James S. Cohen, Esq . McDermott Will & Emery LLP 202.756.8276 jscohen@mwe March 31, 2011

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James S. Cohen, Esq.McDermott Will & Emery [email protected]

March 31, 2011

AdvaMed Medical Technology Learning Institute – Proposed Rule, cGMP for Combination Products: Framework, Impact, and Issues

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Overview

General Principles

Legal & Regulatory Framework

Impact

Alternative Approaches

Issues/Concerns

Take Home

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Combination Products

Combinations of different types of products:

– Drug-device; device-biologic; drug-biologic; drug-device-biologic

– NOT drug-drug, device-device, or biologic-biologic

They can be:

– Physically or chemically combined

– Co-packaged in a kit

– Separately packaged; Cross-labeled

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Purpose

To clarify when, and which, cGMP requirements apply when drugs, devices, and biological products are combined “to create” a combination product (CP)

To set forth “transparent and streamlined” framework for manufacturer to demonstrate compliance with cGMP requirements for “single-entity” and “co-packaged” CP

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Background

FDA responsible for ensuring “consistent and appropriate” postmarket regulation of combination products

– Medical Device User Fee and Modernization Act of 2002; 21 U.S.C. 503(g)

There are now no independent regulations on current good manufacturing practice (cGMP) for combination products (CP’s)

– This is a significant absence

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Underlying Legal Principle

FDA’s legal/regulatory position:

– Each “constituent part” of a CP is a drug, a device, or a biological product independently subject to cGMP regulation under the FDCA

→ Each “distinguished by its [independent] regulatory identity”

– The CP also has an independent identity and is subject to cGMP regulation

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Framework

Draft Guidance 9/24/04

Each constituent part (drug, device, and/or biological product) is subject to its underlying set of cGMP regulations

– Includes human cell, tissue, or cellular or tissue-based products (HCT/P’s) regulated as a drug, device, or biological product

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Framework

Draft Guidance: “during and after” combination, both sets of regulations (for constituent parts) apply

PR: When constituent parts arrive at, are manufactured in, or are combined to create a CP in same facility, both sets apply

PR applies to single-entity and co-packaged CP’s

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Framework

PR recognizes:

– Many facilities operate under one manufacturing system

– cGMP (drug) & QS (device) regulations similar

Each regulation contains key elements based on “unique characteristics” for which each was designed

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Framework

Underlying regulatory principle:

– Compliance with both sets of regulations (for the constituent parts) can generally be achieved:

→ By using either regulation

→ As long demonstrate compliance with key provisions from other set

Identifies provisions of each set that:

– Differ in specificity, and must be followed if operate under one “umbrella” system

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Framework

■ A properly designed/implemented system under one set of regulations will in most instances meet requirements of other set

■ To allow flexibility to select cGMP or QS Regulation as “umbrella” system, but only if can demonstrate compliance with specified provisions from other set

■ CP’s would be subject to similar requirements regardless of lead Center or application type

■ Avoid need for parallel operating systems

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Two Options for Manufacturer

Two options:

– Demonstrate compliance with both sets of underlying cGMP regulations (i.e., cGMP and QS Regulation), or

– Demonstrate compliance with “umbrella” system under one set of underlying cGMP regulations that incorporates required provisions from other set of regulations

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“Umbrella” System

PR identifies the specific provisions of the “other set of regulations” (e.g., cGMP and QS Regulations) for which a manufacturer must demonstrate compliance when operating under an “umbrella” system

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Required Provisions

If operating under a cGMP regulation system:

– Manufacturing controls (21 CFR 820.20)

– Design controls (820.30)

– Purchasing controls (820.50)

– Corrective and Preventive Action (CAPA) (820.100)

– Installation (820.170

– Servicing (820.200)

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Required Provisions

■ If operating under a cGMP regulation system, cont.:

– If CP includes a biological product constituent part, then blood and blood product (21 CFR Part 606), and biological product standards (21 CFR Parts 600-680

– If CP includes a HCT/P constituent part (regulated as a drug, device, or biological product), Current Good Tissue Practice (cGTP) and donor eligibility requirements of 21 CFR Part 1271

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“Umbrella” System

If operating under a QS Regulation system:

– Testing & approval/rejection of components, drug product containers, and closures (21 CFR 211.84)

– Calculation of yield (211.103)

– Tamper-evident packaging for OTC human drug products (211.132)

– Expiration dating (211.137)

– Testing and release for distribution (211.165)

– Stability testing (211.166)

– Special testing requirements (211.167)

– Reserve samples (211.170)

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Required Provisions

■ If operating under a QS Regulation system, cont.:

– If includes a biological product constituent part, blood and blood product (21 CFR Part 606), and biological product standards (21 CFR Parts 600-680

– If includes a HCT/P constituent part (regulated as a drug, device, or biological product), Current Good Tissue Practice (cGTP) and donor eligibility requirements of 21 CFR Part 1271

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Comparison to Draft Guidance

PR adds (1) management responsibility, (2) installation, and (3) servicing from QS Regulation to the required provisions if under cGMP “umbrella” system

PR sets forth all required additional provisions from other set

– whereas Draft Guidance states other additional provisions may apply (as determined by manufacturer or FDA) depending upon the particular CP

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Impact of Prospective Regulation

Would be the most significant CP rulemaking since PMOA rule in 2005

Because there are no current cGMP regulations for CP’s, and because of FDA’s significantly enhanced focus on product safety and enforcement, rule will be a major regulatory action with substantial impact on CP innovation and development

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Alternatives

There are a number of ways in which FDA could seek to regulate cGMP for CP’s. These include:

