PREPARING FOR AN PREPARING FOR AN FDA INSPECTIONFDA INSPECTIONFDA INSPECTIONFDA INSPECTION

August 11, 2011August 11, 2011Kip J. Hanks, InvestigatorKip J. Hanks, InvestigatorBiologics National ExpertBiologics National ExpertBiologics National ExpertBiologics National Expert

FDA Division of Domestic Field InvestigationsFDA Division of Domestic Field Investigations

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IS HE SPEAKING ENGLISH?IS HE SPEAKING ENGLISH?IS HE SPEAKING ENGLISH?IS HE SPEAKING ENGLISH?

•• cGMPcGMP: Current Good : Current Good Manufacturing PracticeManufacturing Practice

•• PHS ActPHS Act: Public Health Service Act: Public Health Service Act

•• EIEI: Establishment Inspection: Establishment Inspection•• EIREIR: EI Report: EI Report•• IOMIOM: Investigations Operations : Investigations Operations

•• CFRCFR: Code of Federal Regulations: Code of Federal Regulations•• CPCP: Compliance Program: Compliance Program•• BLABLA: Biologics License Application: Biologics License Application

ManualManual•• FD&C ActFD&C Act: Food, Drug & Cosmetic : Food, Drug & Cosmetic

ActAct•• INDIND I i i l N D I i i l N D•• HCT/P: HCT/P: Human Cells, Tissues and Human Cells, Tissues and

Cellular and TissueCellular and Tissue--Based ProductsBased Products•• BIMO: BIMO: BIoresearch MOnitoringBIoresearch MOnitoring

•• INDIND: Investigational New Drug: Investigational New Drug•• MS: MS: MusculoSkeletalMusculoSkeletal•• HPC: HPC: Hematopoietic Hematopoietic

stem/Progenitor Cellstem/Progenitor Cellstem/Progenitor Cellstem/Progenitor Cell

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WHAT ARE WE ATTEMPTING WHAT ARE WE ATTEMPTING TODAY?TODAY?

•• ME: Outline FDA’s approach to inspecting ME: Outline FDA’s approach to inspecting cGMPs specifically for facilities processing cGMPs specifically for facilities processing cellular therapy products. cellular therapy products.

•• YOU: Learn how to prepare for an FDA YOU: Learn how to prepare for an FDA p pp pinspection and understand the parameters, inspection and understand the parameters, approaches and concerns of FDA investigators.approaches and concerns of FDA investigators.pp gpp g

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WHAT AM I WHAT AM I NOTNOT ATTEMPTING ATTEMPTING TODAY?TODAY?

•• Give you the history of FDA’s regulation of Give you the history of FDA’s regulation of cellular therapy products.cellular therapy products.

•• Make you an expert on all things FDA.Make you an expert on all things FDA.•• Provide you with any secrets or shortcuts on Provide you with any secrets or shortcuts on Provide you with any secrets or shortcuts on Provide you with any secrets or shortcuts on

how to not receive an FDA 483, Inspectional how to not receive an FDA 483, Inspectional ObservationsObservationsObservations.Observations.

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DO I HAVE “361” OR “351” DO I HAVE “361” OR “351” HCT/Ps?HCT/Ps?

•• 361361–– PHS Act Section 361PHS Act Section 361–– 21 CFR 127121 CFR 1271

M ll f 2M ll f 2

•• 351351–– PHS Act Section 351 & FD&C PHS Act Section 351 & FD&C

ActAct21 CFR 1271 210/211 60021 CFR 1271 210/211 600–– Must meet all of criteria in 21 Must meet all of criteria in 21

CFR 1271.10(a)CFR 1271.10(a)–– Premarket approval not Premarket approval not

requiredrequired

–– 21 CFR 1271, 210/211, 60021 CFR 1271, 210/211, 600--680680

–– Those HCT/Ps that don’t meet Those HCT/Ps that don’t meet 1271.10(a)1271.10(a)qq

