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FABB - 2013 HOT TOPICS Current Issues in Blood Banking Ron Jackson Director, Compliance Branch FDA FLORIDA DISTRICT June 7, 2013 Slide 2 New Labeling Regulations Slide 3 Published in Federal Register Revisions to Labeling Regulations for Blood and Blood Components, including Source Plasma 77 FR 7, January 3, 2012 Became effective July 2, 2012 Codified in Title 21 of the Code of Federal Regulations - April 2012 edition Affects the following regs: 21 CFR 606.121 21 CFR 606.122 21 CFR 640.70 21 CFR 640.74 Slide 4 Most Notable Changes April 2012 CFR contains both the old and new regs Labeling regs were updated to be consistent with current practices Changed the reg citation for certain requirements. For example: Recovered plasma label requirements previously in 21 CFR 606.121(e)(5), are now in 21 CFR 606.121(e)(4) Source Plasma labeling regs. previously in 21 CFR 640.70, were moved to 21 CFR 606.121 Slide 5 Most Notable Changes Unique Facility Identifier (UFI) 21 CFR 606.121(c)(2) Discussed on page 77 FR 11 of the Federal Register UFI now required to be on labels of blood intended for transfusion Blood establishments need to track where unit was collected. The UFI can be: The FDA registration number The ISBT facility code Some other designation that will identify specific location where product was collected Incorporated into donation number and use a validated computer or other recordkeeping system to identify where unit was collected Not applicable to Source Plasma; FDA is aware the approved labels have sufficient information Slide 6 Most Notable Changes Autologous Unit Labeling 21 CFR 606.121(i) Previously all auto units were labeled with For Autologous Use Only Now acceptable auto units that can be crossed over into allogeneic inventory are labeled as Autologous Donor Unacceptable auto units that cannot be crossed over are labeled as For Autologous Use Only Note: AABB standards will only include For Autologous Use Only statement because they discourage crossover For Autologous Use Only can be on all auto units, but these units cannot be crossed over Slide 7 Most Notable Changes Circular of Information Changed name from Instruction Circular to Circular of Information 21 CFR 606.122(m)(3) Removed requirement to administer thawed FFP or PF24 within 6 hours States circular must have instructions when to begin administering FFP and PF24 after thawing Current circular states FFP and PF24 must be administered within 24 hours after thawing Eliminates requirement for 21 CFR 640.120 variance to store thawed FFP and PF24 for up to 24 hours before administering Note: Circular states 5-day Thawed Plasma is unlicensed; CBER will not approve variances for this product Slide 8 Additional Information in Preamble 77 FR 11 (21 CFR 606.121(b) Original labels may be altered to accurately the identify contents of the unit, e.g., after irradiation, washing, etc. This includes reprinting a new full-face label, but blood establishments must be able to re-create all other original information and it must be done with a validated process 77 FR 12 (21 CFR 606.121(c)(11) Source Plasma donors are tested for syphilis every 4 months; it is a donor test (vs. a test on the donation) Confirmed that it is not required to put negative syphilis results on each Source Plasma unit But if syphilis test is reactive, the unit associated with the positive test and all subsequent units from that donor must include positive syphilis test result (until test is negative) Slide 9 Most Notable Changes 77 FR 13 (21 CFR 606.121(c)(11) - It is acceptable for Source Plasma units to have negative infectious disease test results on label before testing has been completed It is acceptable for these units to be shipped to quarantined storage, including to an independent off-site storage facility The storage facilities must be under the control of the Source Plasma firm; this includes those owned by or under contract to the Source Plasma firm If unit is pre-labeled with negative test result but is later found to be positive when testing is completed, the unit must be relabeled; the negative result must be obliterated and replaced with the positive result Slide 10 Summary of Notable Changes Source Plasma labeling regs were removed from 640.70 and are now included in 606.121 Blood establishments must be able to determine from label where each unit was collected For Autologous Use Only can be on the labels of all auto units if they will not be crossed over Variances are no longer needed to store thawed FFP and PF24 for up to 24 