Regulatory Filing & Pre- License/Pre-Approval Inspections of ...

Regulatory Filing & Pre-License/Pre-Approval Inspections ofTherapeutic Biological ProteinsAnastasia G. LolasBiotechnology Manufacturing TeamDivision of Manufacturing and Product QualityOffice of ComplianceCenter for Drug Evaluation and ResearchLean for Biotechnology Symposium, February 20111

Outline‣ Regulatory authority‣ Organization‣ Application review‣ Review issues‣ Pre-license & Pre-approval inspections‣ FDA Form 483 Observations from BMTledinspections2

Regulatory Authority3

Current Laws‣ Public Health Service Act – Section 351(a)(2)(B)• Licensure of biological establishments and products– Biological product is safe, pure, and potent– Facility meets standards to assure a safe, pure, andpotent product– Applicant (or other appropriate person) consents to theinspection of the facility‣ Federal Food, Drug and Cosmetic Act• Interprets that “biological products” are also “drugs”• Applies to a biological product except no applicationrequired under Section 505Inspections under the provisions of both Acts (PHS & FD&C)4

21 CFR Part 601 - LicensingRelevant Sections‣Applications (601.2)‣Issuance and denial of license (601.4)‣Revocation (601.5)‣Suspension (601.6)‣Changes to be reported (601.12)6

Therapeutic Biological ProductsTransferred to CDER in 2003‣ Monoclonal antibodies for in vivo use‣ Proteins intended for therapeutic use that are extractedfrom plants, animals or microorganisms, includingrecombinant versions of these products (except clottingfactors)• Cytokines, growth factors, enzymes, immunomodulators, andthrombolytics‣ Growth factors, cytokines, and monoclonal antibodiesintended to mobilize, stimulate, decrease or otherwise alterthe production of hematopoietic cells in vivo‣ Most that are regulated by CDER are “specified” biologics8

“Specified” Biological Products –Regulatory Differences‣ Certain 600 regulations do not apply (per 601.2(c)):• Exempt from General Safety Testing (610.11)• Package labeling requirements harmonized with NDAregulations (e.g., exempt from 610.62)‣ Complete Establishment Description Section of BLAnot required‣ Official FDA Lot Release (610.2) generally notimplemented9

21 CFR 601.2 - Applications forbiologics licenses; procedures for filing(a) General. To obtain a biologics license…themanufacturer shall submit an application……and the address of each location involved in themanufacture of the biological product shall belisted in the biologics license application. Anapplication for a biologics license shall not beconsidered as filed until all pertinent informationand data have been received…10

21 CFR 601.20 – Biologics licenses;issuance and conditions‣Product examination - compliance withrequirements‣Availability of product for examination andinspection during all phases of manufacture‣Inspection - compliance with requirements‣One biologics license to cover all locations;each location subject to inspection by FDA11

21 CFR 600.20 & 600.21 – Inspectors& Time of Inspection‣ Inspections by an officer of the FDA with specialknowledge of the manufacturing methods andcontrols‣ Inspection conducted while the establishment is inoperation and is manufacturing the completeproduct for which a biologics license is desired‣ Inspection of each licensed establishment and itsadditional location(s) at least once every two years12

Organization13

Biotech Manufacturing Team‣Ensure that safe, pure and potenttherapeutic biological products areavailable to the public‣Accomplished through CMC reviews of BLAand supplement submissions, PLI/PAIinspections and formal meetings withindustry in close collaboration with ONDand OBP14

