Pinnacle Transplant Technologies, LLC

During an inspection of your firm, Pinnacle Transplant Technologies, LLC (hereafter referred to as “Pinnacle”), located at 1125 W. Pinnacle Peak Road, Bldg. 1, Suite 103, Phoenix, AZ 85027, conducted between August 15, 2022 and August 29, 2022, the United States Food and Drug Administration (FDA) documented your manufacture of an amniotic membrane and amniotic fluid derived product, PalinGen® (b)(4), and an amniotic fluid derived product, PalinGen® (b)(4) (hereinafter, your products). You have distributed these products to third-party distributors, some under private label, and directly to health care professionals and medical facilities throughout the United States. Your products are intended for injection and are purported to be sterile.

Information and records gathered prior to and during the inspection and also from your contractor, (b)(4), located at (b)(4), reflect that your products are intended for use in the cure, treatment, or prevention of diseases or conditions, such as wound healing, and/or are intended to affect the structure or function of the body. For example, promotional materials for PalinGen (b)(4) state, “PalinGen (b)(4) contain[s] (b)(4) and “Amniotic tissue (b)(4).” Promotional materials for PalinGen (b)(4) state, “(b)(4).” As a result, your products are drugs as defined in section 201(g)(1) of the Federal Food, Drug, and Cosmetic Act (FD&C Act) [21 U.S.C. 321(g)(1)] and biological products as defined in section 351(i) of the Public Health Service Act (PHS Act) [42 U.S.C. 262(i)].

Because PalinGen® (b)(4) contains amniotic membrane, in addition to being a drug and biological product, it 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, and 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.

Based on a review of the materials described above, Pinnacle Transplant Technologies does not qualify for any exception in 21 CFR 1271.15, and PalinGen® (b)(4) fails to meet all the criterial in 21 CFR 1271.10(a). 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.

For example, PalinGen® (b)(4) fails to meet the minimal manipulation criterion set forth in section 1271.10(a)(1) and defined for structural tissue in section 1271.3(f)(1). During the manufacturing process for PalinGen® (b)(4), amniotic membrane is processed from (b)(4) that can be administered by (b)(4). The amniotic membrane 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 barrier by effectively eliminating its physical integrity, tensile strength, and elasticity.

PalinGen® (b)(4) also fails to meet other criteria set forth 21 CFR 1271.10(a). For example, PalinGen® (b)(4) 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.” PalinGen® (b)(4) is not intended solely to perform the same basic function or functions of amniotic membrane in the recipient as in the donor, such as serving as a selective barrier for the movement of nutrients between the external and in utero environment, protecting the fetus from the surrounding maternal environment, and serving as a covering to enclose the fetus and retain fluid in utero. Rather, PalinGen® (b)(4) is intended, for example, for use in wound healing and tissue regeneration, which are not homologous uses of amniotic membrane as defined in 21 CFR 1271.3(c).1

PalinGen® (b)(4) is not an HCT/P. The definition of HCT/Ps in 21 CFR 1271.3(d) excludes secreted or extracted human products. Accordingly, secreted body fluids, such as amniotic fluid, are not considered HCT/Ps. Because PalinGen® (b)(4) meets the definition of a drug under section 201(g) of the FD&C Act and a biological product under section 351(i) of the PHS Act, it is regulated as a drug under the FD&C Act and a biological product under the PHS Act and requires premarket review and approval.

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. A biological product for which a biologics license application (BLA) has been approved under section 351(a) of the PHS Act is not required to have an approved application under section 505 of the FD&C Act [21 U.S.C. § 355; 42 U.S.C. § 262(j)]. Otherwise, with certain exceptions not applicable here, a new drug may not be introduced or delivered for introduction into interstate commerce without an approved application from FDA in effect, as described in section 505(a) of the FD&C Act. 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 statutory and regulatory requirements [21 U.S.C. 355(i); 42 U.S.C. 262(a)(3); 21 CFR part 312].

