Preparation for FDA Inspections - c.ymcdn.comc.ymcdn.com/.../Regional/Nov_4_-_3_Preparation_for_FDA_Inspection… · Preparation for FDA Inspections Karen Edward, BS, MT (ASCP) Advanced

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Preparation for FDA InspectionsPreparation for FDA Inspections

Karen Edward, BS, MT (ASCP)Advanced Cell & Gene Therapy

ISCT 2007 Regional Meeting Houston

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We hope to provide answers to We hope to provide answers to the following questionsthe following questions……

nn When will the FDA come knocking?When will the FDA come knocking?ll Will focus primarily on FDA, but much applies to FACT and Will focus primarily on FDA, but much applies to FACT and

AABB preparationAABB preparation

nn What do you need to do to prepare?What do you need to do to prepare?ll What SOPs and documents should be in place?What SOPs and documents should be in place?

ll Roles and responsibilities of your staff?Roles and responsibilities of your staff?

ll How do you know you are adequately prepared?How do you know you are adequately prepared?



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AndAnd……nn What are the practical considerationsWhat are the practical considerations

for the day of the inspection?for the day of the inspection?nn What is an inspector allowed to see? What is an inspector allowed to see? nn What information should not be disclosed at the time What information should not be disclosed at the time

of the inspection?of the inspection?nn What are lessons learned?What are lessons learned?ll RealReal--life experiences sharedlife experiences shared



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Facility inspections can be stressfulFacility inspections can be stressfulConsequences of lack of preparationConsequences of lack of preparationll Key people not available the day of inspectionKey people not available the day of inspectionll Practical aspects not in place: conference rooms, etc.Practical aspects not in place: conference rooms, etc.ll Disruption of operationsDisruption of operationsll Employees not trained properly to respond to Employees not trained properly to respond to

inspectors questionsinspectors questionsll CanCan’’t find important documentst find important documentsll Too much information revealed to the inspector putting Too much information revealed to the inspector putting

organization at riskorganization at risk



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Facility inspections can be stressfulFacility inspections can be stressful

Or worseOr worse…………llMany observations (e.g. 483Many observations (e.g. 483’’s)s)llWarning lettersWarning lettersllCease operationsCease operationsllLoss of reputationLoss of reputation



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FDAFDA’’s Authoritys Authority““The inspectional objective for biological products is to assure The inspectional objective for biological products is to assure the the products are safe, effective, and contain the quality and purityproducts are safe, effective, and contain the quality and purity they they purport to possess, and are properly labeled. The inspectional opurport to possess, and are properly labeled. The inspectional objective bjective for HCT/Ps (human cells, tissues, and cellular and tissuefor HCT/Ps (human cells, tissues, and cellular and tissue--based products) based products) is to assure that they are recovered, processed, stored, labeledis to assure that they are recovered, processed, stored, labeled, , packaged and distributed, and the donors are screened and testedpackaged and distributed, and the donors are screened and tested, in a , in a way that prevents the introduction, transmission, or spread of way that prevents the introduction, transmission, or spread of communicable diseases. Facilities will be inspected for conformacommunicable diseases. Facilities will be inspected for conformance with: nce with: 1. Provisions of the PHS Act and FD&C Act, 1. Provisions of the PHS Act and FD&C Act, 2. Applicable regulations in 21 CFR 2102. Applicable regulations in 21 CFR 210--211, 600211, 600--680, and 820. 680, and 820. 3. HCT/P regulations in 21 CFR 1270 and 1271. 3. HCT/P regulations in 21 CFR 1270 and 1271. 4. FDA Policies, which include guidance to the industry, and the4. FDA Policies, which include guidance to the industry, and the Compliance Compliance Policy Guides Chapter 2. Policy Guides Chapter 2.

