Manufacture of Phase I Investigational Drugs Exemption from Requirements of Part 211

1. Manufacture of Phase I Investigational DrugsExemption from Requirements of Part 211

2. July 9, 2008 Federal Register Notice • Announced amendment to 21CFR Part 210 to add paragraph (c) • “An investigational drug for use in a phase 1 study, as described in paragraph 312.21(a) of this chapter, is subject to the statutory requirements set forth in 21 U.S.C. 351(a)(2)(B). The production of such drug is exempt from compliance with the regulations in part 211 of this chapter.” • Exemption does not apply to an investigational drug for use in a Phase 1 study once the investigational drug has been made available for use by or for the sponsor in a phase 2 or phase 3 study or the drug has been lawfully marketed. • FDA also announced availability of “Guidance for Industry: CGMP for Phase 1 Investigational Drugs”

3. Statutory GMPs vs Regulatory GMPs • In notice, FDA distinguished between “statutory CGMPs” and “regulatory CGMPs” • Statutory CGMPs: set forth in U.S.C. Title 21: “A drug… shall be deemed to be adulterated…if it is a drug and the methods used in, or the facilities or controls used for, its manufacture, processing, packing, or holding do not conform to or are not operated or administered in conformity with current good manufacturing practice to assure that such drug meets the requirements of this chapter as to safety and has the identity and strength, and meets the quality and purity characteristics, which it purports or is represented to possess.” • Regulatory CGMPs: specified in Parts 210 and 211

4. Statutory GMPs vs Regulatory GMPs • Statutory CGMPs are mandated by Congress in Food Drug and Cosmetic (FD&C) Act • FDA is charged with responsibility to interpret and enforce the FD&C Act • Parts 210 and 211 are FDA’s interpretation of what the term CGMP means with respect to drugs • FDA has decided that Parts 210 and 211 do not apply to drugs used for Phase 1 investigational studies • Provided FDA follows the proper administrative process, it has authority to make that determination • First attempt through direct rule failed because of significant adverse comments; subsequently, standard notice and comment rulemaking approach was taken

5. FDA’s Committed to Change • “…FDA is amending the scope section of the drug CGMP regulations in part 210 to make clear that production of investigational drugs for use in phase 1 clinical trials conducted under an IND does not need to comply with the regulations in part 211. • “Therefore, this final rule exempts the production of phase 1 investigational drugs from complying with the regulatory requirements set forth in parts 210 and 211.” • Nearly a verbatim restatement of direct final rule published by FDA in January 2006. • Prepared by Working Group from CDER, CBER, ORA

6. FDA Clearly Stated It’s Rationale • “The approach described in this guidance reflects the fact that some manufacturing controls and the extent of manufacturing controls needed to achieve appropriate product quality differ not only between investigational land commercial manufacture, but also among the various phases of clinical trials.” • To “…assist the drug development process by streamlining the application of CGMP that is more appropriate to the manufacture of the earliest stage investigational drug products- those intended for phase 1 clinical trials.”

7. What Does CGMP Compliance Mean in the Context of the New Guidance? • Well-defined, written procedures • Adequately controlled equipment and manufacturing environment • Comprehensive and systematic evaluation of manufacturing setting to identify potential hazards to the quality of the drug • Appropriate actions prior to and during manufacturing to eliminate or mitigate potential hazards • Technologies to facilitate CGMP conformance and streamline product development • Upstream/downstream disposables • Pre-packaged materials • Closed process equipment • Contract or shared CGMP manufacturing facilities

8. Specific Manufacturing Controls • Trained and experienced personnel • Formal QC function • Adequate work areas and equipment • Component control and traceability • Written manufacturing and process control procedures • Manufacturing records • Record of changes in procures and processes • Record of microbiological controls • Laboratory controls • Packaging, labeling and distribution controls • Record keeping

9. Special Manufacturing Considerations • Multi-product facilities • Cross-control • Dedicated equipment • Biological and biotechnological products • Process consistency • Retained samples • Assurance that safety-related functions are effective • Sterile/aseptically processed products • Manual filling of small batches • Time-sensitive or labile products • Personalized medicines • Small batch size • Often autologous

10. Why Necessary? FDA Facing Challenges • Accommodate major changes in new drugs • More pharmacologic specificity and fewer side effects • Directed toward niche applications; fewer blockbuster products • Intended for specific genotypes; personalized drugs • Resolve conflicting pressures on drug approval • Reduce cost of drug development • Make new drugs available as quickly as possible • Zero tolerance for risk • Improve safety of drugs on the market • Improve product review process • Strengthen post-marketing surveillance • Avoid real or perceived conflicts of interest • Increase food safety, regulate tobacco, deal with imports, spurn PDUFA $, hire and train more people 10

11. Clear Benefits for FDA and Industry • Smaller less-costly facilities • Disposables and pre-mixed solutions sanctioned • All levels of manufacturing infrastructure reduced • Time/cost of manufacturing Phase I product reduced • More products can enter Phase 1 • Provides clarity of FDA’s expectations for Phase 1 • Part 211 not being enforced on Phase 1 manufacturing • Phase 1 manufacturing sites virtually never inspected • Better defines CMC requirements for Phase 1 IND • Addresses needs to source product for physician INDs • Allows FDA to focus on later stages of drug development • Serves public interest 11