---

---

---

WARNING LETTER
WL # 659142

July 26, 2023

Dear Dr. Flanigan:

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 January 31, 2014, and most recently on November 22, 2022. From March 21 to April 26, 2022, FDA investigators inspected your facility, US Specialty Formulations LLC, located at 1401 S Albert St, Allentown, PA 18103. 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 intended or expected to be sterile, which put patients at risk.

FDA issued a Form FDA 483 to your facility on April 26, 2022. FDA acknowledges receipt of your facility’s response, dated May 17, 2022, as well as subsequent correspondences. We acknowledge that on May 24, 2022, your firm initiated voluntary recalls of certain drug products intended or expected to be sterile, that were within expiry, due to a lack of sterility assurance. 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

In addition, for a compounded drug product to qualify for the exemptions under section 503B, the labeling of the drug must include certain information (section 503B(a)(10) of the FDCA [21 U.S.C. §353b(a)(10)]).

Furthermore, 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 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’s drug products, for example B-Complex plus Chromic Chloride 30 mL, did not include the following information on the label: the dosage form as required by section 503B(a)(10)(A)(iii) of the FDCA. Furthermore, your facility’s drug products, for example Sarracenia Purpurea 0.17 g/mL, did not include the following information on the label: a list of active and inactive ingredients identified by established name and the quantity or proportion of each ingredient as required by section 503B(a)(10)(A)(iii)(X) of the FDCA.

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.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; (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; (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; and (4) do not provide that adverse events should be reported utilizing FDA’s Safety Reporting Portal (SRP) or Electronic Submission Gateway (ESG).

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 firm used non-sterile wipes within the ISO 5 aseptic processing area. For example:
    a. Prior to production, non-sterile wipes were used to sanitize surfaces within the ISO 5 aseptic processing area.
    b. In preparation for production while removing air from the filling tubing, non-sterile wipes were used to wipe discarded drug product from the (b)(4).
    c. During production, the filling tubing and barbed fitting (used as a filling nozzle) were placed on non-sterile wipes.

2. An operator blocked first air by placing their gloved hands directly over open sterile containers.

3. 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.

4. Your firm did not disinfect materials during transfer from the ISO 7 cleanroom into the ISO 5 hood. For example:
    a. Your filling technician working within your ISO 5 aseptic processing area received vials and stoppers in the ISO 7 buffer room from a support technician who wore non-sterile exam gloves and performed a wipe down of those same components with non-sterile wipes.

5. An operator rested their fingertips on the work surface of the hood during aseptic production. These practices may introduce contamination into the ISO 5 work area. For example:
    a. Your filling technician did not re-sanitize their sterile gloves between resting fingertips on the ISO 5 work surface during pauses in filling operations and rotating trays of finished drug product vials during filling operations.

6. You did not perform adequate product evaluation and take appropriate corrective action after microbial contamination was recovered within the ISO 5 aseptic processing area.

FDA investigators also noted CGMP violations at your facility, that caused your drug product(s) 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 an adequate air supply filtered through high-efficiency particulate air filters under positive pressure in the aseptic processing areas (21 CFR 211.42(c)(10)(iii)).

2. 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)).

3. Your firm failed to establish an adequate system for cleaning and disinfecting the room and equipment to produce aseptic conditions (21 CFR 211.42(c)(10)(v)).

4. Your firm failed to have buildings used in the manufacture, processing, packing, or holding of drug products of a suitable size, construction, and location to facilitate cleaning, maintenance, and proper operations (21 CFR 211.42(a)).

5. Your firm failed to conduct laboratory testing to determine whether each batch of drug product purporting to be sterile and pyrogen-free conforms to such requirements (21 CFR 211.167(a)).

6. Your firm failed to ensure that manufacturing personnel wear clothing appropriate to protect drug product from contamination (21 CFR 211.28(a)).

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

8. 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).

9. Your firm failed to have, for each batch of drug product, appropriate laboratory determination of satisfactory conformance to final specifications for the drug product, including the identity and strength of each active ingredient, prior to release (21 CFR 211.165(a)).

10. Your firm failed to follow required laboratory control mechanisms (21 CFR 211.160(a)).

11. Your firm failed to establish an adequate written testing program designed to assess the stability characteristics of drug products and to use results of stability testing to determine appropriate storage conditions and expiration dates (21 CFR 211.166(a)).

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 also 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.

D. Corrective Actions

We have reviewed your facility’s responses to the Form FDA 483. We acknowledge that on May 24, 2022, your firm initiated voluntary recalls of certain drug products intended or expected to be sterile, that were within expiry, due to a lack of sterility assurance.

