Upload
others
View
11
Download
0
Embed Size (px)
Citation preview
www.ac-gt.com
Preparation for FDA InspectionsPreparation for FDA Inspections
Karen Edward, BS, MT (ASCP)Advanced Cell & Gene Therapy
ISCT 2007 Regional Meeting Houston
www.ac-gt.com
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?
ISCT 2007 Regional Meeting Houston
www.ac-gt.com
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
ISCT 2007 Regional Meeting Houston
www.ac-gt.com
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
ISCT 2007 Regional Meeting Houston
www.ac-gt.com
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
ISCT 2007 Regional Meeting Houston
www.ac-gt.com
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
www.ac-gt.com
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
ISCT 2007 Regional Meeting Houston
www.ac-gt.com
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
ISCT 2007 Regional Meeting Houston
www.ac-gt.com
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
ISCT 2007 Regional Meeting Houston
www.ac-gt.com
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
ISCT 2007 Regional Meeting Houston
www.ac-gt.com
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
ISCT 2007 Regional Meeting Houston
www.ac-gt.com
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
ISCT 2007 Regional Meeting Houston
www.ac-gt.com
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
ISCT 2007 Regional Meeting Houston
www.ac-gt.com
““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?
ISCT 2007 Regional Meeting Houston
www.ac-gt.com
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””
ISCT 2007 Regional Meeting Houston
www.ac-gt.com
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)
ISCT 2007 Regional Meeting Houston
www.ac-gt.com
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.
ISCT 2007 Regional Meeting Houston
www.ac-gt.com
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
ISCT 2007 Regional Meeting Houston
www.ac-gt.com
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!
ISCT 2007 Regional Meeting Houston
www.ac-gt.com
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
ISCT 2007 Regional Meeting Houston
www.ac-gt.com
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
ISCT 2007 Regional Meeting Houston
www.ac-gt.com
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
ISCT 2007 Regional Meeting Houston
www.ac-gt.com
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
ISCT 2007 Regional Meeting Houston
www.ac-gt.com
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
ISCT 2007 Regional Meeting Houston
www.ac-gt.com
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
ISCT 2007 Regional Meeting Houston
www.ac-gt.com
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
ISCT 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
0
5000
10000
15000
20000
25000
1997
1998
1999
2000
2001
2002
2003
2004
2005
2006
Insp
ectio
ns
0
200
400
600
800
1000
1200
1400
War
ning
Let
ters
Inspections Warning Letters
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
0
5
10
15
20
25
30
35
2002 2003 2004 2005 2006
Num
ber o
f Aud
its
0
1
2
3
4
5
6
7
Mon
ths
Number of Audits Average Time to Close (Months)
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
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
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.