workshop10 13 rabe

8/13/2019 Workshop10 13 Rabe

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FDA Inspection andFDA Inspection andManagementManagement

Fran Rabe, MSFran Rabe, MS

Director of QADirector of QA

University of Minnesota, MCTUniversity of Minnesota, MCT

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Hosting a FDA InspectionHosting a FDA Inspection

Preparing for an inspectionPreparing for an inspection

Management of the FDA inspection processManagement of the FDA inspection process

Inspection responseInspection response

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Assignment ProcessAssignment Process

District or headquarters will sendDistrict or headquarters will send

assignment to field inspectorsassignment to field inspectors

-- will include pertinent documents (e.g.:IND,will include pertinent documents (e.g.:IND,

Drug Master File, copy of complaint,Drug Master File, copy of complaint,

adverse event reports)adverse event reports)

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Types of FDA InspectionsTypes of FDA Inspections

Compliance AuditCompliance Audit Unlicensed ProductUnlicensed Product

-- 361 product361 product

-- Manufacturer of devices (e.g.: infectious diseaseManufacturer of devices (e.g.: infectious disease,,

-- Testing laboratory (e.g.: donor screening,Testing laboratory (e.g.: donor screening,microbiological cultures)microbiological cultures)

-- licensed productlicensed product

Biomedical Monitoring (BioMo)Biomedical Monitoring (BioMo)

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-- Clinical trialsClinical trials -- IND or IDEIND or IDE

Biologics License Application (BLA) preBiologics License Application (BLA) pre--licensurelicensure

-- review data used to support the applicationreview data used to support the application


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Categories of InspectionsCategories of Inspections For Cause = DirectedFor Cause = Directed

-- Not a routine inspectionNot a routine inspection-- May be based on;May be based on;

a) product complaint/problem reported by the PI or othera) product complaint/problem reported by the PI or other

b) adverse events too many or too few (as compared tob) adverse events too many or too few (as compared toother investigational sites)other investigational sites)

c) patient complaintc) patient complaint

d) sponsor reports concerns about investigatord) sponsor reports concerns about investigator

e) too may research subjects enrolled (as compared toe) too may research subjects enrolled (as compared toother investigational sites)other investigational sites)

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f) employee notification of problemsf) employee notification of problems

Routine = SurveillanceRoutine = Surveillance

FDA Inspections of Facilities*FDA Inspections of Facilities*

20082008 20092009

Cord Blood and 19 42Cord Blood and 19 42

Peripheral BloodPeripheral Blood

Trends show approximately 30% of inspections resulted inTrends show approximately 30% of inspections resulted inthe issuance of a 483the issuance of a 483

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*Mary Malarkey, Director OCBQ, CBER*Mary Malarkey, Director OCBQ, CBER

66ththAnnual FDA and the Changing Paradigm for HCT/P RegulationAnnual FDA and the Changing Paradigm for HCT/P Regulation


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Inspection ClassificationInspection Classification

(NOI): No Action Indicated. Most(NOI): No Action Indicated. Most

observations fall into this category.observations fall into this category.

-- Favorable outcomeFavorable outcome

-- No objectionable practices were identifiedNo objectionable practices were identified

(VAI): Voluntary Action Indicated(VAI): Voluntary Action Indicated

-- Objectionable conditions were identifiedObjectionable conditions were identified

--

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(OAI): Official Action Indicated(OAI): Official Action Indicated

-- Warning letterWarning letter

FDA Inspection ResultsFDA Inspection ResultsCord Blood and Peripheral BloodCord Blood and Peripheral Blood

NAINAI VAIVAI 0AI0AI

20082008 1515 44 00

20092009 2828 1010 44

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**Mary Malarkey, Director OCBQ, CBERMary Malarkey, Director OCBQ, CBER6th Annual FDA and the Changing Paradigm for HCT/P Regulation6th Annual FDA and the Changing Paradigm for HCT/P Regulation


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A FDA Form 482 versus a 483A FDA Form 482 versus a 483

FDA Form 482FDA Form 482

Notice of InspectionNotice of Inspection

-- FDA has the authority to inspect your facilityFDA has the authority to inspect your facility

