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.

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

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. • 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• FDA Notice – announcing availability of Draft Guidance for Industry,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. 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. 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. 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. 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. 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. 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. Slide 10
Company Confidential
Now for a deeper dive into
bringing your combination
product(s) into compliance with
21 CFR Part 4.

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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. Thank you
Slide 26
Company Confidential