hct/p compliance update 6th annual fda and the changing paradigm for hct/p regulation orlando, fl,...

HCT/P Compliance HCT/P Compliance UpdateUpdate

6th Annual FDA and the Changing 6th Annual FDA and the Changing Paradigm for HCT/P RegulationParadigm for HCT/P RegulationOrlando, FL, February 3-5, 2010Orlando, FL, February 3-5, 2010Mary Malarkey, Director, OCBQ, Mary Malarkey, Director, OCBQ,

CBERCBER

SummarySummary

Inspections by the numbersInspections by the numbers Issues identifiedIssues identified Regulatory actions and Regulatory actions and

citationscitations HCT/P Deviation ReportsHCT/P Deviation Reports RecallsRecalls

InspectionsInspections

FY08 HCT/P FY08 HCT/P Inspections AccomplishedInspections Accomplished *Sum of individual inspections do not equal total due to some inspections

that were conducted for products in multiple categories

Type of HCT/P Type of HCT/P establishmentestablishment

# # Inspections Inspections

AccomplisheAccomplishedd

Hours/Hours/

InspectionInspection

Reproductive tissuesReproductive tissues 158158 42.442.4

Cord blood stem cellsCord blood stem cells

Peripheral blood stem Peripheral blood stem cellscells

1919 31.731.7

All other HCT/Ps All other HCT/Ps

(e.g. (e.g. musculoskeletal, musculoskeletal, ocular, recovery, ocular, recovery, distributors)distributors)

213213 34.434.4

Total/AverageTotal/Average 383*383* 37.537.5

FY09 HCT/P FY09 HCT/P Inspections AccomplishedInspections Accomplished

*Sum of individual inspections do not equal total due to some inspections that were conducted for products in multiple categories


# # Inspections Inspections

AccomplisheAccomplishedd

Hours/Hours/

InspectionInspection

Reproductive tissuesReproductive tissues 167167 42.842.8



4242 41.941.9



234234 40.540.5

Total/AverageTotal/Average 437*437* 41.741.7

OAI/VAI/NAI?OAI/VAI/NAI?

OAI – Official Action Indicated – OAI – Official Action Indicated – objectionable conditions found that objectionable conditions found that warrant actionwarrant action

VAI – Voluntary Action Indicated – VAI – Voluntary Action Indicated – objectionable conditions found but do objectionable conditions found but do not meet the threshold for regulatory not meet the threshold for regulatory actionaction

NAI – No Action Indicated – no NAI – No Action Indicated – no objectionable conditions found objectionable conditions found (generally no FDA-483)(generally no FDA-483)

http://www.fda.gov/ora/inspect_ref/fmdhttp://www.fda.gov/ora/inspect_ref/fmd/fmd86.htm/fmd86.htm

http://www.fda.gov/ora/inspect_ref/fmd/fmd86.htm

http://www.fda.gov/ora/inspect_ref/fmd/fmd86.htm

FY08 HCT/P FY08 HCT/P Inspection ClassificationsInspection Classifications


NAINAI VAIVAI OAIOAI

Reproductive tissuesReproductive tissues 106106 4040 1010



1515 44 00



164164 4646 11

TotalTotal 285285 9090 1111

FY09 HCT/P FY09 HCT/P Inspection ClassificationsInspection Classifications


NAINAI VAIVAI OAIOAI

Reproductive tissuesReproductive tissues 109109 4848 77



2828 1010 44



172172 5454 33

TotalTotal 309309 112112 1414

FY09 HCT/P FY09 HCT/P Inspection ResultsInspection Results

Approx. 30% of HCT/P inspections Approx. 30% of HCT/P inspections resulted in issuance of Form FDA-resulted in issuance of Form FDA-483s; 483s;

Consistent with FY08 and FY07. Consistent with FY08 and FY07.

