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Regulatory Aspects of Regulatory Aspects of Pharmaceutical Pharmaceutical

ExcipientsExcipients

PQRI WorkshopPQRI Workshop

Nick BuhayNick BuhayActing DirectorActing DirectorDivision of Manufacturing and Product Division of Manufacturing and Product QualityQualityOffice of ComplianceOffice of ComplianceCenter for Drug Evaluation and Center for Drug Evaluation and ResearchResearchFood and Drug AdministrationFood and Drug Administration

Marriott Hotel and Convention CenterMarriott Hotel and Convention CenterOctober 10, 2006October 10, 2006

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Oversight of Excipient Oversight of Excipient Manufacturing QualityManufacturing Quality

Current oversight programCurrent oversight program– Monitoring the uses/types of excipientsMonitoring the uses/types of excipients– Monitoring excipient quality Monitoring excipient quality – Monitoring of manufacturing problems Monitoring of manufacturing problems

based on excipient qualitybased on excipient quality– Recognition of use of Voluntary CGMPRecognition of use of Voluntary CGMP– Participation in review of standards, Participation in review of standards,

industry inputindustry input– Oversight of user control of excipients: Oversight of user control of excipients:

application conditions of approval, CGMPapplication conditions of approval, CGMP– ‘‘For cause’ inspection of excipient mfg as For cause’ inspection of excipient mfg as

drug; other regulators’/other FDA drug; other regulators’/other FDA inspectioninspection

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Excipient Excipient ManufacturingManufacturing

Subject to statutory requirements Subject to statutory requirements in section 510 (a) (2) (B) of the in section 510 (a) (2) (B) of the Food, Drug and Cosmetic ActFood, Drug and Cosmetic Act– Excipients must be manufactured, Excipients must be manufactured,

processed, packaged and held in processed, packaged and held in conformity with Current Good conformity with Current Good Manufacturing Practice (CGMP)Manufacturing Practice (CGMP)

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Models for CGMP Models for CGMP ConformanceConformance

FDA has not developed FDA has not developed regulations or specific guidance regulations or specific guidance on CGMP conformance for on CGMP conformance for excipientsexcipients

ICH Q7A GMP Guidance for APIs ICH Q7A GMP Guidance for APIs contains applicable guidancecontains applicable guidance

However, FDA is supportive of the However, FDA is supportive of the IPEC GMP Guide for Bulk IPEC GMP Guide for Bulk Pharmaceutical ExcipientsPharmaceutical Excipients

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Drug Excipient QualityDrug Excipient Quality

Quality characteristics of excipients Quality characteristics of excipients are significant to the overall quality of are significant to the overall quality of the drug products in which they are the drug products in which they are usedused

Drug product manufacturers rely on Drug product manufacturers rely on excipient manufacturers to provide excipient manufacturers to provide excipients of uniform quality, physical excipients of uniform quality, physical and chemical characteristics, e.g., and chemical characteristics, e.g., levels of impuritieslevels of impurities

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Drug Excipient Drug Excipient ManufacturersManufacturers

Specification development based on Specification development based on critical quality attributescritical quality attributes

Process controls that ensure Process controls that ensure consistent conformance with consistent conformance with specificationsspecifications

Every batch is tested to ensure Every batch is tested to ensure conformance with all specificationsconformance with all specifications

Provide reliable test data to drug Provide reliable test data to drug product manufacturersproduct manufacturers

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Drug Product Drug Product ManufacturersManufacturers

Identify excipients needed for Identify excipients needed for drug product formulations, drug product formulations, including physical and chemical including physical and chemical characteristicscharacteristics

Conformance with the CGMP Conformance with the CGMP regulations in 21 CFR 211.84regulations in 21 CFR 211.84

Qualify sources of excipients Qualify sources of excipients

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Drug Product Drug Product ManufacturersManufacturers

21 CFR 211.84(d)(2) requires the 21 CFR 211.84(d)(2) requires the user/drug product manufacturer to test user/drug product manufacturer to test every batch of drug excipient for every batch of drug excipient for conformity with written specifications, conformity with written specifications, for purity, strength and qualityfor purity, strength and quality

However, drug product manufacturers However, drug product manufacturers can rely on their suppliers for this can rely on their suppliers for this testing, provided that the reliability of testing, provided that the reliability of the suppliers’ test results is validated the suppliers’ test results is validated at appropriate intervalsat appropriate intervals

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Drug Product Drug Product ManufacturersManufacturers

The CGMPs are not specific as to The CGMPs are not specific as to the method and frequency of the method and frequency of validating test results provided by validating test results provided by supplierssuppliers

Drug product manufacturers should Drug product manufacturers should have SOPs detailing a scientifically have SOPs detailing a scientifically sound approach to ensure periodic sound approach to ensure periodic validation of suppliers’ test resultsvalidation of suppliers’ test results

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Drug Product Drug Product ManufacturersManufacturers

For excipients that are critical to For excipients that are critical to the quality of the finished dosage the quality of the finished dosage form, testing by the drug product form, testing by the drug product manufacturer may be necessary manufacturer may be necessary to verify the critical attributes of to verify the critical attributes of every batchevery batch

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Drug Excipient QualityDrug Excipient Quality

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