bringing legacy combination products into compliance with 21 cfr part 4

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• FDA Notice – announcing availability of Draft Guidance for Industry, Current Good Manufacturing Practices for Combination Products, October 4, 2004 (69 FR 59239).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 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)


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 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 **


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 Milestones7. Create Design History File and Index 8. Create User-Needs Requirements

Document9. 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” 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)


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.



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.


PROCESS/FUNCTION POTENTIAL FAILURE MODES POTENTIAL CAUSES/INPUT

CONTROLS TEST CONTROLS RISK EVALUATION/ACTIONS

Process Step/ Function

Potential Failure Mode

Potential End Effects

of FailureS

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

3Improper 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.


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.


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.


9. Compile and Conduct Risk Analyses, cont’d– Biocompatibility Risk Assessment per ISO 10993


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


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.



10. Prepare Design Input and Output Documents, cont’d


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.


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).”



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.



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.


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


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.


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”)


Thank you


bringing legacy combination products into compliance with 21 cfr part 4

Health & Medicine