–– Reproductive, MS, ocular and Reproductive, MS, ocular and heart tissue; hematopoietic heart tissue; hematopoietic stem cells; skin; arteries and stem cells; skin; arteries and veins; dura materveins; dura mater

–– Premarket approval may be Premarket approval may be requiredrequired

–– Vaccines; manipulated, Vaccines; manipulated, cultured or expanded cell cultured or expanded cell veins; dura materveins; dura mater

–– CP 7341.002, Inspection of CP 7341.002, Inspection of HCT/PsHCT/Ps

cultured or expanded cell cultured or expanded cell productsproducts

–– CP 7345.848, Inspection of CP 7345.848, Inspection of Biological Drug ProductsBiological Drug Products

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HPCsHPCsHPCsHPCs

•• Regulatory framework for HPCs derived from Regulatory framework for HPCs derived from peripheral or cord blood is dependent upon whether peripheral or cord blood is dependent upon whether the product meets criteria in 21 CFR 1271 10(a) the product meets criteria in 21 CFR 1271 10(a) andandthe product meets criteria in 21 CFR 1271.10(a) the product meets criteria in 21 CFR 1271.10(a) andandthe intended use:the intended use:–– If intended for unrelated allogeneic use, then they’re If intended for unrelated allogeneic use, then they’re

regulated under PHS Act 351 as drugs, devices and/or regulated under PHS Act 351 as drugs, devices and/or biological products.biological products.

–– If intended for autologous use or allogeneic in 1If intended for autologous use or allogeneic in 1stst or 2or 2ndndg gg gdegree blood relatives, and meet criteria in 1271.10(a), degree blood relatives, and meet criteria in 1271.10(a), then they’re regulated under PHS Act 361.then they’re regulated under PHS Act 361.

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REMEMBERREMEMBERREMEMBER…REMEMBER…

•• Many HCT/P establishments that process HPCs Many HCT/P establishments that process HPCs derived from peripheral or cord blood derived from peripheral or cord blood manufacture the products for use in both (1) manufacture the products for use in both (1) unrelated allogeneic and (2) autologous or 1unrelated allogeneic and (2) autologous or 1stst

or 2or 2ndnd--degree blood relative allogeneic use, degree blood relative allogeneic use, i.e. it is common for manufacturers to produce i.e. it is common for manufacturers to produce both HPCs regulated solely under PHS Act 351 both HPCs regulated solely under PHS Act 351 and HPCs regulated under PHS Act 361.and HPCs regulated under PHS Act 361.

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CORD BLOOD BANKSCORD BLOOD BANKSCORD BLOOD BANKSCORD BLOOD BANKS

•• Ellen F. Lazarus, MD’s presentation:Ellen F. Lazarus, MD’s presentation:–– www.fda.gov/downloads/BiologicsBloodVaccines/www.fda.gov/downloads/BiologicsBloodVaccines/

NewsEvents/WorkshopsMeetingsConferences/UCMNewsEvents/WorkshopsMeetingsConferences/UCM200358.ppt200358.ppt

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BIOLOGICAL DRUG PRODUCTS, BIOLOGICAL DRUG PRODUCTS, WHO’S INSPECTING THEM?WHO’S INSPECTING THEM?

•• Team BiologicsTeam Biologics–– Expert investigators in the areas of antitoxins, vaccines, Expert investigators in the areas of antitoxins, vaccines,

ll d i d d i i di i ll i d i d d i i di i ll i plasmaplasma--derived products, in vivo diagnostics, allergenic derived products, in vivo diagnostics, allergenic products, hematopoietic cells and CELL/GENE THERAPIES. products, hematopoietic cells and CELL/GENE THERAPIES.

–– Typically stationed in a field office.Typically stationed in a field office.yp yyp y–– Responsible for ensuring the quality/safety of biologic Responsible for ensuring the quality/safety of biologic

products and working with industry and Agency officials to products and working with industry and Agency officials to i kl l i i i d b i d i i kl l i i i d b i d i quickly resolve inconsistencies and bring products into quickly resolve inconsistencies and bring products into

compliance. compliance. –– Conducts inspections both domestically and internationally.Conducts inspections both domestically and internationally.

