- Delivery Method:
- VIA UNITED PARCEL SERVICE SIGNATURE REQUIRED
- Reference #:
- 23-662942
- Product:
- Biologics
- Recipient:
-
Recipient Name
Joseph H. Capper
-
Recipient Title
Chief Executive Officer
- MiMedx Group, Inc.
1775 W Oak Commons Court NE
Marietta, GA 30062
United States
- Issuing Office:
- Center for Biologics Evaluation and Research (CBER)
United States
Secondary Issuing Offices
WARNING LETTER
December 20, 2023
23-662942
Dear Mr. Capper:
During inspections of your MiMedx Group, Inc. (hereinafter, “MiMedx”) locations at 300 Town Park Dr NW Ste 260, Kennesaw, GA 30144, and 1775 W Oak Commons Court NE, Marietta, GA 30062, conducted between February 22, 2023 and March 2, 2023, the United States Food and Drug Administration (FDA) documented your manufacture of a product derived from the placenta, AXIOFILL™, which you also refer to as “Placental Collagen Matrix” (hereinafter, “your product” or “your Placental Collagen Matrix product”). You have distributed your product directly to healthcare professionals and medical facilities throughout the United States. Your product is applied topically (for example, to “deep, irregular wounds”) and purports to be sterile.
Information and records gathered prior to, during, and after the inspections, including information on your website, www.mimedx.com, reflect that your product is intended for use in the diagnosis, cure, mitigation, treatment, or prevention of disease or a condition in humans. For example, according to your product labeling, AXIOFILL™ is intended “[for] use in the replacement or supplementation of damaged or inadequate integumental tissue.” Clinical use examples referenced on your website include “trauma wounds,” “diabetic foot ulcers,” and “deep, irregular wounds.” Your product is a drug as defined in section 201(g)(1)(B) of the Federal Food, Drug, and Cosmetic Act (FD&C Act) [21 U.S.C. § 321(g)(1)(B)]. Additionally, your 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)].
Your 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), 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.
Based on a review of relevant materials, MiMedx 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). Specifically, your product at minimum 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 placenta related to its utility for reconstruction, repair, or replacement.1 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.
To lawfully market a drug that is a biological product, a valid biologics license application (BLA) 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]. Your product, AXIOFILL™, is not the subject of an approved BLA nor is there an IND in effect for this product. Based upon this information, we have determined that 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) requirements related to your manufacture of AXIOFILL™, including deviations from 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. We note that, at the time of the inspection, you had already manufactured over (b)(4) vials of AXIOFILL™ and distributed (b)(4) vials of AXIOFILL™ since September 2022.
At the conclusion of the inspection, FDA investigators issued a Form FDA-483, List of Inspectional Observations, describing significant deviations applicable to AXIOFILL™ operations at your Town Park facility. FDA identified additional significant deviations upon further review of the information collected during this inspection, as discussed below. These deviations include, but are not limited to, the following:
1. Your firm failed to establish adequate written procedures for production and process control designed to assure that the drug product has the identity, strength, purity, and quality it purports or is represented to possess [21 CFR 211.100(a)]. Specifically, your firm has manufactured and distributed AXIOFILL™ without establishing adequate written procedures to assure that your process is capable of consistently producing product that meets appropriate attributes relating to identity, quality, and purity. Namely, your written protocol, reflected in your Process Performance Qualification Report for Placental Collagen Matrix (PCM) (dated 2/20/23),is deficient in that there is no assessment of AXIOFILL™ identity, you have failed to identify tests to assess product quality, and your testing for purity is incomplete.2
Process validation studies determine whether an initial state of control has been established while routine monitoring of process performance and product attributes determines whether control is maintained. Establishment of appropriate attributes relating to identity, quality, and purity of drug products is essential for assuring product quality over the product lifecycle.
2. Your firm failed 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)]. Specifically, your firm has not established laboratory controls that include appropriate final specifications for testing and release of AXIOFILL™ to assure that each batch conforms to appropriate standards of identity and purity during routine production.
