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Quality By Design - A Generic Industry Perspective

Edmund M. Fry

Vice President of Compliance

IVAX Corp.

Generic Pharmaceutical Association

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A shared vision of quality

GPhA supports the FDA CGMP initiative Generic drug manufacturing companies:

Exist to make affordable drug therapies available to all

Companies, staff, volumes and revenues are smaller

It is completely appropriate that regulatory requirements apply to all companies small and large, as long as regulatory guidance provides flexibility in recognition of more limited resources at smaller firms

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What is Quality by Design?

“You can’t test quality into drug products” has been heard for decades – so what’s new? It’s a culture - incorporates quality principles as well

as strong compliance function Incorporates risk assessment and management Refocuses attention and resources on what’s

important to the customer, i.e. the patients, health professionals, payors and distribution chain

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Quality by Design

Continuous improvement is a hallmark of quality by design G. Taguchi on Robust Design: design changes

during manufacture can result in the last product produced being different from the first product

In pharmaceutical manufacturing, we don’t want this – patients and physicians must count on each batch of drug working just like the batches that came before

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Quality by Design

In generic pharmaceutical manufacturing, there are additional constraintsFixed bioequivalence targetsRegulatory requirements to duplicate

formulation of innovator drugLack of access to innovator development

data

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The Changing Environment

Quality by Design

Adequate resources for quality: number, qualifications, etc.

Self-assessments play key role

Continuous analysis & improvement

Change management based on good science

Focus on what’s important (risk management)

Current Regulatory Situation

Little guidance on adequate resources or qualifications

Self-assessments not trusted Annual product reviews

instead of continuous analysis

Formidable barriers to change, including intimidating enforcement emphasis

Seldom admit that anything is not important; test everything

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Suggested actions

Give credit for good performance Continue to reduce unnecessary supplements Continue to develop the Pharmaceutical

Inspectorate Reward process innovation Eliminate unnecessary testing requirements Address oversight of overseas API mfrs

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Give credit for good performance

Proven ability to operate in compliance should result in reduced regulatory burden, e.g. inspections and pre-approval review requirements

Factors considered by FDA in assigning inspections (D. Horowitz, Sept. 10, ’03): Facility (e.g., compliance history) Product being manufactured at the facility Process used (e.g., process understanding)

Generic pharmaceutical manufacturers must be rated on the same basis as larger companies

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Continue to reduce pre-approval supplements

ExamplesNew manufacturing sitesPost-approval changes for sterile

products

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Continue to develop the Pharmaceutical Inspectorate

FDA is doing a good job of raising technical competence of Investigators

System-based inspections are a meaningful approach

Further opportunities exist to integrate field activities with review activities; integrated uniform training; delegation of more decisions to field personnel

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Reward process innovation

PAT holds promise; effort actually led by FDA instead of industry

Similar encouragement should be provided for other advancing technologies (e.g. advanced aseptic processing)

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Eliminate unnecessary testing and other requirements

Prime example: sterility testingBlend uniformity testing

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Address oversight of overseas API mfrs

Use data from pharmaceutical companies

Support pooling audit information

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International Initiatives

Continue to include all affected parties in policy-making initiatives

Due to the nature of the generic pharmaceutical industry, we may not have equivalent numbers of senior-level technical personnel who can dedicate substantial extramural time to working with ICH and other international activities

However, that does not mean we can’t be at the table

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Conclusion

Quality by Design and the FDA CGMP Initiative make excellent business and scientific sense

The generic pharmaceutical industry welcomes the opportunity to work with FDA