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U.S. Department of Health and Human Services

Vaccines, Blood & Biologics

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Complete Review Letter, August 16, 2012 - ALLOCORD

DEPARTMENT OF HEALTH & HUMAN SERVICES                                                     Public Health Service

                                                                                                                            Food and Drug Administration
1401 Rockville Pike
Rockville, MD 20852-1448



Our STN: BL 125413/0                                                                                 August 16, 2012
SSM Cardinal Glennon Children's Medical Center
Attention: Ms. Donna M. Regan
3662 Park Avenue
St. Louis, MO 63110
Dear Ms. Regan:
This letter is in regard to your biologics license application (BLA) for HPC, Cord Blood manufactured at your St. Louis, Missouri and Kansas City, Missouri locations and submitted under section 351 of the Public Health Service Act (42 U.S.C. 262).
We have completed our review of all your submissions relating to this BLA, with the exception of the information in the amendment dated July 30, 2012. Because of the deficiencies outlined below, we have concluded that we cannot grant final approval of your BLA.
1.         Outstanding inspectional issues identified on the FDA Form 483 for St. Louis Cord Blood Bank (SLCBB), located in St. Louis, Missouri dated April 20, 2012, and the FDA Form 483 for St. Luke’s Cancer Institute (SLCI), located in Kansas City, Missouri dated April 27, 2012 issued at the conclusion of each pre-license inspection, have yet to be resolved. You must satisfactorily resolve these issues prior to approval of the application.
2.         The collection validation summary that you have submitted is not adequate because it does not include all the relevant aspects of the collection procedures that are currently in use (e.g., completion of donor screening documentation, labeling, collection volume, and transportation) with pre-defined acceptance criteria. Please submit the final validation summary for the collection and transportation of cord blood units from the hospitals to the processing laboratories. The validation must be completed at the SLCBB and SLCI facilities. 
3.         Please submit PrepaCyte-CB processing validation protocols.  You will need to establish a validation protocol, with defined acceptance criteria, that is approved by your Quality Unit before performing the validation study. The protocol should be developed using any new standard operating procedures (SOPs) that are implemented in response to the 483 inspection observations. 
4.         The thawing and reconstitution instructions to be provided in the Prescribing Information must be based on validated procedures.  Please provide written instructions and data demonstrating that your instructions have been validated.
5.         Information for training of collection staff for SLCI was not included in the submission. Please provide a description of training of collection personnel for the collection sites providing units to SLCI and a description of the periodic monitoring that occurs to ensure the collections are continually performed on an acceptable basis. 
6.         Please provide the appropriate request for a Categorical Exclusion for the Environmental Assessment. 
7.         Please identify an appropriate reserve sample that will be retained for each lot in compliance with 21 CFR 211.170. One of the segments attached to the cryopreserved HPC, Cord Blood product may be appropriate.
8.         The data that you have submitted are insufficient to establish a product dating period (expiration date). We note that only summary data were included, and no stability protocol has been established. Please provide a stability protocol and data to establish an expiration date for cryopreserved HPC, Cord Blood units made using the PrepaCyte-CB process.  The stability protocol should contain appropriate predefined acceptance criteria.
9.         The submitted validation data do not adequately support a (b)(4) incubation time for the sterility test. For testing the sterility of the licensed product, please incubate all samples for 14 days.
10.       Please update your standard operating procedure (MI.02.01) showing the validated incubation time, temperature, the --(b)(4)-- culture (b)(4) used, and how qualification of each lot of --(b)(4)-- culture -(b)(4)- will be performed. Please submit the updated SOP for FDA review.
11.       No validation data for sterility testing at SLCI were submitted. Please submit these data.
12.       For collected units transported from the hospitals to the SLCBB facility, the transportation SOP should clearly state whether or not you discard units if there is any temperature excursion during transportation of units. Furthermore, your existing measures are not adequate to ensure that the appropriate temperature is maintained throughout the shipping procedure.  We recommend that a continuous temperature monitor be utilized for each shipment to ensure that the temperature is maintained throughout shipping and storage and that the data be reviewed before units undergo further processing.  
13.       The SLCI facility SOP SLCI-CTS 4039.01 states that the acceptable transportation temperature is (b)(4).  However, it is not clear if a continuous temperature recording device (e.g., data logger) or a thermometer that simply displays the temperature is used in the transport coolers and whether units are discarded if the transportation temperature is outside the defined range. Please provide clarification and describe how you will ensure that the appropriate temperature is maintained during the entire transit time.  
14.       In SOP TE.01.03 (Unrelated Umbilical Cord Blood Processing Using PrepaCyte-CB), you state that if a collection from a single donor is received in (b)(4) bags and the total volume is -----(b)(4)-----, the (b)(4) bags may be ------(b)(4)------. The collection procedure (SOP CL.06.07) does not describe collections into (b)(4) bags.  Please confirm whether you perform cord blood collections into (b)(4) bags, and if so, please submit the applicable collection and labeling SOPs.
