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WARNING LETTER

September 1, 2023

23-649343

Dear Dr. Ross:

The United States Food and Drug Administration (FDA) conducted an inspection of your firm, Kimera Labs, Inc. (hereafter “Kimera”), located at 2810 N. Commerce Parkway, Miramar, FL, between July 11, 2022 and July 21, 2022. The FDA documented that you manufacture exosome products, XoGlo® and XoGlo®Pro, and an amniotic fluid product, Amnio2X®, for allogeneic use (collectively, “your products”). You have distributed your products to practitioners and medical facilities throughout the United States. Your products purport to be sterile, and your amniotic fluid product is intended for injection.

Information and records gathered prior to, during, and after the inspection, including information on your website, kimeralabs.com, reflect that your products are intended to treat various diseases or conditions. Additionally, information collected indicates your products fit within the definition of a biological product in the Public Health Service Act (PHS Act) [42 U.S.C. 262(i)]. Therefore, your products 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)]¹.

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). Kimera Labs has an IND in effect for XoGlo®Pro (IND 26535) as of May 12, 2023. However, pursuant to 21 CFR 312.7(b), a sponsor or investigator shall not commercially distribute or test market an investigational new drug.² Based on this information, your actions have violated the FD&C Act and Section 351(a) of the PHS Act.

Additionally, during the inspection, FDA investigators documented evidence of significant deviations from current good manufacturing practice (CGMP) requirements, including section 501(a)(2)(B) of the FD&C Act 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 products. FDA identified additional significant deviations upon further review of the information collected during the July 2022 inspection, as discussed below. These CGMP deviations, involving over 37,000 vials manufactured between April 2020 and June 2022, include, but are not limited to, the following:

1. Failure to establish 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 has failed to validate the aseptic processes used to manufacture XoGlo®, XoGlo®Pro, and Amnio2X®. These products purport to be sterile and are expected to be sterile.

b. You have not established appropriate written procedures for environmental monitoring in the aseptic processing areas where your products are manufactured. Specifically:

    i. Your written procedure for microbiological monitoring of surfaces, air, and personnel in the aseptic processing area indicates your action and alert limits for microorganisms are (b)(4) and (b)(4) CFUs, respectively.³ Your allowance for such high numbers of microorganisms could contribute to product contamination and pose a potentially significant safety concern.

    ii. You have not performed non-viable particulate monitoring of the aseptic processing areas in association with each production batch. This is insufficient to detect problems and demonstrate control of the aseptic processing areas during manufacturing. Additionally, you have not established alert or action limits for particulate monitoring.

2. Written records are not always made of investigations into unexplained discrepancies or the failure of a batch or any of its components to meet specifications whether or not the batch has already been distributed [21 CFR 211.192]. Specifically, you failed to document investigations for all unexplained discrepancies or the failure of batch to meet specifications. For example, you failed to document an investigation into the positive sterility result obtained for XoGlo®Pro lot 4000078P. All (b)(4) vials of this lot were distributed.

3. Each batch of drug product purporting to be sterile and/or pyrogen-free is not laboratory tested to determine conformance to such requirements [21 CFR 211.167(a)]. For example:

a. Sterility samples of Amnio2x® are frozen prior to sterility testing. Freezing product has the potential to destroy any microbial content in the samples before testing; therefore, contamination, if present, may not be detected.

b. Your written procedure for Amnio2x® specifies testing of (b)(4) vials for sterility regardless of lot size, which may consist of as many as (b)(4) vials. This does not ensure that sterility samples are representative of the lot size.

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 [21 CFR 211.160(b)]. Specifically, you have not established scientifically sound and appropriate specifications to assure that your products conform to appropriate standards of identity, strength, quality, and purity. Your specifications are listed as “tentative.”

5. Failure to establish written procedures for production and process controls 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)]. For example, the manufacturing processes for your products have not been validated.

