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AdvaMed Medical Technology Learning
Institute – Proposed Rule, cGMP for
Combination Products: Framework, Impact,
and Issues
James S. Cohen, Esq.
McDermott Will & Emery LLP
202.756.8276
[email protected]
March 31, 2011
www.mwe.com
Boston Brussels Chicago Düsseldorf Houston London Los Angeles Miami Milan Munich New York Orange County Rome San Diego Silicon Valley Washington, D.C.
Strategic alliance with MWE China Law Offices (Shanghai)
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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 Draft Guidance 9/24/04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
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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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Outstanding Issues/Concerns
 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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Outstanding Issues/Concerns
 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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Outstanding Issues/Concerns
 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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Outstanding Issues/Concerns
→ 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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Outstanding Issues/Concerns
■
■
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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Outstanding Issues/Concerns
■ 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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Outstanding Issues/Concerns
■
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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Take Home Considerations
 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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Take Home Considerations
 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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Take Home Considerations
 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/
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