Frontier Biologics, LLC - 686059 - 11/01/2024

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WARNING LETTER

November 1, 2024

CBER 25-686059

Dear Mr. Justice:

The United States Food and Drug Administration (FDA) inspected your facility, located at the above address between February 27, 2024, and March 8, 2024. During the inspection, FDA documented that your company manufactures a human amniotic fluid derived product, (b)(4), as well as a human amniotic membrane derived product, (b)(4), for allogeneic use (collectively, “your products”).¹

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 products are also unlicensed biological products in violation of section 351(a)(1) of the Public Health Service Act (PHS Act), 42 U.S.C. § 262(a)(1). 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. Your introduction or delivery for introduction of your products into interstate commerce, or the causing thereof, is prohibited under sections 301(d) of the FD&C Act, 21 U.S.C. § 331(d).

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 drugs do not conform to CGMP, your 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 products into interstate commerce, or the causing thereof, is a prohibited act under section 301(a) of the FD&C Act, 21 U.S.C. § 331(a).

Unapproved New Drug and Unlicensed Biological Product Violations

Based on information and records reviewed by FDA, 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 products are intended for (b)(4), as evidenced by the following statements in materials collected during the inspection:

• “(b)(4).”
• “(b)(4) Applications [include]:

    o (b)(4)

    o (b)(4)

    o (b)(4)

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).²

Your (b)(4) 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) 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 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 product fails to meet all criteria in 21 CFR 1271.10(a).

For example, your (b)(4) product fails 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 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 product is not intended solely to perform the same basic function or functions of the HCT/P in the recipient as in the donor (e.g., serving as a barrier for amniotic membrane). Rather, your product is intended for use in (b)(4), which is not a basic function of amniotic membrane in the donor.

Therefore, this HCT/P is not regulated solely under section 361 of the PHS Act, 42 U.S.C. § 264, and the regulations in 21 CFR part 1271.3 See 21 CFR 1271.20. In addition to being regulated under section 361 of the PHS Act and 21 CFR part 1271, your product is regulated as a drug as defined in section 201(g)(1) of the FD&C Act, 21 U.S.C. § 321(g)(1), and a biological product as defined in section 351(i) of the PHS Act, 42 U.S.C. § 262(i), as stated above.

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.

CGMP Violations

FDA’s inspection of your facility documented evidence of significant CGMP violations. At the conclusion of the inspection, FDA investigators issued a Form FDA-483, List of Inspectional Observations (Form FDA-483).

The CGMP violations applicable to your products 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, as required by 21 CFR 211.113(b). For example, you failed to adequately validate (i.e., by performing media fill simulations) the aseptic process used to manufacture your (b)(4) product. Your product purports to be sterile and is expected to be sterile.

2. 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, as required by 21 CFR 211.100(a). Specifically,

a. The manufacturing process for your (b)(4) product has not been adequately validated with respect to identity, strength, quality, and purity. During the inspection, you provided a validation study for your amniotic fluid product, which only tested for sterility. However, this is not sufficient to assure the identity, strength, quality, and purity of your product.

b. The manufacturing process for your (b)(4) product has not been validated with respect to identity, strength, quality, and purity.

3. Aseptic processing areas are deficient regarding the system for environmental monitoring to prevent contamination, as required by 21 CFR 211.42(c)(10)(iv). For example, you have not performed non-viable particulate monitoring, personnel monitoring, active or passive viable air sampling, or sampling of critical surfaces for microorganisms in the aseptic processing area in association with each production batch.

4. Aseptic processing areas are deficient regarding the system for cleaning and disinfecting the room and equipment to produce aseptic conditions, as required by 21 CFR 211.42(c)(10)(v). For example, you have not validated your process for cleaning and disinfecting the ISO (b)(4) cleanrooms where your products are manufactured.

5. 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 , as required by 21 CFR 211.192. For example, from March 2023 and June 2023, your firm had two sterility failures during finished product testing of your (b)(4) product. Although you identified the contaminating organisms, you failed to conduct an investigation to determine the root cause of the failures.

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, as required by 21 CFR 211.166(a). Specifically, you assigned a (b)(4) expiration date to your products without supporting data.

Response to the Form FDA-483

We have reviewed your response, dated March 28, 2024, to FDA’s Form FDA-483 in detail. Your response is inadequate because it did not provide sufficient detail for FDA to fully assess the adequacy of your corrective actions. It lacks documentation to demonstrate that you have corrected your violations and fails to include a timeline for completion of all necessary corrective actions. For example, in your response, you note that going forward, any (b)(4) still in house from previously opened lots will be discarded. However, your response does not address the (b)(4), which are used as packaging for your finished amniotic fluid products, that are (b)(4) using a sterilization process that has not been validated. Please be advised that in accordance with 21 CFR 211.113(b), you are required to establish and follow appropriate written procedures designed to prevent microbiological contamination of drug products purporting to be sterile, including procedures for validation of sterilization processes.

Your response also does not address your specific plans for disposition of the inventory of (b)(4) or (b)(4) at your facility that were manufactured under the conditions described in this letter. Further, your response does not address products that have been distributed and remain in the marketplace.

We acknowledge your commitment to voluntarily suspend production activities until you have made corrections to the observations listed on the Form FDA-483. However, your response 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.

Conclusion

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 exist in connection with your products. You are responsible for investigating and determining the causes of any violations and for preventing their recurrence or the occurrence of other violations. It is your responsibility to ensure full compliance with all applicable requirements in the FD&C Act, PHS Act, and all applicable regulations.

This letter notifies you of our concerns and provides you an opportunity to address them. Failure to adequately address these matters may result in action without further notice, including, without limitation, 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.

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.

Sincerely,
/S/

Melissa J. Mendoza
Director
Office of Compliance and Biologics Quality
Center for Biologics Evaluation and Research

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1 At the time of the inspection, FDA collected evidence that your human amniotic fluid derived product is also referred to as “Evexcell™ (b)(4)”. FDA also collected evidence that your human amniotic membrane derived product is also referred to as “(b)(4).”

2 We note that your amniotic fluid product, (b)(4), is not an HCT/P because amniotic fluid is a secreted bodily fluid and the definition of HCT/Ps in 21 CFR 1271.3(d)(3) excludes secreted or extracted human products.

3 Because your product fails to meet at least one criterion in 21 CFR 1271.10(a), this letter does not evaluate all other criteria in 21 CFR 1271.10(a).