation provides an overview of 21 CFR Part 4 and discusses the approach to assure legacy combination drug products are compliant with the final rule.

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Bringing Legacy Combination Products into Compliance with 21 CFR Part 4

  1. 1. Bringing Legacy Combination Products into Compliance with 21 CFR Part 4 Tracy TreDenick, July 19, 2016 CASSS CMC Strategy Forum
  2. 2. Overview • Short History of Medical Devices and Combination Products • Legacy Combination Products: 21 CFR Part 4 Compliance and Exemptions • Key Concepts for Bringing Legacy Combinations Products into Compliance with 21 CFR Part 4 • Major Initiatives - Deeper Dive • Benchmark – Placement of Design Control Information in NDA or BLA Slide 2 Company Confidential
  3. 3. • Final rule issued in Federal Register for Medical Device GMPs on July 21, 1978 and made effective on December 18, 1978. • The Safe Medical Devices Act of 1990 addresses jurisdiction questions involving “combination products” (i.e., products containing a combination of drugs, devices, and biological products). – http://www.fda.gov/ohrms/dockets/98fr/91-27869.pdf • Combination products are defined in 21 CFR Part 3(e) in 56 FR 58756, November 21, 1991 [Docket No. 91N-0257]. – http://www.fda.gov/ohrms/dockets/98fr/91-27869.pdf • Medical Device: Current Good Manufacturing Practices (CGMPs) Final Rule; Quality System Regulation: [61 FR 52654, October 7, 1996], effective date: June 1, 1997 – This is Design Controls • FDA Notice – announcing availability of Draft Guidance for Industry, Current Good Manufacturing Practices for Combination Products, October 4, 2004 (69 FR 59239). Slide 3 Company Confidential Short History of Medical Devices and Combination Products
  4. 4. Legacy Combination Products: 21 CFR Part 4 Compliance and Exemptions • Scope: – Products no longer under development but not retired from a company’s drug development program – Meeting definition of 21 CFR 3.2(e) • Triggers for Bringing Products into Compliance with 21 CFR Part 4: – Change management (regulatory filings) – Acknowledgement of Compliance Gap • Design Control Exemptions: – Legacy products: Marketed before June 1, 1997 – Phase 1 drug (PMOA) / device combination products (possibly exempt) Slide 4 Company Confidential
  5. 5. Legacy Combination Products: 21 CFR Part 4 Compliance and Exemptions Possibly Exempt  Phase 1 Investigational Drugs – Department of Health and Human Services FDA-2009-N-0435 Docket: “An investigational drug for use in a phase 1 study is subject to the statutory requirements set forth in 21 U.S.C. 351(a)(2)(B). The production of such a drug is exempt from compliance with the regulations in part 211. This exemption does not apply to an investigational combination product or constituent part of a combination product for use by or for the sponsor in phase 2 or phase 3 studies, or when the drug has been lawfully marketed.” Not Exempt  Investigational Devices – Under 21 CFR 812.1, investigational devices are exempt from part 820, except for design control requirements under 21 CFR 820.30. Slide 5 Company Confidential
  6. 6. Key Concepts for Bringing a Legacy Product into Compliance with 21 CFR Part 4 • Risk Management – Risk Identification and Mitigation • Design Verification – Review existing documents against design control requirements and remediate gaps based on risk • Central Repository for Design Verification “Evidence” – Design History File (DHF) Slide 6 Company Confidential
  7. 7. Key Concept: Risk Management • A Repetitive Process which includes Risk Assessment, Risk Control, Risk Communication and Risk Review. • Different Risk Management Tools to Apply – ISO 14971: 2007 – Medical Devices – Application of Risk Management • Use Error Analysis – 21 CFR 820.30(g): Risk Analysis • Must identify risks associated with the drug/device design, its manufacturing processes, and intended uses – ISO 10993: Biological Evaluation of Medical Devices • Risk associated with Biocompatibility Slide 7 Company Confidential
  8. 8. Key Concept: Design Verification Verification Concept is Consistent with FDA’s Approach for Legacy Products and Process Validation (2011 Guidance) FDA Guidance: “Manufacturers of legacy products can take advantage of the knowledge gained from the original process development and qualification work as well as manufacturing experience to continually improve their processes. Implementation of the recommendations in this guidance for legacy products and processes would likely begin with the activities described in Stage 3.” Continued Design Verification is similar in concept to Continued Process Verification ** Must demonstrate product is in a state of (Design) Control ** Slide 8 Company Confidential
  9. 9. Key Concept: Central Repository for Design “Verification” Documentation • Design History File, per 21 CFR 820.30(j) – Document Index (DHF Index) organized by categories of information – “Physical” File (electronic or paper) “Each manufacturer shall establish and maintain a DHF for each type of device. The DHF shall contain or reference the records necessary to demonstrate that the design was developed in accordance with the approved design plan and the requirements of this part.” Slide 9 Company Confidential
  10. 10. Slide 10 Company Confidential Now for a deeper dive into bringing your combination product(s) into compliance with 21 CFR Part 4.
