Annovex Pharma, Inc. - 698115 - 03/05/2025

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WARNING LETTER
WL # 698115

March 5, 2025

Dear Dr. Akinbi:

You registered your facility with the U.S. Food and Drug Administration (FDA) as an outsourcing facility under section 503B of the Federal Food, Drug, and Cosmetic Act (FDCA) [21 U.S.C. § 353b]¹ on October 14, 2021, and most recently on November 22, 2024. From August 26, 2024, to September 6, 2024, FDA investigators inspected your facility, Annovex Pharma, Inc. located at 7403 Lockport PI, Suite C-D, Lorton, VA 22079. During the inspection, the investigators noted that drug products you produced failed to meet the conditions of section 503B of the FDCA necessary for drugs produced by an outsourcing facility to qualify for exemptions from certain provisions of the FDCA. In addition, the investigators noted serious deficiencies in your practices for producing drug products which put patients at risk.

FDA issued a Form FDA 483 to your facility on September 6, 2024. FDA acknowledges receipt of your facility’s response, dated September 25, 2024, October 24, 2024, November 27, 2024, and December 27, 2024. Based on this inspection, it appears you produced drugs that violate the FDCA.

A. Compounded Drug Products under the FDCA

Under section 503B(b) of the FDCA, a compounder can register as an outsourcing facility with FDA. Drug products compounded by or under the direct supervision of a licensed pharmacist in an outsourcing facility qualify for exemptions from the drug approval requirements in section 505 of the FDCA [21 U.S.C. § 355(a)], the requirement in section 502(f)(1) of the FDCA [21 U.S.C. § 352(f)(1)] that labeling bear adequate directions for use and the Drug Supply Chain Security Act requirements in section 582 of the FDCA [21 U.S.C. § 360eee-1] if the conditions in section 503B of the FDCA are met.²

An outsourcing facility, which is defined in section 503B(d)(4) of the FDCA [21 U.S.C. § 353b(d)(4)], is a facility at one geographic location or address that — (i) is engaged in the compounding of sterile drugs; (ii) has elected to register as an outsourcing facility; and (iii) complies with all of the requirements of this section. Outsourcing facilities must comply with other applicable provisions of the FDCA, including section 501(a)(2)(B) [21 U.S.C. § 351(a)(2)(B)], regarding current good manufacturing practice (CGMP), and section 501(a)(2)(A) [21 U.S.C. § 351(a)(2)(A)], regarding insanitary conditions. Generally, CGMP requirements for the preparation of drug products are established in Title 21 of the Code of Federal Regulations (CFR) parts 210 and 211.

For a compounded drug product to qualify for the exemptions under section 503B, it must be compounded in an outsourcing facility that is in compliance with the registration and reporting requirements in section 503B(b), including the requirement to submit a report to FDA upon initially registering as an outsourcing facility, once in June of each year, and once in December of each year identifying the drug products compounded during the previous 6-month period (section 503B(b)(2) of the FDCA [21 U.S.C. §353b(b)(2)]) and the requirement to submit adverse event reports to FDA “in accordance with the content and format requirements established through guidance or regulation under section 310.305 of title 21, Code of Federal Regulations (or any successor regulations)” (section 503B(a)(1), (b)(5) of the FDCA [21 U.S.C. § 353b(a)(1), (b)(5)]).

B. Failure to Meet the Conditions of Section 503B

During the inspection, FDA investigators noted that drug products produced by your facility failed to meet the conditions of section 503B. For example, the investigators noted:

1. Your facility failed to submit a report to FDA in June 2024 identifying the drug products that you compounded during the previous 6-month period, including Heparin 4 units/mL in 0.9% Sodium Chloride (b)(4) IV bag, Phenylephrine 100 mcg/ml in 0.9% Sodium Chloride Solution 10ml syringe, and Phenylephrine HCl 25 mg in 0.9% Sodium Chloride 250 mL Bag.

