CTK OTC Laboratories LLC formerly FMK LABS, Inc.

The United States Food and Drug Administration (FDA) inspected your drug manufacturing facility, CTK OTC Laboratories LLC (formerly FMK LABS, Inc.), FEI 3014253278, at 1690 N Delilah St., Corona, California, from December 16 to 31, 2024.

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 January 21, 2025 response to our Form FDA 483 in detail.

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 investigations into out-of-specification (OOS) results. For example, an OOS for bulk base batch (b)(4), documented low potency for one of the active pharmaceutical ingredients (APIs). The corrective action was to re-mix the batch on November 15, 2024, “to make it more uniform.” Upon retesting the batch, it remained sub-potent.

You then adjusted the potency by adding additional APIs and re-mixing the batch. The batch was retested, and the potency assay was found within specification. However, the root cause of the low potency was not determined. Moreover, the bulk base batch had a subsequent OOS result for high viscosity. You failed to investigate the viscosity OOS and the bulk base batch was released and further used to manufacture (b)(4) finished drug batches. (b)(4) of the finished drug batches were tested during stability and again were determined to fail with high viscosity. This failure was not investigated.

You did not thoroughly investigate these unexplained discrepancies or identify failures in a drug product to meet any of its specifications. When an investigation was performed, it was inadequate as you failed to identify the root cause(s), implement appropriate corrective action and preventive action (CAPA), and expand the investigation to evaluate the impact on other batches or products.

In your response, you commit to improve your investigation process. Your response is inadequate. You did not propose to perform any retrospective impact assessment of previously distributed drug products. As a manufacturer, you have a responsibility to fully investigate unexplained discrepancies and failures to assess impact to product quality.

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

In response to this letter, provide:

A comprehensive, independent assessment of your overall system for investigating deviations, discrepancies, complaints, OOS results, and failures. Provide a detailed action plan to remediate this system. Your action plan should include, but not be limited to, significant improvements in investigation competencies, scope determination, root cause evaluation, CAPA effectiveness, quality unit (QU) oversight, and written procedures. Address how your firm will ensure all phases of investigations are appropriately conducted.

A comprehensive review and remediation plan for your OOS result investigation systems. The CAPA should include but not be limited to addressing the following:o QU oversight of laboratory investigations.o Identification of adverse laboratory control trends.o Resolution of causes of laboratory variation.o Initiation of thorough investigations of potential manufacturing causes whenever a laboratory cause cannot be conclusively identified.o Adequately scoping of each investigation and its CAPA.o Revised OOS investigation procedures with these and other remediations.

2. Your firm failed to establish adequate written procedures for production and process control designed to assure that the drug products you manufacture have the identity, strength, quality, and purity they purport or are represented to possess (21 CFR 211.100(a)).

Inadequate Process Validation

You manufacture over-the-counter (OTC) drug products, such as topical creams, including sunscreens. You failed to demonstrate you have adequately validated the manufacturing processes used to manufacture your OTC drug products. For example, you were unable to provide blend uniformity studies to demonstrate your mixing processes assure uniformity and homogeneity. Your lack of process validation is a likely contributing factor to your OOS results detailed earlier in this letter.

While you commit to perform process validation for each product that you currently market, your response is inadequate. You did not include any further supporting documentation. Additionally, you did not provide a timeline for completing the validation of your processes and did not consider a retrospective impact assessment for previously distributed drug products.

Process validation evaluates the soundness of design and state of control of a process throughout its lifecycle. Each significant stage of a manufacturing process must be designed appropriately and assure the quality of raw material inputs, in-process materials, and finished drugs. Process qualification studies include intensive monitoring and testing throughout each significant process stage to characterize intra-batch variation and evaluates batches to determine whether an initial state of control has been established.

Successful process qualification studies are necessary before commercial distribution. Thereafter, ongoing vigilant oversight of process performance and product quality is necessary to ensure you maintain a stable manufacturing operation throughout the product lifecycle. See FDA’s guidance for industry, Process Validation: General Principles and Practices, for general principles and approaches that the FDA considers appropriate elements of process validation at https://www.fda.gov/media/71021/download.

Inadequate Water System Validation

Your firm used water as a component in your OTC drug product manufacturing and equipment cleaning. However, you did not validate your water production process nor was routine maintenance performed on your water system as specified by your procedures. You did not adequately demonstrate that your water was suitable for its intended use, and, at a minimum, meets the (b)(4) Water United States Pharmacopoeia (USP) monograph and appropriate microbial limits. Additionally, your water system was not routinely sanitized. Furthermore, we noted that microbiological water samples demonstrated the presence of bacterial and fungal organisms. However, the samples were not further analyzed to identify any objectionable microorganisms.

