Skye Biologics Holdings LLC

The United States Food and Drug Administration (FDA) inspected your facility, located at 2255 Campus Dr, El Segundo, CA 90245, between November 29, 2022 and December 9, 2022. During the inspection, FDA documented that your company manufactures “placental connective tissue matrix allograft” products derived from umbilical cord, namely BioECM™ (collectively, “your products1”).

This letter is to advise you that your products are unapproved new drugs in violation of section 505(a) of the Federal Food, Drug, and Cosmetic Act (FD&C Act), 21 U.S.C. §355(a). Your introduction or delivery for introduction of your product[s] into interstatecommerce, or the causing thereof, is prohibited under sections 301(d) of the FD&C Act,21 U.S.C. § 331(d). Your products are also unlicensed biological products in violation of section 351(a) of the Public Health Service Act (PHS Act), 42 U.S.C. § 262(a).

This warning letter also summarizes significant violations of current good manufacturing practice (CGMP) requirements, including violations of 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. Because your methods, facilities, or controls for manufacturing, processing, packing, or holding do not conform to CGMP, your drug products are adulterated within the meaning of section 501(a)(2)(B) of the FD&C Act, 21 U.S.C. § 351(a)(2)(B). Your introduction or delivery for introduction of your adulterated products into interstate commerce is a prohibited act under section 301(a) of the FD&C Act, 21 U.S.C. § 331(a).

Based on information and records reviewed by FDA prior to, during, and/or after the inspection, including information on your website, www.skyebiologics.com, your products are intended for use in the diagnosis, cure, mitigation, treatment, or prevention of disease or conditions in humans and/or are intended to affect the structure or function of the body. For example:

Your webpage for “Tissue Transplants Utilizing Extracellular Matrix Preservation (BioECM) Technology”, located at https://www.skyebiologics.com/technology, states that “Not all Placental Allografts are Created Equal… Placental tissues have been shown in the literature to be naturally anti-inflammatory, anti-fibrotic, anti-microbial, to modulate inflammation, promote tissue remodeling and reduce scar tissue formation in clinical applications.”

In a press release regarding your BioECM product, you state that “FastActing Amniotic Membranes are part of HRT’s & Skye’s extensive line of amniotic and placental products designed to help support proper tissue remodeling while modulating scarring and inflammation.”

Therefore, your products are drugs as defined in section 201(g)(1) of the FD&C Act, 21 U.S.C. § 321(g)(1), and biological products as defined in section 351(i) of the 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) are not regulated solely under section 361 of the PHS Act and the regulations in 21 CFR Part 1271. Unless an exception in 21 CFR 1271.15 applies, 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, as applicable, premarket review. Based on a review of relevant materials, your company does not qualify for any exception in 21 CFR 1271.15, and your products fail to meet all criteria in 21 CFR 1271.10(a).

For example, 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. The processing of the umbilical cord from the form of a conduit into a flowable form, drastically alters the physical state of the HCT/P. The umbilical cord is more than minimally manipulated because such processing alters the original relevant characteristics of the HCT/P relating to its utility to serve as a conduit by effectively altering or eliminating its physical integrity and tubular form.

In addition, your products fail to meet the criterion that the HCT/Ps be “intended for homologous use only,” which means that the “labeling, advertising, or other indications of the manufacturer’s objective intent” demonstrate that the HCT/P is intended solely to perform “the same basic function or functions in the recipient as in the donor.” 21 CFR 1271.3(c) and 1271.10(a)(2). Your products are not intended to perform the same basic function or functions of the HCT/P in the recipient as in the donor (e.g., serving as a conduit). Rather, your products are intended for, e.g., modulation of inflammation and promotion of remodeling of tissues; anti-inflammatory, anti-fibrotic, and anti-microbial purposes; and supplementing or filling a void, which are not basic functions of umbilical cord in the donor.

Therefore, these HCT/Ps are not regulated solely under section 361 of the PHS Act, 42 U.S.C. § 264, and the regulations in 21 CFR part 1271.2 In addition to being regulated under section 361 of the PHS Act and 21 CFR part 1271, these products are regulated as drugs as defined in section 201(g)(1) of the FD&C Act, 21 U.S.C. § 321(g)(1), and biological products as defined in section 351(i) of the PHS Act, 42 U.S.C. § 262(i).

Subject to certain exceptions not applicable here, to lawfully introduce or deliver for introduction into interstate commerce a drug that is a biological product, a valid BLA must be in effect under section 351(a)(1) of the PHS Act, 42 U.S.C. § 262(a)(1). Such licenses are issued only after showing that the product is safe, pure, and potent. Your products are not the subject of an approved BLA.

