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