- Delivery Method:
- VIA UNITED PARCEL SERVICE
Recipient NameEliott D. Spencer, PhD
- Utah Cord Bank LLC dba Utah Cell Bank
8675 S. Sandy Parkway, Suite 110
Sandy, UT 84070-6418
- Issuing Office:
- Office of Biological Products Operations - Division 2
August 10, 2021
Warning Letter #OBPO 21-614013
Dear Dr. Spencer:
During an inspection of your firms, Utah Cord Bank LLC (Utah Cord Bank), dba Utah Cell Bank, and FIOR Bioscience LLC (FIOR Bioscience), co-located at 8675 S. Sandy Parkway, Suite 110, Sandy, UT 84070, conducted between February 1 and February 11, 2021, United States Food and Drug Administration (FDA) investigators documented that you manufacture cellular products for allogeneic use, including: human umbilical cord blood, umbilical cord, and amniotic membrane derived cellular products with the brand names StemVive® and StemMaxx™ (also known as Stemii and Stemshot); a human umbilical cord blood derived product with the brand name StemTru™; and a human umbilical cord derived product with the brand name StemCellect™ (collectively, “your products”).1 FIOR Bioscience distributes your products directly to health care professionals and medical facilities. These products are intended for injection and are purported to be sterile.
Information and records gathered prior to and at the time of the inspection, including information on the FIOR Bioscience website, https://fiorbio.com reflect that your products are intended to treat various diseases or conditions. Therefore, these products are drugs as defined in section 201(g) of the Federal Food, Drug, and Cosmetic Act (FD&C Act) [21 U.S.C. 321(g)] and biological products as defined in section 351(i) of the Public Health Service Act (PHS Act) [42 U.S.C. 262(i)].
Your products are also human cells, tissues, or cellular or tissue-based products (HCT/Ps) as defined in 21 CFR 1271.3(d) and are subject to regulation under 21 CFR Part 1271, issued under the authority of section 361 of the PHS Act [42 U.S.C. 264].
HCT/Ps that do not meet all the criteria set forth in 21 CFR 1271.10(a), and when no exception in 21 CFR 1271.15 applies, are not regulated solely under section 361 of the PHS Act [42 U.S.C. 264] and the regulations in 21 CFR Part 1271. Such products are regulated as drugs, devices, and/or biological products under the FD&C Act and/or the PHS Act, and are subject to additional regulation, including appropriate premarket review.
Your establishments do not qualify for any exception in 21 CFR 1271.15, and your products fail to meet all the criteria in 21 CFR 1271.10(a). Therefore, your products are not regulated solely under section 361 of the PHS Act [42 U.S.C. 264] and the regulations in 21 CFR Part 1271.
Specifically, an HCT/P meets the criterion in 21 CFR 1271.10(a)(2) if the HCT/P is “intended for homologous use only, as reflected by the labeling, advertising, or other indications of the manufacturer's objective intent.” StemVive® and StemMaxx™ are not intended to perform the same basic function or functions of umbilical cord blood, umbilical cord, or amniotic membrane in the recipient as in the donor, such as forming and replenishing the lymphohematopoietic system (for cord blood); serving as a conduit (for umbilical cord); or serving as a selective barrier for the movement of nutrients between the external and in utero environment, protecting the fetus from the surrounding maternal environment, and serving as a covering to enclose the fetus and retain fluid in utero (for amniotic membrane). Rather, using these products to treat orthopedic conditions, for example, is not homologous use as defined in 21 CFR 1271.3(c).
In addition, your products fail to meet other criteria set forth in 21 CFR 1271.10(a). For example, StemVive®, StemMaxx™, and StemTru™ fail to meet 21 CFR 1271.10(a)(4). These cellular products, manufactured at least in part from donated umbilical cord blood, are dependent on the metabolic activity of living cells for their primary function and are not for autologous use, allogeneic use in a first-degree or second-degree blood relative, or reproductive use. In addition, StemVive®, StemMaxx™, and StemCellect™ fail to meet the minimal manipulation criterion set forth in 21 CFR 1271.10(a)(1) and defined for structural tissue in 21 CFR 1271.3(f)(1), because your processing alters the original relevant characteristics of the umbilical cord and/or amniotic membrane related to their utility for reconstruction, repair, or replacement.
