Type V Drug Master Files: Comments from CBER s Viewpoint

1. Type V Drug Master Files: Comments from CBER’s Viewpoint Jay Eltermann Director, DMPQ CBER

2. Items to be covered Regulatory framework and recent changes Draft Guidance document Uses for Type V DMFs Problem areas and discussion items Summary

3. Regulatory Framework 21 CFR 314.420 Jan. 12, 2000 FR notice – elimination of Type I DMFs by July 10, 2000 Draft CBER Guideline for Submission of Type V DMFs to CBER CDER Guideline for DMFs (1989)

4. Type V DMFs FDA-accepted Reference Information Information and data inappropriate for Type II-IV DMFs Requires permission prior to submitting Type V DMFs* (exceptions in CBER draft guidance) Reviewed when cross-referenced by another submission (BLA, NDA, IND)

5. Type I to Type V Conversion Elimination of Type 1 DMFs (as of July 10, 2000) DMFs to be eliminated were posted on CBER website Active Type I DMFs were recategorized to other DMF types CBER is accepting facility information as Type V DMFs

6. Sample of Type V DMFs on file at CBER Manufacturing facilities, especially for IND products Contract manufacturing facilities, contract test facilities, procedures Manufacture of diluents CVs for clinical investigators Cell lines and vectors Long-term patient monitoring

7. Types V DMFs on file at CBER CBER has found that DMFs are particularly useful for facility, equipment, and other information in support of facilities being used to manufacture clinical products, especially gene therapy products, or where facilities will be cross-referenced by multiple INDs

8. Format and Content Issues Suggest following CMC guidance (and later CTD) format Information should be “compatible” with information in application General information for facilities/equipment and procedures appropriate in DMF Product-specific information should be submitted in market application

9. Draft CBER Guidance In August 2001 CBER published the draft guidance “Submitting Type V Drug Master Files to the Center for Biologics Evaluation and Research” Certain information could be submitted without letter of intent and highlighted use in support of products under IND

10. Draft CBER Guidance Facilities for production of gene or cellular based therapies under clinical trials Contract facilities for manufacturing or testing Product-specific information is more appropriate under BLA

11. Problem Areas and Discussion Items Where do applicant’s and DMF holder responsibilities begin and end with respect to information to be submitted? What is the best format for information submitted in DMFs? Balance between complete information and proprietary issues (FDA can’t be QA unit for applicant)

12. Problem Areas and Discussion Items Deficiency letters will go to DMF holder, not applicant, so applicant will potentially not know the issues that are in question GMP compliance issues will be discussed with DMF holder (contract location), not applicant Is the information in a DMF suitable to support submissions to different Centers?

13. Problem Areas and Discussion Items How do you ensure that information in DMF is current when reviewed in context of an application? (cross-references, annual updates, etc) Concerns for contract facilities - how to ensure appropriate information is reviewed by applicant Concerns for multi-use facilities

14. Expectations for Contract Manufacturing There needs to be adequate control over the manufacturing process; Contamination or cross-contamination needs to be avoided; and There needs to be lot-to-lot consistency of the product

15. Expectations - continued Need to clearly define the responsibilities of each party (written agreement) Need to define how information will be shared, and what information will be shared (such as changes, new products, compliance issues) Regulatory filing should be harmonized between applicant and contractors

16. Expectations - continued Applicant is responsible for the manufacturing performed by the contract site Should be kept informed of all changes to the facility, process, and problems that may occur (deviations, complaints, adverse events, inspection issues)

17. Multi-Use Facilities Contract facilities are often not dedicated to one product, hence there are concerns related to the other products that are being produced in the facility Dedicated equipment vs shared equipment will impact on the level of concern and data needed to support current processes Campaign vs concurrent?

18. Concerns for Multi-use facilities Introduction of contaminants that are difficult to detect Cross-contamination between products Personnel alternating between two or more processes Manufacture of “unknown” products within the facility

19. Concerns for Multi-use facilities Responsibilities of both parties if problems are encountered; how effective will corrective actions be? Changes made to contract facility or processes; how will this information be conveyed to applicant?

20. Type V DMFs Summary Type V DMFs have been successfully used to submit a wide range of information to support regulatory submissions Need for this type of mechanism to convey important information, and with proper balance this can be achieved Problem areas exist, and with proper discussion and clarification they can be minimized

21. Type V DMFs Summary What guidance or clarification do you feel is needed to make Type V DMFs more useful? Do the processes and information submitted need more harmonization between Centers? Are there specific comments you’d like to make on the draft CBER guidance?

22. Contact and Reference Information Division of Manufacturing and Product Quality (HFM-670) 301 827-3031 Draft CBER guideline: http://www.fda.gov/cber/gdlns/dmfv.htm Eltermann@cber.fda.gov