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Vaccines, Blood & Biologics
The St. Louis Cord Blood Bank (SLCBB) was established in 1995 as a joint effort of SSM Cardinal Glennon Children’s Medical Center and the St. Louis University School of Medicine. The SLCBB submitted an Investigational New Drug application (IND 7183) in 1997 in order to nationally and internationally distribute their inventory of cord blood stem cells to restore hematopoiesis in unrelated donors. In preparation for the submission of this license application, SLCBB had a pre-BLA meeting in June of 2010 to receive guidance from the FDA.
Since the program’s inception, over -(b)(4)- mothers have donated their cord blood to the SLCBB. Approximately -(b)(4)- units met concurrent criteria for further manufacture and more than -(b)(4)- are currently available for transplantation. To date, nearly (b)(4) products have been distributed both domestically and internationally to treat patients with a variety of diseases and disorders.
To arrive at their current manufacturing process, SLCBB has implemented the following changes in cord blood processing:
In November 2007, the use of --(b)(4)-- was implemented in compliance with the National Cord Blood Inventory (NCBI) contract with the Health Resources and Services Administration (HRSA).
In January of 2008, the -----(b)(4)----- replaced the ------------(b)(4)---------------.
In July 2008, the SLCBB entered into a contract manufacturing arrangement with St. Luke’s Cancer Institute in Kansas City MO (SLCI) to collect and process cord blood products in their facility. The SLCI conducts operations within the scope of that arrangement under the direction and identical policies and procedures of the SLCBB. The SLCBB reviews all batch records for product safety, purity and potency prior to approval for transport to the SLCBB site for subsequent donor eligibility determination, long term storage and distribution and furthermore performs quarterly audits of SLCI’s quality indicators.
In November 2009, after evaluating (b)(4) processing techniques against the benchmark ----(b)(4)---- method, PrepaCyte®-CB was selected as the primary system for manufacturing cord blood products.
In April 2010, --------(b)(4)-------- Cord Blood Sterile Collection Bag, FDA NDA approved and CE marked under the Medical Devices Directive for the collection of cord blood in vaginal or cesarean deliveries, replaced the -----------(b)(4)----------- collection bag.
Summary of Outstanding CMC Issues
1) SLCBB validation plans do not contain predetermined acceptance criteria, and they have not identified in-process controls or critical features of their manufacturing process. The validation data that SLCBB supplied consists of comparing data obtained with new protocols to that obtained with older methods. Validation studies, additional validation information, and/or summaries are needed for:
a. PrepaCyte-CB processing procedure
b. Freezing protocol
c. Shipping to clinical sites
d. Current collection procedures
e. Transportation of units from the collection sites to the processing facility -temperature is not continuously monitored during transportation.
f. Total Nucleated Cell lot release
2) Donor Eligibility deficiencies need to be addressed:
a. Donor eligibility determination SOP(s) lack sufficient detail
b. DE determination is not finalized and documented before units get listed in the search inventory
c. SOPs don’t define how birth mothers are assessed for the possibility of plasma dilution (e.g. infusion of >2000ml of crystalloids) prior to obtaining the maternal blood specimens.
3) Sterility testing deficiencies that need to be addressed:
a. The sterility validation data for the principal manufacturing site ( Saint Louis) is incomplete
b. The second manufacturing site (Kansas City) has not validated their sterility assay protocol
c. No (b)(4) was used during assay validation
d. There is no data demonstrating the reliability of the ---(b)(4)--- sample
4) We need to inform SLCBB that they should apply for a categorical exclusion from environmental assessment based on generating products that are normally found in the environment per CFR 25.31(c). In their BLA submission they are addressing this by evaluating the cleanliness of their facility.
5) Sterility testing, donor eligibility, and cell processing information requests have been sent to SLCBB. We are currently awaiting responses to questions related to:
a. Cord blood unit processing and tracking
b. Sterility testing protocol
c. Donor eligibility and cord blood collection