We are unable to fully evaluate some of your corrective actions due to lack of adequate supporting documentation:

1. We acknowledge your commitment to (b)(4) supplies that are used in the BSC to ensure the (b)(4) is opened just outside the BSC. Nevertheless, we have not received a commitment from you requiring sterile glove use within the ISO 7 cleanroom. It is possible that contaminants can be introduced into the ISO 5 environment from the handling of equipment and supplies with non-sterile exam gloves. Furthermore, you did not provide a sterility validation report from (b)(4) for the specific lot number of (b)(4) in question. Neither the certificate of quality, nor the technical specification sheet confirms the wipe lot’s sterility. Without a validation report or another document that affirms sterility, the question of whether the wipes are sterile remains unanswered.

2. We acknowledge that you have updated your Environmental Monitoring Program SOP to adjust the action limits; however, you did not provide updated EM/PM SOP training documentation. Furthermore, an updated QA-0003 non-conformance procedure that prevents a batch from being released with an open nonconformance was not provided.

3. Concerning the July 2021 sitewide power failure investigation, we acknowledge that you have updated SOPs; however, you did not provide documentation to confirm total particulate count, temp, humidity, and pressure differential readings were within specification and verified as such prior to recommencing manufacturing.

4. Regarding the white fibers in vials failure investigation, we acknowledge that you affirmed the white fibers came from your vial supplier who purportedly investigated this nonconformance; however, details regarding the investigation and/or the findings of the investigation were not provided. Furthermore, no preventative actions were provided.

Some of your corrective actions appear deficient:

1. The technique your technician displayed in the FDA 483 response smoke study video is inadequate. The filling movement over open vials is from (b)(4) as stated in your response, however, instead of leading with the filling nozzle, your technician leads with their hand, blocking the first-pass air above multiple open vials in the process. Furthermore, you did not address in your FDA 483 response the filling technician potentially contaminating their sterile gloves by touching the BSC work surface. There is potential for product impact, especially when the technician’s hands and fingers contact the ISO 5 work surface and later block first pass air during filling operations.

2. We acknowledge that you have some of the elements required to validate (b)(4); however, you have not provided documentation of a comprehensive validation study for your parametric release process, including, but not limited to: 1) process understanding, 2) process control, and 3) parametric release documentation (as described in the Guidance for Industry: Submission of Documentation of Applications for Parametric Release of Human and Veterinary Drug Products Terminally Sterilized by Moist Heat Processes).

3. We acknowledge that your (b)(4) performance verification appears to address concerns regarding the (b)(4) and sufficient (b)(4) to the (b)(4) prepared for vial filling operations; however, it does not address the interior drug product contact surface of filling tubing sets used for (b)(4) aseptic filling drug products. Your (b)(4) were placed outside the loop of coiled tubing, instead of inside the tubing.

4. Concerning foreign material found on caps used to seal vials: neither a root cause nor an evaluation was made to identify the foreign material, determine if it originated at the vendor or at (b)(4), examine other lots of caps from the same vendor or other products in which this implicated lot may have been used, and generate controls/CAPA to prevent recurrence.

5. We acknowledge the receipt of your assay method for medroxyprogesterone; however, you have not provided evidence to show that your (b)(4) method is equivalent or better than the compendial method established in the current USP.

6. Concerning the Sarracenia Purpurea 0.17 g/mL for injection drug product, you have neither identified nor provided evidence of the active pharmaceutical ingredient’s strength by a method that is highly specific and uses a reference standard. Furthermore, without being able to identify or establish the strength of the drug product, you cannot incorporate stability-indicating test methods that are reliable, meaningful, and specific that support its 18-month expiration date.

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: The revised labels you submitted contain the dosage form as required by section 503B(a)(10)(A)(iii) of the FDCA. However, you did not address certain other issues related to the conditions of section 503B of the FDCA. More specifically, you did not submit a corrective action with respect to your labels lacking a list of active and inactive ingredients identified by established name and the quantity or proportion of each ingredient as required by section 503B(a)(10)(A)(X) of the FDCA.

Furthermore, you did not address certain issues related to the conditions of section 503B of the FDCA. More specifically, you did not provide the agency with a revised procedure for reporting adverse events.

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.

Send your electronic reply to ORAPHARM1_RESPONSES@fda.hhs.gov. Your written notification should refer to Warning Letter #659142 and include FEI: 3010680515.

If you have questions regarding the contents of this letter, please contact CAPT Liatte Closs, Compliance Officer, at Liatte.Closs@fda.hhs.gov and courtesy copy ORAPHARM1_Responses@fda.hhs.gov.

Sincerely,
/S/

Lisa Harlan
Program Division Director
Division of Pharmaceutical Quality Operations I

______________________

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 Act, [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).