Pilot Plant through Scale-Up Manufacturing

1. Pilot Plant through Scale-Up Manufacturing Martha A. Feldman, RAC Drug & Device Development Co., Inc. P.O. Box 3515 Redmond, WA 98073-3515 USA 1-425-861-8262 FAX: 1-425-869-5854 mfeldman@druganddevice.com Feldman 20 February 2003

2. Pilot Plant • Needed to make supplies for • bench studies, • product characterization, purity • animal studies • toxicology • pharmacokinetics, ADME • efficacy • clinical studies Feldman 20 February 2003

3. Regulations • Code of Federal Regulations Title 21 • Part 210 and 211 - Good Manufacturing Practices for Drugs • Part 600 - 680 Processing of Biological materials • Part 820 - Quality System Regulations for Medical Devices • Subpart C: Design Controls Feldman 20 February 2003

4. Initial Manufacturing Stages • Goals: • increasing compliance with regulations as product moves through testing and evaluation • increasing knowledge about the product • increasing knowledge about the possible problems, snags, pitfalls with manufacturing, processing, packing, storing (and installing) the product Feldman 20 February 2003

5. Drugs and Biologics Feldman 20 February 2003

6. Clinical Trials Supplies for Drugs and Biologics -1 • Prior to phase I: need product safety testing and basic characterization information, cell bank characterization • Phase I/II: requires completed safety profile and further characterization of the product (stress testing), process controls, assay descriptions, beginning specifications or limits Feldman 20 February 2003

7. Clinical Trials Supplies for Drugs and Biologics -2 • Phase III requires full characterization: • Impurities profiles • Specifications: Identity, Potency, Purity, Safety • Raw materials testing • Stability testing Process Validation • Container/closure Analytical Validation • Process controls Equipment Validation • Batch records Facility Validation • Yield expectations Feldman 20 February 2003

8. Good Manufacturing Practices 1 • Part 210 • Current GMPs in manufacturing, processing, packing or holding of drugs • Part 211 • Current GMPs for finished pharmaceuticals • Ten major areas Feldman 20 February 2003

9. Good Manufacturing Practices 2 • Organization and Personnel • Buildings and Facilities • Equipment • Control of components and drug product containers and closures • Production and process controls • Packaging and labeling control • Holding and distribution • Laboratory Controls • Records and reports • Returned and salvaged drug products Feldman 20 February 2003

10. Good Manufacturing Practices 3 • When regulations in Parts 600-680 (biologics) are in conflict with these regulations, the ones most closely pertaining to the drug product will supersede. • This regulation may not be applicable to OTC products that are ordinarily marketed and consumed as human food. Feldman 20 February 2003

11. Biologics Manufacturing (21 CFR Parts 600-680) • Current GMPs for blood and blood components • General biological products standards • General requirements for blood, blood components and blood derivatives • Additional standards for human blood and blood products • Additional standards for diagnostic substances for laboratory tests • Additional standards for miscellaneous products Feldman 20 February 2003

12. Medical Devices Feldman 20 February 2003

13. Initial Development - 1 • Must follow Design Controls from the outset (Design Controls for Medical Device Manufacturers [Mar 1997] http://www.fda.gov/cdrh/comp/designgd.html • Must develop or use validated tests to determine • operating conditions, e.g., temperature, humidity, altitude limits • reliability • durability; robustness • stability; shelf life • biocompatibility • ergonomics, e.g., ease of use Feldman 20 February 2003

14. Initial Development - 2 • sterility • electromagnetic compatibility • radio frequency interference • electromagnetic compatibility • radio frequency interference • electrical leakage • power output • material strength, flexibility, durability, etc. Feldman 20 February 2003

15. Initial Development - 3 • Must develop vendor qualifications • If using contract manufacturer, should obtain prior Inspection Reports (483s), do an independent audit • Must develop training program for others, e.g., receptionist (regarding calls on complaints, visits by FDA inspectors), customer service (re: complaints), etc. Feldman 20 February 2003