– Maintain status quo, with only the current underlying regulations for each constituent part. Some would argue:

→ Not viable, realistic, or consistent with FDA’s statutory mandate, particularly as more innovative and complex CP’s are now being developed and marketed

→ Could lead to inconsistent postmarket regulation of similar or “like” products

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Alternatives

– Expressly require by regulation that each set of underlying regulations apply in all instances

→ Many would view this as impractical, burdensome, costly, and that it would inhibit innovation/improved health care

– Provide that PMOA and/or marketing application determine which set applies

→ Pros: some believe this is the most clear, consistent, and least burdensome approach

→ Cons: some argue it would not account for the unique characteristics, or particular safety concerns, for the underlying (secondary) constituent part(s)

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Alternatives

– PR approach

→ Umbrella, plus required additional provisions

▪ Pros: many believe this is the most realistic and flexible under the current statutory framework for CPs

▪ Cons: still lacks predictability, would impose a demonstration burden on manufacturers, and could often lead to inconsistent enforcement

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Outstanding Issues/Concerns

Proposed Rule published 19 months ago

– no interim guidance has issued

What are key issues and concerns for industry? They include:

What is the legal basis to support the application of each underlying cGMP regulation to each constituent part and to the finished CP?

When is a constituent part considered a finished component?

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Must it be a finished component? (see 21 C.F.R. 210/211, 820)

– As the legal basis for the application of both sets of regulations to all constituent parts and to finished product, preamble relies generally on:

→ Adulteration provisions of section 501 of FDCA

→ General authority to issue regulations in section 701(a) of FDCA

→ General authority to designate CP product jurisdiction, and ensure consistent and appropriate CP postmarket regulation, of CP’s in Section 503(g) of FDCA

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PR further defines “during and after” of Draft Guidance to describe at which point both sets apply

– When two or more constituent parts that are to be included in a CP arrive at, or are manufactured at, same facility

– Has been primary concern for industry

– Should also be in a codified definition

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What is the “flexibility” under “umbrella” system?

– The regulation would list (codify) all required provisions from “other" set of regulations that must be incorporated

→ Except biological product and HCT/P regulations may also apply

– Unlike Draft Guidance, PR does not require that additional provisions from the other set “may also be necessary, as determined by manufacturer or FDA”

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→ But, can still be held accountable for underlying set of cGMP regulations for each constituent part

→ Does not allow manufacturer to request alternatives to a cGMP requirement (as in other regulations)

▪ This should be added to final rule

■ Biological product requirements and “standards” in Parts 600-680

– PR does not explain which “requirements” of 600-680 apply, or how to apply these provisions to the CP or codified scheme (same issue applies for HCT/P’s)

– Preamble notes some provisions of 600-680 are not “requirements,” but PR does not further describe or explain

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■ Preamble recognizes need for “timely comprehensive guidance and training,” but FDA does not plan to issue guidance until after final rule implemented

■ How does/will FDA ensure that its inspections and compliance/enforcement activities are “consistent and appropriate” during PR period (i.e., now)?

– How do/will (a) field investigators and (b) ORA and Center compliance officers regulate manufacturing during period between proposed and final rule?

→ Little guidance available

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■ What is/will be the training for FDA investigators/compliance officers in absence of Compliance Policy Guide?

– Are they/will they be advised to perform inspections/compliance oversight based on the guidance of PR preamble?

– More broadly, how does/will FDA ensure Center review/safety/compliance offices communicate and share information with each other?

→ particularly before FDA’s IT system is updated

Will the regulation apply to products on the market (legacy products)

■ Post-approval changes (“change control”)

→ Which set of regulations to follow

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■ How can manufacturers learn what types of compliance actions FDA has taken for CP’s?

– Not currently independently tracked; few Warning Letters issued/published

■ Will FDA track and publish compliance activity/actions relating to CP’s as it does for other products?

■ Which is FDA’s “current thinking,” PR or earlier Draft Guidance (which remains available on FDA website)?

■ Need to explain the application of the statutory definition of “chemical action” to drug vs. device jurisdictional determinations

– Impacts which system to use under “umbrella” system

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Take Home Considerations

Very important to know that, under FDA’s proposed scheme, CP manufacturer could still be cited for violation of the underlying set(s) of cGMP regulations for each constituent part (i.e., each set of regulations)

Under the proposed regulation, the burden is on manufacturer to demonstrate compliance with regulatory scheme

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If use “umbrella” system, plan how you will address and demonstrate compliance with:

– Required provisions from secondary set(s) of regulations

During pre-application period, generally helpful to request meeting with both Centers present to reach agreement on your “umbrella” system, especially during period between proposed and final rule

– Confirm in writing

– Present to investigators at beginning of inspection

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Final rule will significantly affect all manufacturers

Major step forward, which will be welcomed by many in industry

But, the final regulation must not create burdens or inhibit CP product innovation and development

FDA transparency between PR/final rule is essential

– particularly given FDA policy of limited public information on PMOA and product jurisdiction decisions

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Every CP developer/manufacturer should examine PR and how final rule will affect its development plans/manufacturing operations

If you have any concerns or questions about the application of the scheme to your products, particularly during the period of uncertainty between the proposed and final rule

– contact counsel or OCP or Office of Compliance of appropriate Center

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Thank You

Please feel free to contact me should you have any questions

[email protected]

202.756.8276 (office)

301.312.9808 (mobile)

http://www.mwe.com/fda/

James S. Cohen, Esq . McDermott Will & Emery LLP 202.756.8276 jscohen@mwe March 31, 2011

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