FDA Form 483FDA Form 483

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-- Presented to person of most authorityPresented to person of most authority

-- Not a final determination regarding complianceNot a final determination regarding compliance

Be PreparedBe Prepared

Successful inspections are a resultSuccessful inspections are a result

comprehensive preparationcomprehensive preparation

-- Ensure you facility is compliant withEnsure you facility is compliant with

regulatory requirementsregulatory requirements

-- Have procedures that define the processHave procedures that define the process

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-- Have procedures for responding toHave procedures for responding to

inspection reportinspection report


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Prepare in AdvancePrepare in Advance

(BIOMO advanced notice)(BIOMO advanced notice)

Notify all pertinent staff (and others)Notify all pertinent staff (and others) Reserve dedicated roomReserve dedicated room

Prepare materials:Prepare materials:

-- ProtocolProtocol

-- Investigator brochure and consent formInvestigator brochure and consent form

-- FDA Form(s) 1572 and CV(s)FDA Form(s) 1572 and CV(s)

-- IRB approvalIRB approval

--

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-- Case report formsCase report forms

-- Study related correspondenceStudy related correspondence-- Table of organizationTable of organization

FDA Methods of InspectionFDA Methods of Inspection

ObservationObservation Interviewing staffInterviewing staff

Reviewing documents (SOPs, records)Reviewing documents (SOPs, records)

, , ,, , ,labels, packaging, final productlabels, packaging, final product

Collecting Samples (obtain receipt)Collecting Samples (obtain receipt)

-- Finished productFinished product

-- InIn--process or intermediate productprocess or intermediate product

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---- LabelingLabeling

-- PackagingPackaging


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FDA Methods of InspectionFDA Methods of Inspection

Ensure SOPs meet FDA regulationsEnsure SOPs meet FDA regulations

Establishment follows SOPsEstablishment follows SOPs

-- If it isnt in a SOP, you dont have to do itIf it isnt in a SOP, you dont have to do it

Documentation/records collaborateDocumentation/records collaborate

procedures are being followedprocedures are being followed

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-- If you didnt document it, you didnt do itIf you didnt document it, you didnt do it

Off Limits to FDAOff Limits to FDA Internal audit reportsInternal audit reports

Financial dataFinancial data

Personnel personal data (other thanPersonnel personal data (other thanqualifications)qualifications)

NonNon--IND research dataIND research data

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productionproduction


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Audit ManagementAudit Management

Follow your internal SOPs on auditFollow your internal SOPs on auditmanagementmanagement

Review inspector credentialsReview inspector credentials

Relegate inspectors to dedicateRelegate inspectors to dedicate roomroom

Understand scope and potential length ofUnderstand scope and potential length of

auditaudit

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Example Procedure1. Upon arrival of a FDA inspector, the first contact person will:

- Greet the investigator and get his or her name and ask the purpose

of the visit.

-Escort him to an open meeting room Page the PI or whoever the

and notify him/her of the

2. Contact the Facility Director, Medical/Scientific Director and

Director of Quality Assurance. Where applicable, the PI should be

contacted.

3. The Principal Investigator and/or most senior member greets the

inspector and:

- review their credentials.

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4. Determine the purpose of the visit-For cause or routine inspection

5. Notify all staff of the FDAs presence in the facility

6. For management of audit refer to SOP #234

SOP# 123, version C Effective 00/00/2010


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Inspection ProcessInspection Process

Opening meeting. Provided/request from theOpening meeting. Provided/request from the

a enc :a enc :

-- FDA Form 482FDA Form 482

-- Scope of inspection (Directed versus For Cause)Scope of inspection (Directed versus For Cause)

-- Anticipated lengthAnticipated length

-- Staff expected to be neededStaff expected to be needed

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-- Facilities that will be involvedFacilities that will be involved

-- Review process: will they do summary at end ofReview process: will they do summary at end ofeach day?each day?