16. Clinical Trial Supplies for Medical Devices -1 • Device must meet Design Controls • Design input and output • Design review • Verification and validation • If changes occur during clinical study • Simple modifications: • Clarify Instructions For Use • Annual Report (812.150) • 5-Day Notice (812.35) Feldman 20 February 2003

17. Clinical Trial Supplies for Medical Devices - 2 • Significant changes • Modification to study design or device material • IDE Supplement requiring approval (812.35) • Who decides what to submit? • Decision on which type of submission is manufacturer’s responsibility • Decision is based on • Range of minor to significant • Type of device • Type of modification Feldman 20 February 2003

18. Clinical Trial Supplies for Medical Devices - 3 • Credible information (812.35) • Used to support developmental changes in the device (including manufacturing changes) • Includes data generated under • design control procedures • preclinical/animal testing • FDA-issued testing (e.g., guidance) • peer reviewed published literature • other reliable information (e.g., clinical data) Feldman 20 February 2003

19. Quality System Regulation 1(21 CFR Part 820) • QS Requirements - management responsibility • Design Controls • Document Controls • Identification and Traceability • Production and Process Controls • Acceptance Activities • Nonconforming Product Feldman 20 February 2003

20. Quality System Regulation 2 • Corrective and Preventive Action • Labeling and Packaging Control • Handling, Storage, Distribution and Installation • Records • Servicing • Statistical Techniques Feldman 20 February 2003

21. Software-driven Medical Devices • Software verification, validation and testing required • Must look at integration as features or modules are added • Guidance documents: • General principles of software validation, Guidance for Industry and FDA http://www.fda.gov/cdrh/comp/guidance/938.html (Jan 11, 2002) • Off-the-Shelf Software use in medical devices http://www.fda.gov/cdrh/ode/guidance/585.html (Sep 9, 1999) • Content of Premarket Submissions for software contained in medical devices http://www.fda.gov/cdrh/ode/57.html (May 28, 1999) Feldman 20 February 2003

22. In Vitro Diagnostic Devices Feldman 20 February 2003

23. Clinical Trial Supplies for IVDs • May need to consider both GMP and QSR regulation • Design controls apply for device aspects • Depending on components, may follow parts of 21 CFR 600-680 and 820 • New office in CDRH for IVDs; led by Dr. Steven Gutman Feldman 20 February 2003

24. References • Guideline for the manufacture of in vitro diagnostic products (Jan 10, 1994) http://www.fda.gov/cdrh/comp/918.pdf Feldman 20 February 2003

25. FDA Inspections of Manufacturing Facilities Feldman 20 February 2003

26. FDA Inspections • Medical Device Quality Systems Manual, A Small Entity Compliance Guide, (Apr 14, 1999) http://www.fda.gov/cdrh/dsma/gmp_man.html Feldman 20 February 2003

27. QSIT Approach • Quality System Inspection Technique • 7 major systems • do CAPA and one other • Guide to Inspections of Quality Systems Handbook (Aug 1999) http://www.fda.gov/ora/inspect_ref/igs/qsit/qsitguide.htm Feldman 20 February 2003

28. References • 21 CFR Parts 210, 211, 600 - 680, 820 • Guidance documents • Guide to Inspection of Quality Systems http://www.fda.gov/ora/inspect_ref/igs/qsit/qsitguide.htm • Inspection of Medical Device Manufacturers, Final Guidance for Industry and FDA http://www.fda.gov/cdrh/comp/7382.845.html Feldman 20 February 2003

29. More References • Center for Drug Evaluation and Research, List of Guidance Documents (Jan 6, 2003) http://www.fda.gov/cder/guidance/guidlist.pdf • General Principles of Process Validation • Drug Master Files • Sterilization Process Validation • SUPAC (Scale-Up and Post-Approval Changes) - several documents • etc. Feldman 20 February 2003