FDA Form 483FDA Form 483

““This document lists observations made by the This document lists observations made by the FDA representative(s) during the inspection of FDA representative(s) during the inspection of your facility. They are inspectional observations, your facility. They are inspectional observations, and do not represent a final agency and do not represent a final agency determination regarding your compliance. If you determination regarding your compliance. If you have an objection regarding an observation, or have an objection regarding an observation, or have implemented, or plan to implement, have implemented, or plan to implement, corrective action in response to an observation, corrective action in response to an observation, you may discuss the objection or action with the you may discuss the objection or action with the FDA representative(s) during the inspection or FDA representative(s) during the inspection or submit this information to FDA at the address submit this information to FDA at the address above….”above….”

Inspectional Focus Inspectional Focus in FY09in FY09

Risk-based inspectional approach Risk-based inspectional approach to prioritizing HCT/P inspections. to prioritizing HCT/P inspections. Examples: Examples: – Increase in adverse reaction reports Increase in adverse reaction reports

for corneas – for corneas – CandidaCandida – Eye Banks – Eye Banks– 27 private cord blood banks 27 private cord blood banks

proactively identified for inspection proactively identified for inspection to gauge the industryto gauge the industry

GTP Issues IdentifiedGTP Issues Identified

Eye banks not validating Eye banks not validating processingprocessing (e.g. preparation of corneas for EK, (e.g. preparation of corneas for EK, DSEAK) with respect to prevention of DSEAK) with respect to prevention of contamination and cross contamination and cross contamination during processingcontamination during processing

Cord blood banks not validating Cord blood banks not validating processing with respect to prevention processing with respect to prevention of contamination and cross of contamination and cross contamination during processingcontamination during processing

Other GTP issuesOther GTP issues

Lack of environmental controls Lack of environmental controls and monitoring - to assure and monitoring - to assure consistency and maintain consistency and maintain validated state.validated state.

Lack of or inadequate validation Lack of or inadequate validation of microbiological test methods of microbiological test methods (i.e. part of definition of (i.e. part of definition of processing)processing)

DE Issues – Cord BloodDE Issues – Cord Blood

21 CFR 1271.75(a)(1)21 CFR 1271.75(a)(1) - Donors were not - Donors were not screened by a review of relevant medical screened by a review of relevant medical records for clinical evidence of communicable records for clinical evidence of communicable disease agents and diseases. disease agents and diseases. – Asking questions about the donor's medical Asking questions about the donor's medical

history and relevant social behavior, including history and relevant social behavior, including risk factors for relevant communicable disease risk factors for relevant communicable disease agents and diseases, and communicable agents and diseases, and communicable disease risks associated with disease risks associated with xenotransplantation. xenotransplantation.

– A review of medical records, including a A review of medical records, including a physical assessment for clinical evidence of physical assessment for clinical evidence of cell associated communicable disease agents cell associated communicable disease agents and disease.and disease.

DE Issues – Cord Blood - DE Issues – Cord Blood - 22

21 CFR 1271.47(a) - Procedures for all 21 CFR 1271.47(a) - Procedures for all steps performed in the screening, testing, steps performed in the screening, testing, and determining of donor eligibility of and determining of donor eligibility of HCT/Ps were not established and HCT/Ps were not established and maintained.maintained.– No written procedures for screening donors for No written procedures for screening donors for

clinical evidence of communicable diseases. clinical evidence of communicable diseases. – Testing procedures do not require testing for Testing procedures do not require testing for

HTLV-I/II for donors of viable, leukocyte-rich HTLV-I/II for donors of viable, leukocyte-rich cells or tissue.cells or tissue.

Regulatory ActionsRegulatory Actions

Warning LettersWarning Letters Require a company responseRequire a company response

– You should apply to all sitesYou should apply to all sites Other government agencies notifiedOther government agencies notified Posted on the websitePosted on the website Inadequacies in your 483 response will be Inadequacies in your 483 response will be

addressed if submitted within 15 days of addressed if submitted within 15 days of inspection*inspection*

Usually FDA's last attempt to get company's Usually FDA's last attempt to get company's attention before enforcement actionattention before enforcement action

Warning Letter close out letters from FDA Warning Letter close out letters from FDA now issued and posted on website*now issued and posted on website*

