This slideshare walks through five critical areas of combination drug compliance including: What is 21 CFR Part 4, FDA’s Office of Combination Products, Compliance for legacy combination products, Stability study strategy and more

1. 5 Critical Areas of
Combination Drug Compliance

2. Presentation Contents
• Combination drug product overview
• What is 21 CFR Part 4?
• FDA’s Office of Combination Products
• Legacy Combination Products - Compliance with 21 CFR Part 4
• Product Stability Studies Strategy
• Streamlined Approach for Review and Approval of Some Combination Products
• Summary
• BioTechLogic Contact Information
• Sources

3. Combination Drug Overview
• Combination products are therapeutic and/or diagnostic products that are
composed of any combination of a drug, device, or biologic
• The official definition detailed in 21 CFR 3.2(e)
• Combination drugs are projected to reach $115 billion in global sales by the
end of 2019
• Segment has achieved 7.9% CAGR since 2013, and is projected to continue
at that rate through 2019

4. Combination Drug Overview
Factors driving growth of the combination drug category include:
• Higher levels of patient compliance
• Demand for minimally invasive surgeries
• Opportunities for precise pain relief
• Quicker healing
• Government and non-governmental organizations (NGO) embracing combination
drugs for their ease of administration

5. Combination Drug Overview
Typical classifications of combination products include:
• Monoclonal antibody combined with a therapeutic drug
• Device coated or impregnated with a drug or biologic
• Drug-eluting stent; pacing lead with steroid-coated tip; catheter with antimicrobial coating
• Skin substitutes with cellular components; orthopedic implant with growth factors
• Prefilled syringes, insulin injector pens, metered dose inhalers, transdermal patches
• Drug or biological product packaged with a delivery device
• Surgical tray with surgical instruments, drapes, and lidocaine or alcohol swabs​
• Photosensitizing drug and activating laser/light source
• Iontophoretic drug delivery patch and controller​

6. What is 21 CFR Part 4?
• October 2004, the FDA released draft guidance, Current Good Manufacturing
Practices for Combination Products
• Final rule was published as 21 CFR Part 4 in January 2013 and became effective
July 22, 2013
• 21 CFR Part 4 did not create new requirements, it did clarify which cGMP rules
need to be enforced based on how the product is produced, packaged and
marketed

7. What is 21 CFR Part 4?
The primary rules governing single-entity and co-packaged combination products
are:
• Drug products – 21 CFR Part 210 and 211
• Biologic products – 21 CFR Part 600 - 680
• Medical devices –– 21 CFR Part 820
• Human cell, tissue and cellular & tissue-based products – 21 CFR Part 1271

8. FDA’s Office of Combination Products
• This FDA office is a resource for agency reviewers and industry
• Assigns the lead center (CDRH, CBER or CDER) and designates the primary mode
of action (PMOA) for the product
• PMOA is the action “expected to make the greatest contribution to the overall
intended therapeutic effects of the combination product”
• If PMOA determined to be drug, CDER will likely be the lead center
• Product innovator submits a Request for Designation document that explains the
product’s intended use, therapeutic benefits, how the product works and
recommends the lead center assignment

9. Legacy Combination Products - Compliance
with 21 CFR Part 4
• Regulatory journey for combination products has been long, starting
in the final rule for Medical Device GMPs in 1978
• To assess legacy combination products for compliance, manufacturer
must take appropriate steps
• Risk management and design verification analysis needs to occur

10. Legacy Combination Products - Compliance
with 21 CFR Part 4
Primary initiatives manufacturers of legacy
combination products should undertake include:
• Quality system gap assessment
• CAPA - acknowledge gaps, create high level plan to remediate
• Update policies and create SOPs
• Prepare design and development plan and define high level milestones
• Create Design History File and index
• Create user-needs requirement document
• Compile and conduct risk analyses
• Prepare design input and output documents
• Compile historical design control verifications
• Verify proper design transfer
• Review change controls for design changes
• Conduct design review/verification meetings per 820.30(e)
• Conduct risk-based remediation(s)
• Prepare Design Verification Traceability Matrix (DVTM)
• Finalize the design and development plan and close the Design History File
For more information about bringing legacy
combination products into compliance, access a
presentation delivered by BioTechLogic at the
CASSS CMC Strategy Forum in July 2016:
“Bringing Legacy Combination Products into
Compliance with 21 CFR Part 4”