Additionally, during the inspection, FDA investigators documented evidence of significant violations from CGMP requirements, including violations from 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 violations applicable to your products. FDA identified additional significant deviations upon further review of the information collected during the November 2022 inspection, as discussed below.

The CGMP violations include, but are not limited to, the following:

1. Failure to establish adequate written procedures for production and process controls designed to assure that the drug products have the identity, strength, purity, and quality that they are purported or represented to possess. 21 CFR 211.100(a). Specifically, your firm has not validated the manufacturing processes for your products with respect to identity, strength, quality, and purity.

2. Failure to have an adequate system for monitoring environmental conditions in an aseptic processing area, 21 CFR 211.42(c)(10)(iv), as well as failure to establish and follow appropriate written procedures that are designed to prevent microbiological contamination of drug products purporting to be sterile. 21 CFR 211.113(b). Your written procedures for environmental monitoring of your firm’s aseptic processing areas (e.g., laminar flow hoods) are not sufficient to detect problems and ensure low bioburden levels prior to sterilization. For example,

a. You do not perform nonviable particulate monitoring or viable microbial (b)(4) monitoring within your ISO 5 laminar flow hoods in association with all production shifts. You also do not conduct personnel monitoring of operators who perform processing of your products. Due to the higher risk of microbial contamination in this environment where open processing occurs, environmental monitoring inside the laminar flow hood should be conducted in association with each batch.

b. Your ISO 5 laminar flow hoods, which are used for tissue cleaning, rinsing, and weighing, are located within an unclassified area. The area immediately adjacent to the critical processing areas should be controlled and monitored to minimize the level of potential contaminants in the final product.

3. Failure to establish laboratory controls that include scientifically sound and appropriate specifications, standards, sampling plans, and test procedures designed to assure the components, drug product containers, closures, in-process materials, labeling, and drug products conform to appropriate standards of identity, strength, quality and purity. 21 CFR211.160(b). For example, you have not established appropriate specifications to assure that your products conform to appropriate standards of identity, strength, quality, and purity.

4. Failure to perform appropriate laboratory testing, as necessary, of each batch of drug product required to be free of objectionable microorganisms.21 CFR 211.165(b). Specifically, you failed to perform endotoxin testing on final product batches. Such laboratory testing is necessary as your products are purported to be sterile.

5. 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 been already distributed. 21 CFR 211.192. For example, from January 2021 to August 2022, you failed to investigate three action-level excursions for environmental monitoring observed in the a septic processing area (e.g., laminar flow hoods).

6. Failure to prepare batch production and control records that document each significant step in the manufacture, processing, packing, or holding of your umbilical cord blood products. 21 CFR 211.188(b). Specifically, your batch production records do not include documentation of the accomplishment of each significant step in the manufacture of your products or the person(s) performing each of those steps, for example:

a. The weight of, for e.g., umbilical cord tissue used in processing.

b. The amount of saline used to formulate the final product.

c. Processing of tissue in the (b)(4) machine, including weight of tissue processed, machine operational parameters, run time, and the number of runs completed.

d. Identification of equipment, such as laminar flow hoods, used in processing.

7. 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 has assigned a five-year expiration date for your products without supporting data regarding the stability characteristics of the products.

We acknowledge receipt of your letter received on January 3, 2023, which provides a response to FDA’s inspectional observations (FDA-483). We have reviewed the represented corrective actions outlined in the response, and these actions are not adequate to address the above-noted violations. For example, your response does 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.

Your firm’s response repeatedly asserts that your products should be regulated solely under section 361 of the PHS Act, and that the violations noted above are not applicable to your products. Based on your position, you have not proposed corrective actions which address the CGMP violations noted above. 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 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.

As such, your response further does not adequately address 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.

In addition, we have concerns with your “placental connective tissue matrix allograft” products derived from umbilical cord, namely BioRenew™, and products derived from amniotic and chorionic membrane and umbilical cord, namely HRT® BioPower-A, HRT® BioPower-C, and HRT® NX. In your response, please explain the basis for your determination regarding whether these products require FDA premarket review. For example, if you believe these products meet all criteria in 21 CFR 1271.10(a) for regulation solely under section 361 of the PHS Act, 42 U.S.C. 264, and 21 CFR part 1271, please explain that determination.

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 associated with your products. It is your responsibility to ensure that your establishment is in full compliance with the law.

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.

Send your electronic response to CBERDCMRecommendations@fda.hhs.gov. If you have questions regarding this letter, contact the Division of Case Management, CBER at (240) 402-9156.