  11. 11. Major Initiatives – Deeper Dive 1. Quality System Gap Assessment 2. CAPA 3. Form Cross Functional Team 4. Develop “Device Family” Bracketing Strategy 5. Update Policies and Create SOPs 6. Prepare Design and Development Plan and Define High Level Milestones 7. Create Design History File and Index 8. Create User-Needs Requirements Document 9. Compile and Conduct Risk Analyses Slide 11 Company Confidential 10. Prepare Design Input and Output Documents 11. Compile Historical Design Control Verifications 12. Verify Proper Design Transfer 13. Review Change Controls for Design Changes 14. Conduct Design Review/Verification Meetings per 820.30(e) 15. Conduct Risk-Based Remediation(s) 16. Prepare Design Verification Traceability Matrix 17. Final Plan and Close DHF
  12. 12. Major Initiatives – Deeper Dive, continued 1.Quality System Gap Assessment – Assessment Against 21 CFR 3.2(e), 21 CFR Part 4, and 21 CFR 820 or 21 CFR 210/211 – Start with Quality Manual – Evaluate types of combination products manufactured at facility and associated risks – Evaluate Procedural Gaps • Design Control or Design and Development SOP • Purchasing Control SOP • Design History File SOP • Risk Management and Risk Analyses per 21 CFR 810.30(g) 2. CAPA – Acknowledge gaps, create high level plan to remediate Slide 12 Company Confidential
  13. 13. Major Initiatives – Deeper Dive, continued 3. Form Cross Functional Team – Project Lead – Include Independent Reviewer “for that design stage” – Manufacturing, QA, Regulatory, and others Ad Hoc 4. Develop “Device Family” bracketing strategy, if possible (Different Dosage Forms) 5. Update Policies and Create SOPs – Review SOPs and policies for compliance with additional GMP provisions of the Quality System Regulations – Create new SOPs (e.g. Design Control and DHF SOPs) Slide 13 Company Confidential PFS and Stopper Product Viscosity Excipients User Use Environment Indication Active Ingredient Dosage Form Same Vendor and Make Same Same Same Same Same same 4 mg/2 mL PFS 8 mg/4 mL PFS
  14. 14. Major Initiatives – Deeper Dive, continued 6. Prepare Design and Development Plan and Define High Level Milestones – Systematic plan to facilitate review of existing documentation (e.g., risk analyses, design verifications and design validations) for compliance with Design Controls and strategies for remediation. – Identify stages of review, key deliverables, activities and criteria for moving on to next stage.  Stage 1: Design Control Assessment and Project Design Review Planning  Stage 2: Initial Project Design Review Slide 14 Company Confidential Key Deliverable Activity Description Criteria for Moving on to the Next Stage of Design Review Gap Assessment Evaluate Quality Manual and SOPs for compliance with 21 CFR Part 4, and specifically provisions of 21 CFR 820. Gap assessment complete and copy placed in DHF Key Deliverable Activity Description Criteria for Moving on to the Next Stage of Design Review User Need Requirement Document Document the user needs, market assessment and regulatory requirements for the product in a URS. User requirement document is approved and placed in the DHF.
