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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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