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Conducts inspections both domestically and internationally.Conducts inspections both domestically and internationally.

LET’S TALK NUMBERSLET’S TALK NUMBERSLET’S TALK NUMBERSLET’S TALK NUMBERS

•• Inventory of regulated firms:Inventory of regulated firms:–– Plasma derived products/recombinant analogues: Plasma derived products/recombinant analogues:

4646–– Vaccines/related products: 35Vaccines/related products: 35–– IVD: 25IVD: 25–– Allergenic extracts: 11Allergenic extracts: 11–– CELL THERAPY: 2CELL THERAPY: 2–– Licensed cord blood banks: zilch, nada, noneLicensed cord blood banks: zilch, nada, none

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, ,, ,

ONLY 2 CELL THERAPY FIRMS?ONLY 2 CELL THERAPY FIRMS?ONLY 2 CELL THERAPY FIRMS?ONLY 2 CELL THERAPY FIRMS?

•• This means that most of you cell therapy folks This means that most of you cell therapy folks are conducting studies under IND to prove that are conducting studies under IND to prove that your product is safe and effective.your product is safe and effective.

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WHAT IS AN FDA INSPECTION?WHAT IS AN FDA INSPECTION?WHAT IS AN FDA INSPECTION?WHAT IS AN FDA INSPECTION?

•• We call it an EIWe call it an EI–– An establishment inspection is a careful, critical, An establishment inspection is a careful, critical,

official examination of a facility to determine its official examination of a facility to determine its compliance with the laws enforced by FDA.compliance with the laws enforced by FDA.

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WILL I KNOW YOU’RE COMING?WILL I KNOW YOU’RE COMING?WILL I KNOW YOU’RE COMING?WILL I KNOW YOU’RE COMING?

•• FDA inspections are generally unannounced, FDA inspections are generally unannounced, with a few exceptions:with a few exceptions:–– Medical devicesMedical devices–– Inspections under the BIMO program, unless they Inspections under the BIMO program, unless they p p g , yp p g , y

are forare for--cause/directedcause/directed–– PrePre--licensing biologics inspectionslicensing biologics inspections

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WE LOVE HAVING YOU HERE, BUT WE LOVE HAVING YOU HERE, BUT HOW LONG ARE YOU STAYING?HOW LONG ARE YOU STAYING?

•• Inspection length will depend on the complexity Inspection length will depend on the complexity of operations, product(s) being manufactured, of operations, product(s) being manufactured, size of firm, number/type of problems found size of firm, number/type of problems found and the level of cooperation the firm provides.and the level of cooperation the firm provides.

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WHAT HAPPENS FIRST?WHAT HAPPENS FIRST?WHAT HAPPENS FIRST?WHAT HAPPENS FIRST?

•• Investigator(s) will identify themselves and ask Investigator(s) will identify themselves and ask to see the most responsible individual (MRI) to see the most responsible individual (MRI)

il blil blavailable.available.•• FDA 482, Notice of Inspection, issued to MRI.FDA 482, Notice of Inspection, issued to MRI.•• FDA credentials displayed.FDA credentials displayed.•• Investigator(s) will explain the purpose of their Investigator(s) will explain the purpose of their

“visit” and inform you of the records to review “visit” and inform you of the records to review and personnel to interview.and personnel to interview.

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WHAT CAN I DO IN ADVANCE WHAT CAN I DO IN ADVANCE (1)(1)??WHAT CAN I DO IN ADVANCE WHAT CAN I DO IN ADVANCE (1)(1)??

•• Designate one or more persons to facilitate the Designate one or more persons to facilitate the inspection.inspection.