Please be advised that to lawfully market a drug that is a biological product, a valid biologics license must be in effect [42 U.S.C. 262(a)]. Such licenses are issued only after showing that the product is safe, pure, and potent. While in the development stage, such products may be distributed for clinical use in humans only if the sponsor has an investigational new drug application (IND) in effect as specified by FDA regulations [21 U.S.C. 355(i); 42 U.S.C. 262(a)(3); 21 CFR Part 312]. None of your products are the subject of an approved biologics license application (BLA), nor is there an IND in effect for any of them. Based on this information, we have determined that your actions have violated the FD&C Act and the PHS Act.
Additionally, during the inspection, FDA investigators documented evidence of significant deviations from current good manufacturing practice (CGMP) and current good tissue practice (CGTP) requirements, including deviations from section 501(a)(2)(B) of the FD&C Act and 21 CFR Parts 210, 211, and 1271.
At the close of the inspection, the FDA investigators issued a Form FDA 483 to you listing inspectional observations, which described a number of significant deviations from CGMP and CGTP applicable to your products. The deficiencies include, but are not limited to, the following:
1. Failure to establish and follow appropriate written procedures designed to prevent microbiological contamination of drug products purporting to be sterile, including procedures for validation of all aseptic and sterilization processes [21 CFR 211.113(b)]. For example:
a. Your firm failed to validate the aseptic processes used to manufacture over (b)(4) vials of your StemVive®, StemMaxx™; StemTru™ and StemCellect™ products (i.e., by performing media fill simulations) since your manufacturing operations began. By the nature of their routes of administration, your products purport to be sterile and are expected to be sterile.
b. Your employees use non-sterile personal protective equipment (PPE), for example lab coats, gloves and hair nets, during the manufacture of your products.
2. Failure to have separate or defined areas or such other control systems for your operations as are necessary to prevent contamination or mixups during the course of aseptic processing. [21 CFR 211.42(c)(10)]. For example:
a. You allow two or more operators to process product within the same (b)(4). Processing by more than one technician in the same (b)(4) can significantly increase the potential for contamination.
b. Your manufacturing facility is not classified with respect to air quality. The (b)(4), used to process your products, and operator gowning areas are located within an unclassified environment.
c. Your firm has not established an adequate system for monitoring environmental conditions in the aseptic processing area where your products are manufactured.
d. Your firm does not conduct personnel monitoring of operators working in the aseptic processing area where your products are manufactured.
e. Your firm does not have a validated cleaning process for the aseptic processing area where your products are manufactured.
3. Failure to establish laboratory controls that include scientifically sound and appropriate specifications, standards, sampling plans, and test procedures designed to assure that components, drug product containers, closures, in-process materials, labeling, and drug products conform to appropriate standards of identity, strength, quality, and purity [21 CFR 211.160(b)]. For example:
a. You have not established scientifically sound and appropriate specifications, standards, sampling plans and test procedures to assure that your products conform to appropriate standards of identity, strength, quality, and purity.
b. You do not collect and test sterility samples that are representative of the lot size. You test (b)(4) for sterility and rely on the results of (b)(4) sterility test to determine lot release despite the lot size, which may consist of as many as (b)(4) vials.
4. Failure to include in laboratory records complete data derived from all tests necessary to assure compliance with established specifications and standards, including a statement of each method used in the testing of the sample that indicates the location of data that establish that the methods used in the testing of the sample meet proper standards of accuracy and reliability as applied to the product tested [21 CFR 211.194(a)(2)]. Specifically, lot release of your products is based on sterility testing; however, your in-house sterility test has not been validated. Accordingly, your laboratory records do not include a statement that indicates the location of data that establish that your sterility testing methods meet proper standards of accuracy and reliability as applied to your products.
