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Pilot Plant through Scale-Up Manufacturing

Martha A. Feldman, RACDrug & Device Development Co., Inc.P.O. Box 3515 Redmond, WA 98073-3515 USA1-425-861-8262 FAX: 1-425-869-5854mfeldman@druganddevice.com

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Pilot Plant

• Needed to make supplies for– bench studies,

• product characterization, purity

– animal studies• toxicology• pharmacokinetics, ADME• efficacy

– clinical studies

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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

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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

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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

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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

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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

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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

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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

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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

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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)

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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

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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)

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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

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Quality System Regulation 2

• Corrective and Preventive Action• Labeling and Packaging Control• Handling, Storage, Distribution

and Installation• Records• Servicing• Statistical Techniques

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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)

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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

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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_man.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/qsitguide.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/qsitguide.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

• 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.