Division of Manufacturing and Product Quality (DMPQ) 1/19/2011Joy Sharp (Acting)Senior AdvisorRuby Tiwari (Acting)Special AssistantSheila BanksProject SpecialistVacantAssociate DirectorVacantAssociate DirectorRegulatory ScienceVacantAssociate DirectorDrug Quality AssuranceRick FriedmanDivision DirectorMichael SmedleyDeputy Division DirectorBrian HasselbalchTeam LeaderGuidance and PolicyPam Grant (Acting)Program AnalystPaula KatzGrace McNallyLarry OuderkirkFrank PerrellaDiane RaccasiEllen KemplerProgram AnalystEmily LeonginiRegulatory CounselKennerly ChapmanHelen SacconeKeith OIinProject ManagementOfficersCarmelo Rosa, (Acting)Branch ChiefInternational ComplianceBranchTemeka MooreProgram AnalystTeddi LopezBranch ChiefDomestic CaseManagementBranchRhonda HillProject SpecialistBarry RothmanBranch ChiefManufacturing Assessment &Pre-Approval Compliance BranchSteven J. LynnBranch ChiefRecall and ShortagesBranchLynise Fox(Detail) Project SpecialistRegulatory CounselChristina PicardDouglas Campbell (Acting)Team Leader 1International ComplianceMaan AbduldayemAllison AldridgeRafael ArroyoPaul BalcerSarah Campbell (ORISE)Karthik Iyer (detail)Allison KlineCesar MattoEdwin MelendezMilva MelendezHidee MolinaAlicia MozzachioKristy ZielnyBrian Belz (Acting)Team Leader 2International ComplianceRaphael BrykmanAnthony CharityElizabeth PhilpyYanyan (Jenny) QinKaren TakahashiAllison Kline (ORISE)Doug PhamRegulatory CounselDavid JaworskiTeam Leader 1Domestic CaseManagement TeamTamara ElyTamara Felton-ClarkMetitia GrambyPaul HaynieJennifer StoneRosa MottaTeam Leader 2Domestic CaseManagement TeamCelestina ArowosegbeMilind GanjawalaDonald LechSteven ThurberKathy McLeanProject SpecialistTara GooenTeam Leader 1New and GenericDrugManufacturingVipul DholakiaLori Gorski (on detail)Shawn GouldZi Qiang GuApril InyardMahesh RamanadhamVibhakar ShahDerek Smith (ORISE)M. Toulouse (ORISE)Coki CruzTeam Leader 2New and GenericDrugManufacturingDenise DiGiulioFrancis GodwinSteven HertzJaewon HongColleen Hoyt(CFSAN detail)Hea S. KielTim PohlhausArun ShakyaMarisa StockDona JonesPatricia HughesTeam LeaderBiotechManufacturingTeamBo ChiMichelle Clark-StuartAnastasia LolasMary FarbmanDonald ObenhuberKala SuvarnaMin (Cindy) TangColleen ThomasWilliam Fritsch (Acting)Team LeaderRecall and ShortagesRay BrownSiang DunRichard CharlestonLavonia HuffJoseph TraceyIsrael SantiagoTeam LeaderRecall and ShortagesTeam 2Doris ChinCatherine GouldJuWon LeeBabette MerrittSilvia WanisSteven WolfgangTeam LeaderData Analysis TeamMark BrowningRicardo Wilkinson (on detail)Hui Talia Zhang16

Application Review17

BMT Review of a BLADrug Substance‣ Microbial control‣ Release of bulk drug substance‣ Qualification of in-process and releasemicrobial methods‣ Media and buffers‣ Column cleaning/sanitization/storage‣ Shipping validation18

Drug ProductBMT Review of a BLAMicrobial control, sterility assurance and microbialproduct quality attributes‣ Bulk thaw, hold limits‣ Sterile filtration‣ Depyrogenation and sterilization of components‣ SIP of equipment in direct contact with sterileproduct‣ Media fills19

BMT Review of a BLADrug Product (cont.)Microbial control, sterility assurance and microbialproduct quality attributes‣ Environmental monitoring‣ Lyophilization‣ In-process and release testing (sterility,bioburden, endotoxin, etc.)‣ Stability (sterility, endotoxin, container-closureintegrity, reconstitution conditions, etc.)‣ Shipping validation20

Review Issues‣ Facility registration‣ Preliminary production schedule‣ All manufacturing steps described in detail‣ Microbial control strategy‣ Qualified test methods‣ In-process/intermediate pool hold times‣ Shipping validation22

Review Issues‣ Bulk thaw & hold limits‣ Bacterial filter retention studies‣ Container-closure integrity‣ Moist heat sterilization of components(minimum & maximum loads)‣ Rationale for worst case supported by data23

Pre-License & Pre-ApprovalInspections24

Purpose of Inspection‣Meet statutory obligation in FD&C and PHSActs‣Verify compliance with CGMP and applicablesections of 21 CFR 600 and 21 CFR 210 and 211‣Verify compliance with commitmentssubmitted in the application‣Evaluate process consistency for safe, pureand potent products25

