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Current Good Manufacturing Practice for Combination Products
AdvaMed Medical Technology Learning Institute Conference
Gaithersburg, Maryland
May 25, 2006
James S. Cohen, J.D.
Senior Advisor
Office of Combination Products
Overview
Role of Office of Combination Products
Postmarket Regulation
Draft Guidance (cGMP)
Next Steps
Challenge
Devices
PMA/510(k)/IDE
QSR
MDR
Drugs
NDA/IND
cGMP
AERS
Biologics
BLA/IND
cGMP+
AERS+
Primary Mode of Action
Consultation
Regulations
OCP Roles
Jurisdictional determinations
Oversee/help coordinate premarket review
Ensure consistent/appropriate postmarket regulation
Develop policy, guidance, regulations
OCP Roles, Cont.
Resolve timeliness disputes
Report to Congress
Serve as resource for industry and review staff
Special initiatives
Postmarket Regulation
Ensure
"consistent and appropriate"
postmarket regulation
of combination products
Postmarket Regulation -- CGMP
To date, FDA has not promulgated regulations on cGMP for combination products
FDA has applied provisions from the applicable cGMP regulations for drugs, devices, and biological products
Industry sought further clarity on how to apply cGMP regulatory framework to combination products
Draft Guidance
FDA/OCP issued Draft Guidance for Industry and FDA: Current Good Manufacturing Practice for Combination Products (9/29/04)
Sets forth broad framework for application of cGMP to combination products
Each constituent part (drug, device, and/or biological product) of a combination product is subject to its governing cGMP regulations before combination
Draft Guidance, Cont.
During and after combination, both sets of cGMP regulations apply (single entity and co-packaged products*)
Recognizes that many manufacturing facilities operate under one type of manufacturing system
cGMP and QS regulations are generally similar
* 21 CFR 3.2(e)(1) * 21 CFR 3.2(e)(2)
Draft Guidance, Cont.
Each regulation also contains key elements based upon the unique characteristics of the types of products were designed to address
Compliance with both sets of regulations can generally be achieved by using either regulation
e.g., by using the system in place at a facility and paying special attention to key issues
Draft Guidance, Cont.
If properly implemented, parallel operating systems (e.g., cGMP and QS) should not be necessary
Reasoning: possible to implement a practice under a general requirement in one set, for example, that complies with a more specific requirement of other set
Draft Guidance, Cont.
Identifies key provisions of cGMP and QS regulations that differ in specificity and that should be carefully considered by manufacturer
For example, if operating under cGMP system:
Design controls (21 CFR 820.30)
Purchasing controls (21 CFR 820.50)
CAPA (820.100)
Draft Guidance, Cont.
For example, if operating under QS system:
Testing and approval/rejection of components (21 CFR 211.84)
Calculation of yield (21 CFR 211.103)
Expiration dating (21 CFR 211.137)
Stability testing (21 CFR 211.166)
Containers and closures (21 CFR 211.84)
Draft Guidance, Cont.
Testing and release for distribution (21 CFR 211.165)
Special testing requirements (21 CFR 211.167)
Reserve samples (21 CFR 211.170)
Comments on Draft Guidance
Received approx. 15 comments
Comments largely supportive of FDA's approach
Suggestions included:
Further clarification of terms (e.g., "during and after")
Further guidance on application of overarching framework
Comments, Cont.
Differentiation between co-packaged and single entity process
Additional areas of consideration (e.g., management responsibility)
Training and issuance of compliance policy guide for FDA investigators
Rulemaking
Next Steps
Consideration of how to best ensure that cGMP for combination products is consistent and appropriate, without making them subject to duplicative or unnecessary requirements
Determined proposed rule appropriate
Next Steps, Cont.
Unified Agenda published 4/24/06 (71 Fed. Reg. No. 78, 22565 (2006)
Announces plan to issue Proposed Rule, Current Good Manufacturing Practice for Combination Products
Purpose: clarify and streamline regulatory scheme
Next Steps, Cont.
Would respond to stakeholder requests for more concrete information on cGMP requirements, and stakeholder comments on Draft Guidance, including those suggesting rulemaking
Next Steps, Cont.
How?
Our current thinking is that proposed rule would:
Provide flexible quality management framework
Recognize that, in most instances, a properly implemented quality system program under one set of regulations would meet the requirements of another set
Next Steps, Cont.
Allow flexibility to select either cGMP or QS regulation as overall operating system, provided incorporates key provisions from other part
Avoid necessity to implement parallel operating systems
Avoid duplicative requirements
Recognize and preserve combination nature of the combination product
Next Steps, Cont.
Ensure combination products subject to similar cGMP requirements that address the combination nature of product, regardless of where in FDA regulated or under which regulatory path
Will welcome further stakeholder comment as part of notice and comment rulemaking process
Postmarket Safety Reporting
Similar to approach for cGMP
Request for Comments (9/05):
Postmarket safety reporting requirements for drugs, devices, and biological products are similar
For most combination products, appropriate reporting can likely be achieved by following the regulatory provisions associated with marketing application
Postmarket Safety Reporting, Cont.
When might it be necessary to supplement those provisions to ensure consistent and appropriate regulation, given nature of the combination product?
Key differences under consideration:
Device Malfunction Reporting
5-Day MDR Reporting
Drug and Biological Product 15-day "Alert" Reporting
Blood Related Deaths
Postmarket Safety Reporting, Cont.
Unified Agenda (4/24/06): plan to issue Proposed Rule, Postmarket Safety Reporting for Combination Products
Recommendations
Assess/plan early in development process
Consider appropriate operating manufacturing system for facility/product
If one set of regulations to be applied, consider/plan how you will incorporate the key provisions from other set
Recommendations, Cont.
Discuss with both Centers at table (and with other manufacturer, if applicable) early in and during planning process
Contact OCP
OCP Website: http://www.fda.gov/oc/combination/
Contact Us -- We're Here to Help!
Office of Combination Products
15800 Crabbs Branch Way (HFG-3)
Rockville, MD 20855
(301) 427-1934
combination@fda.gov
http://www.fda.gov/oc/combination/
Conclusion
Thank you!