Untitled LettersUntitled Letters

Communication to the industry on Communication to the industry on concerns concerns

May ask for a responseMay ask for a response Other federal agencies not Other federal agencies not

advisedadvised No warning statementNo warning statement

Regulatory ActionsRegulatory ActionsFY09FY09

Regulatory Actions IssuedRegulatory Actions Issued– 44 Warning Letter (repro) ( Warning Letter (repro) (FY08 – 1FY08 – 1))– 33 Untitled Letter (repro) ( Untitled Letter (repro) (FY08 – 1FY08 – 1))– 1 Order to Cease Manufacturing of 1 Order to Cease Manufacturing of

HCT/Ps (cord blood)HCT/Ps (cord blood)

Regulatory Actions Regulatory Actions FY10*FY10* Regulatory Action IssuedRegulatory Action Issued

– 5 Untitled Letters5 Untitled Letters 3 repro3 repro 1 eye bank1 eye bank 1 cord blood bank1 cord blood bank

* As of 1/15/10

FY09- FY10 Regulatory FY09- FY10 Regulatory Actions: Deviations Cited Actions: Deviations Cited

- Repro- Repro Failure to test specimens from anonymous or Failure to test specimens from anonymous or

directed reproductive donors for evidence of directed reproductive donors for evidence of infection due to relevant communicable infection due to relevant communicable diseases [21 CFR 1271.85(a)(b) and (c)].diseases [21 CFR 1271.85(a)(b) and (c)]. HIV, HIV, HCV, HTLV – I/II, CMV, Chlamydia, Neisseria.HCV, HTLV – I/II, CMV, Chlamydia, Neisseria.

Failure to screen an anonymous or directed Failure to screen an anonymous or directed reproductive donor of cells or tissue by reproductive donor of cells or tissue by reviewing the donor's relevant medical reviewing the donor's relevant medical records for risk factors for, and clinical records for risk factors for, and clinical evidence of, relevant communicable disease evidence of, relevant communicable disease agents and diseases [21 CFR 1271.75(a)]. agents and diseases [21 CFR 1271.75(a)].

FY09- FY10 Regulatory FY09- FY10 Regulatory Actions: Deviations Cited Actions: Deviations Cited

- Repro- Repro Failure to collect a donor specimen for Failure to collect a donor specimen for

testing for relevant communicable testing for relevant communicable diseases within 30 days prior to oocyte diseases within 30 days prior to oocyte recovery or up to seven days after recovery or up to seven days after oocyte recovery or up to seven days oocyte recovery or up to seven days before or after recovery for semen before or after recovery for semen donors [21 CFR 1271. 80(b)].donors [21 CFR 1271. 80(b)].

Failure of a responsible person to Failure of a responsible person to determine and document the eligibility determine and document the eligibility of an anonymous or directed donor of of an anonymous or directed donor of reproductive cells or tissue [21 CFR reproductive cells or tissue [21 CFR 1271.50(a)].1271.50(a)].

Vista Cord, LLC (Vista Cord)Vista Cord, LLC (Vista Cord)Order to Cease Manufacturing of Order to Cease Manufacturing of

HCT/Ps (cord blood)HCT/Ps (cord blood) Immediately cease manufacturing operations and Immediately cease manufacturing operations and

continue to store cord blood in compliance with continue to store cord blood in compliance with 21 CFR 1271.26021 CFR 1271.260

To Vista Cord and its CEO and owner, Aubrey B. To Vista Cord and its CEO and owner, Aubrey B. AllenAllen

FDA determined that the violations uncovered at FDA determined that the violations uncovered at Vista Cord, because of their serious nature, Vista Cord, because of their serious nature, provided reasonable grounds to believe that there provided reasonable grounds to believe that there is a danger to health. The Order was effective is a danger to health. The Order was effective immediately.immediately.