FDA Investigation Operations Manual, Chapter 5, 2007FDA Investigation Operations Manual, Chapter 5, 2007ISCT 2007 Regional Meeting Houston


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When will they come?When will they come?üü Licensed products : FDA Team Biologics schedules Licensed products : FDA Team Biologics schedules

bienniallybienniallyüü PrePre--approval (PAI) inspection: part of review of Biologics approval (PAI) inspection: part of review of Biologics

License Application (BLA) are scheduledLicense Application (BLA) are scheduledüü Facility inspections for IND products: can happen, Facility inspections for IND products: can happen,

usually triggered through clinical protocol, notification usually triggered through clinical protocol, notification occurs through principal investigatoroccurs through principal investigator

üü FDA GTP inspections: typically unannounced, not FDA GTP inspections: typically unannounced, not routinely scheduled at this timeroutinely scheduled at this timeww Jan 2007: # of inspections 354 out of total of 2000 (mostly tissJan 2007: # of inspections 354 out of total of 2000 (mostly tissue recovery, 36 ue recovery, 36

hematopoietichematopoietic facilities)facilities)

ww Latest FDA Human Tissue Task Force report recommends biennial foLatest FDA Human Tissue Task Force report recommends biennial for high risk r high risk facilities, and triennial for all othersfacilities, and triennial for all others



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First things firstFirst things first……make sure you are make sure you are compliant with all pertinent regulationscompliant with all pertinent regulationsnn If accredited by AABB, FACT and other standard setting If accredited by AABB, FACT and other standard setting

organizations, you should be reasonably preparedorganizations, you should be reasonably preparednn Assess quality systems periodicallyAssess quality systems periodically

ww Review current regulations/guidance docsReview current regulations/guidance docsww Identify GapsIdentify Gapsww Good internal auditing helpsGood internal auditing helpsww Periodic external audits usefulPeriodic external audits usefulww Fill gaps, improve systemsFill gaps, improve systems



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Organizational involvement Organizational involvement

nn Senior managementSenior managementnn Legal and Regulatory AffairsLegal and Regulatory Affairsnn Quality AssuranceQuality Assurancenn Manufacturing and recovery operations Manufacturing and recovery operations nn All employees who may have interaction with All employees who may have interaction with

inspectors require traininginspectors require training



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Identify inspection coordinator Identify inspection coordinator ØØ Represents the organization during inspectionRepresents the organization during inspectionØØ Answers InspectorAnswers Inspector’’s questions in consistent manner, avoiding s questions in consistent manner, avoiding

contradictionscontradictionsØØ Possesses thorough knowledge of pertinent regulationsPossesses thorough knowledge of pertinent regulationsØØ Possesses good knowledge of facility procedures, quality systemsPossesses good knowledge of facility procedures, quality systems, ,

corporate policies/procedurescorporate policies/proceduresØØ Previous experience with regulatory inspections a plusPrevious experience with regulatory inspections a plusØØ Usually QA Manager, should have backup Usually QA Manager, should have backup person(sperson(s))ØØ Stays with inspector at all timesStays with inspector at all timesØØ Interacts with key managers and other employees of various Interacts with key managers and other employees of various

departmentsdepartmentsØØ Responsible for documenting all aspects of inspectionResponsible for documenting all aspects of inspection



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Prepare documentsPrepare documents

üü List of key individuals to be notifiedList of key individuals to be notifiedüü Organizational overview and chartsOrganizational overview and chartsüü Facility description, including floor plansFacility description, including floor plansüü Summaries of recovery and manufacturing Summaries of recovery and manufacturing

processesprocessesüü SOPs/policies guiding inspection preparationSOPs/policies guiding inspection preparation



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Write SOP: “How to Prepare for an FDA Inspection”üü NotificationNotificationüü Introductions, schedulingIntroductions, schedulingüü Organizational policiesOrganizational policiesüü Employee behavior and responsibilitiesEmployee behavior and responsibilitiesüü Inspection processInspection processüü Daily debriefingsDaily debriefingsüü Exit interviewExit interviewüü Documentation and followDocumentation and follow--upup



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Practice§§ A A ““MockMock”” inspection can help prepare and inspection can help prepare and

train the team for the real thingtrain the team for the real thingØØSimulates the inspection process in your Simulates the inspection process in your

organizationorganization

ØØSomeone role plays as Inspector Someone role plays as Inspector -- either either internal or external resourceinternal or external resource

ØØIf internal, should be someone with inspection If internal, should be someone with inspection experienceexperienceØØImportant to have senior managementImportant to have senior management

support as preparation takes resourcessupport as preparation takes resources



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““MockMock”” inspections inspections §§Use relevant regulatory guidelines as referenceUse relevant regulatory guidelines as referenceØØ e.g. FDA Compliance Program for Inspection of HCT/Pse.g. FDA Compliance Program for Inspection of HCT/Ps

§§Tests internal SOPs Tests internal SOPs

§§Tests staffTests staffØØ How are logistics of notification handled?How are logistics of notification handled?