•• Determine how you will handle requests for Determine how you will handle requests for photocopies.photocopies.p pp p

•• Don’t expect the facilitator(s) to have all of the Don’t expect the facilitator(s) to have all of the answers to questions asked designate in answers to questions asked designate in answers to questions asked, designate in answers to questions asked, designate in advance who is best suited to answer them.advance who is best suited to answer them.

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IN ADVANCE IN ADVANCE (2)(2)IN ADVANCE IN ADVANCE (2)…(2)…

•• Consider having an SOP on how to handle FDA Consider having an SOP on how to handle FDA inspections, e.g. think of logistics (space, etc.) inspections, e.g. think of logistics (space, etc.) ahead of time.ahead of time.

•• SOPs: keep an updated hardcopy or at least a SOPs: keep an updated hardcopy or at least a p p pyp p pytable of contents.table of contents.

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IN ADVANCE IN ADVANCE (3)(3)IN ADVANCE IN ADVANCE (3)…(3)…

•• Know which CPs Know which CPs ((www.fda.gov/downloads/BiologicsBloodVaccines/GuidanceComplianceRegulatorywww.fda.gov/downloads/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/ComplianceActivities/Enforcement/CompliancePrograms/UCM095419Information/ComplianceActivities/Enforcement/CompliancePrograms/UCM095419Information/ComplianceActivities/Enforcement/CompliancePrograms/UCM095419.Information/ComplianceActivities/Enforcement/CompliancePrograms/UCM095419.

pdfpdf) and Guidances for Industry ) and Guidances for Industry ((www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformationwww.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation((/Guidances/CellularandGeneTherapy/default.htm/Guidances/CellularandGeneTherapy/default.htm) apply to you.) apply to you.

•• Stay current with the FDA Stay current with the FDA yy((www.fda.gov/AboutFDA/CentersOffices/CBER/ucm125685.htmwww.fda.gov/AboutFDA/CentersOffices/CBER/ucm125685.htm).).

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DURING THE INSPECTION DURING THE INSPECTION (1)(1)DURING THE INSPECTION DURING THE INSPECTION (1)(1)

•• Don’t be afraid to ask questions … avoid Don’t be afraid to ask questions … avoid miscommunication.miscommunication.

•• Okay fine, your policy is to never let the investigator Okay fine, your policy is to never let the investigator Okay fine, your policy is to never let the investigator Okay fine, your policy is to never let the investigator roam around unescorted roam around unescorted –– but really … to the but really … to the restroom?restroom?

•• If d ’t k th t ti fi d If d ’t k th t ti fi d •• If you don’t know the answer to a question ... find If you don’t know the answer to a question ... find someone who does.someone who does.

•• The investigator will take lots of notes … don’t you The investigator will take lots of notes … don’t you g yg yhate it when someone attempts to read over your hate it when someone attempts to read over your shoulder?shoulder?

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DURING THE INSPECTION DURING THE INSPECTION (2)(2)DURING THE INSPECTION DURING THE INSPECTION (2)(2)

•• Don’t be evasive.Don’t be evasive.•• Investigators will need time alone to discuss amongst Investigators will need time alone to discuss amongst

th lth lthemselves.themselves.•• Provide requested records ASAP; explain why there Provide requested records ASAP; explain why there

might be any delay.might be any delay.might be any delay.might be any delay.•• You might use different terminology; ensure everyone You might use different terminology; ensure everyone

is “on same page”.is “on same page”.•• At the end of each day, ask the investigator what At the end of each day, ask the investigator what

he/she covered and if there are any deficiencies.he/she covered and if there are any deficiencies.