Control the InspectionControl the Inspection

EnsureEnsure allall staff know the FDA is in your facilitystaff know the FDA is in your facility

Limit idle business conversation byLimit idle business conversation by allall staffstaff

-- Do not want FDA to overhear any informationDo not want FDA to overhear any information

that is not pertinent to the inspectionthat is not pertinent to the inspection

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Accompany inspector at all times when they are inAccompany inspector at all times when they are in

your facilityyour facility


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How to Answer QuestionsHow to Answer Questions

TruthfullyTruthfully

OK to say I dont know, but Ill get you theOK to say I dont know, but Ill get you the

answeranswer

OK to ask for clarity related to questionOK to ask for clarity related to question

OK to disagree and provide a clarification orOK to disagree and provide a clarification or

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,,

applicable)applicable)

PolitePolite

Audit ManagementAudit Management Maintain a copy of all documents providedMaintain a copy of all documents provided

Keep notesKeep notes

Maintain a list of documents provided to the agency,Maintain a list of documents provided to the agency,w c ey a e w emw c ey a e w em

Obtain a receipt for products, materials,Obtain a receipt for products, materials,packing/labeling taken by the FDApacking/labeling taken by the FDA

End each day with a synopsis with the FDA ofEnd each day with a synopsis with the FDA offindings/concernsfindings/concerns

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help with remaining audit timehelp with remaining audit time

Generate potential corrective action immediately toGenerate potential corrective action immediately topresent to FDA the following daypresent to FDA the following day


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Handling 483Handling 483

Response not requiredResponse not required

-- But, lack of response is viewed as a lack ofBut, lack of response is viewed as a lack of

concernconcern

Immediately respond to reportImmediately respond to report

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-- Response within 15 days can result inResponse within 15 days can result in

revised 483s (to your benefit)revised 483s (to your benefit)

483 Response483 Response

FactualFactual

-- do not speculatedo not speculate

Describe interim controlsDescribe interim controls

emons ra e eva ua on o roo cause anemons ra e eva ua on o roo cause ansystems that may have contributed to problemsystems that may have contributed to problem

Provide comprehensive description of correctedProvide comprehensive description of correctedsystem controlssystem controls

Address impact to past previously distributeAddress impact to past previously distributeproductproduct

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ress mpac o quaran ne pro uc nven oryress mpac o quaran ne pro uc nven ory Address prevention of future problemsAddress prevention of future problems

Provide dates for completion of all correctiveProvide dates for completion of all correctiveactionaction


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Inaccurate Observation FindingsInaccurate Observation Findings

Demonstrate where finding is incorrectDemonstrate where finding is incorrect

-- provide documents and/or referencesprovide documents and/or references

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Establishment Inspection ReportEstablishment Inspection Report

(EIR)(EIR)

A detailed narrative of the inspection. IncludesA detailed narrative of the inspection. Includes,,

the facility was audited. A detailed summarythe facility was audited. A detailed summaryof the inspection. Includes identification ofof the inspection. Includes identification ofspecific records reviewed, identification ofspecific records reviewed, identification ofparticipating staff, staff commentsparticipating staff, staff comments

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inspection process isinspection process is closedclosed

Available to pubic throughAvailable to pubic through Freedom ofFreedom ofInformation ActInformation Act


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Example EIRExample EIR

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FOIFOI The Freedom of Information Act (FOIA) and FDA'sThe Freedom of Information Act (FOIA) and FDA's

regulations governing disclosures require releaseregulations governing disclosures require releaseof inspection information to the publicof inspection information to the public

-- --

-- EIR (attachments and exhibits are excluded fromEIR (attachments and exhibits are excluded fromrequirement)requirement)

-- Warning letters communication with theWarning letters communication with theregulated establishment must be disclosed uponregulated establishment must be disclosed uponrequest by any member of the publicrequest by any member of the public

""

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rooms" with electronic search and indexingrooms" with electronic search and indexingfeaturesfeatures


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FOIFOI-- RequestsRequests

Requests must be in writing (do not accept eRequests must be in writing (do not accept e--mail)mail)

AA. Requestor's name, address, and telephone number.. Requestor's name, address, and telephone number.

