Fagron Compounding Services, LLC dba Fagron Sterile Service

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 2, 2015, and most recently on October 18, 2024. From June 18 to June 28, 2024, an FDA investigator inspected your facility, Fagron Compounding Services, LLC dba Fagron Sterile Services, located at 8710 East 34th Street North, Wichita, KS 67226. During the inspection, the investigator collected evidence 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 investigator 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 June 28, 2024. FDA acknowledges receipt of your facility’s responses, dated July 19, 2024, August 30, 2024, September 27, 2024, and October 25, 2024. FDA further acknowledges that on August 15, 2024, your firm initiated a voluntary recall of four lots of Lidocaine HCl Injection, 2% due to lack of sterility assurance. Based on this inspection, it appears you produced drugs that violate 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)]).

During the inspection, the FDA investigator noted that drug products produced by your facility failed to meet the conditions of section 503B. For example, the investigator collected evidence of the following deficiencies with your facility’s drug product labels:

1. The drug product label did not include the dosage form. Examples include: Tropicamide 1%/Cyclopentolate 1%/Phenylephrine 2.5%/Ketorolac 0.5%, 5mL and Fentanyl Citrate 2mcg/mL (100mcg/50mL)/Ropivacaine HCl 0.15% (1.5mg/mL) (75mg/50mL).

2. The drug product label did not include the established name of the drug. Examples include: Tropicamide 1%/Cyclopentolate 1%/Phenylephrine 2.5%/Ketorolac 0.5%, 5mL; Sodium Citrate 4% (40mg/mL) containing Gentamicin 320mcg/mL Injection, 3mL, 5 mL, and 30 mL; and Epinephrine (1mg/mL), Sterile Solution for Injection.

3. The drug product label did not include a list of active ingredients identified by established name. Examples include: Tropicamide 1%/Cyclopentolate 1%/Phenylephrine 2.5%/Ketorolac 0.5%, 5mL; Sodium Citrate 4% (40mg/mL) containing Gentamicin 320mcg/mL Injection, 3mL, 5 mL, and 30 mL; and Epinephrine (1mg/mL), Sterile Solution for Injection.

Further, the investigator collected evidence of the following deficiencies with your facility’s container labels:

1. The container from which the individual units of the drug are removed for dispensing or for administration did not include directions for use, including, as appropriate, dosage and administration. Examples include: Epinephrine (1mg/mL), Sterile Solution for Injection; Phenol Injection 6% (60 mg/mL), in Sterile Water for Injection, 10 mL in Multi-Dose Vial; Sodium Citrate 4% (40mg/mL) containing Gentamicin 320mcg/mL Injection, 3mL, 5 mL, and 30 mL; and Dexamethasone Sodium Phosphate 10 mg/mL Solution for Injection, 2 mL in Multi-Dose Vial.

2. The container from which the individual units of the drug are removed for dispensing or for administration did not include a list of active ingredients identified by established name. Examples include: Tropicamide 1%/Cyclopentolate 1%/Phenylephrine 2.5%/Ketorolac 0.5%, 5mL; Sodium Citrate 4% (40mg/mL) containing Gentamicin 320mcg/mL Injection, 3mL, 5 mL, and 30 mL; and Epinephrine (1mg/mL), Sterile Solution for Injection.

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.

The FDA investigator 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 investigator observed that.

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

2. Your firm produced drug products while construction was underway without adequate controls to prevent contamination of the product environment and products.

The FDA investigator 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 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).

2. Your firm failed to maintain the buildings used in the manufacture, processing, packing, or holding of a drug product in a clean and sanitary condition (21 CFR 211.56(a)).

3. 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)).

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.

You do not have any FDA-approved applications on file for drug products that you compound.3 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.

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.4 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.

We have reviewed your facility’s responses to the Form FDA 483. We acknowledge your firm’s recall of four lots of Lidocaine HCl Injection, 2% due to lack of sterility assurance.

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. Pertaining to the Chaetomium globosum recovery referenced, you stated the operator “was in training at the time of the recovery.” The investigation into the recovery, DEV-2024-0174, states the operator, “was not fully trained” and “left unsupervised by a qualified trainer, which is a deviation” from procedure. Your firm identified this deviation after reviewing footage of batch (b)(4). However, upon discovering this deviation, your investigation did not expand to other lots produced or operations conducted by the “not fully trained” operator.

Some of your corrective actions appear deficient. You stated in your response, “For the personnel samples, the samples were taken after the completion of the (b)(4) process, prior to removal of waste and disinfection/sanitization of the ISO 5 hood and equipment. In review of the batch record, the operators for Succinylcholine lot (b)(4), Rocuronium lot (b)(4) and Lidocaine lot (b)(4) had performed staging, support and (b)(4) activities prior to taking the glove samples. This included sanitizing materials into the hood, removing filled bags, insertion of sterile needle into the bag ports and batch record documentation. None of these activities impacted the filling of the child batches as each child batch did not have a recovery and sterility testing for each passed.” We disagree with your assessment. The operator was involved in critical process parameters, including (b)(4) of the parent batch. This parent batch was used to fill four child batches. The child batches were not (b)(4). We acknowledge your recall of child batches of the parent lot: Lidocaine HCl 2%, Lot# (b)(4), within expiry on August 9, 2024.

Please note, microbial contamination, when present, is not uniformly distributed within a batch; therefore, it may not be identified in a sterility test. Compounding facilities producing drug products intended to be sterile under insanitary conditions should not rely upon or cite a passing sterility test result as an indication of product sterility.

We acknowledge your commitments in response to our concerns noted with your upcoming facility expansion. During the next FDA inspection, we will assess the potential impact of the upcoming planned construction activities on the quality of sterile drug products that were produced and distributed to patients.

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).]

In addition, regarding issues related to the conditions of section 503B of the FDCA, some of your corrective actions appear adequate: You have initiated CAPA-2024-0105 and CAPA-2024-0106 to address label issues concerning dosage form, established name of the drug and directions for use. However, no corrective actions have been provided to the agency to address label issues concerning a list of active ingredients identified by established name.

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.

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.

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 (#698861) and include a subject line that clearly identifies the submission as a Response to Warning Letter.