Chem-Tech, Ltd.

The U.S. Food and Drug Administration (FDA) inspected your drug manufacturing facility, Chem-Tech, Ltd., FEI 1927341, at 1006 Business Highway 5, Pleasantville, IA, from September 17 to 20, 2024.

This warning letter summarizes significant violations of Current Good Manufacturing Practice (CGMP) regulations for finished pharmaceuticals. See Title 21 Code of Federal Regulations, 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 product is 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 October 11, 2024, response to our Form FDA 483 in detail. Your response is inadequate because you failed to provide supportive documentation for evaluation or adequate evidence of corrective actions taken to bring your operations into compliance with CGMP.

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

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).

Your firm failed to conduct adequate manufacturing investigations into out-of-specification (OOS) results obtained by your external laboratory for your (b)(4), an over-the-counter (OTC) drug product. As such, root cause(s) for the OOS results were not determined and no corrective and preventive actions (CAPA) were identified.

For example,

Batch (b)(4) reported (b)(4) assay for (b)(4) content of 0.423% (specification, (b)(4)). Despite no supportive documentation from an investigation, you identified a separation issue as the root cause for the OOS result and failed to consider the batch was also outside the established (b)(4) hold time. The batch was reworked to adjust the (b)(4) content and released on March 22, 2022.

Batch (b)(4) reported a (b)(4) assay for (b)(4) content of 0.246% (specification (b)(4)). Your deviation report indicated that the OOS was due to improper mixing without a full manufacturing investigation. You mixed the batch for (b)(4) as the corrective action. The batch was retested for assay and upon passing, the batch was released on July 7, 2023.

In addition, your firm lacks mixing process validation and finished product hold time studies that are scientifically supported, as required by 21 CFR 211.110(a). For example, your validation report only includes the filling operation and does not include mixing parameters. The holding time was initially established as (b)(4) and changed to (b)(4) without supporting data. There is evidence that (b)(4) batch (b)(4) was held for up to 120 days prior to filling without additional testing. The extended hold time of the finished drug product and inadequate validation of the process may contribute to both the high- and low-OOS assay results reported, and your cursory investigation lacked appropriate CAPA.

Without adequate manufacturing investigations, you lack sufficient evidence to determine if the process is contributing to the OOS results obtained. As a manufacturer, you have a responsibility to fully investigate OOS results and process deviations that may impact product quality.

For more information about process validation and handling failing, OOS, out-of-trend, or other unexpected results and documentation of your investigations, see FDA’s guidance documents: Process Validation: General Principles and Practices at https://www.fda.gov/media/71021/download and Investigating Out-of-Specification (OOS) Test Results for Pharmaceutical Production at https://www.fda.gov/media/158416/download.

2. Your firm failed to clean, maintain, and sanitize and/or sterilize equipment and utensils at appropriate intervals to prevent malfunctions or contamination that would alter the safety, identity, strength, quality, or purity of the drug product beyond the official or other established requirements, and you failed to establish and follow adequate written procedures for cleaning and maintenance of equipment (21 CFR 211.67(a) and (b)).

You failed to maintain your drug manufacturing facility in a good state of repair. For example, your mixing tank and filling lines for your OTC drug product are in a large, unclean area. The investigator observed a layer of dirt and a dead insect on the lid of your mixing tank that was only partially covered by a plastic sheet. It is essential your facility is in a good state of repair, and sanitary conditions are maintained to ensure ongoing suitability for drug manufacturing and to protect the product from contamination.

Additionally, the investigator observed leftover drug product pooled at the bottom of your mixing tank, along with orange-red discoloration on the inside walls and bottom of the mixing tank. You had last manufactured drug products on this equipment approximately 1 month prior and that you would (b)(4) and (b)(4) prior to starting a new manufacturing run. You have no validated cleaning procedure to demonstrate that this is sufficient to clean your equipment.

Your firm also lacked a preventive maintenance program with procedures for maintenance and cleaning of equipment. For example, we noted that the meter used to charge potable water into the drug product has never been calibrated.

Your firm’s quality unit failed to have procedures for GMP training, handling OOS results, and change management. In addition, the procedures for handling deviations and complaints are inadequate. For example, the deviations procedure lacks details for the investigation process, and the complaints procedure states they are managed by your firm’s only customer but lacks information about how your customer will communicate when complaints are received, the outcome, and any needed actions including CAPA.

Your firm’s quality systems are inadequate. See FDA’s guidance document Quality Systems Approach to Pharmaceutical CGMP Regulations for help implementing quality systems and risk management approaches to meet the requirements of CGMP regulations 21 CFR, parts 210 and 211 at https://www.fda.gov/media/71023/download.

On (b)(4), you issued a voluntary recall of (b)(4) due to GMP violations cited after the inspection conducted from September 17 to 20, 2024. The company announcement was posted to the FDA website: (b)(4)

We acknowledge your commitment to cease production of (b)(4) drug at this facility.

If you plan to resume any drug manufacturing operations, notify this office. You are responsible for resolving all deficiencies and systemic flaws to ensure 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 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 six-system audit1 of your entire operation for CGMP compliance and evaluate the completion and efficacy of your corrective actions and preventive actions 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 1927341 and ATTN: Vilmary Negrón Rodríguez.