ØØ How are questions answered?How are questions answered?

ØØ Are documents retrievable?Are documents retrievable?



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Meet and greetMeet and greet

üü Reception personnel need to be prepared in advance Reception personnel need to be prepared in advance whom to contact (include backup personnel)whom to contact (include backup personnel)

üü Inspection coordinator greets and escorts inspector Inspection coordinator greets and escorts inspector into appropriate conference roominto appropriate conference room

üü Request inspector credentials and record informationRequest inspector credentials and record informationüü Inspector should present document, e.g. FDA Form Inspector should present document, e.g. FDA Form

482 482 ““Notice of InspectionNotice of Inspection””



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Opening meetingOpening meeting

§§ Determine the purpose of the inspectionDetermine the purpose of the inspection§§ Inform the inspector of organizational policiesInform the inspector of organizational policies

oo Donor/recipient confidentiality Donor/recipient confidentiality oo Company proprietary informationCompany proprietary informationoo Operations Operations -- protocols in patient care areas, gowning protocols in patient care areas, gowning

and safety proceduresand safety proceduresoo Taking of photographs Taking of photographs -- generally not allowedgenerally not allowedoo Product samples Product samples -- many cell therapy products patient many cell therapy products patient

specific, contain protected health information (PHI)specific, contain protected health information (PHI)



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Schedule the daySchedule the day

§§ Immediately inform senior management and Immediately inform senior management and applicable staff that inspection is underway applicable staff that inspection is underway

§§ Work out a schedule ensuring critical personnel are Work out a schedule ensuring critical personnel are availableavailable

§§ Inspection coordinator should accompany the Inspection coordinator should accompany the inspector at all timesinspector at all times

§§ Assign additional staff to retrieve documents, scribe, Assign additional staff to retrieve documents, scribe, etc.etc.



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Inspection Inspection ““DosDos…”…”

§§ Communicate clearly and effectivelyCommunicate clearly and effectively§§ Project a positive, courteous and professional Project a positive, courteous and professional

attitudeattitude§§ Focus on the positiveFocus on the positive§§ Direct questions to Direct questions to ““subject matter expertssubject matter experts””§§ Answer the question directly and honestlyAnswer the question directly and honestly



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Inspection Inspection ““DonDon’’tsts…”…”

§§ Guess, lie, or make misleading statementsGuess, lie, or make misleading statements§§ Get too uptight, overly anxious, or defensiveGet too uptight, overly anxious, or defensive§§ Volunteer more information than necessary to Volunteer more information than necessary to

answer the questionanswer the question§§ Engage in unconstructive argumentEngage in unconstructive argument§§ Offer to buy lunch! Offer to buy lunch!



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What will the What will the inspectorinspector want to see?want to see?ww Tour facilities Tour facilities –– need to be appropriately attired and need to be appropriately attired and

adhering to safety SOPsadhering to safety SOPsww Observe actual manufacturing processesObserve actual manufacturing processesww Review SOPs, policies and plans describing Review SOPs, policies and plans describing

manufacturing processes, QC testing, and quality manufacturing processes, QC testing, and quality systemssystemsww Review completed Review completed MBRsMBRs, worksheets, reports, training , worksheets, reports, training

records, audit reports, and other data (e.g. validation and records, audit reports, and other data (e.g. validation and stability data, data in support of IND submission)stability data, data in support of IND submission)ww Request copies of documentsRequest copies of documents

•• Documents containing Protected Health Information (PHI) Documents containing Protected Health Information (PHI) should be redacted such that patient identifiers are not readablshould be redacted such that patient identifiers are not readablee



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What information should not be What information should not be disclosed?disclosed?

