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Recipient NameLeonid Macheret, MD
Recipient TitleChief Executive Officer
- RenatiLabs Inc.
1368 Cox Ave
Erlanger, KY 41018
- Issuing Office:
- Division of Biological Products Operations I
June 1, 2023
Dear Dr. Macheret:
During an inspection of your firm, RenatiLabs Inc. (“RenatiLabs”), located at 1368 Cox Ave., Erlanger, KY 41018-1002, conducted between August 2, 2022, and August 12, 2022, the United States Food and Drug Administration (FDA) documented that you manufacture WJMAX™, a product derived from human umbilical cord, for allogeneic use (hereinafter, “your product”). You have distributed your product directly to physicians throughout the United States. Your product is intended to be administered by intra-articular injection or topically to open wounds and purports to be sterile.
Information and records gathered during and after the inspection and information available on your website, www.rlregen.com, reflect that your product is intended to treat various diseases or conditions. Therefore, your product is a drug as defined in section 201(g) of the Federal Food, Drug, and Cosmetic Act (FD&C Act) [21 U.S.C. 321(g)] and a biological product as defined in section 351(i) of the Public Health Service Act (PHS Act) [42 U.S.C. 262(i)].
Your product is also a human cell, tissue, or cellular or tissue-based product (HCT/P) as defined in 21 CFR 1271.3(d) and is 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.
RenatiLabs does not qualify for any exception in 21 CFR 1271.15, and your product fails to meet all the criteria in 21 CFR 1271.10(a). Specifically, WJMAXTM fails to meet the criterion in 21 CFR 1271.10(a)(2) that the HCT/P be “intended for homologous use only, as reflected by the labeling, advertising, or other indications of the manufacturer’s objective intent.” This product is not intended to perform the same basic function or functions of umbilical cord in the recipient as in the donor, such as serving as a conduit. Rather, using the product for orthopedic use or to heal wounds, for example, is not homologous use as defined in 21 CFR 1271.3(c).
In addition, WJMAX™ fails 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 product is not regulated solely under section 361 of the PHS Act [42 U.S.C. 264] and the regulations in 21 CFR Part 1271. Because this HCT/P does not meet all the criteria in 21 CFR 1271.10(a), and RenatiLabs does not qualify for any exception in 21 CFR 1271.15, the product is regulated as a drug as defined in section 201(g) of the FD&C Act [21 U.S.C. 321(g)] and a biological product as defined in section 351(i) of the PHS Act [42 U.S.C. 262(i)].
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); and 21 CFR Part 312]. WJMAX™ is not the subject of an approved biologics license application (BLA), nor is there an IND in effect for this product. 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 CGMP deviations applicable to your product. FDA identified additional significant deviations upon further review of the information collected during the inspection that we are bringing to your attention. These CGMP deviations, involving over (b)(4) vials of WJMAX™ manufactured since January 2021, include, but are not limited to, the following:
1. Drug products failing to meet established standards or specifications and any other relevant quality control criteria are not rejected [21 CFR 211.165(f)].
You failed to reject WJMAX™ lot REN20210205 after this lot failed sterility testing, due to contamination with Staphylococcus epidermidis, according to the final report from your contract laboratory dated March 22, 2021. Your Quality Representative and Management with Executive Responsibility approved this lot for release for distribution on June 14, 2021, and June 22, 2021, respectively. You have sold numerous vials of this lot, as recently as (b)(4).
2. 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)].
a. Your firm failed to validate the aseptic process used to manufacture WJMAX™ (i.e., by performing media fill simulations). By the nature of its route of administration, and per your product labeling, your product purports to be sterile and is expected to be sterile.
b. You failed to conduct environmental monitoring for any of the (b)(4) processing runs of WJMAX™ in the aseptic processing areas.
3. Failure to establish written procedures for production and process control designed to assure drug products have the identity, strength, quality, and purity they purport or are represented to possess [21 CFR 211.100(a)].
The manufacturing process for WJMAX™ has not been validated with respect to identity, strength, quality, and purity.
4. 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 [21CFR 211.160(b)].
a. Sterility samples of WJMAX™ are stored at (b)(4) prior to sterility testing. Freezing in this manner has the potential to destroy any microbial content in the samples before testing; therefore, contamination, if present, may not be detected.
b. You have not collected and tested sterility samples that are representative of the lot size. You have tested (b)(4) vials for sterility regardless of lot size, which may consist of as many as (b)(4) vials.