Pre-License & Pre-ApprovalInspections‣Conducted by CDER reviewers in DMPQ/BMTand OBP/DMA or OBP/DTP with BMT as thelead‣District invited to participate (domesticinspections)‣PLIs and PAIs are announced‣Biennial (or surveillance) inspections areconducted after approval typically by ORA26

Inspection StrategySystems-based‣Quality System‣Facilities and Equipment‣Production System‣Materials‣Laboratory Controls‣Packaging and Labeling27

Inspection Classification‣No action indicated (NAI)• Form FDA 483 not issued, EIR written‣Voluntary action indicated (VAI)• Form FDA 483 issued• Responsible person must respond regardingobservations‣Non-concur approval• Non approval of BLA or supplement• Manufacturer has opportunity to correct28

Inspection Outcome & Approval‣A response to 483 observations is required inorder to receive approval & licensing‣Response to 483 observations must be sentwithin 15 business days‣DMPQ reviews response and providesrecommendation for final action29

FDA Form 483 Observationsfrom BMT-led Inspections30

Quality Oversight‣Inadequate quality oversight• Drug substance batches with high bioburdencounts released• Batches that exceeded validated parameterranges upstream and were processeddownstream• Missed water samples, inadequate tracking anddocumentation to ensure that water andenvironmental monitoring samples are obtainedat the specified frequencies31

RecordsRecord control is inadequate. Batch records forbuffer, media lost and not reviewed orapproved by QA.32

SOPs‣ SOPs are not executed consistently for themanagement of deviations, change control,laboratory records, and logbooks.‣ Standard operating procedures are not alwaysfollowed by operators. Specifically, several criticalnon-conformances resulted from disregard ofstandard operating procedures by both operatorsand second verifiers of critical operations.‣ Numerous deviations due to SOPs been withdrawn& newer version not available at different areas ofthe facility.33

Facility Premises‣ Pest control issues‣ Not clean and well-maintained facilities‣ Environmental monitoring issues (mold, etc.)34

Utilities‣High bioburden counts for water used asfinal rinse for equipment cleaning‣No monitoring of process gases‣Utility area found in disrepair (corrosion,leaking pipe)35

Equipment‣Inadequate validation of sterile hold time forbioreactor‣Ineffective schedules and procedures forpreventive maintenance of equipment (largenumber of production process deviations dueto equipment failures)‣Inadequate validation of dirty hold times36

Production‣Discrepancies between manufacturing processsubmitted in the BLA and batch records‣Inadequate aseptic technique observedduring final bulk filtration‣Hold times for in-process intermediates andeluates not validated‣Effect of used and repacked resins on productquality not qualified‣UF/DF membrane lifetime not established37

Production (cont.)‣ Product “Y” commercial process lacks consistentprocess control (significant adjustments after processvalidation, inconsistent yields)‣ Incomplete process validation (addition of processcontrol parameters, modifications to set points,changes to process design after “validation”)‣ Inadequate microbial control‣ Resin and UF/DF lifetime not monitored formicrobial control‣ Inadequate management of buffer and productcontacthoses38

Laboratory‣Assays not appropriate for their intendedpurpose and/or not qualified‣Laboratory records for the potency assay donot have sufficient detail, do not crossreference appropriate procedures to ensureconsistent method execution, and do notdescribe all steps‣Inappropriate handling and storage of thereference standard39

Materials‣ Validated expiration or use-by dates forcritical raw materials not supported by data(cell culture medium)‣ Materials not appropriately segregated(quarantined, released, etc.)40

Additional Information/Resources‣ FD&C and PHS Acts‣ 21 CFR 210, 211, 600s‣ CP 7356.002M “Inspections of Licensed BiologicalTherapeutic Drug Products”‣ Investigations Operations Manual‣ Guidance documents‣ MAPP 4730.3 “Office of Biotechnology Products and Officeof Compliance Division of Manufacturing & Product QualityInteractions on BLA Assessments”‣ “CMC Microbiology Review of Biologics License Applicationsand Pre-License/Pre-Approval Inspections: TherapeuticBiological Proteins” in American Pharmaceutical Review,March 201041

Acknowledgements• Patricia Hughes, Ph.D.• Kalavati Suvarna, Ph.D.• Bo Chi, Ph.D.Thank you!42

Contact InformationAnastasia Lolas301-796-1566anastasia.lolas@fda.hhs.gov43