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  5. Invitrx Therapeutics, Inc. - 630712 - 11/09/2022
  1. Warning Letters

WARNING LETTER

Invitrx Therapeutics, Inc. MARCS-CMS 630712 —

Delivery Method:
VIA UNITED PARCEL SERVICE
Product:
Biologics
Recipient:
Recipient Name
Habib Torfi
Recipient Title
Chief Executive Officer
Invitrx Therapeutics, Inc.

20503 Crescent Bay Drive
Lake Forest, CA 92630
United States

Issuing Office:
Division of Biological Products Operations II

United States

WARNING LETTER

November 9, 2022

[OBPO 22-630712]

Dear Mr. Torfi:

During an inspection of your firm, Invitrx Therapeutics, Inc. (“Invitrx”), located at 20503 Crescent Bay Drive, Lake Forest, CA 92630, conducted between March 1, 2022 and March 22, 2022, the United States Food and Drug Administration (FDA) documented that you manufacture cellular and acellular products for allogeneic use. This includes the following products (collectively “your products”): a human umbilical cord derived cellular product, Invitra UC-MSC™, and exosome products, Invitra EX™ and Invitra EV-OP™. You have distributed your products directly to healthcare professionals and medical facilities throughout the United States.1 Your products are intended to be administered by injection, ophthalmically, or by nebulization and purport to be sterile.

Information and records gathered during the inspection and information available on your website, www.invitrx.com, reflect that your products are intended to treat various diseases or conditions. Therefore, these 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)].

Your umbilical cord derived cellular product, Invitra UC-MSC™, 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 [42 U.S.C. 264] and the regulations in 21 CFR Part 1271. 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 appropriate premarket review.

Invitrx does not qualify for any exception in 21 CFR 1271.15, and your umbilical cord derived cellular product, Invitra UC-MSC™, fails to meet all the criteria in 21 CFR 1271.10(a). Specifically, your umbilical cord derived cellular product, Invitra UC-MSC™, 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.” This product is not intended to perform the same basic function or functions of the umbilical cord in the recipient as in the donor, such as serving as a conduit. Rather, using this product to treat orthopedic conditions, such as osteoarthritis, for example, is not homologous use as defined in 21 CFR 1271.3(c).

In addition, Invitra UC-MSC™ fails 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.

Therefore, Invitra UC-MSC™ is not regulated solely under section 361 of the PHS Act [42 U.S.C. 264] and the regulations in 21 CFR Part 1271. Because this HCT/P does not meet all the criteria in 21 CFR 1271.10(a), and Invitrx does not qualify for any exception in 21 CFR 1271.15, the product is regulated as a drug as defined in section 201(g) of the FD&C Act [21 U.S.C. 321(g)] and a biological product as defined in section 351(i) of the PHS Act [42 U.S.C. 262(i)].

With regard to your unapproved exosome products, Invitra EXTM and Invitra EV-OPTM, we direct your attention to FDA’s Public Safety Notification on Exosome Products, available at www.fda.gov/vaccines-blood-biologics/safety-availability-biologics/publicsafety-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.

Your exosome products, marketed for the treatment of diseases and conditions in humans, are regulated as drugs under the FD&C Act and biological products under the PHS Act and are subject to premarket review and approval requirements.

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), nor is there an IND in effect for any of them. Based on this information, your actions have violated the FD&C Act and the PHS Act.

Additionally, during the inspection, FDA investigators documented evidence of significant deviations from current good manufacturing practice (CGMP) and current good tissue practice (CGTP) requirements, including deviations from section 501(a)(2)(B) of the FD&C Act, 21 CFR Parts 210 and 211, and 21 CFR Part 1271. Many of the deviations are repeat deficiencies that FDA documented during the March-April 2019 inspection of your firm. The deviations in manufacturing observed, as well as those noted in documents collected during the inspection, indicate that the use of your products raises potential significant safety concerns. For example, your deficient donor screening practices, inadequate aseptic practices, unvalidated manufacturing processes, and deficient environmental monitoring, as described below, pose a significant risk that your products may be contaminated with microorganisms or have other serious product quality defects.

At the close of the inspection, FDA investigators issued a Form FDA-483, List of Inspectional Observations, which described significant deviations applicable to your products. FDA also identified additional significant deviations upon further review of the information collected during the March 2022 inspection, as discussed below. These deviations, involving over (b)(4) vials of product manufactured since March 2020, include, but are not limited to, the following:

1. Failure of a responsible person to determine and document the eligibility of a cell or tissue donor based upon the results of donor screening and donor testing [21 CFR 1271.50(a)]. For example:

a. Invitrx is the establishment responsible for making the donor eligibility determination, but since operations began, Invitrx has failed to determine and document the eligibility of hundreds of tissue donors. Tissue from these donors was used to manufacture your products, including Invitra UC-MSCTM.

b. Invitrx has not reviewed relevant medical records it has received from its umbilical cord tissue suppliers to determine donor eligibility.