3. In-process control procedures are deficient in that your control procedures do not include bioburden testing [21 CFR 211.110(a)(6)]. According to your Process Performance Qualification Report for Placental Collagen Matrix (PCM) (effective 2/20/23), your firm removed (b)(4) bioburden testing from routine commercial production of AXIOFILL™ after completing “validation production.” Your product is (b)(4) sterilized. In-process bioburden testing is critical for assuring that bioburden levels do not exceed the validated sterility assurance level (SAL).
4. Drug product samples are not representative of the entire batch [21 CFR 211.160(b)(3)]. For example, samples of AXIOFILL™ tested for residual moisture as a measure of purity per your finished product specification are not representative of the entire batch. According to CSOP220.116, Product Visual Inspection (revision 54, effective 12/09/22), only (b)(4) of each lot of your Placental Collagen Matrix product is collected for residual moisture testing. There are no considerations for batch size. This is not representative because, when products are lyophilized,moisture content can vary across the lot.
5. Your firm has failed to conduct at least one test to verify the identity of each component of a drug product using specific identity tests, if they exist [21 CFR 211.84(d)(1)]. Specifically, your firm does not perform at least one test to verify the identity of each lot of “Placental Collagen Matrix (PCM) (b)(4)” using the specific identity test that exists. Although your firm indicated that the test used to determine the concentration of PCM (b)(4) is considered an identity test, only concentration results and not identity are reported to you by the contract laboratory. PCM (b)(4) is used to manufacture AXIOFILL™.
6. Your firm failed to withhold each lot of components from use until the lot has been sampled, tested, or examined, as appropriate, and released for use by the quality control unit. Your firm further failed to take representative samples of each shipment of each lot of components for testing or examination [21 CFR 211.84(a) and 21 CFR 211.84(b)].Specifically, your firm failed to withhold each lot of PCM (b)(4) from use in AXIOFILL™ processing until the lot had been tested to assure compliance with your specification and released for use by your quality unit. According to your PCM (b)(4) specification, SPC300.034 (effective8/24/22), results of “composition” testing (also referred to as “concentration analysis”) are not required for release. Although your specification requires an investigation if results are failing, this procedure allows your use of components whose testing has not been reviewed prior to release, which creates the potential for your use of noncomplying components in drug processing. Additionally, according to this same specification, only (b)(4) from each PCM (b)(4) lot received is collected for concentration analysis. Sampling is not based on the lot size, which fails to ensure that samples are representative of each lot.
Additionally, with respect to your final specifications used for testing and release of AXIOFILL™, we have concerns that your firm has failed to include specifications for elemental impurities and endotoxin, although your firm has identified “elemental impurities from product surfaces” and endotoxin as critical quality attributes in your Process Performance Qualification Report for Placental Collagen Matrix (PCM) (effective 2/20/23).
We are also concerned that your firm did not provide a disinfectant efficacy study for (b)(4), used in your processing facility and on production equipment, during the inspection, although it was requested. 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.
We acknowledge receipt of your correspondences, dated March 23, 2023 and October 23, 2023, responding to FDA’s inspectional observations on the FDA-483 issued to your Town Park facility. We have reviewed your responses and have determined that your responses are inadequate to address the deficiencies noted above. We note that “MIMEDX does not agree that the CGMP requirements are legally applicable to AXIOFILL” and that your responses contain no corrective actions directly related to the FDA-483 observations.
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.
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.
Your response should be sent via email to: Jason D. Abel, Compliance Officer, U.S. Food and Drug Administration, Office of Biological Products Operations – Division 1, email address: Jason.Abel@fda.hhs.gov. If you have any questions, please contact Jason D. Abel via email.
Sincerely,
/S/
Michael W. Roosevelt
Program Division Director
Office of Biological Products Operations – Division I
_____________________
1 Because your product fails to meet the minimum manipulation criterion at 21 CFR 1271.10(a)(1), this letter does not further evaluate the other criteria in 21 CFR 1271.10(a).
2 Your Placental Collagen Matrix product specification indicates that your firm tests AXIOFILL™ for purity via residual moisture testing. However, purity is not limited to relative freedom from residual moisture. Refer to the definition of purity in 21 CFR 600.3(r). U.S. Food and Drug Administration Office of Biological Products Operations www.fda.gov
