- Delivery Method:
- VIA UNITED PARCEL SERVICE
- Reference #:
- OBPO 638823
Recipient NameTyler C. Barrett
Recipient TitlePresident and Chief Executive Officer
- Row1 Inc. dba Regenative Labs
1700 W. Main Street, Suite 500
Pensacola, FL 32502
- Issuing Office:
- Division of Biological Products Operations I
June 21, 2023
Warning Letter #OBPO 638823
Dear Mr. Barrett:
During an inspection of your firm, Row1, Inc. (dba Regenative Labs), located at 1700 W. Main Street, Suite 500, Pensacola, FL 32502, conducted between March 21, 2022 and March 30, 2022, the United States Food and Drug Administration (FDA) documented your manufacture of cellular products derived from human umbilical cord, namely ProText™, CoreText™, CryoText™ Pro, CryoText™ Plus, SecreText™, and SecreText™ Pro (collectively, “your products”). You have distributed your products to physicians and medical clinics throughout the United States. These products are intended for various routes of administration, including injection, and purport to be sterile.
Information and records gathered prior to, during, and/or after the inspection, including information on your website, www.regenativelabs.com, reflect that your products are intended for clinical use in humans to treat a variety of diseases or conditions. Therefore, your 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 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.
Regenative Labs does 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). Specifically, your products fail to meet the criterion in 21 CFR 1271.10(a)(2) 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.” Your products are not intended to perform the same basic function or functions of the umbilical cord in the recipient as in the donor, such as serving as a conduit. Using your products to treat orthopedic diseases or conditions, for example, is not homologous use as defined in 21 CFR 1271.3(c).
In addition, your products 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 related to its utility for reconstruction, repair, or replacement.
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. Because your products do not meet all the criteria in 21 CFR 1271.10(a), and Regenative Labs does not qualify for any exception in 21 CFR 1271.15, your 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)].
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, 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) requirements, including deviations from section 501(a)(2)(B) of the FD&C Act [21 U.S.C. 351(a)(2)(B)] and 21 CFR Parts 210 and 211.
At the close of the inspection, FDA investigators issued a Form FDA-483, List of Inspectional Observations, which described significant deviations applicable to your products. FDA identified additional significant deviations upon further review of the information collected during the March 2022 inspection, as discussed below.
The CGMP deviations, involving over (b)(4) vials of products manufactured between February 2020 and March 2022, 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. The aseptic processes used to manufacture your products have not been validated (e.g., by performing (b)(4)) since your firm’s manufacturing operations began in February 2020. Your products purport to be sterile and are expected to be sterile.
b. You have not established appropriate written procedures for environmental monitoring in your firm’s aseptic processing area where your products are manufactured. For example:
i. Your action limits for microbiological monitoring (i.e., active viable air, surface samples, and personnel gloved fingertips) within the critical area (i.e., inside the biological safety cabinet (BSC)) were observed to be (b)(4) colony forming units (CFUs) per m3, greater than (b)(4) CFUs per “plate and floor”, and (b)(4) CFUs per plate, respectively. Such high numbers of microorganisms could contribute to product contamination and pose a potentially significant safety concern.
ii. Your action limit for active viable air samples within the cleanroom was observed to be greater than or equal to (b)(4) CFUs per m3. Such high numbers of microorganisms could contribute to product contamination and also pose a potentially significant safety concern.
iii. You do not perform non-viable particulate monitoring, active or passive viable air sampling, or sampling of critical surfaces in the BSC for microorganisms in association with each production batch.
c. During the inspection, FDA investigators observed personnel practices that do not adequately protect against microbiological contamination of your products. For example:
i. Operators were observed processing ProTextTM (ID: (b)(6), (b)(7)(C)) without changing or disinfecting the outer pair of sterile gloves donned in the ISO 8 hallway. Processing steps include (b)(4) of birth tissue, including removing debris and aseptic transfer of in-process material.
ii. Operators performing aseptic processing of ProTextTM (ID: (b)(6), (b)(7)(C)) were also observed repeatedly passing gloved hands and sleeves over containers of open, in-process umbilical cord tissue within the BSC as well as using gloved hands as a seal to cover open containers of in-process umbilical cord tissue during processing.
2. 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, you have not validated the manufacturing processes for your products with respect to identity, strength, quality, and purity. For example, your validation for umbilical cord processing only included bioburden testing as a measurement of product attributes.
3. 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 appropriate storage conditions and expiration dates [21 CFR 211.166(a)]. Specifically, you assign a five-year expiration date to your products without supporting data regarding the stability characteristics of the products.1
We have received and reviewed your written responses, dated April 20, 2022 and August 22, 2022, to FDA’s inspectional observations on the Form FDA-483. We acknowledge that you represent that you have corrected the CGMP deficiencies documented on the FDA-483. However, the corrective actions described in your responses are not adequate to address the above-noted violations. For example, your response does not address your failure to validate your aseptic manufacturing process. Additionally, you contend that your manufacturing process does not require process validation, and your proposed stability study does not include all stability-indicating characteristics of your products. As another example, your revised gowning procedure indicates exam gloves should be removed in the ISO-7 cleanroom prior to performing a (b)(4) hand scrub and donning sterile gloves. We have concerns that this may result in exposure of skin in the aseptic processing area, which may increase the risk of contamination during the manufacturing process.
Additionally, your responses do not address your firm’s continued manufacture and distribution of your products or your plans for disposition of your current inventory manufactured under the violative conditions outlined above.2
While you assert that your products should be regulated solely under section 361 of the PHS Act, as explained above, the available evidence shows that your products do not meet all the criteria in 21 CFR 1271.10(a) for regulation solely under section 361 of the PHS Act and the regulations in 21 CFR Part 1271. Your response also does not adequately address your failure to have an IND in effect to study your products addressed in this letter or 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 for that product, 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 be associated with your products. It is your responsibility to ensure that your establishment is in 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 Therapeutic Products, at (240) 402-8190, or OTPRPMS@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 believe that your products are not in violation of the FD&C Act, the PHS Act, and 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 timeframe for completion.
Your response should be sent to the following address: Amy Graf, Compliance Officer, U.S. Food & Drug Administration, Office of Biological Product 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, Compliance Officer at (313) 393-2034 or via e-mail.
Michael W. Roosevelt
Program Division Director
Office of Biological Products Operations – Division 1
1 In your written response to the FDA-483 dated April 20, 2022, you indicate your firm has begun an ongoing container closure integrity study and has begun performing sterility testing to establish sterility over a five-year period. This is insufficient to assess all stability indicating characteristics of your products.
2 During FDA’s inspection, you represented that although you have stopped manufacturing CoreText™, you still have CoreText™ inventory that you intend to distribute until the inventory is exhausted.