5. Failure to establish written procedures for production and process control designed to assure that the drug products have the identity, strength, quality, and purity they purport or are represented to possess [21 CFR 211.100(a)]. Specifically, the manufacturing processes for your products have not been validated.
6. Failure to establish and follow written procedures describing in sufficient detail the receipt, identification, storage, handling, sampling, testing, and approval or rejection of components and drug product containers and closures [21 CFR 211.80(a)]. For example:
a. There are no written procedures describing in sufficient detail the criteria for approval or rejection of incoming human umbilical cord blood or human umbilical cord.
b. There are no written procedures describing in sufficient detail the acceptance criteria for components used in manufacturing, including (b)(4) micron and (b)(4) micron filters, (b)(4) (glass) bottles, and (b)(4), and drug product containers and closures.
7. Failure to establish and follow written procedures for cleaning and maintenance of equipment used in the manufacture, processing, packing, or holding of a drug product [21 CFR 211.67(b)]. For example:
a. Your firm failed to validate the cleaning process for your (b)(4).
b. There are no data or rationale for the cleaning agents used or their rotation for the cleaning of the (b)(4) where manufacturing is performed.
c. Your firm has not established written procedures for the (b)(4) sterilization of the (b)(4) filter and the (b)(4) funnel that come into direct contact with your products during processing.
8. Failure to thoroughly investigate any unexplained discrepancy, or the failure of a batch or any of its components to meet any of its specifications, whether or not the batch has already been distributed [21 CFR 211.192]. Specifically, from July 2017 to January 2020, you failed to thoroughly investigate 16 sterility failures. The failed lots were discarded; however, there was no further evaluation to identify the contaminating microorganism, determine a root cause or determine if other product lots may have been affected by the failures.
9. Failure to establish and follow a written testing program designed to assess the stability characteristics of drug products and to use the results of such stability testing to determine the appropriate storage conditions and expiration dates [21 CFR 211.166(a)]. Specifically, you assign a two-to-six year expiration date to your products without supporting data.
10. Failure to establish and follow written procedures describing the handling of all written and oral complaints regarding a drug product [21 CFR 211.198(a)]. For example:
a. Although your firm received multiple complaints regarding your products, there was no supporting documentation to show that you performed an adequate follow-up and/or investigation of those complaints. We note that these complaints were categorized as adverse events on your complaint log.
b. Written procedures describing the handling of all written and oral complaints do not include procedures for review of a complaint to determine whether the complaint represents a serious and/or unexpected adverse experience.
11. Failure to prepare batch production and control records for each batch of drug product produced that include complete information relating to the production and control of each batch, including documentation that each significant step in the manufacture, processing, packing, or holding of the batch was accomplished [21 CFR 211.188(b)]. For example:
a. Your batch production record does not include documentation of the accomplishment of each significant step in the processing of your products as described in your work instructions. These work instructions include GLP-DOC-0008 entitled “Amniotic Membrane Injectable Product Isolation Processing Work Instruction”; GLP-DOC-0009, Revision 01 entitled “Cord Tissue and Blood Injectable Product Isolation Processing Work Instruction”; and GLP-DOC-010 entitled “Cord Tissue Flowable Product Isolation Processing Work Instruction.”
b. The batch production record does not include documentation of the identity of each batch of component or in-process material used in the processing of your products.
c. The batch production record does not consistently document the results of product sterility testing.
d. The batch production record does not include a statement of the actual yield and a statement of the percentage of theoretical yield at appropriate phases of processing (i.e., the quantity of vials produced in each product lot).
12. Failure to establish, when appropriate, time limits for the completion of each phase of production to assure the quality of the drug product [21 CFR 211.111]. Specifically, your firm stores (b)(4) product ((b)(4)) in a (b)(4) ml glass container in a commercial refrigerator in your unclassified lab area for up to (b)(4) prior to aliquoting the (b)(4) into a (b)(4) ml or (b)(4) ml final container. Your firm failed to validate the time limit the (b)(4) can be stored in such a manner without negatively impacting the final product.