§§ Financial DataFinancial Data§§ Personnel data, except qualifications, Personnel data, except qualifications,

competency and training recordscompetency and training records§§ Research data, except to support safety or Research data, except to support safety or

efficacy claimsefficacy claims§§ Donor or recipient PHIDonor or recipient PHI



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Daily DebriefingsDaily Debriefings

§§ Good idea if the inspection lasts more than one dayGood idea if the inspection lasts more than one day§§ Include appropriate management personnel specific to Include appropriate management personnel specific to

each area under inspectioneach area under inspection§§ Discuss any issues that require clarificationDiscuss any issues that require clarification§§ Discuss any corrections madeDiscuss any corrections made§§ Ask the inspector if there are any problems, concernsAsk the inspector if there are any problems, concerns§§ Document the debriefingDocument the debriefing§§ Establish an agenda for the next dayEstablish an agenda for the next day



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Exit InterviewExit Interview

§§ Include key operational and management staff (including Include key operational and management staff (including senior management, legal and regulatory affairs)senior management, legal and regulatory affairs)§§ If the inspector issues observations (e.g. FDA form 483, List If the inspector issues observations (e.g. FDA form 483, List

of Observations) review each one for accuracy and of Observations) review each one for accuracy and interpretationinterpretation§§ If it is the opinion that the observation is erroneous, request If it is the opinion that the observation is erroneous, request

the inspector change the observation or note the the inspector change the observation or note the disagreement in their reportdisagreement in their report§§ Inform the inspector of any corrections or confirmed plans for Inform the inspector of any corrections or confirmed plans for

correctioncorrection§§ Indicate the intent to respond to all observations and Indicate the intent to respond to all observations and

determine a timeframedetermine a timeframe



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Inspection DocumentationInspection Documentation

§§ InspectorInspector’’s credentialss credentials§§ Facilities and other area inspectedFacilities and other area inspected§§ Names of all key personnel involved in the inspectionNames of all key personnel involved in the inspection§§ Records, data, procedures inspectedRecords, data, procedures inspected§§ All key questions asked during the inspection and All key questions asked during the inspection and

responsesresponses§§ Minutes for all meetingsMinutes for all meetings§§ Corrective actions and responseCorrective actions and response



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ReferencesReferences1)1) FDA, 21 CFR parts, 312.58, 312.68, 600.20, 600.21, 600.22, FDA, 21 CFR parts, 312.58, 312.68, 600.20, 600.21, 600.22,

1271.4001271.4002)2) FDA, Investigations Operation Manual: FDA, Investigations Operation Manual:

http://http://www.fda.gov/ora/inspect_ref/iom/iomtc.htmlwww.fda.gov/ora/inspect_ref/iom/iomtc.html3)3) Biotechnology Inspection Guide: Biotechnology Inspection Guide:

http://http://www.fda.gov/ora/inspect_ref/igs/biotech.htmlwww.fda.gov/ora/inspect_ref/igs/biotech.html4)4) Inspection of Biologic and Tissue Establishments:Inspection of Biologic and Tissue Establishments:

http://www.fda.gov/cber/cpg/7341002tis.htmhttp://www.fda.gov/cber/cpg/7341002tis.htmhttp://www.fda.gov/cber/cpg/7345848.pdfhttp://www.fda.gov/cber/cpg/7345848.pdf

5)5) FDA/CBER Human Tissue Task Force ReportFDA/CBER Human Tissue Task Force Reporthttp://www.fda.gov/cber/tissue/httfo7report.htmhttp://www.fda.gov/cber/tissue/httfo7report.htm



http://www.fda.gov/ora/inspect_ref/iom/iomtc.html

http://www.fda.gov/ora/inspect_ref/iom/iomtc.html

http://www.fda.gov/ora/inspect_ref/igs/biotech.html

http://www.fda.gov/ora/inspect_ref/igs/biotech.html

http://www.fda.gov/cber/cpg/7341002tis.htm

http://www.fda.gov/cber/cpg/7341002tis.htm

http://www.fda.gov/cber/cpg/7345848.pdf

http://www.fda.gov/cber/cpg/7345848.pdf

http://www.fda.gov/cber/tissue/httfo7report.htm

http://www.fda.gov/cber/tissue/httfo7report.htm

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Thank you! Questions?Thank you! Questions?

Karen EdwardKaren EdwardAdvanced Cell & Gene TherapyAdvanced Cell & Gene Therapy

201.214.5112201.214.5112kedward@[email protected]

www.acwww.ac--gt.comgt.com



www.ac-gt.comISCT 2007 Regional Meeting Houston


Preparing Cell Therapy Production Facilities for Team Biologics Inspections

Insert Picture Here

ISCT Regional MeetingNovember 3, 2007

John Duguid

§Preparing for an FDA inspection is like cramming for a final exam.