hours before administering Full-face labels on modified products can be re-created using a validated process Source Plasma units can be pre-labeled with negative infectious disease test results before testing is completed and shipped to storage facilities under firms control; positive units must be relabeled Source Plasma units must be labeled with positive syphilis test results (index unit and subsequent units until test is negative) Slide 11 References Federal Register 77 FR 7, January 3, 2012 Title 21 CFR April 2012 21 CFR 606.121 21 CFR 606.122 21 CFR 640.70 21 CFR 640.74 CBER - Blood and Plasma Branch CSOs 301-827-3543 Slide 12 New Apheresis Plasma Products Slide 13 Plasma Frozen Within 24 Hours After Phlebotomy (PF24) Plasma Frozen Within 24 Hours After Phlebotomy Held At Room Temperature Up To 24 Hours After Phlebotomy (PF24RT24) Slide 14 Apheresis Devices approved and/or cleared to manufacture new Plasma products Fenwal ALYX Fenwal Amicus TerumoBCT Trima Accel Slide 15 Plasma Frozen Within 24 Hours After Phlebotomy (PF24) Must be stored at 1 6C within 8 hours of collection and prepared and frozen within 24 hours after phlebotomy. Indicated for replacement of non-labile clotting factors. This product is not equivalent to Fresh Frozen Plasma. Slide 16 Plasma Frozen Within 24 Hours After Phlebotomy Held At Room Temperature Up To 24 Hours After Phlebotomy (PF24RT24) Can be stored at room temperature for up to 24 hour after collection. Product must be prepared and frozen within 24 hours after phlebotomy. Indicated for replacement of non-labile clotting factors. This product is not equivalent to Fresh Frozen Plasma. Slide 17 Example of Instructions for Use Slide 18 Slide 19 Circular of Information 21 CFR 606.122 Circular of information. A circular of information must be available for distribution if the product is intended for transfusion. Slide 20 Circular of Information The December 2009 version of the AABB COI may be modified by the following FDA accepted statement: http://www.aabb.org/resources/bct/Pages/aabb_coi.aspx Slide 21 This may either be glued or stapled into the current December 2009 edition Slide 22 Please Note Whole Blood PF24 has been a licensable product for > 20 years PF24RT24 has NOT been cleared or approved to be manufactured from Whole Blood Slide 23 Platelet Manufacturing Rest Period and Agitation Slide 24 The Science Centrifugated platelets aggregate irreversibly if subjected to rough agitation The procedures should describe a Rest Period for 10 minutes to an hour prior to resuspension. Slide 25 The Regulations 21 CFR 640.25 [Platelets] General requirements. (a)Storage. Immediately after resuspension, Platelets shall be placed in storage at the selected temperature range. If stored at 20 to 24 deg. C, a continuous gentle agitation of the platelet concentrate shall be maintained Slide 26 Additional Information Trima Accel Slide 27 Additional Information CaridianBCT Guide to Platelet and Plasma Collections 2001 Slide 28 Additional Information Fenwal Amicus Slide 29 Guidance for Industry Implementation of an Acceptable Abbreviated Donor History Questionnaire (aDHQ) and Accompanying Materials for Use in Screening Frequent Donors of Blood and Blood Components Slide 30 Defined Donor Criteria for Frequent Donor Two previous donations using the full-length Donor History Questionnaire (DHQ), one within last 6 months Includes deferral of less than 6 months duration, if within 6 months of successful donation. (usable component, not a factor) Deferrals greater than 6 months disqualify approval for use of aDHQ must start over Slide 31 SOP should state actions to be taken if: a. Incorrect questionnaire administered b. Questionnaire is incomplete c. Ensure that donor unit quarantined until eligibility issued are resolved. If unit distributed, BDPR required Investigation required New questions both full-length DHQ and aDHQ for 1 year from date added. Slide 32 Eligibility for using the aDHQ Administered on day of donation Donor must meet the defined criteria for Frequent donor AND blood collection facility has a system in place to determine appropriateness Slide 33 Methods of Administration Written Procedure (SOP) May be Self-Administered with f/u review by trained donor historian May be administered by donor historian Donor may be deferred prior to completion of entire questionnaire, if specified in SOP Encourage donor to ask questions Slide 34 Day of Donation (aDHQ ) Must read Donor Education Materials prior to completing questionnaire Must be given Medication Deferral List and List of BSE countries to be used