Quality By Design - A Generic Industry Perspective

1. Quality By Design - A Generic Industry Perspective Edmund M. Fry Vice President of Compliance IVAX Corp. Generic Pharmaceutical Association

2. 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

3. 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

4. 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

5. Quality by Design In generic pharmaceutical manufacturing, there are additional constraints • Fixed bioequivalence targets • Regulatory requirements to duplicate formulation of innovator drug • Lack of access to innovator development data

6. 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 The Changing Environment

7. 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

8. 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

9. Continue to reduce pre-approval supplements Examples • New manufacturing sites • Post-approval changes for sterile products

10. 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

11. 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)

12. Eliminate unnecessary testing and other requirements • Prime example: sterility testing • Blend uniformity testing

13. Address oversight of overseas API mfrs • Use data from pharmaceutical companies • Support pooling audit information

14. 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

15. 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