Initial Review Letter, July 16, 2012 - HPC, Cord Blood BLA 125432
DEPARTMENT OF HEALTH & HUMAN SERVICES Public Health Service
Food and Drug Administration
1401 Rockville Pike
Rockville, MD 20852-1448
Our STN: BLA 125432/0
LifeSouth Community Blood Centers, Inc.
Attention: Nancy Eckert
4039 Newberry Road
Gainesville, Florida 32607
Dear Ms. Eckert:
This letter is in regard to your biologics license application (BLA) submitted under section 351 of the Public Health Service Act.
We have completed an initial review of your application dated May 14, 2012 for HPC, Cord Blood to determine its acceptability for filing. Under 21 CFR 601.2(a) we have filed your application today. The review goal date is March 18, 2013. This acknowledgment of filing does not mean that we have issued a license nor does it represent any evaluation of the adequacy of the data submitted.
We will contact you regarding your proposed labeling no later than February 18, 2013. If post marketing study commitments (506B) are required, we will contact you no later than February 18, 2013.
While conducting our filing review, we identified the following potential review issues:
Chemistry, Manufacturing, and Controls
1. Please provide a more detailed description of the reserve sample(s) that you maintain for each lot of your product (see 21 CFR 211.170). Please include a description of how the sample(s) is obtained and stored along with an explanation of the testing that could be performed on the sample(s).
2. Regarding SOP CB.11.6.2 (Volume B, page B-287) you state that the HPC, Cord Blood segment viability must be ---------(b)(4)----------------. Please clarify if you intend to transplant units which have post thaw viability of less than 85%.
3. For identity testing, please confirm that confirmatory HLA typing is performed on all units prior to the final distribution.
4. In regard to the --(b)(4)- Validation study results, you have noted that two out of --(b)(4)-- tested did not pass the acceptance criteria. However, you state under the summary of validation discrepancy investigation that these two units were not processed following the normal workflow. Please provide a justification why these two units were processed and what corrective actions were taken to prevent similar units from being processed in the future.
5. Cryopreservation of the processed cord blood units is performed using the -----(b)(4)----------------------------. Please provide detailed validation study results including a freezing curve demonstrating that the final product cryopreservation can be performed reproducibly as intended.
6. In regard to the validation study for thawing and washing of HPC, Cord Blood, please confirm that the units used for this study were cryopreserved using the validated ---------------(b)(4)------------------.
7. You perform a (b)(4) assay for your -------(b)(4)------------ validation. Please clarify if the (b)(4) assay will be performed on the licensed HPC, Cord Blood units prior to the final distribution.
8. In terms of accuracy, precision and linearity range only the data but not the statistics for CV, correlation coefficient, slope and range was submitted. Please submit the relevant statistics that correlate with the data provided.
9. How many flow cytometers ----(b)(4)-----will be used for CD34 enumeration at your facility? If there will be more than one instrument used then show that there is no significant difference between them.
10. Please provide data on operator differences.
11. Please submit SOPs that describe the relevant risk factors considered during the review of the donors’ medical records (birth mother and baby) and the physical examination reports. We note that you receive a copy of the birth mother’s medical records; however your SOP CB10.4 does not define which specific RCDAD risk factors you look for during the review. For additional information, you may refer to sections IV.F and IV.G in the Guidance for Industry: Eligibility Determination for Donors of Human Cell, Tissues, and Cellular and Tissue-Based Product (HCT/Ps). http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/Tissue/ucm073964.htm
12. In SOP CB-MO.1.4 Review CBU Lot Records, the test results listed are not clearly defined (e.g. does 2HCV mean anti-HCV as well as NAT HCV). Please clarify the listed tests.
13. SOPs CB-MO.1.4 and CB 10.4 seem to be one document. Please clarify why there are two different document numbers.
14. We are not able to determine whether you finalize the donor eligibility determination based on the results of the donor screening and test results before the HPC, Cord Blood units get listed in the registry and who is responsible for making the final DE determination. Please provide applicable SOPs that describe the final DE determination process.