2. 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:

a. Your firm has failed to validate the aseptic processes used to manufacture Invitra UC-MSCTM, Invitra EXTM, and Invitra EV-OPTM. By the nature of their routes of administration, these products purport to be sterile and are expected to be sterile.

b. During the inspection, FDA investigators observed primary product containers for products purporting to be sterile, including vial caps for Invitra EV-OP™, being stored on a shelf in an open bag in your aseptic processing area, specifically, cleanroom (b)(4). The caps are received in bulk and do not undergo further cleaning or sterilization.

c. Your environmental monitoring procedures for your firm’s aseptic processing area where your products are manufactured are inadequate.
For example:

i. You have not performed environmental monitoring of the aseptic processing area on a sufficient frequency to demonstrate control of this area during manufacturing.

ii. You have not established environmental monitoring using settle plates.

iii. Your written procedure in place at the time of the inspection, SOP Q-QA-010, Environmental Monitoring Program (Effective Date 01/02/2019), states that sampling is to be performed (b)(4). This procedure is insufficient to demonstrate control of the aseptic processing area during manufacturing because it does not include air sampling for non-viable and viable particulates during aseptic processing operations.

3. Failure to satisfy general biological products standards for sterility testing [21 CFR 610.12]. For example:

a. Your firm began conducting in-house sterility testing in January 2021. Your firm was still conducting in-house sterility testing at the time of the inspection, but your sterility testing method(s) has not been validated to demonstrate that it can reliably and consistently detect the presence of viable contaminating microorganisms in your products. This also represents a failure to establish and document the accuracy, sensitivity, specificity, and reproducibility of test methods you employ, as required by 21 CFR 211.165(e).

b. The number of samples for sterility testing specified in your “Batch Record for (b)(4) WJ MSC-Derived Exosomes,” used to manufacture Invitra EX™, is not appropriate in that it does not consider the size and volume of the final product lot.

c. Your firm did not document performance or results of sterility testing of your products that was conducted in-house from January 2021 to March 2022.

4. Failure to establish written procedures for production and process control 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.

5. 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)]. For example, you have not established appropriate specifications and test procedures to assure that your products conform to appropriate standards of identity, strength, quality, and purity.

6. Failure to withhold from use each lot of components, drug product containers, and closures 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)]. For example, you failed to appropriately test or examine before release for use (b)(4) ((b)(4)) used in your products and the vials that contain the final product.

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 the appropriate storage conditions and expiration dates [21 CFR 211.166(a)]. For example, you have assigned two-year expiration dates to your exosome products without supporting data.

8. Failure to follow written procedures describing the handling of all written and oral complaints regarding a drug product [21 CFR 211.198(a)]. For example, you have not investigated complaints received related to your products, including complaints involving reports of adverse events, in accordance with your written procedures, SOP Q-QC-005, Adverse Events Evaluating and Reporting, Rev. 00, Ver. 00 (Effective Date 01/27/2021) and SOP Q-QA-006, Complaint Investigation, Rev. 1.0 (Effective Date 09/25/2019).

9. Failure to prepare batch production and control records for each batch of drug product produced that include complete information relating to the production and control of each batch, including documentation that each significant step in the manufacture, processing, packing, or holding of the batch was accomplished [21 CFR 211.188(b)]. For example:

a. You have not maintained batch production records for your in-process conditioned media or for your finished products, including Invitra UC-MSC and Invitra EV-OP, which are manufactured from human umbilical cord tissue.

b. You have not documented the identity of each batch of component or in-process material used, for example the in-process conditioned media used to manufacture your products.

10. Equipment used in the manufacture, processing, packing or holding of drug products is not of appropriate design to facilitate operations for its intended use [21 CFR 211.63]. For example, incubators used for sterility testing have not been qualified for that use.

We also note that some of the written procedures collected during the inspection that your firm uses to manufacture Invitra UC-MSC™, Invitra EX™, and Invitra EV-OP™ were identified as “draft.” Your response to this letter should include copies of any revised procedures along with documentation of their implementation.

