1. Feldman 20 February 20031 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

2. Feldman 20 February 20032 Pilot Plant Needed to make supplies for –bench studies, product characterization, purity –animal studies toxicology pharmacokinetics, ADME efficacy –clinical studies

3. Feldman 20 February 20033 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

4. Feldman 20 February 20034 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

5. Feldman 20 February 20035 Drugs and Biologics

6. Feldman 20 February 20036 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

7. Feldman 20 February 20037 Clinical Trials Supplies for Drugs and Biologics -2 Phase III requires full characterization: –Impurities profiles –Specifications: Identity, Potency, Purity, Safety –Raw materials testing –Stability testingProcess Validation –Container/closureAnalytical Validation –Process controlsEquipment Validation –Batch recordsFacility Validation –Yield expectations

8. Feldman 20 February 20038 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

9. Feldman 20 February 20039 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

10. Feldman 20 February 200310 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.

11. Feldman 20 February 200311 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

12. Feldman 20 February 200312 Medical Devices

13. Feldman 20 February 200313 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

14. Feldman 20 February 200314 Initial Development - 2 –sterility –electromagnetic compatibility –radio frequency interference –electromagnetic compatibility –radio frequency interference –electrical leakage –power output –material strength, flexibility, durability, etc.

15. Feldman 20 February 200315 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.

16. Feldman 20 February 200316 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)

17. Feldman 20 February 200317 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

18. Feldman 20 February 200318 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)

19. Feldman 20 February 200319 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

20. Feldman 20 February 200320 Quality System Regulation 2 Corrective and Preventive Action Labeling and Packaging Control Handling, Storage, Distribution and Installation Records Servicing Statistical Techniques

21. Feldman 20 February 200321 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)

22. Feldman 20 February 200322 In Vitro Diagnostic Devices

23. Feldman 20 February 200323 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

24. Feldman 20 February 200324 References Guideline for the manufacture of in vitro diagnostic products (Jan 10, 1994) http://www.fda.gov/cdrh/comp/918.pdf

25. Feldman 20 February 200325 FDA Inspections of Manufacturing Facilities

26. Feldman 20 February 200326 FDA Inspections Medical Device Quality Systems Manual, A Small Entity Compliance Guide, (Apr 14, 1999) http://www.fda.gov/cdrh/dsma/gmp_m an.html

27. Feldman 20 February 200327 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/qsit guide.htm

28. Feldman 20 February 200328 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/qsit guide.htm –Inspection of Medical Device Manufacturers, Final Guidance for Industry and FDA http://www.fda.gov/cdrh/comp/7382.845.html

29. Feldman 20 February 200329 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.