Strukmyer LLC dba Strukmyer Medical - 692686 - 01/30/2025

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Warning Letter 320-25-37

January 30, 2025

Dear Mr. Kancherla:

The U.S. Food and Drug Administration (FDA) inspected your drug manufacturing facility, Strukmyer LLC dba Strukmyer Medical, FEI 3000205837, at 1801 Big Town Blvd. Ste. 100, Mesquite, TX, from July 8 to August 1, 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 August 22, 2024 response to our Form FDA 483 in detail and acknowledge receipt of your subsequent correspondence.

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).

On over 60 occasions, your firm isolated objectionable microorganisms (e.g., Burkholderia, Pseudomonas, Staphylococcus, Bacillus, and Aspergillus species) from your (b)(4) water system used as a component to manufacture over-the-counter (OTC) drug products intended for use in wounds and on burns between November 1, 2022 and July 10, 2024. For example, Pseudomonas and Burkholderia were recovered from samples of your (b)(4) water system on August 15 and August 21, 2023, respectively, and water from this system was used to manufacture (b)(4) batches (b)(4) and (b)(4) on August 21, 2023. You failed to adequately investigate and implement corrective actions to determine root causes and prevent recurrence of these contamination incidents. We note that this drug product was previously the subject of a recall in 2020 for microbial contamination with Burkholderia cepacia.

In your response, you state that you updated your (b)(4) water monitoring procedures to include specifications for the absence of objectionable organisms. You also state that you conducted an investigation into the implicated (b)(4) lots and incidents of Burkholderia and Pseudomonas isolates in your water system and concluded there is no product impact because subsequent water samples collected at the time the water was used to manufacture the drug product were tested and results were observed to be within limits. Further, you state that your finished drug products met your microbial specifications.

Your response is inadequate. Your investigation did not adequately identify the root cause of the contamination of your (b)(4) water system with objectionable microorganisms and failed to consider the impact to your distributed drug products that were manufactured with (b)(4) water contaminated with objectionable microorganisms. Microbial contamination is not typically uniformly distributed, especially in a deficient system, and thus samples may not be representative of the type or level of contamination that may exist in other individual units of a batch.

Inadequate investigations can lead to unidentified root causes, ineffective corrective actions and preventive actions (CAPA), and recurring problems that compromise the ability to manufacture safe and effective drug products. Frequent microbiological excursions suggest that your purified water system may not be in an adequate state of control.

In response to this letter, provide:

• A comprehensive, independent assessment of the design and control of your firm’s manufacturing operations, with a detailed and thorough review of all microbiological hazards.
• A detailed risk assessment addressing the hazards posed by distributing drug products with potentially objectionable contamination. Specify actions you will take in response to the risk assessment, such as customer notifications and product recalls.
• Complete investigations into all batches with potential objectionable microbial contamination or an out-of-specification (OOS) microbiological result (whether or not later invalidated). The investigations should detail your findings regarding the root causes of the contamination.
• Appropriate microbiological batch release specifications (i.e., total counts, identification of bioburden to detect objectionable microbes) for each of your drug products.
• All chemical and microbial test methods used to analyze each of your drug products.
• A summary of results from testing retain samples of all drug product batches within expiry. You should test all appropriate quality attributes including, but not limited to, identity and strength of active ingredients and microbiological quality (total counts and identification of bioburden to detect any objectionable microbes) of each batch. If testing yields an OOS result, indicate the corrective actions you will take, including notifying customers and initiating recalls.
• 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 oversight, and written procedures. Address how your firm will ensure all phases of investigations are appropriately conducted.
• An independent assessment and remediation plan for your CAPA program. Provide a report that evaluates whether the program includes effective root cause analysis, ensures CAPA effectiveness, analyzes investigations trends, improves the CAPA program when needed, implements final quality unit decisions, and is fully supported by executive management.

