WARNING LETTER

Banco Vida Corp. MARCS-CMS 606288 — August 12, 2020

Delivery Method:: VIA UNITED PARCEL SERVICE
Product:: Biologics

Recipient:: Recipient Name

Jose R. Huerta Rebozo, MD, FACOG; Recipient Title

Chief Executive Officer; Banco Vida Corp.; 239 Arterial Hostos Avenue, Suite 604
Capital Center Building Torre Sur
San Juan 00918
Puerto Rico

Issuing Office:: Center for Biologics Evaluation and Research (CBER); United States

WARNING LETTER

August 12, 2020

[OBPO 20-606288]

Dear Dr. Huerta:

The United States Food and Drug Administration (FDA) conducted an inspection of your firm, Banco Vida Corporation, located at #239 Arterial Hostos Avenue, Suite 604, Capital Center Building, Torre Sur, San Juan, PR 00918, between September 9, 2019 and September 18, 2019, and your facility, Laboratorio Banco Vida, located at UPR Comprehensive Cancer Center, San Juan, PR 00935, between September 11, 2019 and September 18, 2019. During the inspections, FDA investigators documented that your firm manufactures human umbilical cord blood for allogeneic use within the meaning of 21 CFR 1271.3(e). FDA investigators further documented your recovery of umbilical cord blood and processing of an umbilical cord blood product (hereinafter, “cord blood intermediates”) in your facility. You have distributed your cord blood intermediates to (b)(4), for further manufacturing into (b)(4)¹, an allogeneic umbilical cord blood derived product intended for injection and purported to be sterile.² You also distribute umbilical cord blood for allogeneic use for further manufacturing to (b)(4).

Such umbilical cord blood and cord blood intermediates are human cells, tissues, or cellular or tissue-based products (HCT/Ps)³ as defined in 21 CFR 1271.3(d) and subject to regulation under 21 CFR Part 1271, issued under authority of section 361 of the PHS Act [42 U.S.C. 264].⁴ We refer to these products collectively as “your HCT/Ps” in this letter. Under FDA regulations, donors of cells or tissue who are identified as having a risk factor for, or clinical evidence of, any relevant communicable disease agents or diseases for which screening is required under 21 CFR 1271.75(a)(1), (b), or (c), must be determined to be ineligible [21 CFR 1271.75(d)]. FDA has identified Zika virus (ZIKV) as a relevant communicable disease agent or disease (RCDAD) under 21 CFR 1271.3(r)(2). Because your firm recovers cells or tissue in Puerto Rico, which is an area considered at increased risk for ZIKV, your donors have a risk factor for ZIKV and cannot be determined as eligible.⁵ Nevertheless, from January 2018 to September 2019, you distributed (b)(4) HCT/Ps from umbilical cord blood to third-parties for further manufacturing.

Information and records gathered during the inspections of Banco Vida Corporation and Laboratorio Banco Vida and other relevant information reflect that your HCT/Ps, following further manufacture, are intended to treat a variety of diseases or conditions. Therefore, they are drugs as defined in section 201(g) of the Federal Food, Drug, and Cosmetic Act (the 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)]. As noted above, your HCT/Ps are also subject to regulation under 21 CFR Part 1271. However, Banco Vida Corporation does not qualify for any exception in 21 CFR 1271.15, and your HCT/Ps fail to meet all the criteria in 21 CFR 1271.10(a). Therefore, they are not regulated solely under section 361 of the PHS Act [42 U.S.C. 264] and the regulations in 21 CFR Part 1271.

For example, your umbilical cord blood and umbilical cord blood intermediates fail to meet 21 CFR 1271.10(a)(2)’s criterion that the HCT/Ps be “intended for homologous use only, as reflected by the labeling, advertising, or other indications of the manufacturer’s objective intent.”⁶ These HCT/Ps, which are intended after further manufacture to treat a variety of diseases or conditions, are not intended to perform the same basic function or functions of umbilical cord blood in the recipient as in the donor, such as forming and replenishing the lymphohematopoietic system.

These HCT/Ps fail to meet other criteria set forth in 21 CFR 1271.10(a). Your umbilical cord blood and cord blood intermediates fail to meet 21 CFR 1271.10(a)(4), because they 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.

As stated above, because these HCT/Ps do not meet all the criteria in 21 CFR 1271.10(a), and Banco Vida Corporation does not qualify for any exception in 21 CFR 1271.15, the products are regulated as drugs as defined in section 201(g) of the FD&C Act [21 U.S.C. 321(g)] and biological products as defined in section 351(i) of the PHS Act [42 U.S.C. 262(i)].⁷ 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]. Your HCT/Ps are not the subject of an approved biologics license application (BLA) nor is there an IND in effect for the products. Based on this information, we have determined that your actions have violated the FD&C Act and the PHS Act.