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WHAT DOES THE FDA WHAT DOES THE FDA INVESTIGATOR KEEP LOOKING INVESTIGATOR KEEP LOOKING INVESTIGATOR KEEP LOOKING INVESTIGATOR KEEP LOOKING

AT?AT?•• IOMIOM•• CP 7345.848, Inspections of Biological Drug CP 7345.848, Inspections of Biological Drug , p g g, p g g

Products (CBER)Products (CBER)•• Guidances for IndustryGuidances for IndustryGuidances for IndustryGuidances for Industry•• Previous EIRsPrevious EIRs

//•• His/her assignment (FDA eyes only)His/her assignment (FDA eyes only)

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CP 7345.848, INSPECTION OF CP 7345.848, INSPECTION OF BIOLOGICAL DRUG PRODUCTS BIOLOGICAL DRUG PRODUCTS (1)(1)

•• CPs are used by FDA investigators to, in CPs are used by FDA investigators to, in conjunction with the CFR, help guide them conjunction with the CFR, help guide them through the inspectional processthrough the inspectional process

•• Current version: 10Current version: 10--11--1010•• Addresses preAddresses pre--approval, preapproval, pre--licensing and licensing and

postpost--market inspectionsmarket inspectionspostpost--market inspectionsmarket inspections

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CP 7345 848 CP 7345 848 (2)(2)CP 7345.848 CP 7345.848 (2)(2)

•• EI is performed to ensure that manufacturers EI is performed to ensure that manufacturers are making product that:are making product that:–– Meet provisions of regs: 21 CFR 200, 201, 210, Meet provisions of regs: 21 CFR 200, 201, 210,

211, 600, 601, 610, 640, 660, 680, 1271211, 600, 601, 610, 640, 660, 680, 1271–– Meet BLA conditions (if licensed product)Meet BLA conditions (if licensed product)

•• SystemsSystems--based, riskbased, risk--management inspectional management inspectional yy ,, g pg papproachapproach

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SYSTEMS APPROACHSYSTEMS APPROACHSYSTEMS APPROACHSYSTEMS APPROACH

•• SYSTEMS:SYSTEMS:–– QualityQuality

•• CRITICAL ELEMENTS OF CRITICAL ELEMENTS OF EACH SYSTEM:EACH SYSTEM:

–– Facilities/equipmentFacilities/equipment–– MaterialsMaterials

P d tiP d ti

–– SOPsSOPs–– TrainingTraining

RecordsRecords–– ProductionProduction–– Packaging/labelingPackaging/labeling–– Laboratory controlLaboratory control

–– RecordsRecords

Laboratory controlLaboratory control–– Donor eligibilityDonor eligibility

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QUALITY SYSTEM, WHAT ARE WE QUALITY SYSTEM, WHAT ARE WE LOOKING FOR?LOOKING FOR?

•• Has the QC unit fulfilled its responsibilities to review/approve Has the QC unit fulfilled its responsibilities to review/approve SOPs related to production, QC and QA, and to ensure the SOPs related to production, QC and QA, and to ensure the SOPs are adequate/current for their intended use?SOPs are adequate/current for their intended use?

•• We will review records related to release of components/inWe will review records related to release of components/in--process materials, product recall, product deviations, process materials, product recall, product deviations, complaints, out of specification results, rejects and failure complaints, out of specification results, rejects and failure complaints, out of specification results, rejects and failure complaints, out of specification results, rejects and failure investigations. investigations.

•• We will verify that the firm reviews its records pertinent to the We will verify that the firm reviews its records pertinent to the manufacture of lots prior to their release or distributionmanufacture of lots prior to their release or distributionmanufacture of lots prior to their release or distribution.manufacture of lots prior to their release or distribution.

•• We will assess the data collected in order to identify quality We will assess the data collected in order to identify quality problems that may be linked to other systems. problems that may be linked to other systems.

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FACILITIES/EQUIPMENT SYSTEMFACILITIES/EQUIPMENT SYSTEMFACILITIES/EQUIPMENT SYSTEMFACILITIES/EQUIPMENT SYSTEM

•• We will verify the appropriateness of We will verify the appropriateness of buildings/facilities, including maintenance; equipment buildings/facilities, including maintenance; equipment

lifi i (i ll i / i ) i lifi i (i ll i / i ) i qualifications (installation/operation); equipment qualifications (installation/operation); equipment calibration/preventative maintenance; validation of calibration/preventative maintenance; validation of cleaning processes as appropriate; prevention of cleaning processes as appropriate; prevention of cleaning processes as appropriate; prevention of cleaning processes as appropriate; prevention of contamination/cross contamination; and utilities that contamination/cross contamination; and utilities that are not intended to be incorporated into the product; are not intended to be incorporated into the product; p p ;p p ;such as HVAC, compressed gases, and steam and such as HVAC, compressed gases, and steam and water systems.water systems.

