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 [email protected]

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Pilot Plant

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

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 3

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 4

Drugs and Biologics

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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 6

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 – Container/closure Process Validation Analytical Validation – Process controls – Batch records – Yield expectations Equipment Validation Facility Validation Feldman 20 February 2003 7

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 8

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 9

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.

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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 11

Medical Devices

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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 13

Initial Development - 2

– sterility – electromagnetic compatibility – radio frequency interference – electromagnetic compatibility – radio frequency interference – electrical leakage – power output – material strength, flexibility, durability, etc.

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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.

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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 16

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 17

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 18

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 19

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 20

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) 21

In Vitro

Diagnostic Devices

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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 23

References

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

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FDA Inspections of Manufacturing Facilities

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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

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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

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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

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More References

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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.

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