13. Failure to routinely calibrate, inspect or check automatic, mechanical or electronic equipment or other types of equipment, including computers, or related systems that will perform a function satisfactorily, that are used in the manufacture, processing, packing and holding of a drug product, according to a written program designed to assure proper performance [21 CFR 211.68(a)]. Specifically, you failed to validate the software used to maintain your sterility testing results according to a written program designed to assure the software’s proper performance.
14. Failure to assign and label each HCT/P that you manufacture with a distinct identification code in accordance with the requirements in 21 CFR 1271.290(c). Specifically, you do not ensure that each HCT/P that you manufacture is assigned and labeled with a distinct identification code that relates the HCT/P to the donor and to all records pertaining to the HCT/P and that labeling includes information designed to facilitate effective tracking, using the distinct identification code, from the donor to the recipient and from the recipient to the donor.
FDA received your written responses, dated March 5 and April 16, 2021, to the inspectional observations on the Form FDA 483 issued at the conclusion of the inspection, and we have reviewed the contents. FDA acknowledges your commitment to voluntarily cease the manufacture and processing of new HCT/Ps until your third-party consultant has reviewed and audited your firm’s processes and procedures. We also acknowledge your commitment to not distribute HCT/Ps that remain in inventory until they have been resampled and retested for contamination. These commitments, along with the corrective actions described in the rest of your response, are not adequate to address the above-noted violations.
Your response also does not adequately address your failure to have an IND in effect to study your products and your lack of an approved BLA to lawfully market your products. As noted above, to lawfully market a drug that is a biological product, a valid biologics license must be in effect [42 U.S.C. 262(a)]. Such licenses are issued only after showing that the product is safe, pure, and potent. While in the development stage, such a product may be distributed for clinical use in humans only if the sponsor has an IND in effect, as specified by FDA regulations, that covers such clinical use [21 U.S.C. 355(i); 42 U.S.C. 262(a)(3); 21 CFR Part 312].
Neither this letter nor the observations noted on the Form FDA 483, which were discussed with you at the conclusion of the inspection, are intended to be an all-inclusive list of deficiencies that may exist at your facilities. It is your responsibility to ensure full compliance with the FD&C Act, PHS Act, and all applicable regulations.
This letter notifies you of our findings and provides you an opportunity to address them. Failure to adequately address these matters may lead to regulatory action without further notice. Such actions include seizure and/or injunction.
For further information about IND requirements for biological products, contact the Center for Biologics Evaluation and Research (CBER), Division of Regulatory Project Management, Office of Tissues and Advanced Therapies, at (240) 402-8190, or OTATRPMS@fda.hhs.gov. Please include a copy of this letter with your initial submission to CBER.
We request that you respond in writing within fifteen (15) working days from your receipt of this letter, outlining the specific steps you have taken or plan to take to address any violations and prevent their recurrence. Include any documentation necessary to show that the matters have been addressed. If you do not believe your products are in violation of the FD&C Act, PHS Act, or applicable regulations, include your reasoning and any supporting information for our consideration. If you cannot address these matters completely within fifteen (15) working days, please explain the reason for your delay and the time frame for completion.
Your response should be sent to the following address: Amy Graf, Compliance Officer, U.S. Food and Drug Administration, Office of Biological Products Operations – Division 2, 300 River Place Drive, Suite 5900, Detroit, MI 48207 or emailed to Amy.Graf@fda.hhs.gov. If you have any questions, please contact Amy Graf at (313) 393-2034 or via e-mail.
Program Division Director
Office of Biological Products Operations - Division 2
1 This letter does not pertain to HCT/Ps intended for autologous use or allogeneic use in a first-degree or second-degree blood relative. Accordingly, references in this letter to “HCT/Ps” or “your products” do not include products you manufacture that are intended for autologous use or allogeneic use in a first-degree or second-degree blood relative. FDA issued a separate Warning Letter to you, dated May 11, 2021, that pertains to those HCT/Ps.