While you commit to perform validation of your water production process, your response is inadequate. For example, you did not provide a detailed remediation plan or timeline for implementation, nor did you consider retrospective testing of retained finished drug products that used water as a component.

Water must be suitable for its intended use and routinely tested to ensure ongoing conformance with appropriate chemical and microbiological attributes. Routine monitoring of microbial counts and identity of contamination in the system is integral to ensuring oversight of ongoing state of control and suitability of water for use in pharmaceutical manufacturing operations.

In response to this letter, provide:

A detailed summary of your validation program for ensuring a state of control throughout the product lifecycle, along with associated procedures. Describe your program for process performance qualification (PPQ), and ongoing monitoring of both intra-batch and inter-batch variation to ensure a continuing state of control.

A timeline for performing PPQ for each of your marketed drug products.

PPQ protocols and written procedures for qualification of equipment and facilities.

A detailed program for designing, validating, maintaining, controlling, and monitoring each of your manufacturing processes that includes vigilant monitoring of intra-batch and inter-batch variation to ensure an ongoing state of control. Also, include your program for qualification of your equipment and facility.

A comprehensive remediation plan for the design, control, and maintenance of the water system.o A (b)(4) water system validation report. Also include the summary of any improvements made to system design and to the program for ongoing control and maintenance.

Your total microbial count limits to monitor whether this system is producing water suitable for the intended uses for each of your products.

A detailed risk assessment addressing the potential effects of the observed water system failures on the quality of all drug product batches currently within expiry. Specify actions that you will take in response to the risk assessment, such as customer notifications and product recalls.

3. Your firm failed to establish laboratory controls that include scientifically sound and appropriate specifications, standards, sampling plans, and test procedures designed to assure that components, drug product containers, closures, in-process materials, labeling, and drug products conform to appropriate standards of identity, strength, quality, and purity (21 CFR 211.160(b)).

Your firm failed to demonstrate that your microbiological test methods were appropriate to assure that your product conforms to appropriate standards of identity, strength, quality, and purity. Specifically, you could not provide evidence of method suitability for microbiological testing performed at your facility. Additionally, you were unable to show that you performed growth promotion studies or negative control testing to support the release testing of your OTC drug products.

In your response, you commit to “validate” your methods in accordance with USP requirements. However, your response is inadequate because you did not provide sufficient detail or adequate evidence of corrective actions (e.g., protocol or procedure). You did not provide a timeline for verification of the methods or describe your plans for testing in the interim. Furthermore, you did not address whether a retrospective impact assessment would be performed for previously distributed drug products that are still within expiry.

The ability of microbial testing methods to detect objectionable microorganisms in the presence of each drug product must be established. Results generated using unverified or unvalidated methods may put consumers at risk.

In response to this letter, provide:

A comprehensive, independent assessment of your laboratory practices, procedures, methods, equipment, documentation, and analyst competencies. Based on this review, provide a detailed plan to remediate and evaluate the effectiveness of your laboratory system.

A list of chemical and microbial specifications, including test methods, used to analyze each batch of your drug products before a batch disposition decision.o An action plan and timelines for conducting full chemical and microbiological testing of retain samples to determine the quality of all batches of drug product distributed to the United States that are within expiry as of the date of this letter.o A summary of all results obtained from testing retain samples from each batch. If such testing reveals substandard quality drug products, take rapid corrective actions, such as notifying customers and product recalls.

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. The qualified consultant should also perform a comprehensive six-system audit 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. See FDA’s guidance for industry, Quality Systems Approach to Pharmaceutical CGMP Regulations, at https://www.fda.gov/media/71023/download.

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.

Drugs must be manufactured in conformance with CGMP. FDA is aware that many drug manufacturers use independent contractors such as production facilities, testing laboratories, packagers, and labelers. FDA regards contractors as extensions of the manufacturer.

You are responsible for the quality of drugs you produce as a contract facility regardless of agreements in place with product owners. You are required to ensure that drugs are made in accordance with section 501(a)(2)(B) of the FD&C Act for safety, identity, strength, quality, and purity. See FDA’s guidance document Contract Manufacturing Arrangements for Drugs: Quality Agreements at https://www.fda.gov/media/86193/download.

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.

After you receive this letter, respond to this office in writing within 15 working days. In response to this letter, you may provide additional information for our consideration as we continue to assess your activities and practices, and/or submit a request to schedule an FDA inspection.

Send your electronic reply to CDER-OC-OMQ-Communications@fda.hhs.gov. Identify your response with FEI 3014253278 and ATTN: Frank Wackes.