risk-based cmc review - ogd perspective
DESCRIPTION
Advisory Committee for Pharmaceutical Science Manufacturing Subcommittee. Risk-Based CMC Review - OGD Perspective. Gary J. Buehler, R.Ph. Director Office of Generic Drugs. July 21, 2004. Mission. To provide quality (safe and effective) generic drug products to the American public. - PowerPoint PPT PresentationTRANSCRIPT
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Risk-Based CMC Review - OGD Perspective
Gary J. Buehler, R.Ph.Director
Office of Generic Drugs
July 21, 2004
Advisory Committee for Pharmaceutical ScienceManufacturing Subcommittee
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Mission
To provide quality (safe and effective) generic drug products to the American public.
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Original ANDA Receipts
335 346326 335
307
361
449
566
0
100
200
300
400
500
600
1997 1998 1999 2000 2001 2002 2003 2004
Fiscal Year
Nu
mb
er o
f S
ub
mis
sion
s
Projection of FY 04 TotalJun 30, 2004
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ANDA Chemistry Supplements
2499
2282
2519 2516
2767
23342208
2370
2017
2567
3448
2552
0
500
1000
1500
2000
2500
3000
3500
4000
1999 2000 2001 2002 2003 2004
Fiscal Year Totals
Nu
mb
er
of
Su
bm
issio
ns
Receipts of Orig Chemistry Supplements Chemistry Supplements Approved
Projection of FY 04 Total as of Jun 30, 2004
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WHAT is QUALITY?
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Assurance of Pharmaceutical Quality
Current Paradigm
• Quality standards comparable to Reference Listed Drug (RLD) established by Chemistry, Manufacturing, & Control (CMC) review
• Product manufactured in compliance with current Good Manufacturing Practices (cGMP)
• Process and specifications are conditions of approval that require approval for any subsequent changes
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Examples of Practical Effects
Original ANDAs
• Extensive negotiations for specifications
• Internal study found 40% of all deficiency comments on first cycle review were requests to tighten specifications
• This takes time – contributing to estimated average of 18 months for approval
• High number of supplements necessary
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New Approach
Extent of product knowledge is key
Drives the range of risk-based decisions based on supportive data to assure a quality product
That is, a product with established quality attributes, purity, potency/strength, identity, bioavailability/delivery, labeling/packaging, physical performance, etc)
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Voluntary!!!
FDA will work with you
We do not want to unnecessarily impede optimization of manufacturing processes
We realize many firms will not be able to do this
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Desired State
Review completed in one cycle within the statutory time frame
Regulations based on knowledge and science providing flexibility in approval conditions
Need for supplements based on knowledge of the risk of the change(s) affecting the quality of the product
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Internal Changes to Enhance Approvals
Changing work assignment to optimize review resources
Improve communications with DMF holders; re-review only as needed
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Internal Changes to Enhance Approvals (cont.)
Incorporating aspects of CMC risk-based initiative
• Identify CBE supplements suitable for expedited approvals
• Expect to deal with comparability protocols
• Utilize in-house knowledge for specific drug products to identify review elements critical for product quality to provide PAS relief
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Industry Role
Formulation and process design based on inherent mechanistic understanding of drug and its impact on product quality and performance
Specifications determined by knowledge of process and product; clear rationale for selection
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Industry Role (cont.)
Process understanding to mitigate risk associated with drug substance properties
Continuous process improvement
Identify parameters critical for product manufacture and product shelf life (stability)
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Making it Work – Reaching the Desired State
Staff will follow guidances; current scientific literature
Training of staff and regulated industry
Represents a fundamental change in thinking – review based on knowledge of the product and what manufacturing changes will make a difference
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Why Should You Do This?
Greater flexibility in optimizing your manufacturing process
Lessened post-marketing supplement burden
Reducing “No Assignable Cause” results in investigations
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International Conference on Harmonization (ICH)
Provides Basic Outline for Communicating Product Understanding Common
Technical Document (CTD)
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ICH – Q8
More fully defined, developed pharmaceutical development description in CTD
Directed at product rationale instead of simple data reporting
Better understanding of critical aspect effects on quality attributes
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ICH – Q9
Description of risk-based decision making and tool sets that might be helpful
Supports Q-8 rationale
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ICH – Q10
Quality System Guidelines applicable to assuring the processes and evaluation addressed in Q-8 and Q-9
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ICH – Impact
Potentially broader development programs for generic drug products
Increased regulatory certainty for firms
Organized approach allowing more efficient (effective?) regulatory decision making
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Additionally Dr. McClellan stated “other high-tech
industries have achieved enormous productivity gains...we should expect nothing less from the pharmaceutical industry”
Yet, the Wall Street Journal on September 3, 2003, stated “FDA regulations leave drug manufacturing processes virtually frozen in time”
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Continued...
It is true that regulations designed to protect the public’s health make this a very special industry and they promote a conservative risk-averse mentality
FDA also counters that the drug companies resistance to change is also partly to blame
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FDA Has Made the First Step: Encourage the use of equipment and
protocols for continuous monitoring of manufacturing processes (PAT)
Moving to risk-based cGMPs to free the industry from rules that do little or nothing to ensure quality
We are willing to facilitate initiatives as long as they improve quality and reduce risk
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Acknowledge Generic Industry
Experts in manufacturing drug products
Know the advances in pharmaceutical sciences and manufacturing technologies
Can identify and articulate the financial impact; both for changing and for losses with current technology
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Challenges
Avoid perception of two-tiered product quality system
The partnership assumes product quality is about providing flexible regulatory impact based on product understanding
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Challenges
Because system includes a continuum of information, how this flexibility is applied needs to be well understood to ensure even treatment and outcomes
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Challenges
FDA is not in the business of manufacturing
Question to FDA:
“What do we need to do?”
Question to Generic Industry:
“What do you think needs to be done?”
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Office of Generic Drugs (HFD-600)7500 Standish PlaceRockville, MD 20855
301-827-5845