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Tobias Massa, Ph.D. Executive Director Global Regulatory Affairs Eli Lilly and Company

PhRMA Perspective on Risk Based CMC Review of Manufacturing Changes (Reducing CMC Requirements for Drugs of No or Low Risk with Respect to Quality). Tobias Massa, Ph.D. Executive Director Global Regulatory Affairs Eli Lilly and Company. Drugs of No/Low Risk. PhRMA welcomes the approach.

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Tobias Massa, Ph.D. Executive Director Global Regulatory Affairs Eli Lilly and Company

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  1. PhRMA Perspective onRisk Based CMC Review ofManufacturing Changes(Reducing CMC Requirements for Drugs of No or Low Risk with Respect to Quality) Tobias Massa, Ph.D. Executive Director Global Regulatory Affairs Eli Lilly and Company

  2. Drugs of No/Low Risk • PhRMA welcomes the approach. • Applauds bold and innovative proposal by FDA. • If fully implemented, would reflect the true spirit of FDAMA section 116.

  3. Drugs of No/Low Risk • This should not be understood as reducing the data required to support proposed manufacturing changes. • Any reduction in "regulatory burden" would be in filings ONLY.

  4. Drugs of No/Low Risk • Validation and Product Characterization • There will be NO reduction in product quality. • To be eligible, older products should be brought up to current standards • ICH (specifications,impurities, etc.) • appropriate validation • cGMP

  5. Phased Approach Desirable • Proposed inclusion of 10% of product represents an appropriate first step. • Phased-in program desirable to ensure no risks to consumers. • FDA workload (new legislation, regulation, and guidelines) too heavy to justify applicability to only 10% of marketed products. • Remember- 70% of approved products are IRs.

  6. Existing Guidance Structure Needs Support • Majority of products will remain under 314.70 and Manufacturing Changes Guidance(s). • Taking first step (10%) should not jeopardize completion of work on key guidelines: • 314.70 and guidance • Updated SUPACS • BACPACS • PAC-SAS • PAC-PAC.

  7. 314.70 SUPACs Low Risk 2010 2005 Year

  8. Specific Comments • Biotech products are not no/low risk in this timeframe. • Should not impact 314.70.g

  9. What are the inclusion criteria? • Is the substance/product adequately characterized to current standards? • Q6A: specifications • Q3: impurities • Q1A: stability • Pre-ICH situations? • New stability guidance • existing data • "no significant changes"

  10. What are the inclusion criteria? • BCS Classification 1 (2 or 3 also?) • In vivo/in vitro correlation when available.

  11. What are the inclusion criteria? • Is the substance/product properly validated? • cGMP requirement

  12. What are the inclusion criteria? • Is the facility GMP? • No warning letters (period to be defined) • Adequate quality systems • ICH Q7A: API GMPs

  13. What are the inclusion criteria? • Process/Physical Properties, etc. • Issue is not simple process/chirality/absence of polymorphs/particle size, etc. • Key is whether the approved, validated process consistently and reproducibly results in a substance/product that meets specs.

  14. What are the inclusion criteria? • Process/Physical Properties, etc. (Con't) • Based on experience and controls, can you detect issues associated with potential changes? • What happens if something goes "wrong" with a process? • Safety implications • Potentially toxic impurity • Therapeutic index

  15. What are the inclusion criteria? • Manufacturing history • 10 years too long (no benefit to innovator) • SUPAC: 3 or 5 years • Perhaps base "history" on # of years and/or # of batches + minimum of 1 real-time shelf life with commercial material. • No recalls (period to be defined) related to API or product in question.

  16. What are the inclusion criteria? • Uncouple substance from product • Recognition that some API changes could have critical impact on product (inhalation, ER, MR, etc.) • May be able to distinguish low risk bulk or bulk changes from higher risk product and vice versa • Key principle of low risk API changes already established in separating BACPAC 1 and 2 (need to define this better) • Long synthesis more robust to early changes than short ones.

  17. What are the inclusion criteria? • These criteria could apply to any substance or product type. • Most likely candidates for initial inclusion are IRs, oral solutions, simple sterile solutions.

  18. Moving Guidance Forward(No/Low Risk + SUPACs) • Industry prepared to actively support progress. • Industry participation and open discussions key to efficient development of optimal guidances.

  19. Conclusions • PhRMA supports the Approach in principle. • PhRMA looks forward to discussions to establish criteria. • Key to success is establishing inclusion criteria. • Base decisions on sound science and regulatory experience, not "what if".

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