5. Failure to prepare batch production and control records for each batch of drug product produced that include documentation that each significant step in the manufacture, processing, packing, or holding of the batch was accomplished [21 CFR 211.188(b)].
a. Your batch records do not include documentation of all investigations made according to 21 CFR 211.192. For example:
i. Your batch record for WJMAX™ lot REN20210205 does not include documentation of any investigation into the sterility failure for this lot reported to you on March 22,2021.1
ii. The batch record for WJMAX™ lot REN20210205 does not include documentation of any investigation into the umbilical cord described as “Slightly yellow in areas” under the “Abnormal/Additional Findings” section of the batch record.2 Your Quality Representative and Management with Executive Responsibility approved this lot for release for distribution on June 14, 2021, and June 22, 2021, respectively.
b. Your batch record for WJMAX™ does not include documentation of each significant step described in QP220.101a, “Wharton Jelly/Umbilical Cord Suspension Procedure” (dated 09/01/2020), such as the addition of (b)(4) for homogenization, the (b)(4) program used for tissue dissociation, and the (b)(4) as required for cryopreservation.
6. Failure to establish and follow a written testing program designed to assess the stability characteristics of drug products and to use results of such stability testing to determine appropriate storage conditions and expiration dates [21 CFR 211.166(a)].
You assigned a four-year expiration date to batches of WJMAX™ without supporting stability testing data.
FDA has reviewed your written response, dated September 1, 2022, to the inspectional observations on the Form FDA-483 issued at the conclusion of the inspection. The corrective actions described in your response are not adequate to address the above-noted violations. We note that some planned corrective actions did not include a timeline for completion and cannot be evaluated because of a lack of supporting documentation. Our concerns regarding your response to specific FDA-483 observations include but are not limited to, the following:
1. In response to FDA-483 Observation 2, your proposal to “perform the tissue dispersion or reduction purely (b)(4)” or “quantify total protein” “if deemed necessary” would not alter the regulatory status of your product as a drug and biological product. Moreover, the method suitability test referenced in your response is insufficient to assure that your product has the identity, strength, quality, and purity it purports or is represented to possess as required by 21 CFR 211.100(a).
2. In response to FDA-483 Observation 3, you state that storage of sterility samples at (b)(4) not affect detection of microbial contamination. FDA disagrees. There is no assurance that microorganisms, which may be weakened by the manufacturing process, would survive freezing and be reliably detected by sterility testing.
3. In response to FDA-483 Observation 5, you stated that you have a “robust system for environmental monitoring which is documented in [your] SOPs” and it was developed with (b)(4), a third-party microbiology lab. You also stated that your firm “intends to adhere to [your] robust environmental monitoring for future tissue processing” and that testing would be conducted (b)(4). Your environmental monitoring procedure provided during the inspection, QP 195.102 Air, Surface, & Personnel Environmental Monitoring, Revision 00 (Effective Date 09/01/2020), is inadequate to detect problems and demonstrate control of the aseptic processing area. For example, this procedure does not specify the frequency of non-viable particulate monitoring, surface sampling, or use of settle plates to ensure this monitoring is performed in association with each production batch. Additionally, this procedure does not sufficiently address alert and action levels and the appropriate response to deviations from alert and action levels.
Notably, your response does not address your firm’s plans regarding product that has been distributed or that remains in inventory that was manufactured under the violative conditions noted above. We note, according to your firm’s materials, your products carry a four-year shelf life.
Regarding your plans to continue manufacturing and distributing your product, your response states, “RenatiLabs is committed to adhere to the compliance regime to process and deliver tissue products under section 361 of the FDA compliance regulations.” As noted above, WJMAX™ is not regulated solely under section 361 of the PHS Act [42 U.S.C. 264].
Your response states that you intend “to eventually engage in IRB and IND directed studies.” 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 [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 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 of 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, 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 time frame for completion.
Your response should be sent to Colleen M. Aspinwall, Compliance Officer, U.S. Food & Drug Administration, Office of Biological Products Operations – Division 1 at the email address: Colleen.Aspinwall@fda.hhs.gov. If you should have any questions, please contact Colleen Aspinwall at 561-416-1065, ext. 1105 or via e-mail.
Michael W. Roosevelt
Program Division Director
Office of Biological Products Operations - Division I
1 At this time, it does not appear as if you conducted an investigation, as required by 21 CFR 211.192.
2 At this time, it does not appear as if you conducted an investigation, as required by 21 CFR 211.192.