BRS Analytical Services, LLC

The United States Food and Drug Administration (FDA) inspected your drug manufacturing facility and contract testing laboratory, BRS Analytical Services, LLC, FEI 3023604380, at 11697 Lakeside Crossing Court, St. Louis, from March 10 to 26, 2025.

This warning letter summarizes significant violations of Current Good Manufacturing Practice (CGMP) regulations for finished pharmaceuticals. See Title 21 Code of Federal Regulations (CFR), parts 210 and 211 (21 CFR parts 210 and 211).

Because your methods, facilities, or controls for manufacturing, processing, packing, or holding do not conform to CGMP, your drug products are adulterated within the meaning of section 501(a)(2)(B) of the Federal Food, Drug, and Cosmetic Act (FD&C Act), 21 U.S.C. 351(a)(2)(B).

We reviewed your April 14, 2025 response to our Form FDA 483 in detail and acknowledge receipt of your subsequent correspondence.

During our inspection, our investigators observed specific violations including, but not limited to, the following.

1. Your firm failed to perform operations within specifically defined areas of adequate size and to have separate or defined areas or such other control systems necessary to prevent contamination or mix-ups in aseptic processing areas. Your firm also failed to use equipment in the manufacture, processing, packing, or holding of drug products that is of appropriate design, adequate size, and suitably located to facilitate operations for its intended use and for its cleaning and maintenance (21 CFR 211.42(c)(10) and 211.63).

Cleanroom Design

Your ISO 5 area used for aseptic compounding and filling sterile over-the-counter (OTC) (b)(4) drug products was fundamentally unsuitable for its intended use. For example, your ISO 5 area had gaps in the wall intended to separate it from the immediately surrounding unclassified warehouse, including large gaps between most wall sections and the floor. Some of these gaps contained mesh screens that appeared to be dirty. Furthermore, you failed to maintain an adequate differential pressure between the ISO 5 area and the warehouse, and did not continuously monitor that pressure. The lack of both physical and aerodynamic segregation in your aseptic processing facility design posed an unacceptable risk to product sterility.

The ISO 5 area is critical because sterile drug products are exposed and are therefore vulnerable to contamination. Your aseptic manufacturing facility, equipment, and process must be designed, and operations must be executed, to minimize contamination hazards to your sterile drug product. The unacceptable design of your operation precluded the ability to maintain asepsis.

Environmental Monitoring

You failed to establish an adequate system for monitoring environmental conditions. For example, you did not routinely perform viable air monitoring during production, despite a procedural requirement to do so. In addition, your nonviable particle monitor was placed on top of the enclosed cabinet in which filling occurred instead of inside it, rendering the resulting data non-representative of the environmental conditions near the areas of critical exposure on the aseptic processing line. Finally, you failed to routinely review environmental monitoring data prior to batch release.

Vigilant and responsive environmental and personnel monitoring programs provide meaningful information on the state of control of the aseptic processing operation, and enable an early warning system that identifies emerging contamination hazards before sterility is compromised. Operations that include highly (b)(4) intensive aseptic activities warrant a more extensive environmental and personnel monitoring program, including but not limited to an emphasis on increased sampling that monitors ongoing batch production conditions more extensively.

Facility Maintenance Deficiencies

During the inspection, we observed your facility to be in a state of disrepair or unclean in several instances. This includes, but is not limited to, the following deficiencies within your aseptic processing room:

• Discoloration and apparent residue on light panels above the aseptic filling equipment during operations.• Chipped paint on a floor scale.• Discoloration on the (b)(4) sterilizer and a table.

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)).

Poor Aseptic Behavior

We observed poor practices in ISO 5 areas during your (b)(4) intensive aseptic processing of sterile (b)(4) drug products, including but not limited to:

• Operators blocked unidirectional airflow during routine production by placing their gloved hands and hooded, masked heads directly over open sterilized bottles.• The skin surrounding operators’ safety glasses was exposed in the ISO 5 area.• Use of nonsterile face masks.• Use of nonsterile paper towels in the ISO 5 area, including inside the filling cabinet.• Failure to seal a vessel containing sterile drug product. Instead of a securely fitted cap, you used an (b)(4) intended to cover an open port in the sterile (b)(4) holding tank in the ISO 5 area during the filling process, which was typically run for (b)(4) days and did not include additional sterilizing (b)(4). In addition, our investigators observed condensation inside the (b)(4), as well as air gaps that provided an avenue for ingress of (b)(4) air.

Inadequate Media Fill Program

Your media fills failed to accurately simulate commercial operations. You only incubated approximately (b)(4) of units for each media fill, rather than (b)(4) units. In contrast, your protocols required (b)(4) units that passed inspection to be incubated. In addition, each media fill lasted only approximately (b)(4) or less, although your commercial aseptic filling operations typically lasted (b)(4) days.

It is essential that (b)(4) media fill units be incubated and examined for evidence of microbial contamination. Also, to accurately simulate contamination risks, the duration of the process simulation for (b)(4) intensive lines normally should be no less than the length of the actual manufacturing process.