Order to Cease Manufacturing of HCT/Ps was Order to Cease Manufacturing of HCT/Ps was issued on September 24, 2009.issued on September 24, 2009.

http://www.fda.gov/BiologicsBloodVaccines/SafetyAvailabilihttp://www.fda.gov/BiologicsBloodVaccines/SafetyAvailability/TissueSafety/ucm183756.htmty/TissueSafety/ucm183756.htm

http://www.fda.gov/BiologicsBloodVaccines/SafetyAvailability/TissueSafety/ucm183756.htm

http://www.fda.gov/BiologicsBloodVaccines/SafetyAvailability/TissueSafety/ucm183756.htm

Vista Cord Public Health Vista Cord Public Health NotificationNotification

Issued on September 25, 2009, to inform the Issued on September 25, 2009, to inform the health care community and the public of the health care community and the public of the Order.Order.

““FDA has identified deviations from requirements FDA has identified deviations from requirements regarding donor eligibility screening and testing, regarding donor eligibility screening and testing, processing controls, environmental control and processing controls, environmental control and monitoring, equipment and facilities, supplies and monitoring, equipment and facilities, supplies and reagents, process validation, labeling controls, reagents, process validation, labeling controls, and receipt of products.” and receipt of products.”

““FDA staff are aware that these units are FDA staff are aware that these units are important to the donor families, and were important to the donor families, and were collected, processed and stored at significant collected, processed and stored at significant expense….We will work to facilitate the transfer expense….We will work to facilitate the transfer of units to other storage facilities identified by of units to other storage facilities identified by the donor families.”the donor families.”

HCT/P Deviation HCT/P Deviation Reports and IssuesReports and Issues

HCT/P Deviation ReportsHCT/P Deviation ReportsProducts InvolvedProducts Involved

ProductProductFY0FY066

FY0FY077

FY0FY088

FY0FY099

Peripheral Blood Stem Peripheral Blood Stem CellsCells 7171 9898 108108 8484

Cornea/ScleraCornea/Sclera 5050 3535 4242 5151

SkinSkin 55 66 2727 4343

Pancreatic Islet Cells, Pancreatic Islet Cells, autoauto 00 11 1919 3030

MusculoskeletalMusculoskeletal 2323 1515 2323 5151

Cord Blood Stem CellsCord Blood Stem Cells 22 44 44 1010

Therapeutic CellsTherapeutic Cells 66 1010 1212 99

HCT/P Deviations ReportedHCT/P Deviations ReportedReportable HCT/P Reportable HCT/P DeviationsDeviations

FY FY 0606

FY FY 0707

FY 08FY 08 FY0FY099

Donor EligibilityDonor Eligibility 3232 2424 3737 3434

Donor ScreeningDonor Screening 1212 88 1717 77

Donor TestingDonor Testing 3333 5454 5454 3838

Environmental ControlEnvironmental Control 11 22 00 00

Supplies and ReagentsSupplies and Reagents 33 66 11 00

RecoveryRecovery 22 88 88 1414

ProcessingProcessing 1414 1717 6868 101101

Labeling ControlLabeling Control 22 11 22 22

StorageStorage 11 00 00 00

Receipt, Pre-Dist., Dist.Receipt, Pre-Dist., Dist. 4343 3232 3636 5858

TotalTotal 143143 152152 223223 254254

Non-ReportableNon-Reportable 7777 4848 6363 4545

HCT/P Deviation Reports HCT/P Deviation Reports Non-Reportable EventsNon-Reportable Events

No products were distributedNo products were distributed Not associated with disease transmission or Not associated with disease transmission or

contaminationcontamination Not related to core GTPNot related to core GTP Product released under urgent medical needProduct released under urgent medical need Product not subject to HCT/P deviation Product not subject to HCT/P deviation

reportingreporting– Reproductive tissueReproductive tissue– Unrelated Allogeneic Stem CellsUnrelated Allogeneic Stem Cells

Reporting establishment is not an HCT/P Reporting establishment is not an HCT/P manufacturermanufacturer

HCT/P Deviation Reports HCT/P Deviation Reports Non-Reportable EventsNon-Reportable Events