6. Failure to test your non-penicillin drug products for the presence of penicillin although a reasonable possibility exists that the non-penicillin drug products have been exposed to cross contamination with penicillin [21 CFR 211.176]. For example, (b)(4) is one of the components in the Complete Media for your XoGlo® and XoGlo®Pro products, and you have not performed testing of these products for penicillin prior to final product release.

7. Failure to establish an adequate system for cleaning and disinfecting the room and equipment to produce aseptic conditions [21 CFR 211.42(c)(10)(v)]. For example, at the time of the inspection:

a. You failed to validate your written cleaning procedure for your laminar flow (b)(4) and your cleanrooms where your products are manufactured. Additionally, you failed to establish the effectiveness of disinfectants used in this procedure.

b. Your written procedure for cleaning the (b)(4) and cleanroom did not specify the contact time for disinfectants.

c. Your firm documented major and minor cleaning of (b)(4) and cleanrooms used in manufacturing of your products; however, your written procedures did not define the minor and major cleaning methods.

8. Failure to establish and document the accuracy, sensitivity, specificity, and reproducibility of test methods [21 CFR 211.165(e)]. For example, at the time of the inspection, you had not validated the test methods used for testing XoGlo® and XoGlo®Pro for identity, strength, quality, and purity.

9. Failure to ensure that each lot of components, drug product containers, and closures are withheld from use until the lot has been sampled, tested, or examined, as appropriate, and released for use by the quality control unit [21 CFR 211.84(a)]. Specifically, your firm lacks evidence, such as testing, to demonstrate components meet all specifications of identity, strength, quality, and purity. For example, you lack evidence that (b)(4) media, used in production of XoGlo® and XoGlo®Pro, were tested prior to release. Additionally, these two components are labeled “For research use only” but are incorporated into products that are injected into/used by humans.

10. 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, your firm assigned a one-year expiration date to XoGlo® and XoGlo®Pro lots without adequate data regarding the stability characteristics of the products. All product used for the stability study was from (b)(4) of the XoGlo®Pro product.

Because the FDA investigators had some difficulty obtaining unredacted records, including batch records, from you during the inspection, we encourage you to review FDA Guidance for Industry, Circumstances that Constitute Delaying, Denying, Limiting, or Refusing a Drug Inspection, available at https://www.fda.gov/regulatory-information/search-fda-guidance-documents/circumstances-constitute-delaying-denying-limiting-or-refusing-drug-inspection⁴.

During the inspection, FDA investigators documented that you continued to manufacture and distribute XoGlo® and XoGlo®Pro to treat diseases or conditions in humans without an approved BLA or IND in effect for those products, after FDA issued an Untitled letter to your firm in April 2020. FDA’s Untitled letter notified you that exosome products intended for such uses are regulated as drugs and biological products and are subject to premarket review and approval requirements. Although you stated during the inspection that your exosome products are for cosmetic use, you have continued to market your exosome products to treat diseases or conditions, for example, skin damage⁵. Therefore, these products continue to meet the definition of a drug as defined in section 201(g) of the FD&C Act [21 U.S.C. 321(g)], and biological product as defined in section 351(i) of the PHS Act [42 U.S.C. 262(i)].

We acknowledge receipt of your correspondences, dated August 11, 2022, October 20, 2022, and February 8, 2023, responding to FDA’s inspectional observations on the FDA-483. We have reviewed their contents, and the corrective actions described in your responses are not adequate to address the above-noted violations. In your October 2022 response, you “committed to cease manufacture and distribution of Amnio2x,” and “committed to ending use of [your] (b)(4) stem cell master line to make XoGlo® and XoGlo®Pro products for commercial distribution.” However, you indicated that Kimera Labs would continue to distribute the existing inventory to US practitioners until “no later than the end of (b)(4).” In a letter dated December 15, 2022, we informed you that we do not agree with your decision to continue to distribute these products without a BLA or IND in effect. Your response to FDA, received on February 8, 2023, indicated that Kimera Labs would “cease all distribution of existing batches of XoGlo and XoGlo Pro by Friday, February 10, 2023, for uses outside of” the IND that you submitted for XoGlo®Pro. Your continued distribution of your products violates the FD&C Act and PHS Act.