Additionally, during the inspections, FDA investigators documented evidence of significant deviations from current good manufacturing practice (CGMP) and current good tissue practice (CGTP),⁸ including deviations from section 501(a)(2)(B) of the FD&C Act and 21 CFR Part 1271. The deviations in manufacturing observed as well as those noted in documents collected during the inspections indicate that the use of your products raises potential significant safety concerns. For example, Banco Vida Corporation’s deficient donor screening practices, inadequate aseptic practices, unvalidated manufacturing processes, and deficient environmental monitoring, as described below, pose a significant risk that your products may be contaminated with microorganisms or have other serious product quality defects.

The observations documented on the Form FDA-483, List of Inspectional Observations, were presented and discussed at the conclusion of FDA’s inspections. These items of concern include, but are not limited to, the following:

1. Failure to screen a donor of cells or tissue by reviewing the donor’s relevant medical records for risk factors for, and clinical evidence of, relevant communicable disease agents and diseases [21 CFR 1271.75(a)]. Since recovery operations began in 2018, Banco Vida Corporation has recovered (b)(4) umbilical cord blood units from allogeneic donors for further manufacturing by third parties.

a. FDA has identified Zika virus (ZIKV) as a relevant communicable disease agent or disease (RCDAD) under 21 CFR 1271.3(r)(2). The (b)(4), Version 5, dated February 29, 2016, entitled “Donor Risk Assessment Interview”, was used to screen certain donors until June 6, 2019, and did not adequately assess a donor’s risk for ZIKV. For example, the form did not adequately assess residence in, or travel to, areas with increased risk for ZIKV transmission.

b. The (b)(4), Version 5, dated February 29, 2016, used to screen certain donors until June 6, 2019, did not adequately assess a donor’s risk for human transmissible spongiform encephalopathy, including Creutzfeldt-Jakob disease. For example, the form did not adequately assess if the donor has been diagnosed with Creutzfeldt-Jakob disease (CJD) or variant Creutzfeldt-Jakob disease (vCJD).

c. The (b)(4), Versions 5 and 6, did not adequately assess a donor’s risk for human transmissible spongiform encephalopathy. For example, the form did not adequately assess if the donor has been diagnosed with dementia or any degenerative or demyelinating disease of the central nervous system or other neurological disease of unknown etiology.

d. The (b)(4), Version 4, entitled “Health Assessment,” is used as a relevant medical record to determine donor eligibility of HCT/Ps distributed to (b)(4). However, the form does not adequately assess a donor’s risk for human transmissible spongiform encephalopathy, including Creutzfeldt-Jakob disease. For example, the firm did not adequately assess the following:

i. If the donor has been diagnosed with variant Creutzfeldt-Jakob disease (vCJD); and
ii. If the donor has been diagnosed with dementia or any degenerative or demyelinating disease of the central nervous system or other neurological disease of unknown etiology.

Additionally, FDA observed significant deviations in the manufacture of your cord blood intermediates at Laboratorio Banco Vida. Specific areas of concern include, but are not limited to:

PRODUCTION AND PROCESS CONTROLS

1. Your firm has not adequately established and followed appropriate written procedures designed to prevent microbiological contamination of your cord blood intermediates used to manufacture drug products purporting to be sterile. For example:

a. You have not adequately validated the aseptic process used to manufacture approximately (b)(4) batches of your cord blood intermediates since manufacturing began in January 2019. Your cord blood intermediates are used to manufacture products that, by the nature of their routes of administration, purport to be sterile and are expected to be sterile.

b. There is no written procedure for gowning. Appropriate gowning reduces the potential for manufacturing personnel to inadvertently contaminate the cord blood intermediates during the aseptic manufacturing process.

c. During the inspections, FDA investigators observed personnel practices that do not adequately protect against microbiological contamination of your cord blood intermediates. Specifically, an operator was observed touching her hair and face mask with gloved hands and subsequently re-entering the BSC without changing or sanitizing her gloves prior to continuing processing.

2. Your firm has not established written procedures for production and process control designed to assure that the cord blood intermediates have the identity, strength, quality, and purity they purport or are represented to possess. For example:

a. Your firm has not adequately validated the manufacturing process for your cord blood intermediates.

b. Your firm has not adequately assured that the (b)(4) used during the manufacture of your cord blood intermediates, did not alter their identity, strength, quality, and purity. These reagents are labeled “For R&D use only” or “For research use only.” In addition, expired (b)(4) was used in the manufacture of at least (b)(4) batches.

c. There are no time limits for manufacturing steps to ensure the identity, strength, quality, and purity of your cord blood intermediates. For example, in-process cord blood was observed (b)(4).

EQUIPMENT

3. Your firm has not established and followed adequate written procedures for cleaning and maintenance of the equipment used in the manufacture, processing, packing, or holding of your cord blood intermediates. For example:

a. You have not validated the cleaning process for your Biological Safety Cabinet (BSC).

b. There is no data or rationale for the cleaning agents used or their rotation.

c. Expired (b)(4) were used to clean the BSC prior to and after the manufacture of at least (b)(4) batches of your cord blood intermediates.

BUILDINGS AND FACILITIES

4. Environmental and personnel monitoring for the presence of microorganisms is not conducted during the manufacture of the cord blood intermediates, which are subject to contamination.