§If you haven’t been doing the work all along, you’re probably not going to pass.

Team Biologics§ Partnership between ORA and CBER to Address

Inconsistency and Technical Depth§ Comprehensive regulatory posture§ Uniformity§ Highly trained, professional work force§ Inspections with clearly defined roles§ Rapid and effective process for resolving differences§ Approach that fits within FDA's existing systems§ Consistent quality§ Maximum efficiency§ New methods of implementing inspection and enforcement

§ ORA: Office of Regulatory Affairs§ CBER: Center for Biologics Evaluation and Research

Inspection and Enforcement Trends

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Current Agency Thinking

§Risk-based approach to Regulation§ Target Inspections to High-Priority Sites§ Reduce Inspections at Less Risky Facilities§Reorganize ORA§ Streamline Reporting Structure§ Close 7 of 13 Field Labs§ Team Biologics Improvements§ Implement Quality-Management Systems Approach

US RegulationsCFR Title 21 FOOD AND DRUGS

Part 11 Electronic records; electronic signaturesPart 210 Current good manufacturing practice in

manufacturing, processing, packing, or holding of drugs; general

Part 211 Current good manufacturing practice for finished pharmaceuticals

Part 610 General biological products standardsPart 820 Quality system regulation (medical devices)Part 1270 Human tissue intended for transplantationPart 1271 Human cells, tissues, and cellular and

tissue-based products

§ CFR: Code of Federal Regulations

GMP/GTP Background§ GMPs§ Well-established (decades)§ Focused on product

adulteration§ Encompass all aspects of

drug/biologics manufacture and require demonstration of potency, purity, identity§ Include cell therapies

meeting the definition of 351 products

§ GTPs§ Recently established (years)§ Focused on transmission of

communicable disease§ Encompass core GTPs as

subset of broader regulation and tissue management practices§ Limited to HCT/Ps meeting

the definition of 361 products

§ High volume - each patient constitutes a unique manufacturing lot§ 100% of lots tested§ Limited shelf life (48-72 hr) governing processing activities§ Variability in biopsy source material§ Patient-specific cell growth characteristics require control of in-

process ex vivo cell propagation§ Mechanism of action from biopsy through implantation should be

characterized§ Inconsistency in critical raw materials (fetal bovine serum)§ QC assays need development and validation§ Potential variability in cellular product§ High degree of human involvement requiring aseptic processing

techniques§ Emerging regulatory requirements

Autologous Products

Essential Elements of Quality§ Standard Operating Procedures (SOPs)§ Personnel Training and Qualification§ Trend and Deviation Assessment§ Corrective and Preventative Actions (CAPA)§ Complaint Handling and Contamination Notification§ Management Review§ Facility Development§ Environmental Control§ Equipment Calibration/IQ, OQ, PQ§ Computer System Validation§ Raw Materials Inspection and Disposition§ Records and Documentation§ Process Validation§ Patient/Lot Segregation§ Test Methods – Safety, Potency, Identity

Assessment of Compliance§ Mock Audits§ Assess current state of compliance§ Useful before first regulatory audit

§ Internal Audit Program§ Assess ongoing state of compliance§ Most useful when audited to standards

§ Gap Analysis§ Before first regulatory audit§ After regulations change

§ Remediation Plan§ Specific: clear objectives§ Measurable: defined deliverables§ Accepted: organizational commitment§ Realistic: available resources (staff, finances)§ Timebound: concrete deadlines

§ Risk Analysis

Compliance Development Program§ Format§ Weekly Meeting§ All Operations Departments

§ Agenda§ New Business/Emerging Issues§ Business Updates§ Customer Complaints§ Deviations and CAPA§ Material Review Board§ Audits§ Change Control§ International Site Issues§ Regulatory Activity§ Safety§ Training

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Inspectional Guidance§ Display Credentials§ Provide Written Notice of Inspection (FDA Form 482)§ Review Recalls, Medical Device Reports (MDR), Biological Product

Deviation Reports (BDR), Complaint Files§ Become Familiar with the Operation and Plan Inspection

