Marshalls Traditional Healthcare CC

The U.S. Food and Drug Administration (FDA) inspected your drug manufacturing facility, Marshalls Traditional Healthcare CC, FEI 3014740544, at 560 Main Reef Road, Germiston, from September 19 to 23, 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 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 and acknowledge receipt of your subsequent correspondence.

1. 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. Your firm also failed to conduct, for each batch of drug product, appropriate laboratory testing, as necessary, required to be free of objectionable microorganisms (21 CFR 211.165(a) and 211.165(b)).

Your firm manufactures an over-the-counter (OTC) (b)(4) drug product. Your firm failed to conduct adequate finished product release testing for each batch of your drug product, including but not limited to, testing the identity and strength of the active ingredient, (b)(4) and testing for objectionable microorganisms.

In your response, you state that you developed and validated an updated test method, and updated release specifications, for the labeled active ingredient, (b)(4). You also state that you will perform all appropriate USP <61> and <62> testing for your finished drug products. Your response is inadequate as you did not provide sufficient details regarding the specific tests to be performed for each batch of finished drug product. You also did not consider a risk assessment or retrospective review of products that have been released without appropriate testing.

Without adequate finished product release testing, you do not have scientific evidence that each batch of drug product conforms to appropriate specifications before release.

In your 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 lot of your drug products before a lot disposition decision.

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, and to follow all of your written production and process control procedures (21 CFR 211.100(a) and 211.100(b)).

Inadequate Process Validation

You did not have data to demonstrate that you adequately validate your manufacturing processes used to manufacture your OTC drug products and demonstrate that your processes are reproducible and controlled to consistently yield drugs of uniform character and quality. For example, your validation plan, “VALIDATOIN MASTER PLAN (VMP),” describes requirements for process validation and hold time studies. However, the protocol implementing your validation planed, “PROCESS VALIDATION PROTOCOL,” failed to include operating parameters, such as bulk hold times, or processing limits, such as acceptance criteria for process parameters.

In your response, you provided your updated process validation protocol. Your response is inadequate as it did not include hold times and lacked appropriate details such as adequate sampling instructions. The updated protocol also did not include the batch production record associated with the first validation batch.

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 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 FDA considers appropriate elements of process validation at https://www.fda.gov/media/71021/download.

Inadequate Control of (b)(4) System

Your firm uses (b)(4) as a component to manufacture your OTC drug product. You failed to ensure that your (b)(4) system is suitable for producing (b)(4) used in the formulation of your drug product. For example, you turned your (b)(4) system off when not in use, stopping its circulation, which deviates from its design use as a continuously recirculating system. In addition, you failed to demonstrate that your (b)(4) system is adequately monitored to ensure it consistently produces (b)(4) that meets appropriate chemical and microbial attributes.

In your response, you state that your (b)(4) system will continuously (b)(4). Your response is inadequate. You did not address the adequacy of your overall (b)(4) system design to ensure that your (b)(4) meets, at a minimum, the USP (b)(4) monograph and appropriate microbial limits. You also did not provide interim measures and assess the impact of using (b)(4) from an inadequately validated (b)(4) system on the quality of drug products you manufacture.

Pharmaceutical (b)(4) 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 maintaining a state of control and suitability of (b)(4) for use in manufacturing operations.

In your 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 appropriate PPQ for each of your marketed drug products.

Process performance protocol(s), 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 (b)(4) system.

A (b)(4) 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 (b)(4) suitable for the intended uses for each of your products.

A detailed risk assessment addressing the potential effects of the observed (b)(4) system failures on the quality of all drug product lots currently in U.S. distribution. Specify actions that you will take in response to the risk assessment, such as customer notifications and product recalls.

A procedure for your (b)(4) system monitoring that specifies routine microbial testing of (b)(4) to ensure its acceptability for use in each batch of drug products produced by your firm.

A procedure governing your program for ongoing control, maintenance, and monitoring that ensures the remediated system consistently produces (b)(4) that meets (b)(4), USP monograph specifications and appropriate microbial limits.

We acknowledge that you delisted your OTC drug product with FDA. In response to this letter, clarify whether you intend to resume manufacturing drugs for the U.S. market at this facility in the future.

If you plan to resume any manufacturing operations regulated under the FD&C Act, notify this office before resuming your drug manufacturing operations. 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 corrective actions and preventive actions (CAPAs).

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 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 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.

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.

In addition, we note that some of the products you manufacture may be regulated as cosmetics, as defined in section 201(i) of the FD&C Act [21 U.S.C. 321(i)]. Any cosmetics you manufacture must comply with applicable statutory and regulatory requirements, including the FD&C Act. Under section 301(a) of the FD&C Act [21 U.S.C. 331(a)], it is a prohibited act to introduce or deliver for introduction into interstate commerce a cosmetic that is adulterated or misbranded.

Further, your facility may be subject to requirements of the Modernization of Cosmetics Regulation Act of 2022 (MoCRA). Information on MoCRA requirements may be found athttps://www.fda.gov/cosmetics/cosmetics-laws-regulations/modernization-cosmetics-regulation-act-2022-mocra.

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. 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 any violations.

Failure to address any violations may also result in the FDA refusing admission of articles manufactured at Marshalls Traditional Healthcare CC, FEI 3014740544, at 560 Main Reef Road, Germiston, Gauteng 1400, South Africa, into the United States under section 801(a)(3) of the FD&C Act, 21 U.S.C. 381(a)(3). Articles under this authority that appear to be adulterated may be detained or refused admission, in that the methods and controls used in their manufacture do not appear to conform to CGMP within the meaning of section 501(a)(2)(B) of the FD&C Act, 21 U.S.C. 351(a)(2)(B).

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 3014740544 and ATTN: Christopher M. Jenner.