INCELL Corporation LLC

The United States Food and Drug Administration (FDA) inspected your facility located at the above address between September 25, 2023, and September 29, 2023. During the inspection, FDA documented that your company manufactures a product derived from amniotic fluid, (b)(4), pursuant to a contract with (b)(4) (hereinafter, “(b)(4)” or “your product”).

This letter is to advise you that your product is an unapproved new drug 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 into interstate commerce is prohibited under section 301(d) of the FD&C Act, 21 U.S.C. § 331(d). Your product is also an unlicensed biological product in violation of section 351(a)(1) of the Public Health Service Act (PHS Act), 42 U.S.C. § 262(a)(1)(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 drugs do not conform to CGMP, your product is adulterated within the meaning of section 501(a)(2)(B) of the FD&C Act, 21 U.S.C. § 351(a)(2)(B). Furthermore, (b)(4) is also misbranded under sections 502(a) of the FD&C Act, 21 U.S.C. § 352(a).

Your introduction or delivery for introduction of (b)(4), an adulterated and misbranded drug, into interstate commerce is a prohibited act under section 301(a) of the FD&C Act, 21 U.S.C. § 331(a). U.S. Food and Drug Administration

Based on information and records gathered prior to, during, and after the inspection and other information available to FDA, including (b)(4) website (b)(4), your product is intended for use in the diagnosis, cure, mitigation, treatment, or prevention of disease or conditions in humans and/or is intended to affect the structure or function of the body. According to (b)(4) product specification sheet collected from INCELL Corporation LLC during the inspection of INCELL Corporation LLC, (b)(4) is intended for “(b)(4).” As noted above, you manufacture (b)(4) for (b)(4) pursuant to a contract with (b)(4) promotional material obtained from (b)(4) states the following: “(b)(4)”. Further, (b)(4) website indicates that “(b)(4) is a (b)(4)” and describes (b)(4) as “(b)(4).” Your product is therefore a drug as defined in section 201(g)(1) of the FD&C Act, 21 U.S.C. § 321(g)(1). Additionally, your product is a biological product as defined in section 351(i) of the PHS Act, 42 U.S.C. § 262(i).1

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 biologics license application (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 products are safe, pure, and potent. Your product is not the subject of an approved BLA.

During the inspection, FDA investigators also documented evidence of significant violations of CGMP requirements applicable to your product, including violations of section 501(a)(2)(B) of the FD&C Act and 21 CFR parts 210 and 211. At the conclusion of the inspection, FDA investigators issued a Form FDA-483, List of Inspectional Observations. Your CGMP violations 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 CFR211.113(b)]. For example, the aseptic processes used to manufacture your product have not been validated (e.g., by performing media fill simulations) since your firm’s manufacturing operations for the subject product began in February 2020. Your product purports to be sterile and is expected to be sterile.

We acknowledge your October 18, 2023, response to this violation. It is noted that you have no plans of performing aseptic processing validation for the manufacturing of your product. You assert that you test (b)(4) and other sterile liquid fill products and there have been no sterility failures. You also assert that you monitor customer complaints. This is not suitable justification for the absence of aseptic processing validation. Sterility tests are limited in their ability to detect contamination because of the small sample size typically used. To ensure the sterility of products purporting to be sterile, all aseptic and sterilization processes must be adequately validated in accordance with 21 CFR 211.113(b). Typically, aseptic process validation is performed using a media fill that includes exposing microbiological growth medium to product contact surfaces of equipment, container closure systems, critical environments, and process manipulations to closely simulate where (b)(4) is exposed to the environment during processing.

2. 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 [21 CFR211.160(b)]. For example, you have not established scientifically sound and appropriate specifications to assure that your product conforms to appropriate standards of identity. Your specification for finished product testing does not include a requirement to perform identity testing.

We acknowledge your October 18, 2023, response to this violation. You state that while specific markers have not been routinely included in the (b)(4) release protocol, you have done extensive studies on amniotic fluid and its composition and characterization. You also state, however, that you have not used the results from these studies for routine testing including release and stability testing. Documentation related to proposed release and stability tests using these results have not been provided for review. Further, you have not described any actions to be taken for violative product on the market that remains within the labeled expiry.

3. Failure to establish 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)]. Specifically, your certificate of analysis for your product states that the expiry period is (b)(4), while your instructions for use (IFU) labels your product as having a “(b)(4).” You therefore assigned (b)(4) expiration dates to your product without supporting data regarding the stability characteristics of the product.

We acknowledge your October 18, 2023, response to this violation. It is noted that you intend to (b)(4). However, documentation related to these studies has not been provided for review nor have you notified FDA that these studies have been performed. Further, you have not described any actions to be taken for violative product on the market that remains within the unsubstantiated label expiry. A suitable expiration date, supported with data, is needed to ensure product quality over the shelf life of the product.

Your product is also misbranded under section 502(a) of the FD&C Act, 21 U.S.C. § 352(a), because your labeling is false or misleading. Specifically, the IFU for your product indicates that “(b)(4).” This description implies that your product is provided as (b)(4) when it is actually a (b)(4). Further, as noted above, your certificate of analysis for your product states that the expiry period is (b)(4), while your IFU states that your product has a “(b)(4).” Neither of these statements about the stability of your product are supported with stability data. These false or misleading representations about your product on your labeling cause this product to be misbranded under section 502(a) of the FD&C Act, 21 U.S.C. § 352(a).

We acknowledge your October 18, 2023, response to the labeling discrepancies. You state that the errors in the description and expiration date resulted from a miscommunication between the distributor ((b)(4)) and the manufacturer of your product (INCELL Corporation LLC). As indicated above, you state that new stability studies are being conducted and the expiry date will be corrected once these studies are complete. Additionally, you state, “a newly created form addressing these issues will be implemented for a revised contract with (b)(4), and all new contracts should eliminate any miscommunications or misunderstandings”. While the corrective actions for these discrepancies appear acceptable, you have not provided any documentation related to these changes for review. Please provide your revised IFU for review. Further, you have not described any actions to be taken for violative product on the market that contain these errors and are within labeled expiry. The IFU guides the patient or physician on how to safely and effectively use your product and commonly includes instructions on preparation, administration, handling, storage, and disposal. If inaccurate IFU are provided to patients or physicians, the safety and effectiveness of your product may be compromised.

It is noted that in 2020, you manufactured (b)(4), which is also a product derived from amniotic fluid. Please clarify if you are currently manufacturing (b)(4) or plan to resume manufacturing it.

Further, documents provided during the inspection lack evidence that adequate environmental monitoring takes place in the (b)(4) ISO (b)(4) manufacturing environment where (b)(4) is exposed to the environment during processing. Specifically, results associated with batch records only include passive microorganism monitoring (i.e., (b)(4)) and non-viable particulate monitoring. There is no mention of viable microorganism monitoring such as (b)(4) sampling and personnel monitoring in association with each batch. Various sampling methods are needed to adequately identify potential routes of contamination.

Neither this letter nor the observations noted on the Form FDA-483 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 result in 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.