Positive pre-implant culture is in Positive pre-implant culture is in general not reportable as a deviationgeneral not reportable as a deviation– Unless a complaint results in an Unless a complaint results in an

investigation that reveals a departure investigation that reveals a departure from GTPs orfrom GTPs or

– If the recipient had an adverse reaction If the recipient had an adverse reaction then might be reported as an adverse then might be reported as an adverse reaction not HCT/P deviationreaction not HCT/P deviation

HCT/P Deviation ReportingHCT/P Deviation ReportingFY09FY09

HCT/P Deviation CodeHCT/P Deviation CodeCellularCellularHCT/PHCT/P

TissueTissueHCT/PHCT/P TotalTotal

Processing and Processing Processing and Processing ControlsControls 6666 3535 101101 39.8%39.8%

Receipt, Pre-Distribution, Receipt, Pre-Distribution, Shipment & DistributionShipment & Distribution 5353 55 5858 22.8%22.8%

Donor TestingDonor Testing 44 3434 3838 15.0%15.0%

Donor EligibilityDonor Eligibility 22 3232 3434 13.4%13.4%

RecoveryRecovery 66 88 1414 5.5%5.5%

Donor ScreeningDonor Screening 00 77 77 2.8%2.8%

Labeling ControlsLabeling Controls 00 22 22 0.8%0.8%

Supplies and ReagentsSupplies and Reagents 00 00 00 0.0%0.0%

Environmental ControlEnvironmental Control 00 00 00 0.0%0.0%

StorageStorage 00 00 00 0.0%0.0%

TotalTotal 131131 123123 254254 100%100%

HCT/P Deviation Reporting FY08

HCT/P Deviation HCT/P Deviation CodeCode

Cellular Cellular HCT/PHCT/P

Tissue Tissue HCT/PHCT/P TotalTotal

Donor EligibilityDonor Eligibility 44 3333 373716.616.6

%%

Donor ScreeningDonor Screening 22 1515 1717 7.6%7.6%

Donor TestingDonor Testing 4242 1212 545424.224.2

%%

Environmental Environmental ControlControl 00 00 00 0.0%0.0%

Supplies and Supplies and ReagentsReagents 11 00 11 0.4%0.4%

RecoveryRecovery 88 00 88 3.6%3.6%

Processing and Processing and Processing ControlsProcessing Controls 5050 1818 6868

30.530.5%%

Labeling ControlsLabeling Controls 00 22 22 0.9%0.9%

StorageStorage 00 00 00 0.0%0.0%

Receipt, Pre-Receipt, Pre-Distribution, Distribution, Shipment & Shipment & DistributionDistribution 3333 33 3636

16.116.1%%

TotalTotal 140140 8383 223223100100%%

Tissue HCT/P Reports - Tissue HCT/P Reports - 11 Processing and process controls – Processing and process controls – 3535

– HCT/P contaminated, potentially HCT/P contaminated, potentially contaminated or cross contaminated – contaminated or cross contaminated – 3434

– In-process controls not followed – In-process controls not followed – 11

Microorganisms involved:Microorganisms involved:– Bacillus, Candida, Clostridium, Bacillus, Candida, Clostridium,

Enterobacter, Group D Enterococcus, Enterobacter, Group D Enterococcus, Staphylococcus, SerratiaStaphylococcus, Serratia

Tissue HCT/P Reports - Tissue HCT/P Reports - 22 Donor Testing – Donor Testing – 3434

– Unacceptable specimen testedUnacceptable specimen tested storage condition not met – storage condition not met – 2525 Specimen collected >7 days before or Specimen collected >7 days before or

after recovery - after recovery - 11

– Testing incorrectly performed – Testing incorrectly performed – 55– Testing not performed or documented Testing not performed or documented

– – 22– Inappropriate test or test lab used - Inappropriate test or test lab used - 11

Tissue HCT/P Reports - Tissue HCT/P Reports - 33 Donor Eligibility – Donor Eligibility – 3232 reports reports

– Donor accepted when risk factors, clinical Donor accepted when risk factors, clinical evidence or physical evidence identified – evidence or physical evidence identified – 1818