  15. 15. Major Initiatives – Deeper Dive, continued 7. Create Design History File and Index – A compilation of documents/records necessary to demonstrate that the design was verified in accordance with the approved plan and specified requirements. – Any item added to the DHF must be reviewed and approved, and a clear explanation provided for why it was included in the file (e.g. Vendor Technical Dossier and list of Change Controls). 8. Create User-Needs Requirement Document – Capture QTPP-like information, device use characteristics and proposed method of verification/validation. Slide 15 Company Confidential
  16. 16. Major Initiatives – Deeper Dive, continued 9. Compile and Conduct Risk Analyses – Quality Risk Assessment per 21 CFR 820.30 g • Combination Product Functional Performance (does not function) • Risk Remediation: – Update Design and Development Plan to identify actions required to verify existing design controls and facilitate remediation, as needed. – Prepare User Error Analysis Report to assess market complaints or issues to determine if additional testing is needed. Slide 16 Company Confidential PROCESS/ FUNCTION POTENTIAL FAILURE MODES POTENTIAL CAUSES/INPUT CONTROLS TEST CONTROLS RISK EVALUATION/ACTIONS Process Step/ Function Potential Failure Mode Potential End Effects of Failure S Potential Causes of Failure Input Controls O Test Controls D RPN Residual Risk Risk Remediation (18) Combination Product Functional Performance Combo product does not function properly over shelf life of product. Not able to use combination product for intended purpose 3 Improper design and assembly None. (No design controls) 3 Each batch of syringes, stoppers, backstops, and plunger rods are accepted based on a review of the COC and are evaluated for conformance to the visual, physical, and functional specifications. Extractable volume is tested at release on every batch. No testing for “Syringeability” 2 18 High. Functional performance studies not performed on the combination product to demonstrate functionality through the end of shelf life. No Design Control Documents. No on-going tests for functional performance of combination product. 1. Prepare User Error Analysis Report to assess market complaints or issues. 2. Create Design and Development plan to identify actions required to verify existing design controls and facilitate remediation as needed.
  17. 17. Major Initiatives – Deeper Dive, continued 9. Compile and Conduct Risk Analyses, cont’d – Use-Error Risk Analysis per ISO 14971 • Post Marketing Surveillance: Search MAUDE (MDR) and FAERS databases (e.g. inaccurate delivery, delivery system failure, leak, etc.), and review Medwatch Alerts and Medsun Reports for hazards associated with similar device constituent parts. • Conclusion: The results of this risk analysis indicate that the product does not create any significant risk to the users or patient. Based on the outcome of this risk analysis, the human factors aspects of this product are appropriately controlled. No further action is required. Slide 17 Company Confidential Task Use Error Severity Score Clinical Impact / Harm Probability of occurrence Overall Risk Level Acceptance Level Justification Capable of Administering full dose Failure to fully inject drug 4 Patient not receiving intended dose, resulting in lack of treatment 1 4 Acceptable based on Justification The PFS is clear glass with space to view contents. Instructions for use has dedicated statement that product is a 0.5 mL dose. No post marketing issues reported.
  18. 18. Major Initiatives – Deeper Dive, continued 9. Compile and Conduct Risk Analyses, cont’d – Biocompatibility Risk Assessment per ISO 10993 Slide 18 Company Confidential Safety Assessment Actions Taken Biocompatibility Risk Level Reference Selection of Materials to be Used in the Device Constituent Part Manufacture Syringe Barrel The prefilled syringe system consists of a glass syringe barrel and an elastomeric tip cap. The syringe barrel is a product contact component and is an industry standard component utilized by the biopharmaceutical industry. The barrel was assessed by the vendor per ISO-XXX. The safety of the components as presented in the vendor supplied documentation has been reviewed as part of the Design History File and found acceptable for use. Low –None of the individual components that are part of the final finished form are directly in contact with the body (e.g. implantable or injected) Results from vendor supplied ISO 10993 assessment were reviewed and found acceptable, and are documented in Vendor/Supplier Technical Dossier Vendor/Supplier Technical Dossier DMF XX – Letter of Authorization Tip Cap The tip cap was assessed by the vendor per ISO-XXX. The respective DMFs provide additional information regarding biocompatibility. The safety of the components as presented in the vendor supplied documentation has been reviewed as part of the Design History File and found acceptable for use. Vendor/Supplier Technical Dossier DMF XX – Letter of Authorization
  19. 19. Major Initiatives – Deeper Dive, continued 10. Prepare Design Input and Output Documents – Design Input Document • Ensures all user requirements are translated into measureable physical and performance requirements that can establish criteria for evaluation of the design outputs. • The Design Inputs (requirements) should cover a range of categories including non-clinical and clinical, design features, safety, compatibility, functional performance and stability requirements. – Design Output Document • The work products and deliverables (e.g., diagrams, drawings, specifications and procedures) that allow the adequate evaluation of conformance to design input requirements. • Contain or make reference to criteria, specifications, requirements or regulations that must be met for the proper design of the combination product. Slide 19 Company Confidential
  20. 20. Major Initiatives – Deeper Dive, continued 10. Prepare Design Input and Output Documents, cont’d Slide 20 Company Confidential UR ID Design Input Design Output Acceptance Criteria /Standard UR-1 Clinical studies demonstrate that the product is safe for human use and effective for its intended therapy. Clinical study data that demonstrates the safety and efficacy of the product in patients. Studies conducted according to GCP standards and meet protocol end points. UR-2 Container closure system must be demonstrated to be integral throughout the shelf-life of the product. Seal integrity data that demonstrates the product’s container closure system is integral. • FDA Draft Guidance on Glass Syringes Technical Information to Supplement ISO 11040-4, Section IV(B)(3), • FDA Guidance on Container Closure Integrity Testing in Lieu of Stability, and • FDA Guidance on Container Closure Systems. • USP <1207>: Sterile Product Packaging – Integrity Evaluation Example of Design Inputs with associated Design Outputs.