Inadequate Assurance of Sterilization

• The validation of the (b)(4) sterilization process used to sterilize direct product contact parts, including transfer hoses and sterilizing (b)(4), was inadequate. For example, the (b)(4) sterilization validation process did not include the use of biological indicators. Instead, (b)(4) water was placed in jars and tested for sterility. Notably, one of these jars of water tested positive for growth, but you did not conduct an investigation.• Sterilizing (b)(4) were not integrity tested for each batch of drug products manufactured.

It is essential that product contact equipment is sterile to be suitable for its intended use. Sterilization cycle validation is established through studies that incorporate rigorous physical and biological measurements. Between uses, sterile equipment must be held under ISO 5 conditions and continuously maintained in a manner that prevents contamination.

Inadequate Smoke Study

Your smoke study did not adequately demonstrate unidirectional air flow in the ISO 5 area that was used for the aseptic filling of (b)(4) drug products. For example:

• Your smoke study did not evaluate unidirectionality. Instead, you turned off the HEPA-(b)(4) fans, filled the ISO 5 area with smoke, then turned the fans on and verified that the room was cleared of smoke.• You failed to conduct a smoke study with your actual filling equipment present.• Your smoke study was not conducted under dynamic conditions.

3. Your firm’s quality control unit failed to exercise its responsibility to ensure drug products manufactured are in compliance with CGMP, and meet established specifications for identity, strength, quality, and purity (21 CFR 211.22)

Your quality unit (QU) failed to maintain adequate CGMP oversight and allowed the distribution of sterile (b)(4) drug products manufactured under unacceptable conditions, which included poorly designed facilities, an unsuitable aseptic manufacturing process, and deficient environmental monitoring. You also failed to ensure implementation of an effective qualification and validation program, and perform adequate antimicrobial effectiveness studies for your multi-dose aqueous-based sterile (b)(4) drug products.

In addition, you failed to ensure that adequate procedures were followed describing the roles and responsibilities of the QU including, but not limited to, raw material supplier qualification.

Significant findings in this letter indicate that your QU was not fully exercising its authority or responsibility. Your firm must provide the QU with the appropriate authority and sufficient resources to carry out its responsibilities and consistently ensure drug quality.

On April 17, 2025, FDA held a teleconference with you recommending that you remove from the U.S. market all batches of (b)(4) drug products currently in distribution. On April 21, 2025, you committed to ceasing the manufacture and distribution of all (b)(4) drug products and agreed to a voluntary recall of all (b)(4) drug products currently in distribution in the U.S. On April 23, 2025, you issued a voluntary recall of all (b)(4) drug products due to CGMP deviations and lack of assurance of sterility. The company announcement was posted to the FDA website: https://www.accessdata.fda.gov/scripts/ires/?Event=96741.

We acknowledge your commitment dated June 24, 2025, to permanently cease production of all drugs at this facility.

Notify this office if you intend to resume your drug manufacturing operations at this site or in another location. You are responsible for resolving all deficiencies and systemic flaws to ensure that your firm is capable of ongoing CGMP compliance. In your notification to the Agency, provide a summary of your remediations to demonstrate that you have appropriately completed all corrective actions and preventive actions (CAPA).

Based upon the nature of the violations we identified at your firm, you should engage a consultant qualified as set forth in 21 CFR 211.34 to evaluate your operations and to assist your firm in meeting CGMP requirements if your firm intends to resume manufacturing drugs for the U.S. market. The qualified consultant should also perform a comprehensive (b)(4)1 of your entire operation for CGMP compliance and evaluate the completion and efficacy of your CAPA before you pursue resolution of your firm’s compliance status with FDA.

Your use of a consultant does not relieve your firm’s obligation to comply with CGMP. Your firm’s executive management remains responsible for resolving all deficiencies and systemic flaws to ensure ongoing CGMP compliance.

The violations cited in this letter are not intended to be an all-inclusive list of violations that exist 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.

Correct any violations promptly. Failure to promptly and adequately address this matter may result in regulatory or legal action without further notice including, without limitation, seizure and injunction. Unresolved violations may also prevent other Federal agencies from awarding contracts.

Failure to address violations may also cause FDA to withhold issuance of Export Certificates. FDA may withhold approval of new applications or supplements listing your firm as a drug manufacturer until any violations are completely addressed and we confirm your compliance with CGMP. We may re-inspect to verify that you have completed corrective actions to address any violations.

This letter notifies you of our findings and provides you an opportunity to address the above deficiencies. After you receive this letter, respond to this office in writing within 15 working days. Specify what you have done to address any violations and to prevent their recurrence. In response to this letter, you may provide additional information for our consideration as we continue to assess your activities and practices. If you cannot complete corrective actions within 15 working days, state your reasons for delay and your schedule for completion.

Send your electronic reply to CDER-OC-OMQ-Communications@fda.hhs.gov. Identify your response with FEI 3023604380 and ATTN: Russell Riley.