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MATERIALS SYSTEMMATERIALS SYSTEMMATERIALS SYSTEMMATERIALS SYSTEM

•• This system includes the measures and activities to This system includes the measures and activities to control finished products, such as components, source control finished products, such as components, source

i l / h i d i h i l / h i d i h materials, water/gases that are incorporated into the materials, water/gases that are incorporated into the product, and containers/closures. product, and containers/closures.

•• W ill i th lid ti f t i d W ill i th lid ti f t i d •• We will review the validation of computerized We will review the validation of computerized inventory control processes, product storage, inventory control processes, product storage, distribution controls and records. distribution controls and records. distribution controls and records. distribution controls and records.

•• We will evaluate routine monitoring of the utility We will evaluate routine monitoring of the utility systems.systems.

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sys e s.sys e s.

PRODUCTION SYSTEMPRODUCTION SYSTEMPRODUCTION SYSTEMPRODUCTION SYSTEM

//•• Are you following/documenting performance of Are you following/documenting performance of approved manufacturing SOPs?approved manufacturing SOPs?

•• We will review batch formulation, inWe will review batch formulation, in--process testing, process testing, We will review batch formulation, inWe will review batch formulation, in process testing, process testing, lot release, and process validation.lot release, and process validation.

•• Are records: complete and relate to the Are records: complete and relate to the hi t /di iti f d t d d/di t ib t d hi t /di iti f d t d d/di t ib t d history/disposition of products produced/distributed; history/disposition of products produced/distributed; legible/indelible; identify the person performing the legible/indelible; identify the person performing the work, including dates of the various entries; show test work, including dates of the various entries; show test

l /i i h i i d i d l /i i h i i d i d results/interpretation; show expiration date assigned results/interpretation; show expiration date assigned to specific products; and as detailed as necessary to to specific products; and as detailed as necessary to provide a complete history of the work performed?provide a complete history of the work performed?

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PACKAGING/LABELING SYSTEMPACKAGING/LABELING SYSTEMPACKAGING/LABELING SYSTEMPACKAGING/LABELING SYSTEM

•• We will review your SOPs regarding We will review your SOPs regarding packaging/labeling controls.packaging/labeling controls.

•• We will observe how you examine, store, issue We will observe how you examine, store, issue and use labels.and use labels.

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LABORATORY CONTROL SYSTEMLABORATORY CONTROL SYSTEMLABORATORY CONTROL SYSTEMLABORATORY CONTROL SYSTEM

•• This system includes all the various measures and activities that This system includes all the various measures and activities that are related to laboratory procedures; analytical methods are related to laboratory procedures; analytical methods development; validation or verification; and the stability development; validation or verification; and the stability program program program. program.

•• We will review your SOPs for control of microbiological We will review your SOPs for control of microbiological contamination and environmental monitoring; review of records contamination and environmental monitoring; review of records for source materials infor source materials in process and finished product testing; process and finished product testing; for source materials, infor source materials, in--process and finished product testing; process and finished product testing;

•• We will evaluate your methods for sampling and testing We will evaluate your methods for sampling and testing products for identity, potency, safety, sterility and conformance products for identity, potency, safety, sterility and conformance with final specificationswith final specificationswith final specifications.with final specifications.

•• We will review a sampling of records for operations We will review a sampling of records for operations performed and verify that they are complete and maintained performed and verify that they are complete and maintained as required.as required.

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as required.as required.

