US Regulatory Perspectives on Biologics Evaluation and Control

Ruth WolffBiologics Consulting Group

Legal Basis

Federal Food, Drug and Cosmetic ActPublic Health Service Act

Section 351

Jurisdiction

FD&C ActDrugsDevicesBiological products

Public Health Service ActBiological products

PHS Act

Requires a biologics licensePermits suspension and revocation of licensesReview of the manufacturing facility is integral to review of the product

Biological ProductVirusTherapeutic serumToxinAntitoxinVaccineBlood, blood component or derivativeAllergenic productTrivalent organic arsenic compoundAnalogous product

ExamplesDrug

Small moleculeOrgan derived product

Biological productVaccinePlasma fractionation product

DeviceBlood supply test kitAntibody based cell sorter

Code of Federal Regulations21CFR 312 Investigational drugs 21CFR 314 Drugs 21CFR 600 Biological products 21CFR 812 Investigational Devices21CFR 814 Devices21CFR 1271 Cells and Tissues21CFR 211 cGMP21CFR 820 Device Quality Systems

Product Evolution

Recombinant technologySynthetic moleculesSource material concernsProgress in health careCombination products

Combination Product

Two or more regulated components that are combined or mixed and produced as a single entityTwo or more separate products packaged together into a single package or unit

Recombinant Technology

Monoclonal antibodiesBiologic, analogous to blood

EnzymesBiologicDrug if predicate is organ – derived

Synthetic

PeptidesDrugBiologic

Nucleic acidsDrug

Source Material Concerns

Emerging health issuesRecombinant growth hormone - Drug

Supply concernsRecombinant clotting factor – BiologicRecombinant glucocerebrosidase – Drug

Health Care

Antibody conjugatesBiologic if radiolabeledBiologic if toxin conjugateDrug if chemical conjugate

Paired treatmentsCoated implantsInterferon and ribavarin

Product Jurisdiction

1990 amendment to FD&C ActConcept of combination productsClarification of product jurisdiction

1991 Intercenter AgreementsCDER/CBERCDER/CDRHCBER/CDRH

Intercenter AgreementsIntended to clarify product review assignmentsFor biological products, potential for inconsistenciesVariable expectations

Product understandingClinical programType of applicationRegulatory requirements

Governing regulations

Investigational products21CFR 312 for Drugs and Biologics21CFR 812 for Devices

Market applications21CFR 314 for Drugs21CFR 600 for Biologics21CFR 814 for Devices

Quality21CFR 211 for Drugs and Biologics21CFR 820 for Devices

Current thinking

Office of Combination ProductsCentral role in regulationDecisions on product jurisdiction

2005 Final RuleDefines Primary Mode of ActionProvides algorithm for assignment of lead center for product review

CDER / CDRH and CBER / CDRHGuidance to clarify distinction between drug and device (PMOA)Additional guidance in areas not envisioned by original documents

CBER / CDERAccount for transfer of therapeutic biological productsClarify assignment of single entity productsIntention to rescind agreement as obsolete

Changing ParadigmsFocused collaborations

Regulatory scienceImproved manufacturing methodologiesTools for effective drug developmentDelivery systemsContaminant detection systems

Medical sciencePredicting safety and efficacyBiomarkersClinical trial designData collection

Quality systems and risk managementHarmonize pharmaceutical and device requirements Incorporate advances in manufacturing scienceSix system inspection modelQuality by design

Practicalities

Today at FDAIncreasing responsibilities in all disciplinesDecreasing resourcesFocused attention on specific items

Process ValidationGreater understanding of process capabilitiesGreater scrutiny of small scale studies as predictors of commercial scale performanceVariability in validation requirements

SpecificationsData on which justifications are based

Test methodsFormal study to identify stability indicating assaysAppropriateness of host cell protein assay reagentsMethods to assess immunogenicity

Product comparabilityAppropriateness of methods usedCorrelation with clinical data

Greater scrutiny of clinical dataEndpoints chosenMeasurements of success

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