15. We suggest that you add your final DE determination to the Certificate of Analysis. Please note that only units from eligible donors are qualified for licensure.
16. In the BLA summary, on pages 14, 17, and 45, for several infectious disease tests (e.g. ----------------(b)(4)-----------------), you have listed the incorrect manufacturer’s name. Please verify the manufacturer of all test kits used and submit the corrected information
Collection of Cord Blood Units (CBU)
17. We are unable to determine which collection bags you are using because of the following discrepancies:
a. In the “Cord Blood Collection Process Validation” protocol, there are references to both ---(b)(4)----- collection bags.
b. In the BLA summary, there is only reference to (b)(4)l collection bags.
c. In SOP 5.2, the type of bag for collection is not stated.
Please clarify whether or not you use both collection bags. If yes, please submit the SOPs that provide the instructions for use for each bag.
CBU Collection Validation
18. Please address the following related to the “Cord Blood Collection Process Validation” protocol:
a. How many units were collected for this validation?
b. You have listed as an acceptance criteria, a microbial contamination rate of (b)(4). Is the listed rate related to the total number of units that were collected for the validation?
c. You state that (b)(4) of collected units must meet a minimum weight of (b)(4) (for the (b)(4) collection set) or (b)(4) (for the ---------(b)(4)-------). Please define how this weight was used to determine the acceptable volume of the CBU before processing.
d. You listed acceptable contamination rate for collected CBU in the protocol but you did not provide results of the sterility tests performed for this validation.
19. Please provide a list of major equipment and/or devices used in cord blood processing, testing, storage and shipping, including those single-use/ disposable, reusable, dedicated and shared, if applicable.
20. In reference to your Environmental Monitoring Plan and Validation Document, Section 10 references Certificates of Performance for each lot of RODAC plates and settling plates. Please provide information supporting the growth promotion of RODAC and settling plate during the environmental monitoring validation.
21. In reference to Section 126.96.36.199 Initial Cleaning Validation, please provide a copy of the cleaning validation protocol and summary report performed for the facility and the major equipment to include Biological Safety Cabinet (BSC).
22. Please provide information on your plans to segregate all aspects of the cord blood IND units from the licensed HPC, Cord Blood product.
23. The categorical exclusion language you are applying for in 21 CFR Part 25 needs to be clarified as to the specific section that is applicable (i.e. 21 CFR 25.31 (a) or (c)).
24. Please provide a table of all critical parameters for manufacturing HPC, Cord Blood to include but not limited to hold time between procedures and indicate any tolerance.
25. In reference to the Unprocessed Umbilical Cord Blood True Pack Transport Container shipping validation report, please indicate if you intend to revalidate the small shipping container or validate the large shipping container with the minimum number of CBUs. In addition, please provide a complete summary report of the CBU shipping validation to include deviations, investigation and corrective actions for any failures associated with the study.
26. Please provide the following information:
a. One dataset (in Microsoft Excel spreadsheet or SAS transport file format, incorporating the data presented in the spreadsheets entitled “October, 2011,” and “March, 2012”).
b. One variable in the dataset that uniquely identifies each patient (patient ID).
c. A definition of each variable listed in the spreadsheet (i.e., data dictionary).
27. Please specify the number of the docket that you refer to in your package insert.
We are providing the above comments to give you preliminary notice of potential review issues. Our filing review is only a preliminary evaluation of the application and is not indicative of deficiencies that may be identified during our complete review. Issues may be added, deleted, expanded upon, or modified as we review the application. If you respond to these issues during this review cycle, we may not consider your response before we take an action on your application. Following a review of the application, we shall advise you in writing of any action we have taken and request additional information if needed.
If you have any questions, please contact the Regulatory Project Manager, Candace Jarvis, B.S., at (301) 6536.
Raj K. Puri, M.D., Ph.D.
Division of Cellular and Gene Therapies
Office of Cellular, Tissue, and Gene Therapies
Center for Biologics Evaluation and Research