11. Product Stability Studies Strategy for
Combination Drug Products
• Assessment is needed to determine if device and drug should be:
studied together, independent of one another, or if both studies are necessary before
submission to the FDA
• Is there a risk of the drug and the device altering one another once paired?
• Will the pairing of the drug and device alter stability of the finished combination
product over the course of the product’s defined shelf life?
• Shock and vibration studies of paired product might also be needed

12. Streamlined Approach for Review and Approval of
Some Combination Products
The final rule, 21 CFR 4.4 (a), requires that a single entity or co-
packaged combination product must meet all GMP requirements for
the combination product’s constituent parts:
• 21 CFR 2107 and 2118 for finished pharmaceuticals
• 21 CFR 8209 for devices
• 21 CFR 600-68010 for biological products
• 21 CFR 127111 for human cell, tissue, and cellular and tissue-based products

13. Streamlined Approach for Review and Approval of
Some Combination Products
• FDA did acknowledge the similarities of the GMP requirements for these rules
• Streamlined option was made available for products where the “drug and device
components have arrived at, or are being manufactured at the same facility”
• 21 CFR 210/211 can be used as umbrella quality system provided they also
incorporate the following provisions from the Quality System Regulations (21 CFR
820) within their quality system:
design controls, purchasing controls, corrective and preventive action (CAPA), management
responsibility, installation, and servicing

14. Summary
• Innovation is advancing rapidly. For example, nanoparticle and device combinations
like the injectable clot-busting nanotherapeutic targeting blockages with an intra-
arterial device that restores blood flow to obstructed vessels being developed by a
team co-led by Wyss Institute founding director Donald Ingber and University of
Massachusetts Medical Professor of Radiology Ajay Wakhloo
• Combination products that using monitoring, gene therapy and tissue engineering
are in development
• FDA is working to handle upcoming and ongoing regulatory complexity – formation
of the Combination Products Policy Council in April 2016 is one such initiative

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16. Sources
• “Combination Product Definition,” FDA, 21 CFR 3.2(e)
• Transparency Market Research, “Drug Device Combination Products Market - Global Industry Analysis, Size, Share, Growth, Trends
and Forecast, 2013 - 2019"
• “Current Good Manufacturing Practice Requirements for Combination Products – Final Rule,” FDA, 21 CFR 4
• “Frequently Asked Questions About Combination Products,” FDA website
• “Bringing Legacy Combination Products into Compliance with 21 CFR Part 4,” Tracy TreDenick, BioTechLogic, CASSS CMC Strategy
Forum presentation, July 2016
• “6 Guidelines To Follow When Developing Combination Products,” Winston Brown, VP of Global Quality, Phillips-Medisize, Med
Device Online, December 2015
• 6. “Current Good Manufacturing Practice in Manufacturing, Processing, Packing or Holding of Drugs; General,” FDA, 21 CFR 210
• “Current Good Manufacturing Practices for Finished Pharmaceuticals,” FDA, 21 CFR 211
• “Medical Devices Quality Systems Regulation,” FDA, 21 CFR 820
• “Biological Products,” FDA, 21 CFR 600-680
• “Human Cells, Tissues, and Cellular and Tissue-Based Products,” FDA, 21 CFR 1271
• "Developing a Consensus Voice: The Combination Products Policy Council," Nina L. Hunter, Ph.D. and Rachel E. Sherman, M.D.,
M.P.H., FDA Voice, April 2016
• Blood Clot Breakthrough Uses Drug-Device Combo,” Harvard Gazette, October 2015