  21. 21. Major Initiatives – Deeper Dive, continued 11. Compile Historical Design Control Verifications – Collect previously performed Risk Analyses, Design Verifications, and Design Validations. What do you already have? 12. Verify Proper Design Transfer – Verify that production procedures were completed and accurate, reviewed and approved, and available prior to design validation (e.g. PPQ batches). 13. Review Change Controls for Design Changes – FDA, “Your firm failed to establish and maintain procedures for the identification, documentation, validation or where appropriate verification, review, and approval of design changes before their implementation, as required by 21 CFR 820.30(i).” Slide 21 Company Confidential
  22. 22. Major Initiatives – Deeper Dive, continued 14. Conduct Design Review/Verification Meetings per 820.30(e) – Discrepancy Resolution / Risk Based Corrective Actions. 15. Conduct Risk-Based Remediation(s) – Remediation activities should be identified as an outcome of the risk management tools applied through this process. 16. Prepare Design Verification Traceability Matrix (DVTM) – A matrix document that lists Design Inputs and Design Outputs, and then identifies risk analyses, design verifications and design validations that were performed to demonstrate that the design outputs meet the design input requirements. – Place the completed DVTM in the DHF as evidence of design control verification. Slide 22 Company Confidential
  23. 23. Major Initiatives – Deeper Dive, continued 16. Prepare Design Verification Traceability Matrix (DVTM), cont’d – Example of a DVTM Matrix. This is the mechanism you use to verify that your design outputs meet the design input requirements. Slide 23 Company Confidential UR ID Design Input Design Output Acceptance Criteria/Standard Design Control Verifications Risk Analysis Design Verifications Design Validation UR 2 Product integrity remains intact during handling, storage, shipment and while in-use (Container Closure Integrity) – evaluation of final finished product without connecting device. Container closure integrity data shows final finished product is integral. • FDA Draft Guidance on Glass Syringes Technical Information to Supplement ISO 11040-4, Section IV(B)(3), • FDA Guidance Container Closure Integrity Testing in Lieu of Stability, and • FDA Guidance on Container Closure Systems. • USP <1207>: Sterile Product Packaging – Integrity Evaluation Quality Risk Assessment per 21 CFR 820.30g (Doc. # XXX) Acceptable container closure integrity results in Microbial Ingress Challenge of the Pre-Filled Syringe Container Closure System (Doc. # XXX) N/A
  24. 24. Major Initiatives – Deeper Dive, continued 17. Finalize the Design and Development Plan and Close the Design History File – Prior to closing the DHF, perform a final confirmation that the risk analyses, design verifications, and design validations performed according to the design output specifications met the design input requirements and user needs (e.g. DVTM). – The DHF is closed and the design verification process is considered complete after the final design review meeting, and only updated when design changes are made to the combination product. Slide 24 Company Confidential
  25. 25. Benchmark: Placement of Design Control Information in an NDA or BLA • 3.2.P.2.4: Container Closure System – Description of functional performance tests performed and summary of results • Most of these tests are only performed once. But each test must be performed with a statistically significant number of units. – Include Biocompatibility Risk Assessment • 3.2.P.2.3: Manufacturing Process Development – Include Combination Product – Quality Risk Assessment per 21 CFR 820.30(g) • 3.2.P.3.3 (or 3.2.P.7): Description of Manufacturing… – DVTM hyperlinked to supporting information throughout the dossier • 3.2.P.7: Container Closure System – Include functional performance and dimensional specifications for the final finished form with a cross reference to the results in 3.2.P.2.4 – Include co-packaging/convenience kit information – Provide a summary of the Device Quality System procedures (e.g. just those that are implemented to comply with the “provisions of the Quality System regulations”) Slide 25 Company Confidential
  26. 26. Thank you Slide 26 Company Confidential

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