Alternatively, one or all lists can be prominently displayed at donation site for donors use while donors complete aDHQ Slide 35 Common Problems in Biologics Inspections Slide 36 Source: Turbo EIR Database Slide 37 Scope Timeframe 01/2012 to 12/2012 Approx. # of Inspections in Database 1,038 Approx. # of Observations in Database 343 Slide 38 Applicable Regulations Blood GMPs 43% relate to Written SOPs 27% cite records deficiencies 22% pertain to performance failures 4% identify training and/or personnel issues 4% specify equipment calibration issues Slide 39 Frequency of Observations 21 CFRCount 606.100(b) - 147 606.160(a)(1) - 70 606.100(c) - 46 606.160(b) - 22 606.20(b) - 15 606.60(b) - 15 606.65(e) - 15 606.171 - 13 Slide 40 606.100(b) SOPs Cited in 147 inspections Written standard operating procedures including all steps to be followed in the [collection] [processing] [compatibility testing] [storage] [distribution] of blood and blood components for [homologous transfusion] [autologous transfusion] [further manufacturing purposes] are not always [maintained] [followed] [maintained on the premises]. Specifically, *** Slide 41 606.100(c) Cited in 46 inspections Failure to [perform a thorough investigation] [make a record of the conclusions and follow- up] of [an explained discrepancy] [a failure of a lot or unit to meet any of its specifications]. Specifically, *** Slide 42 606.160(a)(1) Cited in 29 inspections Records fail to [identify the person performing the work] [include dates of the various entries] [show test results] [include interpretation of the results] [show the expiration date assigned to specific products] [be as detailed as necessary] so as to provide a complete history of the work performed. Specifically, *** Slide 43 606.160(a)(1) contd : Cited in 28 inspections Records are not concurrently maintained with the performance of each significant step in the [collection] [processing] [compatibility testing] [storage] [distribution] of each unit of blood and blood components so that all steps can be clearly traced. Specifically, *** Slide 44 606.160(a)(1) contd: Cited in 13 inspections Records are [illegible] [not indelible] Specifically, *** Slide 45 606.160(b) Cited in 22 inspections Failure to maintain [donor] [processing] [storage and distribution] [compatibility testing] [quality control] [general] records. Specifically, *** Slide 46 606.65(e) Cited in 15 inspections Failure to use supplies and reagents in a manner consistent with instructions provided by the manufacturer. Specifically, *** Slide 47 606.60(b) Cited in 15 inspections Equipment used in the [collection] [processing] [compatibility testing] [storage and distribution] of blood and blood components is not [observed] [standardized] [calibrated] on a regularly scheduled basis as prescribed in the SOP Manual. Specifically, *** Slide 48 606.20(b) Cited in 15 inspections The personnel responsible for the [collection] [processing] [compatibility testing] [storage] [distribution] of blood or blood components are not adequate in [number] [educational background] [training and experience, including professional training as necessary] to assure competent performance of their assigned functions, and to ensure that the final product has the safety, purity, potency, identity and effectiveness it purports or is represented to possess. Specifically, *** Slide 49 606.171 Cited in 13 inspections Failure to submit a biological product deviation report [within 45 days from the date you acquired information suggesting that a reportable event occurred] Specifically, *** Slide 50 Top 10 Biologics Observations Used in Turbo EIR Between 01/01/2012 And 12/31/2012 Slide 51 FDA Enforcement Statistics Summary Fiscal Year 2012 Seizures8 Injunctions17 Warning Letters4,882 Recall Events4,075 Recalled Products9,469 Debarments 20 Slide 52 Seizures by FDA Center Fiscal Year 2012 Slide 53 Injunctions by FDA Center Fiscal Year 2012 Slide 54 Warning Letters by FDA Center Fiscal Year 2012 Slide 55 Total Recalled Products by FDA Center Fiscal Year 2012 Class I, II and III Slide 56 Recalled Products All Centers Fiscal Years 2007 2012 Slide 57 FDA Recalls By Center - All Classes Fiscal Year 2012 Slide 58 FDA Recalls Class I By Center Fiscal Year 2012 Slide 59 FDA Recalls - Class II By Center Fiscal Year 2012 Slide 60 FDA Recalls - Class III By Center Fiscal Year 2012 Slide 61 FLA-DO Legal Actions Slide 62 Questions?? Slide 63 Contact Information: CBER - Blood and Plasma Branch CSOs: (301) 827-3543 FLA-DO: Biologics Specialist: (904) 281-1924 ext. 116 FLA-DO District Office: (407) 475-4700