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Bringing Legacy Combination Products into Compliance with 21 CFR Part 4
Tracy TreDenick, July 19, 2016CASSS CMC Strategy Forum

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 2Company Confidential

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FDA Notice announcing availability of Draft Guidance for Industry, Current Good Manufacturing Practices for Combination Products, October 4, 2004 (69 FR 59239).
Short History of Medical Devices and Combination Products

Legacy Combination Products: 21 CFR Part 4 Compliance and Exemptions
Scope: Products no longer under development but not retired
from a companys 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)

Legacy Combination Products: 21 CFR Part 4 Compliance and ExemptionsPossibly 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.

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)

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

Key Concept: Design Verification
Verification Concept is Consistent with FDAs 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 **

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.

Company Confidential
Now for a deeper dive into bringing your combination
product(s) into compliance with 21 CFR Part 4.

Major Initiatives Deeper Dive
1. Quality System Gap Assessment 2. CAPA3. Form Cross Functional Team4. Develop Device Family Bracketing
Strategy5. Update Policies and Create SOPs6. 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
10. Prepare Design Input and Output Documents
11. Compile Historical Design Control Verifications
12. Verify Proper Design Transfer13. Review Change Controls for
Design Changes14. 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

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

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 bracketingstrategy, 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)
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

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
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.

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.
UR ID User Requirement Proposed Method of Verification /ValidationUR-1 The product must be safe and effective for . Non-Clinical and Clinical
Studies
UR-2 The product must be a sterile injectable with a suitable container closure system that maintains the integrity of the product.
Design Verification and Validation Studies

9. Compile and Conduct Risk Analyses Q