Strategy/Depth from Preliminary Tour§ Use a Systems-Based Approach§ Quality§ Facilities and Equipment§ Environmental Controls

§ Materials§ Production§ Packaging and Labeling§ Laboratory Controls

§ Provide Written Inspectional Observations (FDA Form 483)

Preparations for Initial Meeting

§ Inspection Readiness Kit§ Floor Plan§ Organizational Chart§ Annual Report§ Tour§ Prepared Script§ Senior Management§ Technology Overview§ Organized Presentation§ Senior Scientist

FDA Inspection SOP

§Employee Interactions§Practical Considerations§Roles and Responsibilities§ Inspected Information Considerations§Managing the Inspection§Close out Meeting§Dealing with Observations

Employee Interactions§ Procedural Training§ Ensure all employees are trained in the FDA Inspection SOP

§ Attitude “DOs”§ DO Establish rapport based on mutual respect§ DO Remain positive and non-adversarial§ DO Be cooperative, but not unnecessarily revealing§ DO Tell the truth

§ Behavioral “DON’Ts”§ DON’T Take the opportunity to justify your existence (I told

them…)§ DON’T Tell “war” stories (if you think that was bad…)§ DON’T Ask the inspector overly personal questions§ DON’T Complain about the government§ DON’T Guess

Practical Considerations

§Conference Room§Restrooms§ Food§Beverages§Site Security (ID Badges)§Safety (product and inspector)§ PPE§ Cleanroom garb

Roles and Responsibilities§ Reception§ Identifies and contacts escort§ Notifies relevant departments

§ Main Point of Contact§ Escort§ QS, MFG OPS, RA§ Facilitates inspection and interviews

§ Regulatory Affairs§ Maintains inspection records

§ Quality Systems§ Provides documentation

§ Senior Management§ Attends close out meeting

Subject Matter Experts

§ Involve people in their area of expertise to give ownership§Pride in organization comes through§SME Matrix

FDA Team Biologics Inspection Coverage MatrixMajor Area Sub Area Subsection SMExpert 1 SMExpert 2 SMExpert 3 Escort Alt. EscortQuality RA1 RA2Facilities and EquipmentMaterials

Specifications QC1 QC2 QC3Inspection/Disposition QC1 QC2 QC3Test Methods

Cell Culture QC3 QC4 QC5Analytical QC1 QC2 QC3

Warehouse, Storage, Distribution MM1 MM2 MM3Vendor Qualification QA1 VA1 QC1Water VA1 QC6Sterilization VA1

ProductionPackaging and LabelingLaboratory Controls

§ FDA Authority§ broad, but not unlimited for inspection of equipment,

materials, products, labeling, and certain records§Records and Documentation§ readily available§ data stored offsite retrievable within a day§Photocopies§ provide if requested§ make duplicates marked confidential, keep one

Information – What can they ask for

§ Databases§ can be useful for rapid retrieval of requested information§ exercise caution about how the data are presented§ decision-making data systems must be validated – they’ll ask

§ Photographs§ many firms declare by SOP that photography is forbidden to

protect proprietary information§ US courts have rules that photographs may lawfully be taken as

part of an inspection§ Affidavits§ legal document; formal sworn statement§ employees do not have to sign them

§ Contracts§ Raw Material Vendors§ Contract Services

Information – Other Considerations

§ Financial Data§ e.g. audit records, financial statements

§ Sales Data§ unless related to shipments or volume

§ Pricing Information§ Personnel Records§ HR Files – No§ Qualification Information – Yes

§ Research§ unless related to lifecycle of product inspected

§ Internal Audit Reports

Information – What can’t they ask for

Managing the Inspection§ Notes§ appoint a scribe for each inspector to record conversations and potential

observations§ Photocopies§ make duplicate photocopies of documents provided to inspectors

§ Document Log§ keep a log of all documents/records viewed, even if photocopies are not

provided§ Daily Debriefing§ meet after inspectors leave to discuss potential observations

§ Transcript§ combine notes/debriefing into a comprehensive transcript and distribute

appropriately§ Instant CAPA§ correct simple observations immediately and present to inspectors§ shows that you take the process seriously§ inspector may minimize or annotate 483 observations