DONOR ELIGIBILITY SYSTEMDONOR ELIGIBILITY SYSTEMDONOR ELIGIBILITY SYSTEMDONOR ELIGIBILITY SYSTEM

//•• This system includes the measures/controls that are related to determining This system includes the measures/controls that are related to determining the donor eligibility of allogeneic and familythe donor eligibility of allogeneic and family--related allogeneic HCT/P related allogeneic HCT/P products, including donor screening and testing. products, including donor screening and testing.

•• We will review your SOPs for all steps performed in screening, testing and We will review your SOPs for all steps performed in screening, testing and y p p g, gy p p g, gdetermining donor eligibility, including who made the determination, and the determining donor eligibility, including who made the determination, and the results and interpretation of all donor screening and testing for relevant results and interpretation of all donor screening and testing for relevant communicable disease agents. communicable disease agents.

•• We will assess your SOPs for quarantine of biological drug products We will assess your SOPs for quarantine of biological drug products We will assess your SOPs for quarantine of biological drug products We will assess your SOPs for quarantine of biological drug products pending completion of the donor eligibility determination, the identification pending completion of the donor eligibility determination, the identification and storage of products from donors determined to be ineligible, and the and storage of products from donors determined to be ineligible, and the labeling and limited use of such products under the provisions of urgent labeling and limited use of such products under the provisions of urgent medical needmedical needmedical need.medical need.

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WITHIN EACH SYSTEM, WE COVER WITHIN EACH SYSTEM, WE COVER ,,(1)…(1)…

•• SOPsSOPs–– For each system, you should have approved written procedures and For each system, you should have approved written procedures and

associated records, e.g., testing, maintenance, cleaning, etc., that associated records, e.g., testing, maintenance, cleaning, etc., that d dh h dd dh h ddocument adherence to the procedures. document adherence to the procedures.

–– We will verify through actual observation whether or not you adhere to We will verify through actual observation whether or not you adhere to the SOPs. the SOPs. W ill d t i if th SOP i l d ll t t b f ll d i th W ill d t i if th SOP i l d ll t t b f ll d i th –– We will determine if the SOPs include all steps to be followed in the We will determine if the SOPs include all steps to be followed in the processing, testing, labeling, and distribution of biological drug processing, testing, labeling, and distribution of biological drug products. products.

–– We will verify the most current version of approved SOPs is readily We will verify the most current version of approved SOPs is readily We will verify the most current version of approved SOPs is readily We will verify the most current version of approved SOPs is readily available for use by key personnel in the areas where the procedures available for use by key personnel in the areas where the procedures are performed. are performed.

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WITHIN EACH SYSTEM, WE COVER WITHIN EACH SYSTEM, WE COVER ,,(2)…(2)…

//•• Training/personnelTraining/personnel–– Do you have an adequate number of trained personnel, Do you have an adequate number of trained personnel,

including supervisors, for all assigned functions and including supervisors, for all assigned functions and operations, for each of the systems?operations, for each of the systems?

–– We will verify that all personnel responsible for supervising, We will verify that all personnel responsible for supervising, processing, testing, packing, and distribution of biological processing, testing, packing, and distribution of biological drug products have the appropriate educational drug products have the appropriate educational background, training and experience to perform their background, training and experience to perform their assigned functions. Training should also include CGMP assigned functions. Training should also include CGMP regulations as necessary; to ensure the final product has the regulations as necessary; to ensure the final product has the regulations, as necessary; to ensure the final product has the regulations, as necessary; to ensure the final product has the safety, purity, potency, identity and effectiveness it purports safety, purity, potency, identity and effectiveness it purports or is represented to posses.or is represented to posses.

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WITHIN EACH SYSTEM, WE COVER WITHIN EACH SYSTEM, WE COVER ,,(3)…(3)…

•• RecordsRecords–– Are records maintained concurrently with the performance of each Are records maintained concurrently with the performance of each

significant step in the processing, testing, and distribution of biological significant step in the processing, testing, and distribution of biological drug products so all steps can be clearly traced and documented?drug products so all steps can be clearly traced and documented?drug products so all steps can be clearly traced and documented?drug products so all steps can be clearly traced and documented?