RECORDS AND REPORTS

5. Batch production and control records do not accurately document incoming umbilical cord blood temperature controls. For example, in one instance, the incoming cord blood was documented as “Chilled sample (ice/gel pack)” despite transit of the cord blood with no gel or ice pack.

We acknowledge receipt of your letters dated September 23, 2019, October 16, 2019, and March 25, 2020. We also acknowledge your commitment to cease manufacturing of your cord blood intermediates at Laboratorio Banco Vida. Your responses, however, do not address the violations set forth above, or are inadequate to correct these violations. Our concerns with your responses, include, but are not limited to, the following:

1. You state that your donors are tested for ZIKV and only those with non-reactive ZIKV test results are accepted as donors. There are currently no available tests for ZIKV that are considered appropriate for preventing transmission of ZIKV through HCT/Ps. As indicated in Item 1 of this letter, you must screen donors for risk factors for and clinical evidence of ZIKV.

2. We acknowledge (b)(4), Version 7, dated October 18, 2019, entitled “Donor Risk Assessment Interview.” However, as indicated in Item 1 of this letter, you must screen donors for risk factors for and clinical evidence of human transmissible spongiform encephalopathy. This form does not, for example, ask about dementia or any degenerative or demyelinating disease of the central nervous system or other neurological disease of unknown etiology.

3. Your responses also do not address your shipment of umbilical cord blood or umbilical cord blood intermediates for further manufacturing without an IND in effect to study these products, nor an approved BLA to lawfully market these 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 products may be distributed for clinical use in humans only if the sponsor has an 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].

Neither this letter nor the observations noted on the Form FDA 483, which were discussed with you at the conclusion of the inspections, are intended to be an all-inclusive list of deficiencies that may exist at your facility. It is your responsibility to ensure full compliance with the FD&C Act, PHS Act, and all applicable regulations.

You should take prompt action to correct these violations. Failure to promptly do so may result in regulatory action without further notice. Such actions include seizure and/or injunction.

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 correct the noted violations and prevent their recurrence. Include any documentation necessary to show that correction has been achieved. 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 complete all corrections within fifteen (15) working days, please explain the reason for your delay and the time frame within which the remaining corrections will be completed.

Your response should be sent to the following address: U.S. Food and Drug Administration, Amy Graf, 300 River Place Suite 5900, Detroit, MI 48207 or emailed to amy.graf@fda.hhs.gov. If you should have any questions, please contact Amy Graf, Compliance Officer at (313) 393-2034 or via e-mail.

Sincerely,
/S/

Elizabeth Waltrip
Program Division Director
Office of Biological Products Operations – Division 1

cc:

(b)(6), Chief Executive Officer
(b)(4)

(b)(6), President
(b)(4)

(b)(6), Chief Executive Officer
(b)(4)

(b)(6), President and Chief Executive Officer
(b)(4)

____________________________

1 (b)(4).

2 FDA investigators also observed an (b)(4) employee processing allogeneic human umbilical cord blood at the same time as one of your employees using the Laboratorio Banco Vida facility and equipment.

3 This letter does not pertain to HCT/Ps 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 March 4, 2020, that pertains to those HCT/Ps.

4 HCT/Ps are defined as “articles containing or consisting of human cells or tissues that are intended for implantation, transplantation, infusion, or transfer into a human recipient.” 21 CFR 1271.3(d).

5 ZIKV is a relevant communicable disease agent or disease as defined in 21 CFR 1271.3(r)(2) based on the risk of transmission, severity of effects, and availability of appropriate screening measures. In general, an area is considered to have an increased risk for ZIKV transmission when locally transmitted, mosquito-borne ZIKV has been reported or the potential is suspected based on epidemiological evidence. Puerto Rico is considered at increased risk for ZIKV based on its prior reports of mosquito-borne ZIKV transmission. For further discussion, see Guidance for Industry, Donor Screening Recommendations to Reduce the Risk of Transmission of Zika Virus by Human Cells, Tissues, and Cellular and Tissue-Based Products (updated May 2018).

6 Under 21 CFR 1271.3(e), manufacture “means, but is not limited to, any or all steps in the recovery, processing, storage, labeling, packaging, or distribution of any human cell or tissue, and the screening or testing of the cell or tissue donor.”

7 FDA investigators also documented that you distribute amniotic fluid. The definition of HCT/Ps in 21 CFR 1271.3(d) excludes secreted or extracted human products; accordingly, secreted bodily fluids, such as amniotic fluid, are generally not considered HCT/Ps subject to regulation under 21 CFR Part 1271. Although not an HCT/P, amniotic fluid intended to treat diseases or conditions in humans is generally regulated as a drug and biological product under section 351 of the PHS Act and the FD&C Act.

8 Your CGTP violations set forth below are not limited to umbilical cord blood, but also include your manufacture of other HCT/Ps, namely, umbilical cord and placenta; however, as noted, this letter does not pertain to HCT/Ps intended for autologous use or allogeneic use in a first-degree or second-degree blood relative.