During the inspection, FDA investigators documented that you continued to manufacture and distribute products regulated as drugs and biological products without an approved BLA or an IND in effect for those products (Invitra CBSC Suspension™, Invitra WJ-C™, Invitra WJ-Acellular, Invitra A™, and Invitra AF™) until December 2020, after FDA issued a Warning Letter to your firm in March 2020, notifying you that because those products were not the subject of an approved BLA and because there was not an IND in effect for them, your actions violated the FD&C Act and the PHS Act. The March 2020 Warning Letter also detailed your CGMP violations in the manufacture of those products.

FDA’s March 2020 Warning Letter also notified you that, as a general matter, exosome products intended to treat diseases or conditions in humans are regulated as drugs and biological products and are subject to premarket review and approval requirements. After FDA brought this to your attention, you continued to manufacture and distribute exosome products, including Invitra EX™, and you started manufacturing another exosome product, Invitra EV-OP.

We acknowledge receipt of your correspondence, dated April 25, 2022, responding to FDA’s inspectional observations on the FDA-483. We have reviewed the corrective actions outlined in the response and determined that the response is inadequate. You state that you have, “suspended all manufacture of all clinical drug substance and drug product batches at the 20503 Crescent Bay Drive, Lake Forest California facility intended for use in domestic clinical trials.” It is unclear from this statement whether you have suspended manufacture of all products identified in the FDA-483. Further, it is unclear, based on your response, whether you will manufacture your products at any of your other locations for distribution. Your response also describes “interim control[s]” you plan to implement prior to completing certain corrective actions, which suggests that Invitrx will resume manufacturing prior to adequately addressing the existing deficiencies.

Additionally, we cannot fully assess the adequacy of your responses to many of the observations because they do not provide sufficient detail on the corrective actions you state that you have implemented, lack a timeline for completion of all necessary corrective actions, and fail to provide supporting documentation for your planned corrective actions.

Your response also does not adequately address the failure to have an IND in effect for clinical investigations of your products and 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, 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].

We acknowledge that, in your response, you commit to recall distributed product within expiry after performing a risk assessment. Your response to this letter should include the outcome of this assessment and any subsequent actions.

Finally, during the inspection, your firm described certain products that it manufactures to the FDA investigators as intended for autologous use. However, based on the information obtained during the inspection and included in your correspondence regarding the FDA-483, including information on the customers to whom you are distributing, it is unclear whether these products are also intended for allogeneic use in a first-degree or second-degree blood relative. Please clarify the intended use of these 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.

For further information about IND requirements, please contact the Center for Biologics Evaluation and Research (CBER), Division of Regulatory Project Management, Office of Tissues and Advanced Therapies, at (240) 402-8190, or OTATRPMS@fda.hhs.gov. Please include a copy of this letter with your initial submission to CBER.

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 and explain your rationale for your continued manufacture and distribution of products that were the subject of FDA’s March 2020 Warning Letter. We also request that you clarify whether you will continue manufacturing at any of your other locations under the “interim control[s]” described in your response prior to completing all planned corrective actions.

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. If you cannot address these matters completely within fifteen (15) working days, please explain the reason for your delay and the timeframe for completion.

We also request your attendance at a Regulatory Meeting to discuss the status of the specific steps you have taken since the inspection to address any violations. We will host the meeting at the FDA Lost Angeles District Office located at 19701 Fairchild, Irvine, CA 92612 on either Tuesday, December 13, 2022, from 9:00am to 10:00am Pacific Time or Wednesday, December 14, 2022, from 10:00am to 11:00am Pacific Time. This meeting will allow you to ask questions and provide FDA with additional information regarding the implementation of your corrective actions. Please contact Amy Graf, Compliance Officer, using the information below, date preference by Tuesday, November 15, 2022. Please provide a list of attendees with title and company name, if other than Invitrx, as well as a list of any questions to ensure the appropriate FDA parties are in attendance, by Wednesday, November 30, 2022.

Your response should be emailed to Amy.Graf@fda.hhs.gov or sent to the following address: Amy Graf, U.S. Food & Drug Administration, Office of Biological Product Operations – Division 2, 300 River Place Drive, Suite 5900, Detroit, MI 48207. If you have any questions, please contact Amy Graf, Compliance Officer at (313) 393-2034 or via e-mail.

Sincerely,
/S/

Karlton T. Watson
Program Division Director
Office of Biological Products Operations – Division 2

cc:
(b)(4)

______________________

1 Invitrx manufactures human umbilical cord derived cellular products for (b)(4), branded as (b)(4), and (b)(4), branded as (b)(4), using the same manufacturing process used for Invitra UC-MSCTM.

Invitrx manufactures exosome products for (b)(4), branded as (b)(4), and (b)(4), branded as (b)(4), using the same manufacturing process used for Invitra EXTM.

 
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