HCT/P Compliance HCT/P Compliance Update Update 6th Annual FDA and the 6th Annual FDA and the Changing Paradigm for HCT/P Changing Paradigm for HCT/P Regulation Regulation Orlando, FL, February 3-5, Orlando, FL, February 3-5, 2010 2010 Mary Malarkey, Director, Mary Malarkey, Director, OCBQ, CBER OCBQ, CBER
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HCT/P Compliance Update 6th Annual FDA and the Changing Paradigm for HCT/P Regulation Orlando, FL, February 3-5, 2010 Mary Malarkey, Director, OCBQ, CBER.
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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
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)
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
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
- 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)].
- 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.
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
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
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
– 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
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
*- 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
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