15.       Please submit the final Donor Eligibility (DE) SOPs/forms used at the SLCBB and SLCI facilities. The final SOPs/forms should address the following issues in the draft SOPs in your June 25, 2012 submission:
                        a.         Please clarify in Draft SOP CL.03.07 whether donors with the listed findings are considered "eligible" or "ineligible" for DE determination purposes and specify that donor conditions such as elevated temperature in mother/infant or receipt of antibiotics during labor are acceptable only in absence of any suspicion related to infection.
                        b.         Please define in Draft SOP CL.06.08 how information regarding the possibility of plasma dilution in the birth mother (e.g., administration of >2000ml IV fluid) is factored into the DE determination.
                        c.         There is no category in the Draft Product Documentation/Tech Review form for HPC, Cord Blood units collected from donors for whom DE determination was not completed and it is not clear whether an HPC, Cord Blood unit categorized as “available” is acceptable for licensure or release under IND. Also, please submit the corresponding form used at SLCI.
16.       You stated in your June 25, 2012 submission that CMV (b)(4) testing is performed on the (b)(4) sample of the unit and you will not release the product if the CMV (b)(4) result is positive.  Therefore, we consider this to be a release criterion and the assay must be validated.
17.       Please provide information regarding the unique donor identification numbering system that is used at the SLCI facility.
18.       Please submit the maternal specimen shipping information for the SLCI facility.
19.       We note that no data were provided for the -------------(b)(4)--------------- instrument at SLCI. Please submit qualification data on this instrument, including analysis of cord blood samples for relevant parameters (e.g., ---(b)(4)---).
20.       Regarding your December 12, 2011 submission that included cell count "linearity data" for the SLCI --------------(b)(4)-------------------- instrument, please clarify the types of samples tested and clarify your acceptance criteria.
21.       Adequate information was not submitted to evaluate SLCI's use of ---(b)(4)--- as a primary method for viability testing.  Please submit SLCI's method comparison of cord blood viability using ---------------------(b)(4)---------------------- and an evaluation of viability sample stability.
22.       Inadequate information was submitted to evaluate SLCI's use of ------(b)(4)------- to enumerate viable CD34+ cells in cord blood samples.  Please submit the following information:  
                        a.         Please submit qualification data for the --------------------------------------(b)(4)--------------------------------------------- that includes analysis of cord blood samples for relevant parameters (e.g., CD34/-----(b)(4)-------).
                        b.         Regarding the SLCI report titled "New Instrument Validation ----------------------------------(b)(4)--------------------" from your December 12, 2011 submission, please provide additional description on the type of samples analyzed throughout this report and clarify the acceptance criteria for all parameters.
23.       Regarding your December 12, 2011 submission, inadequate information was submitted to evaluate inter-laboratory precision of cord blood ------(b)(4)------- comparison between SLCI and SLCBB.  Please clarify your acceptance criteria used for this comparison.
24.       During the telephone conversation of July 30, 2012 between you and representatives of this office, you stated your intention to implement a container and package label system according to ISBT128. Please submit revised container and package labels.
25.       We note you have included the name “AlloCORD” on your example of a proposed label to be affixed to the HPC, Cord Blood product. Please submit a proprietary name request according to Guidance for Industry “Contents of a Complete Submission for the Evaluation of Proprietary Names” available at http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM075068.pdf.
26.       We reserve comment on the proposed labeling until the application is otherwise acceptable. We may have comments when we see the proposed final labeling.
Within 10 days after the date of this letter, you should take one of the following actions: (1) amend the application; (2) notify us of your intent to file an amendment; or (3) withdraw the application.
You may request a meeting or teleconference with us to discuss the steps necessary for approval. Please contact the regulatory project manager. For details, please also follow the instructions described in CBER’s SOPP 8101.1: Scheduling and Conduct of Regulatory Review Meetings with Sponsors and Applicants.  This document also is available on the internet at http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/ProceduresSOPPs/ucm079448.htm, or may be requested from the Office of Communication, Outreach, and Development.
Please be advised that, as stated in 21 CFR 601.3(c), if we do not receive your complete response within one year of the date of this letter, we may consider your failure to resubmit to be a request to withdraw the application.  Reasonable requests for an extension of time in which to resubmit will be granted. However, failure to resubmit the application within the extended time period may also be considered a request for withdrawal of the application.
We acknowledge receipt of your amendment dated July 30, 2012. Please be aware that we have stopped the review clock with the issuance of this letter. We will reset and start the review clock when we receive your complete response. You may cross reference applicable sections of the amendment dated July 30, 2012 in your complete response to this letter and we will review those sections as a part of your complete response.
If you have any questions regarding the above, please contact the Regulatory Project Manager, Lori Tull, at (301) 827-5359.
Sincerely yours,
Stephanie Simek, Ph.D.
Deputy Director
 Office of Cellular, Tissue and Gene Therapies
Center for Biologics Evaluation and Research