Neither PalinGen® (b)(4) nor PalinGen® (b)(4) are the subject of an approved BLA or an approved application under section 505(a) of the FD&C Act. Based on our review, these products are unapproved new drugs, and your firm’s introduction or delivery for introduction of these products into interstate commerce violates sections 301(d) [21 U.S.C. § 331(d)] and 505(a) of the FD&C Act and section 351(a)(1) of 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 and 21 CFR Parts 210 and 211.

At the close of the inspection, the FDA investigators issued a Form FDA-483, List of Inspectional Observations, which described a number of significant CGMP deviations applicable to your products. FDA identified additional significant deviations upon further review of the information collected during the inspection. These deficiencies 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, your firm failed to adequately validate the aseptic process used to manufacture over (b)(4) units of PalinGen® (b)(4) and PalinGen® (b)(4) since your manufacturing operations began in March 2020. More specifically, it was observed during record reviews that the media fill simulations did not follow your commercial manufacturing process for the products. Additionally, critical manufacturing steps were not simulated during the validations. Your products are purported to be sterile and are expected to be sterile.

2. Failure to establish laboratory controls that include scientifically sound and appropriate specifications designed to assure that drug products conform to appropriate standards of identity, strength, quality, and purity [21 CFR 211.160(b)]. For example, your finished product testing is limited to sterility testing and endotoxin testing as measurements of product attributes, and such testing does not demonstrate, for example, the identity and/or strength of your products.

3. 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]. Specifically, between July 2020 and February 2022, your firm failed to investigate 8 sterility failures. While you identified the contaminating organisms, you did not conduct an investigation to determine the root cause of the failures or implement corrective and preventative actions. Examples of contaminating organisms include (b)(4).

4. Failure to have an adequate system for monitoring environmental conditions in an aseptic processing area [21 CFR 211.42(c)(10)(iv)]. Specifically, environmental monitoring samples within your ISO-(b)(4) are not positioned in critical areas that pose the most microbiological risk to your products during aseptic processing operations. During the inspection, FDA investigators observed passive (b)(4) positioned on a (b)(4), within the (b)(4) portion of the ISO-(b)(4), during aseptic filling operations. This practice is insufficient to demonstrate control of the critical manufacturing areas during aseptic processing.

5. Failure to establish an adequate system for cleaning and disinfecting the room to produce aseptic conditions [21 CFR 211.42(c)(10)(v)]. Your cleaning validation is inadequate. For example, at the time of the inspection, you failed to validate the efficacy of the disinfectants used to clean and disinfect your cleanroom.

6. Failure to maintain equipment and utensils at appropriate intervals to prevent contamination that would alter the safety, identity, strength, quality or purity of the drug product [21 CFR 211.67(a)]. For example, your firm performed HEPA filter integrity testing (b)(4) on your ISO-(b)(4), despite the detection of a gross leak in the HEPA filter during (b)(4) testing.2 Your ISO-(b)(4) are used to aseptically process your (b)(4) products which are purported to be sterile.

We acknowledge receipt of your responses dated September 16, 2022, October 14, 2022, November 15, 2022, December 1, 2022, December 15, 2022, December 22, 2022, January 16, 2023, February 16, 2023, March 16, 2023, June 1, 2023, July 20, 2023, and August 16, 2023, which provide responses and corrective actions to FDA’s inspectional observations (FDA-483). We have reviewed the corrective actions outlined in the response, and we have determined that the corrective actions are inadequate to address our concerns. For example, even though you have added the missing manufacturing steps to the process simulations, the use of a sterile substitute for the tissue does not accurately represent real-world situations or the worst-case scenario for potential cross-contamination of the processing area. Further, you performed a retrospective analysis of sterility failures, which showed a correlation between sterility failures and pre-processing cultures, but you did not investigate this correlation.

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. 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 include seizure and/or injunction.

We also have concerns regarding your (b)(4) amniotic fluid derived product, (b)(4). Based on our review, this product is a biological product as defined in section 351(i) of the Public Health Service Act (PHS Act) [42 U.S.C. 262(i)]. It is also either a drug under section 201(g) of the FD&C Act or a device under section 201(h) of the FD&C Act. To lawfully market a biological product, either a valid biologics license or, as applicable, an appropriate device premarket authorization must be in effect. If you would like more information on which pathway is appropriate for this product, please contact us.

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.