BB. A description of the records being sought. The records. A description of the records being sought. The records..

for specific records that are releasable to the public can befor specific records that are releasable to the public can beprocessed much more quickly than a request for "allprocessed much more quickly than a request for "allinformation" on a particular subject. Also fees for a moreinformation" on a particular subject. Also fees for a morespecific and limited request will generally be less.specific and limited request will generally be less.

CC. Separate requests should be submitted for each firm or. Separate requests should be submitted for each firm orproduct involved.product involved.

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DD. A statement concerning willingness to pay fees,. A statement concerning willingness to pay fees,including any limitations.including any limitations.

FDA web:FDA web: http://www.fda.gov/RegulatoryInformation/FOI/HowtoMakeaFOIARequest/default.htmhttp://www.fda.gov/RegulatoryInformation/FOI/HowtoMakeaFOIARequest/default.htm

FDA LettersFDA Letters

Untitled versus WarningUntitled versus Warning-- Both Intend to Notify ofBoth Intend to Notify ofPractices that Need to be AmendedPractices that Need to be Amended

Warnin Letter:Warnin Letter:

Expresses FDAs stance (based on statue orExpresses FDAs stance (based on statue orrules)rules)

Not a commitment to enforcement, but a preludeNot a commitment to enforcement, but a preludetoto possiblepossible enforcementenforcement

Serious stuff (call your lawyer)Serious stuff (call your lawyer)

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Intended to induce voluntary compliance withIntended to induce voluntary compliance withregulationsregulations

Does not include a statement about potentialDoes not include a statement about potentialenforcement actionenforcement action


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Warning LettersWarning Letters

Letter states requirement timeLetter states requirement time--line forline for

response (usually 15 days)response (usually 15 days)

Letter of closure issued after correctiveLetter of closure issued after corrective

actions have been satisfactorily addressedactions have been satisfactorily addressed

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-- app ca e o warn ng e ers ssue a erapp ca e o warn ng e ers ssue a er

9/1/20099/1/2009

FDA LettersFDA Letters

FDA posts warning letters on their web site:FDA posts warning letters on their web site:

http://www.fda.gov/ICECI/EnforcementActions/WarningLetters/default.htmhttp://www.fda.gov/ICECI/EnforcementActions/WarningLetters/default.htm

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16/22

CSL Biotherapies Untitled LetterBrian McNamee

Chief Executive Officer (CEO)

CSL Biothera ies

[Example of Actual Untitled Letter]

45 Poplar Road

Parkville, Victoria 3052

Australia

Dear Mr. McNamee:

The Food and Drug Administration (FDA) conducted an inspection of CSL

Biotherapies, located at 45 Poplar Road, Parkville, Victoria 3052, Australia, between

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pr an pr , . ur ng e nspec on, nves ga ors ocumen e

deviations from current good manufacturing practice (CGMP) requirements in the

manufacture of licensed biological vaccine products and monovalent influenza bulks.

We would like to meet with you and other senior management at CSL Biotherapies to

further discuss the issues cited in this letter and how you will address them going

forward..

Regenerative Sciences, Inc

July 25, 2008

CERTIFIED MAIL

RETURN RECEIPT REQUESTED

Christopher J. Centeno, M.D.

Medical Director

Regenerative Sciences, Inc.

11080 Circle Point Road

[Example of Actual Untitled Letter]

Building 2, Suite 140

Westminster, Colorado 80020

Dear Dr. Centeno:

The Food and Drug Administration (FDA) has reviewed your website at Internet

address: http://www.regenexx.com and has determined that you are promoting your

use of mesenchymal stem cells under conditions that cause these cells to be drugs

under section 201(g) of the Federal Food, Drug, and Cosmetic Act (the Act) [21

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U.S.C. 321(g)] and biological products, as defined in section 351(i) of the PublicHealth Service Act (PHS Act) [42 U.S.C. 262].

We request that you notify this office, in writing, of the steps you have taken or will

take to address the violations noted above and to prevent their recurrence. Your

response should be sent to me at the following address: U.S. Food and Drug

Administration, Center for Biologics Evaluation and Research, HFM-600, 1401

Rockville Pike, Suite 200 N, Rockville Maryland 20852-1448.