–– If any records, which are required by regulation, are maintained in an If any records, which are required by regulation, are maintained in an electronic format in place of paper format, the record keeping system electronic format in place of paper format, the record keeping system should comply with 21 CFR Part 11 (see Guidance for Industry, Part 11, should comply with 21 CFR Part 11 (see Guidance for Industry, Part 11, Electronic Records Electronic Signatures Electronic Records Electronic Signatures Scope and Application Scope and Application Electronic Records; Electronic Signatures Electronic Records; Electronic Signatures –– Scope and Application, Scope and Application, August 2003).August 2003).

–– Are records legible and indelible, and must identify the person Are records legible and indelible, and must identify the person performing the work, including dates of the various entries; show test performing the work, including dates of the various entries; show test

l ll h i i f l h h i i d l ll h i i f l h h i i d results as well as the interpretation of results; show the expiration date results as well as the interpretation of results; show the expiration date assigned to specific products; and be as detailed as necessary to assigned to specific products; and be as detailed as necessary to provide a complete history of the work performed? provide a complete history of the work performed?

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THE INSPECTION IS OVER (THE INSPECTION IS OVER (), ), NOW WHAT?NOW WHAT?

•• The investigator(s) will have a closing meeting The investigator(s) will have a closing meeting with, at minimum, the MRI.with, at minimum, the MRI.

•• If objectionable If objectionable conditions/deviations/deficiencies were found, conditions/deviations/deficiencies were found, / / ,/ / ,an FDA 483, Inspectional Observations, might an FDA 483, Inspectional Observations, might be issued (be issued ())..(( ))

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FDA 483, INSPECTIONAL FDA 483, INSPECTIONAL OBSERVATIONSOBSERVATIONS

•• Observations made by the FDA representative(s) Observations made by the FDA representative(s) during the EI.during the EI.

•• In the experience, judgment and knowledge of the In the experience, judgment and knowledge of the FDA representative(s), the enumerated issues are FDA representative(s), the enumerated issues are

t ti l i l ti f FDA l d l tit ti l i l ti f FDA l d l tipotential violations of FDA laws and regulations.potential violations of FDA laws and regulations.•• The citations do not represent the final Agency The citations do not represent the final Agency

determination regarding compliance or whether/not determination regarding compliance or whether/not determination regarding compliance or whether/not determination regarding compliance or whether/not the product or license is approved.the product or license is approved.

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DISCUSSION ITEMSDISCUSSION ITEMSDISCUSSION ITEMSDISCUSSION ITEMS

•• The FDA representative(s) may bring up issues The FDA representative(s) may bring up issues of concern that are not placed on an FDA 483.of concern that are not placed on an FDA 483.

•• These “discussion items” will be included on the These “discussion items” will be included on the narrative EIR and will be reviewed by narrative EIR and will be reviewed by yyCompliance Branch.Compliance Branch.

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RESPONDING TO AN FDA 483RESPONDING TO AN FDA 483RESPONDING TO AN FDA 483RESPONDING TO AN FDA 483

•• It is encouraged, but not required, to respond It is encouraged, but not required, to respond to the discussion items or FDA 483.to the discussion items or FDA 483.

•• You can respond verbally during the final You can respond verbally during the final discussion and/or in writing to the District discussion and/or in writing to the District / g/ gOffice address as noted on the form.Office address as noted on the form.

•• If you choose to respond in writing do so within If you choose to respond in writing do so within If you choose to respond in writing, do so within If you choose to respond in writing, do so within 15 business days.15 business days.

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GOOD LUCK!GOOD LUCK!GOOD LUCK!GOOD LUCK!

I LOOK FORWARD TO I LOOK FORWARD TO MEETING YOU IN PERSONMEETING YOU IN PERSONMEETING YOU IN PERSONMEETING YOU IN PERSON

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