2. Your facility did not submit adverse event reports to FDA in accordance with the content and format requirements established through guidance or regulation under section 310.305 of title 21, Code of Federal Regulations (or any successor regulations).³ Specifically, your facility’s procedures for reporting adverse events are inadequate. For example, your documented procedures for reporting adverse events (1) do not include a definition of what constitutes a “serious” and “unexpected” adverse event (21 CFR 310.305(b)); (2) do not include a requirement to report each adverse drug experience received or otherwise obtained that is both serious and unexpected as soon as possible, but in no case later than 15 calendar days of initial receipt of the information (21 CFR 310.305(c)(1)(i)); (3) do not include a requirement to promptly investigate and submit a follow-up report regarding a serious, unexpected adverse event within 15 calendar days of receipt of new information or as requested by FDA (21 CFR 310.305(c)(2)); (4) do not include a requirement that the firm investigate four data elements when an adverse event report is received – Identifiable Patient, Identifiable Reporter, Suspect Drug Product, Serious Adverse Event (21 CFR 310.305(d)); and (5) do not provide that adverse events should be reported utilizing FDA’s Safety Reporting Portal (SRP) or Electronic Submission Gateway (ESG) (21 CFR 310.305(e)).

Because your compounded drug products have not met all of the conditions of section 503B, they are not eligible for the exemptions in that section from the FDA approval requirements of section 505, the requirement under section 502(f)(1) that labeling bear adequate directions for use, and the Drug Supply Chain Security Act requirements described in section 582 of the FDCA.

Specific violations are described below.

C. Violations of the FDCA

Adulterated Drug Products

FDA investigators noted that drug products intended or expected to be sterile were prepared, packed, or held under insanitary conditions, whereby they may have become contaminated with filth or rendered injurious to health, causing your drug products to be adulterated under section 501(a)(2)(A) of the FDCA. For example, the investigators observed that:

1. Your media fills were not performed under the most challenging or stressful conditions. In addition, your firm continued to produce and distribute drug products intended to be sterile despite positive growth being identified in 10% of filled units during your January 2024 media fill. Your firm failed to investigate the positive growth and discarded all units that showed signs of microbial contamination. Therefore, there is a lack of assurance that your firm can aseptically produce drug products within your facility.

2. Your firm failed to perform adequate smoke studies under dynamic conditions to demonstrate unidirectional airflow within the ISO 5 area. Therefore, your products intended to be sterile are produced in an environment that may not provide adequate protection against the risk of contamination.

FDA investigators also noted CGMP violations at your facility, that caused your drug products to be adulterated within the meaning of section 501(a)(2)(B) of the FDCA. The violations include, for example:

1. Your firm failed to establish and follow appropriate written procedures that are designed to prevent microbiological contamination of drug products purporting to be sterile and that include validation of all aseptic and sterilization processes (21 CFR 211.113(b)).

2. Your firm failed to thoroughly investigate any unexplained discrepancy or failure of a batch or any of its components to meet any of its specifications, whether or not the batch has already been distributed (21 CFR 211.192).

3. Your firm failed to establish an adequate system for monitoring environmental conditions in aseptic processing areas (21 CFR 211.42(c)(10)(iv)).

4. Your firm failed to exercise appropriate controls over computer or related systems to assure that only authorized personnel institute changes in master production and control records, or other records (21 CFR 211.68(b)).

Outsourcing facilities must comply with CGMP requirements under section 501(a)(2)(B) of the FDCA. FDA’s regulations regarding CGMP requirements for the preparation of drug products have been established in 21 CFR parts 210 and 211. FDA intends to promulgate more specific CGMP regulations for outsourcing facilities. FDA has issued a revised draft guidance, Current Good Manufacturing Practice — Guidance for Human Drug Compounding Outsourcing Facilities under Section 503B of the FD&C Act. This draft guidance, when finalized, will describe FDA’s expectations regarding outsourcing facilities and the CGMP requirements in 21 CFR parts 210 and 211 until more specific CGMP regulations for outsourcing facilities are promulgated.