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FDA NEWS RELEASE

For Immediate Release:August 6, 2010

Media Inquiries: Shelly Burgess, 301-796-4651,

[email protected]

Consumer Inquiries: 888-INFO-FDAFDA Seeks Injunction Against Colorado

Manufacturer of Cultured Cell Product

Example of Actual FDA

News Release Regarding

Action

The U.S. Food and Drug Administration is seeking an injunction

in federal court against Regenerative Sciences LLC, of

Broomfield, Colo., citing violations of current good

manufacturing practice (cGMP) that cause its cultured cell

roduct to be adulterated. The roduct is also misbranded due

3333http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm221656.htm

to the lack of adequate directions for use and the failure to bear

the Rx only symbol.

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EnforcementEnforcement RecallsRecalls

InjunctionInjunction-- a civil action to prevent cease production and/ora civil action to prevent cease production and/ordistributiondistribution

e zure o na pro ucte zure o na pro uct

FinesFines

Consent decreeConsent decree

-- an legal agreement to correct. Details exactan legal agreement to correct. Details exactrequirements.requirements.

Criminal investigationsCriminal investigations

--

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actionsactions

http://www.fda.gov/Safety/Recalls/EnforcementReports/default.htmhttp://www.fda.gov/Safety/Recalls/EnforcementReports/default.htm

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Dr. Cook Warning LetterDr. Cook Warning Letter

We acknowledge your July 2009 response and commitment to developWe acknowledge your July 2009 response and commitment to developaa (b)(4)(b)(4). Please provide a copy of your. Please provide a copy of your (b)(4)(b)(4)..

In addition, if not included in theIn addition, if not included in the (b)(4)(b)(4) provide corrective actions toprovide corrective actions toprevent similar deviations from recurring.prevent similar deviations from recurring.

Note that failure to have an adequate number of qualified personnelNote that failure to have an adequate number of qualified personnelis not justification to circumvent your adherence to CGMPis not justification to circumvent your adherence to CGMPrequirements.requirements.

We acknowledge your July 2009 response that indicates theWe acknowledge your July 2009 response that indicates the (b)(4)(b)(4) ininthe completion of your APRs and your commitment tothe completion of your APRs and your commitment to (b)(4)(b)(4) totocomplete APRs.complete APRs.

Please provide timeframes for the completion of thePlease provide timeframes for the completion of the (b)(4)(b)(4). In. In

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,,

please provide corrective actions to prevent similar deviationsplease provide corrective actions to prevent similar deviationsregarding your failure to follow your APR procedure.regarding your failure to follow your APR procedure.

Note that failure to have an adequate number of qualified personnelNote that failure to have an adequate number of qualified personnelis not justification to circumvent your adherence to CGMPis not justification to circumvent your adherence to CGMPrequirements.requirements.

Gibson LaboratoriesGibson Laboratories Your firm rejected 14 lots of product in 2008 due toYour firm rejected 14 lots of product in 2008 due to

contamination and the corrective action was to retraincontamination and the corrective action was to retrainemployees on aseptic technique.employees on aseptic technique.

This corrective action was not effective. In 2009, yourThis corrective action was not effective. In 2009, your

rejected 13 lots of product due to contamination.rejected 13 lots of product due to contamination.

Additionally, your firm's failure investigations intoAdditionally, your firm's failure investigations intononconforming products do not include reviewing thenonconforming products do not include reviewing theresults of environmental testing of the fill room for the daysresults of environmental testing of the fill room for the daysin which contaminated product has been produced.in which contaminated product has been produced.

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that identifies the root cause of contaminationthat identifies the root cause of contamination

You have not taken a corrective action that reducesYou have not taken a corrective action that reducesthe trend of contaminated product.the trend of contaminated product.


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Washington Homeopathic Products, Inc.Washington Homeopathic Products, Inc.