Close out meeting

§ Invite All Audit Participants§Obtain Clarification of Ambiguous Observations§ understand specific issues§ determine what would be deemed acceptable§No Point Arguing – Observations Already Written§Ensure Senior Management Representation§ important for future resource allocation§ shows organizational commitment to compliance

Thank Inspector

Dealing with Observations

§Coordinate through Regulatory Affairs§Respond in a timely manner§Outline proposal to reestablish compliance with

timelines§Determine when and how to push back§ Some issues to consider§ Technical feasibility§ Financial feasibility§ Compromise product safety or effectiveness

§ Sometimes it’s easier to comply with a simple request rather than argue the point, even if you’re right

What we’ve learned from FDA

§ FDA Inspectors – free consultants?§ No, but don’t be afraid to have discussions§ Inspectors are well trained, have technical

expertise, and have seen a lot of facilities§ Just a few examples…§ Hand disinfectant not sterile§ Enzyme fermented from bacteria needs mycoplasma

test because bacterial culture medium contains bovine components§ Optimal temperature for development of rapid sterility

test

What FDA’s learned from us

§How to regulate cell therapy products§ first US approved cell therapy product§ first US approved xenotransplantation device§ combination products (device/biologic)§Revisions to biologics regulations§ general safety test§ FDA has used our site for inspector training§ Improvements to compendial methodology§ sterility test

Epicel™ Wins Marketing Approval for Severe Burn Victims

October 25, 2007!

Compendial Sterility Test§ Products with short shelf-lives

need to have improved microbial detection times§ Products have 2-3 day shelf life;

sterility test takes 14 days§ Significant sample handling§ Costly in an environment where

each patient constitutes a unique lot with multiple tests per lot

§ Cellular products may appear turbid due to cell suspension impacting microorganism detection

Improved Sterility Test for Cell Therapy§ BacT/Alert System will detect

organisms faster than standard methods§ Most organisms detected within

3 days§ Minimal processing§ Cost effective in an environment

where each patient constitutes a unique lot with multiple tests per lot

§ Turbidity of sample does not affect microorganism detection because detection is based on production of CO2

Acknowledgements

§Gary C. du Moulin§Barbara J. Seymour

Thank you for your attention!

§Questions?

References• 21 CFR Parts 16, 1270, and 1271 Current Good Tissue Practice for Human Cell, Tissue, and

Cellular and Tissue-Based Product Establishments; Inspection and Enforcement; Final Rule. Federal Register. Washington, DC: Office of the Federal Register, National Archives and Records Administration: 2004;69:68612-68688.

• Compliance Program Guidance Manual: Inspection of Human Cells, Tissues, and Cellular and Tissue-Based Products (HCT/Ps). Rockville, Md: U.S. Department of Health and Human Services, Public Health Service, Food and Drug Administration: 2005.

• Greb E. FDA Inspections and Warning Letters Continue to Decline. Pharmaceutical Technology. May 2, 2007:22.

• Investigations Operations Manual 2007. Rockville, Md: U.S. Department of Health and Human Services, Public Health Service, Food and Drug Administration, Office of Regulatory Affairs, Office of Regional Operations, Division of Field Investigations: 2007;5:198-298.

• Kaeding P. Who's that knocking at the door? Preparing for an FDA inspection. Wisconsin Technology Network Web site. 2005. Available at: http://wistechnology.com/article.php?id=1978. Accessed June 11, 2007.

• The Enforcement Story: Fiscal Year 2001. Rockville, Md: U.S. Department of Health and Human Services, Public Health Service, Food and Drug Administration, Office of Regulatory Affairs, Office of Enforcement: 2003.

• The Enforcement Story: Fiscal Year 2006. Rockville, Md: U.S. Department of Health and Human Services, Public Health Service, Food and Drug Administration, Office of Regulatory Affairs, Office of Enforcement: 2007.

• Wechsler J. FDA Seeks Streamlined, More Effective GMP Inspections. Pharmaceutical Technology. May 2, 2007:30-38.

• Zoon KC, Chesemore RG. Team Biologics: A Plan For Reinventing FDA'S Ability To Optimize Compliance of Regulated Biologics Industries. FDA Web site. 2002. Available at: http://www.fda.gov/cber/genadmin/ teambio.htm. Accessed May 10, 2007.

http://wistechnology.com/article.php?id=1978

http://www.fda.gov/cber/genadmin/