Under section 301(a) of the FDCA [21 U.S.C. § 331(a)], the introduction or delivery for introduction into interstate commerce of any drug that is adulterated is a prohibited act. Further, it is a prohibited act under section 301(k) of the FDCA [21 U.S.C. § 331(k)] to do any act with respect to a drug, if such act is done while the drug is held for sale after shipment in interstate commerce and results in the drug being adulterated.

Unapproved New Drug Products

You do not have any FDA-approved applications on file for drug products that you compound.⁴ Under sections 505(a) and 301(d) of the FDCA [21 U.S.C. §§ 331(d)] a new drug may not be introduced into or delivered for introduction into interstate commerce unless an application approved by FDA under section 505 of the FDCA is in effect for the drug. Marketing of these products, or other applicable products, without an approved application violates these provisions of the FDCA.

Misbranded Drug Products

You compound drug products that are intended for conditions not amenable to self-diagnosis and treatment by individuals who are not medical practitioners; therefore, adequate directions for use cannot be written so that a layman can use these products safely for their intended uses. Consequently, their labeling fails to bear adequate directions for their intended uses causing them to be misbranded under section 502(f)(1) of the FDCA.⁵ The introduction or delivery for introduction into interstate commerce of these products therefore violates section 301(a) of the FDCA. Further, it is also a prohibited act under section 301(k) of the FDCA to do any act with respect to a drug, if such act is done while the drug is held for sale after shipment in interstate commerce and results in the drug being misbranded.

Failure to Report Drugs

As noted above, your facility failed to submit a report to FDA in June 2024 identifying the drug products that you compounded during the previous 6-month period (section 503B(b)(2) of the FDCA). The failure to report drugs by an entity that is registered with FDA in accordance with section 503B(b) is a prohibited act under section 301(ccc)(3) of the FDCA [21 U.S.C. § 331(ccc)(3)].

D. Corrective Actions

We have reviewed your facility’s responses to the Form FDA 483.

Some of your corrective actions appear adequate; however, we cannot fully evaluate the adequacy of the following corrective actions due to lack of adequate supporting documentation: Regarding your smoke studies, we acknowledge your commitments, including your plan to perform updated dynamic smoke studies during your (b)(4) cleanroom certification; however, you have not provided sufficient supporting documentation for our review, such as your smoke study protocol.

Some of your corrective actions appear deficient:

1. Regarding your media fills, we acknowledge your commitments going forward and the revised procedures provided in your responses. However, we remain concerned with your firm’s failure to investigate the positive growth observed during your January 2024 media fill simulation. Any contaminated unit should be considered objectionable and investigated. The investigation should survey the possible causes of contamination and should assess the impact of products produced since the last successful media fill.

In addition, your responses do not include data to adequately demonstrate a consistent ability to maintain aseptic operating conditions. During your latest media fill simulation, conducted in July 2024, you did not incubate all (b)(4) units, but instead only incubated (b)(4) randomly selected units. Your firm has provided no evidence that you have successfully performed additional media fill runs to ensure your aseptic processing operation is validated and your firm continues to produce via aseptic processing and distribute drug products intended to be sterile.

2. Regarding your firm’s failure to provide our investigators with your 2023 media fill records due to technical issues, you provided a new procedure, SOP-0261 Retention of Records, which details document retention requirements; however, this procedure does not specify how and where documents will be retained or how these retained documents will be controlled. We acknowledge your statement that you have purchased a dedicated secure server system and that you have hired a validation consult to complete installation, operational, and performance qualification; however, you have not provided details on how you are currently retaining and securing documents while waiting for the server to be qualified. Complete and accurate records are necessary to ensure that manufacturing processes are consistently followed and reproducible. Additionally, incomplete manufacturing records deprive you of the ability to reliably conduct batch record review, adequately investigate deviations and batch failures, and to ensure a continued state of validation processes.

3. Your firm provided several updated written procedures with your responses; however, they appear to be in draft form as the approval signature manifests are incomplete. Therefore, the effective date of these revised procedures cannot be verified.