Broken glass was identified in filled 15 cc glass bottles of TBroken glass was identified in filled 15 cc glass bottles of T--GoneGone

Remedies Type 4 (lotRemedies Type 4 (lot (b)(4)(b)(4)) on January 20, 2009, during product filling) on January 20, 2009, during product fillingoperations. This lot was rejected and destroyed on January 29, 2009.operations. This lot was rejected and destroyed on January 29, 2009."Deviation Report," dated January 22, 2009, stated: "Broken glass was"Deviation Report," dated January 22, 2009, stated: "Broken glass wasin the prepackaged and sealed bottles from the distributor. No risksin the prepackaged and sealed bottles from the distributor. No riskswere nvo ve . ro uc was pu e an es roye on anuary , .were nvo ve . ro uc was pu e an es roye on anuary , .The broken glass inside the bottles accrued at the distributor'sThe broken glass inside the bottles accrued at the distributor'soperation. The drug product with the broken glass was destroyed andoperation. The drug product with the broken glass was destroyed andall other products that were used with that component was recheckedall other products that were used with that component was recheckedand all were all were clear."and all were all were clear."

The investigation failed to identify other related products andThe investigation failed to identify other related products andlots manufactured with the implicated glass vials to assure nolots manufactured with the implicated glass vials to assure noadditional broken glass was present.additional broken glass was present.

Finally, the specific lot number of the problematic glass bottlesFinally, the specific lot number of the problematic glass bottles

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(components) used to fill T(components) used to fill T--Gone Remedies Type 4 (lot (b)(4)) onGone Remedies Type 4 (lot (b)(4)) onJanuary 20, 2009 was not documented in the investigation.January 20, 2009 was not documented in the investigation.

Dr. Cook Warning LetterDr. Cook Warning Letter

We acknowledge your July 2009 response andWe acknowledge your July 2009 response andcommitment to complete stability testing,commitment to complete stability testing, (b)(4)(b)(4) to ensureto ensure

..

However, we believe your response does not provideHowever, we believe your response does not provideadequate preventive actions becauseadequate preventive actions because (b)(4)(b)(4) do not addressdo not addressthe failure of the QCD to ensure your procedures arethe failure of the QCD to ensure your procedures arefollowed and training is effective. Please provide correctivefollowed and training is effective. Please provide correctiveaction to prevent recurrence of similar deviations. Foraction to prevent recurrence of similar deviations. Forexample, you may develop a contingency plan to sendexample, you may develop a contingency plan to send

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laboratory, or you may reduce your product line to reducelaboratory, or you may reduce your product line to reducethe laboratory workload.the laboratory workload.


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483 Response483 Response

Ensure safety of this product/lot # identified.Ensure safety of this product/lot # identified.Determine dispositionDetermine disposition

Evaluate status of product collected and remaining inEvaluate status of product collected and remaining inestablishment quarantine/released inventoryestablishment quarantine/released inventory

Evaluate status of product (same type and/or lot #)Evaluate status of product (same type and/or lot #)that has been release and may be in (hospital)that has been release and may be in (hospital)inventoryinventory

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Ensure future products are problem freeEnsure future products are problem free

483 Response Approach483 Response Approach

Root Cause AnalysisRoot Cause Analysis Exact CauseExact Cause

Prevent reoccurrence through application ofPrevent reoccurrence through application ofquality systems. E.G.:quality systems. E.G.:

-- design controldesign control

--

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-- quality review (trending, etc.)quality review (trending, etc.)

-- early detection of problems (through audit)early detection of problems (through audit)


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Lessons LearnedLessons Learned A good relationship with headquarters does not impact the inspectionA good relationship with headquarters does not impact the inspection

processprocess

-- the inspectors are from the fieldthe inspectors are from the field

Cellular Therapy area is new for FDACellular Therapy area is new for FDA

-- Not always very familiar with processes or application of regulationsNot always very familiar with processes or application of regulations

Every inspection is unique:Every inspection is unique:

-- Focus variesFocus varies

-- Adverse findings will vary and/or conflicts with previous inspectionsAdverse findings will vary and/or conflicts with previous inspections

Respond to 483 promptly and appropriatelyRespond to 483 promptly and appropriately

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QuestionsQuestions

Fran RabeFran Rabe

[email protected]@umn.edu

612612--625625--56325632

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workshop10 13 rabe

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