– Donor accepted when reactive for relevant Donor accepted when reactive for relevant communicable disease – communicable disease – 66

– Donor incorrectly evaluated for plasma Donor incorrectly evaluated for plasma dilution –dilution – 4 4

– Donor eligibility not performed or Donor eligibility not performed or documented - documented - 44

Cellular HCT/P Reports - Cellular HCT/P Reports - 11 Processing and process controls – Processing and process controls – 6666

– HCT/P contaminated, potentially HCT/P contaminated, potentially contaminated or cross contaminated during contaminated or cross contaminated during processing – processing – 5959

Syringe integrity compromised - Syringe integrity compromised - 1313– In process controls not followed – In process controls not followed – 77

Microorganisms involved:Microorganisms involved:– Bacillus, Candida, Diphtheroids, Bacillus, Candida, Diphtheroids,

Enterobacter, Group D Enterococcus, Enterobacter, Group D Enterococcus, Klebsiella, Micrococcus, Peptostreptococcus, Klebsiella, Micrococcus, Peptostreptococcus, Propionibacterium, StaphylococcusPropionibacterium, Staphylococcus,, StreptococcusStreptococcus

Cellular HCT/P Reports - Cellular HCT/P Reports - 22 Distribution – Distribution – 5353

– Contaminated or potentially contaminated Contaminated or potentially contaminated HCT/P – HCT/P – 5050

– Distribution without sign off by a Distribution without sign off by a responsible person – responsible person – 22

– Distribution without review of required Distribution without review of required records - records - 11

Microorganisms involved:Microorganisms involved:– Bacillus, Micrococcus, Propionibacterium, Bacillus, Micrococcus, Propionibacterium,

Staphylococcus, StreptococcusStaphylococcus, Streptococcus

Classified RecallsClassified RecallsFY 2009FY 2009

*In addition, there were 118 “mixed” Class II and III blood recalls

HCT/PHCT/P

RecallsRecallsCBER Total CBER Total Recalls *Recalls *

(all (all products)products)

FY 09 Class IFY 09 Class I 00 00

FY 09 Class FY 09 Class IIII

99 807807

FY 09 Class FY 09 Class IIIIII

44 312312

Classified RecallsClassified RecallsFY 2008*FY 2008*

*- This table does not include 3 “mixed class” recalls

HCT/PHCT/P

RecallsRecallsCBER Total CBER Total

Recalls Recalls

(all (all products)products)

FY 08 Class IFY 08 Class I 33 44

FY 08 Class FY 08 Class IIII

1111 950950

FY 08 Class FY 08 Class IIIIII

77 345345

HCT/P RecallsHCT/P Recalls

0

5

10

15

20

25

30

35

40

45

FY00 FY02 FY04 FY06 FY08

Class I

Class II

Class III

Vision for CBERVision for CBER

INNOVATIVE TECHNOLOGY INNOVATIVE TECHNOLOGY ADVANCING PUBLIC HEALTHADVANCING PUBLIC HEALTH

CBER uses sound science and regulatory CBER uses sound science and regulatory expertise to:expertise to:

Protect and improve public and Protect and improve public and individual health in the US and, where individual health in the US and, where feasible, globally feasible, globally

Facilitate development, approval and Facilitate development, approval and access to safe and effective products access to safe and effective products and promising new technologies and promising new technologies

Strengthen CBER as a preeminentStrengthen CBER as a preeminent regulatory organization for biologicsregulatory organization for biologics

We’re Here to Help You!We’re Here to Help You!http://www.fda.govhttp://www.fda.gov

Email CBER:Email CBER:–Manufacturers: Manufacturers: [email protected]@cber.fda.gov

–Consumers, health Consumers, health carecare

–[email protected]@cber.fda.gov Phone:Phone:

–+1-301-827-1800+1-301-827-1800

hct/p compliance update 6th annual fda and the changing paradigm for hct/p regulation orlando, fl,...

Documents

prioritizing hctp inspections

hctp regulationorlando

fda form

fda representatives

sum of individual inspections

communicable disease

issuance of form fda

cross contamination