In addition to the issues discussed above, you should note that CGMP requires the implementation of quality oversight and controls over the manufacture of drugs, including the safety of raw materials, materials used in drug manufacturing, and finished drug products. See section 501 of the FDCA. If you choose to contract with a laboratory to perform some functions required by CGMP, it is essential that you select a qualified contractor and that you maintain sufficient oversight of the contractor’s operations to ensure that it is fully CGMP compliant. Regardless of whether you rely on a contract facility, you are responsible for assuring that drugs you produce are neither adulterated nor misbranded. [See 21 CFR 210.1(b), 21 CFR 200.10(b).]

Regarding issues related to the conditions of section 503B of the FDCA, some of your corrective actions appear adequate: You state that you are “implementing improved tracking and reporting systems to ensure that all compounded products are accurately and timely reported in future submissions.”

In addition, regarding issues related to the conditions of section 503B of the FDCA, some of your corrective actions appear deficient: Your revised procedures for reporting adverse event reporting do not adequately address adverse event reporting. For example, your revised procedures do not include a requirement to promptly investigate and submit a follow-up report regarding a serious, unexpected adverse event within 15 calendar days of receipt of new information or as requested by FDA.

Should you continue to compound and distribute drug products that do not meet the conditions of section 503B, the compounding and distribution of your drugs would be subject to the new drug approval requirement, the requirement to label drug products with adequate directions for use, and the Drug Supply Chain Security Act requirements.

FDA strongly recommends that your management undertake a comprehensive assessment of operations, including facility design, procedures, personnel, processes, maintenance, materials, and systems. In particular, this review should assess your aseptic processing operations. A third party consultant with relevant sterile drug manufacturing expertise should assist you in conducting this comprehensive evaluation.

E. Conclusion

The violations cited in this letter are not intended to be an all-inclusive statement of violations at your facility. 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 that your firm complies with all requirements of federal law, including FDA regulations.

You should take prompt action to address any violations. Failure to adequately address any violations may result in legal action without further notice, including, without limitation, seizure and injunction.

Within fifteen (15) working days of receipt of this letter, please notify this office in writing of the specific steps that you have taken to address any violations. Please include an explanation of each step being taken to prevent the recurrence of violations, as well as copies of related documentation. This letter notifies you of our concerns and provides you an opportunity to address them. If you believe your products are not in violation of the FDCA, include your reasoning and any supporting information for our consideration. If you cannot completely address this matter within fifteen (15) working days, state the reason for the delay and the time within which you will do so.

Your response and any questions regarding the contents of this letter should be sent to compoundinginspections@fda.hhs.gov. In your response, refer to the Warning Letter Number above (# 698115) and include a subject line that clearly identifies the submission as a Response to Warning Letter.

Sincerely,
/S/

F. Gail Bormel, JD, RPh
Director
Office of Compounding Quality and Compliance
Office of Compliance
Center for Drug Evaluation and Research

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1 See Pub. L. No. 113-54, § 102(a), 127 Stat. 587, 587-588 (2013).

2 We remind you that there are conditions, other than those discussed in this letter, that must be satisfied to qualify for the exemptions in section 503B of the FDCA.

3 For more information, see, FDA’s guidance, “Adverse Event Reporting for Outsourcing Facilities Under Section 503B of the Federal Food, Drug, and Cosmetic Act,” which can be found at https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM434188.pdf.

4 The specific products made by your firm are drugs within the meaning of section 201(g) of the FDCA [21 U.S.C. § 321(g)] because they are intended for use in the diagnosis, cure, mitigation, treatment, or prevention of diseases and/or because they are intended to affect the structure or any function of the body. Further, they are “new drugs” within the meaning of section 201(p) of the FDCA [21 U.S.C. § 321(p)] because they are not generally recognized as safe and effective for their labeled uses.

5 Your compounded drug products are not exempted from the requirements of section 502(f)(1) of the FDCA by regulations issued by the FDA (see, e.g., 21 CFR 201.115).