Postmarketing SafetyReporting and cGMP

Requirements forCombination Products

Katlin McKelvie Backfieldwww.backfieldpllc.com

November 2, 2017

Background: What is a Combination Product?

Combination product: a product composed of two or more different typesof medical products (i.e., a combination of a drug, device, and/or biologicalproduct with one another).

Constituent parts: the medical products (i.e., drugs, devices, and biologicalproducts) included in combination products

Types of combination products:• Single entity: e.g., prefilled syringe, drug-eluting stent, transdermal patch• Co-packaged: e.g., surgical or first-aid kit• Cross-labeled: e.g., a light-emitting device for use with a light-activated drug

Background: Key Concepts

•Each constituent part of a combination productretains its regulatory status (as a drug, device, orbiological product) after the parts are combined

•A combination product is subject to distinctrequirements in addition to those requirementsthat apply to each of its constituent parts

Current Good ManufacturingPractice Requirements for

Combination Products

Regulatory History

PublicHearing

(November2002)

Draftguidance(October

2004)

ProposedRule

(September2009)

Publicworkshop(January

2010)

Final rule(January

2013)

Draftguidance(January

2015)

Finalguidance(January

2017)

Final Rule Issued January 2013

•Added 21 CFR Part 4

•Does not impose any new substantive manufacturingrequirements; clarifying in nature

•Overarching principle: constituent parts retain theirregulatory status after they are combined

•Focuses on how to demonstrate compliance with CGMP

•Provides two options to combination productmanufacturers for demonstrating compliance with CGMPrequirements

Regulatory Framework for Compliance

•Combination product manufacturers can demonstratecompliance with either:

• All CGMP regulations applicable to each constituent part; or

• “Streamlined approach”: Either drug GMP or device QSR; and specifiedprovisions from the other of the two sets of requirements (GMP orQSR); and requirements specific to biological products and HCT/Ps

•Constituent parts that are manufactured at a separate facilityfrom the other constituent parts to be included in acombination product must comply with CGMP applicable tothat constituent part

Option 1: Drug CGMP-based streamlined approach:CGMP + select provisions of QSR

Ifthe combination product includes device and drug constituent parts,

and the combo product manufacturer chooses to comply with drug CGMP,

the following provisions of the device QSR must be satisfied:

• Section 820.20 (management responsibility)

• Section 820.30 (design controls)

• Section 820.50 (purchasing controls)

• Section 820.100 (corrective and preventive action)

• Section 820.170 (installation)

• Section 820.200 (servicing)

Option 2: Device QSR-based streamlined approach:QSR + select provisions of drug CGMP

Ifthe combination product includes both device and drug constituent parts,and the combo product manufacturer chooses to comply with QSR,

the following provisions of the drug CGMP regulations must besatisfied:

• Section 211.84 (testing and approval or rejection of components,drug product containers, and closures)

• Section 211.103 (calculation of yield)• Section 211.132 (tamper-evident packaging requirements for

OTC human drug products)• Section 211.137 (expiration dating)• Section 211.165 (testing and release for distribution)• Section 211.166 (stability testing)• Section 211.167 (special testing requirements)• Section 211.170 (reserve samples)

Streamlined approach:Biological products and HCT/Ps

Ifthe combination product includes:• a biological product constituent part, must also comply

with requirements applicable to that biological product ifit were not part of a combination product;

• an HCT/P, must also comply with all current good tissuepractice requirements (including donor eligibilityrequirements in part 1271) if it were not part of acombination product

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Final Guidance Issued January 2017

General considerations, definitions, terminology• E.g., guidance relating to investigational products, convenience kits

Discussion of the select drug CGMP and device QSR regulatoryprovisions manufacturers must demonstrate compliance with underthe streamlined approaches

Discussion of requirements applicable to biological products andHCT/Ps

Examples of three types of combination products: prefilled syringe;drug-coated mesh; drug-eluting stent

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Case Study: Antibiotic Bone Cement

•Factual scenario

•Choice of options to demonstratecompliance with CGMP

•Considerations for ensuring compliancewith CGMP

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What’s Next?

Section 3038 of 21st Century Cures Act requires FDA to publish aproposed list of combination products and manufacturingprocesses for which:

• GMP requirements may vary from 21 CFR Section 4.4; or

• the requirements of Section 4.4 can be satisfied throughalternative or streamlined mechanisms.

Proposed list must be published within 18 months

After public comment period, FDA must publish a final list in theFederal Register and periodically review it

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Postmarketing SafetyReporting Requirements for

Combination Products

Regulatory History

PublicHearing

(November2002)

Publicworkshop(July 2003)

ProposedRule

(October2009)

PublicWorkshop(January

2010)

Final Rule(December

2016)

16

Core Requirements

•Reporting

•Information sharing

•Submissions

•Recordkeeping

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Core Requirements: Reporting

•Application-type based reportingrequirements• For constituent part applicants• For combination product applicants

•Additional reporting requirements• For combination product applicants

18

Pg11

PMSR requirements applicable to BOTH combinationproduct & constituent part applicants

www.fda.gov

Source of PMSRRequirements

Application Type

ANDA. NDA BLA Device application*

21 CFR 314 X

21 CFR 600 X

21 CFR 606 X

21 CFR 803 X

21 CFR 806 X

* Device applications =PMA, 510(k), de novo,PDP, HDE (see 21 CFR4.101)

19

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Additional PMSR requirements for combination product applicants

www.fda.gov

NDA, ANDA, BLA (if combinationproduct includes a deviceconstituent part)

BLA or device application* (ifcombination product includes adrug constituent part)

NDA or device application* (ifcombination product includes abiological product constituentpart)

5-day reports (21 CFR 803.3, .53,.56)

Field alert reports (FARs) (21 CFR341.81)

Biological product deviation reports(BPDRs) (21 CFR 600.14m .171)

Malfunction reports (21 CFR803.50)

15-day reports (21 CFR 314.80)(with 30-day deadline ifmarketed under a deviceapplication)

15-day reports (21 CFR 600.80)(with 30-day deadline if marketedunder a device application)

Correction or removal reportsand records (21 CFR 806.10,806.20)

*Device applications = PMA, 510(k), de novo, PDP, HDE (see 21 CFR 4.101)

Other reports:- Combination product applicants marketing under an NDA, ANDA, and BLA must address 5-day andmalfunction reports in periodic reports (21 CFR 314.80, 600.80).- Combination product applicants marketing under a device application must provide additional reportsonly as required and specified in writing by FDA.

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Core Requirements: Information Sharing,Submissions, Reporting

•Information sharing requirements• For constituent part applicants

•Submissions--how and where to submit• For constituent part applicants• For combination product applicants

•Recordkeeping• For constituent part applicants• For combination product applicants

21

Streamlined Reporting for ICSRs

Consolidated ICSR

Malfunctionreports

Seriousinjury or

deathreports

5 and 15day reports

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Effective Date and Compliance Dates

Effective Date: January 19, 2017

Compliance Dates: 18 months following the effective date (i.e.,July 19, 2018) for certain provisions:

• Additional reporting requirements applicable to combination productapplicants only (slide 20)

• Information sharing requirements for constituent part applicants

• Recordkeeping requirements for constituent part applicants andcombination product applicants

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What’s next?

• Agency is developing draft guidance

• Not on Agency guidance agenda for 2017; likely willbe on Agency guidance agenda for 2018, in light ofcompliance dates for provisions listed above

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