Furthermore, your responses do not address lots of XoGlo®, XoGlo®Pro, and Amnio2x® that were manufactured and distributed under the CGMP violations described above and may still be within expiry. We note your products carry a one-year expiration date.

With regard to your unapproved exosome products, XoGlo® and XoGlo®Pro, we direct your attention to FDA’s Public Safety Notification on Exosome Products, available at www.fda.gov/vaccines-blood-biologics/safety-availability-biologics/public-safety-notification- exosome-products. FDA issued this public safety notification following multiple reports of serious adverse events experienced by patients who were treated with exosome products.

Neither this letter nor the observations noted on the 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 facility. 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 may 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 address any violations and prevent their recurrence. Include any documentation necessary to show that the matters have been addressed. If you cannot address these matters within fifteen (15) working days, please explain the reason for your delay and the timeframe for completion. 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.

Your response should be sent to the following: Colleen Aspinwall, Compliance Officer, U.S. Food and Drug Administration, Office of Biological Products Operations – Division 1, 1515 North Federal Highway, Suite 111, Boca Raton, FL 33432 or Valerie Grecek-Trinh, Compliance Officer, U.S. Food & Drug Administration, Office of Biological Products Operations–Division 1, 400 W. Bay Street, Suite 401, Jacksonville, FL 32202 or emailed to Colleen.Aspinwall@fda.hhs.gov or Valerie.grecektrinh@fda.hhs.gov. If you should have any questions, please contact Colleen Aspinwall, Compliance Officer at 561-416-1065 ext. 1105 or Valerie Grecek-Trinh at 904-353-4560 ext. 118 or via e-mail.

Sincerely,
/S/

Michael W. Roosevelt Program Division Director
Office of Biological Products Operations – Division 1

_______________________

¹ Please be advised that the definition of human cells, tissues, or cellular or tissue based products (HCT/Ps) in 21 CFR 1271.3(d) excludes secreted or extracted human products. 21 CFR 1271.3(d)(3). Accordingly, secreted body fluids, such as amniotic fluid, are not considered HCT/Ps and are not regulated under section 361 of the Public Health Service Act and the regulations in 21 CFR Part 1271. Amniotic fluid intended to treat diseases or conditions in humans is generally regulated as a drug under the FD&C Act and a biological product under the PHS Act and requires premarket review and approval.

2 See also 21 CFR 312.7(a), which provides that “a sponsor or investigator, or any person acting on behalf of a sponsor or investigator, shall not represent in a promotional context that an investigational new drug is safe and effective for the purposes for which it is under investigation or otherwise promote the drug.” This provision is not intended to restrict the full exchange of scientific information concerning the drug, including dissemination of scientific findings in scientific or lay media. Rather, its intent is to restrict promotional claims of safety or effectiveness of the drug for a use for which it is under investigation and to preclude commercialization of the drug before it is approved for commercial distribution.

3 Your procedure indicates environmental monitoring for microorganisms should be done “at least (b)(4) unless otherwise warranted.” Please be advised that such monitoring should be performed in association with each production batch. For additional information, we recommend that you review FDA Guidance for Industry, Sterile Drug Products Produced by Aseptic Processing – Current Good Manufacturing Practice, available at https://www.fda.gov/downloads/Drugs/Guidances/ucm070342.pdf. FDA’s guidance documents do not establish legal requirements.

4 We note that FDA’s guidance documents do not establish legal requirements.

5 Specifically, an indication of XoGlo is “treatment of skin damage after cosmetic or other facial injury by heat, light, physical, or chemical damage” according to labeling collected during the inspection.