2. Your firm failed to test samples of each component for identity and conformity with all appropriate written specifications for purity, strength, and quality. Your firm also failed to validate and establish the reliability of your component supplier’s test analyses at appropriate intervals (21 CFR 211.84(d)(1) and 211.84(d)(2)).

You failed to perform adequate incoming testing of each component lot used in the manufacture of your OTC drug products, such as Therabreath Mild Mint Toothpaste intended for use in children. You also relied on your suppliers’ certificate of analysis (COA) without establishing the reliability of your component suppliers’ test analyses at appropriate intervals.

Glycerin

You failed to adequately test each shipment of each lot of glycerin for identity, a component at high-risk of diethylene glycol (DEG) or ethylene glycol (EG) contamination. Identity testing for glycerin and certain other high-risk drug components¹ includes a limit test in the United States Pharmacopeia (USP) to ensure the component meets the relevant safety limits for levels of DEG or EG. Because you did not perform identity testing on each shipment of each lot using the USP identification test that detects these hazardous impurities, you failed to assure the acceptability of these components for use in the manufacture of your drug products.

The use of ingredients contaminated with DEG or EG has resulted in various lethal poisoning incidents in humans worldwide. See FDA’s guidance document Testing of Glycerin, Propylene Glycol, Maltitol Solution, Hydrogenated Starch Hydrolysate, Sorbitol Solution, and Other High-Risk Drug Components for Diethylene Glycol and Ethylene Glycol to help you meet the CGMP requirements when manufacturing drugs containing ingredients at high-risk for DEG or EG contamination at https://www.fda.gov/media/167974/download.

In your response, you state that you would update the specifications for your glycerin component to include identity testing, including DEG and EG testing, at a (b)(4) testing frequency. Additionally, you state that you tested retain sample of one glycerin lot from each (b)(4) since May 2023 to verify the quality of previously manufactured batches. You also committed to performing DEG and EG testing on the first lot of glycerin received each (b)(4) to confirm the reliability of the testing results on the supplier’s COA.

Your response is inadequate. CGMP requires that each shipment of each lot of a component undergo appropriate identity testing (which for glycerin, as noted above, includes a limit test for DEG and EG) before use in drug product manufacturing. Your response also did not include an evaluation of the quality of your drug products currently on the U.S market with inadequate component testing.

Component testing is fundamental to quality. Without adequate testing, you do not have scientific evidence that your incoming components conform to appropriate specifications before us in the manufacture of drug products.

In response to this letter, provide:

• A description of how you will test each component lot for conformity with all appropriate specifications for identity, strength, quality, and purity. If you intend to accept any results from your supplier’s COA instead of testing each component lot for strength, quality, and purity, specify how you will robustly establish the reliability of your supplier’s results through initial validation as well as periodic revalidation. In addition, include a commitment to always conduct at least one specific identity test for each incoming component lot. In the case of glycerin, propylene glycol, and certain additional high-risk components we note that this includes the performance of parts A, B, and C of the USP monograph.
• The chemical quality control specifications you use to test each incoming lot of high-risk drug components to determine acceptability for use in manufacturing.
• A comprehensive, independent review of your material system to determine whether all suppliers of components, containers, and closures, are each qualified and the materials are assigned appropriate expiration or retest dates. The review should also determine whether incoming material controls are adequate to prevent use of unsuitable components, containers, and closures.
• A summary of your program for qualifying and overseeing contract facilities that test the drug products you manufacture.
• A summary of results obtained from testing all components to evaluate the reliability of the COA from each component manufacturer. Include your standard operating procedure (SOP) that describes this COA validation program.

3. Your firm failed to clean, maintain, and, as appropriate for the nature of the drug, 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 (21 CFR 211.67(a)).

You failed to demonstrate your cleaning and disinfection practices are adequate to remove all contaminants from the equipment used to manufacture your topical OTC drug products. For example, your cleaning validation only tested for the absence of Gram-negative bacteria, but you have previously isolated fungi and gram-positive microorganisms from your water system.

Inadequate removal of microbial organisms from manufacturing equipment during cleaning can result in contamination of your drug products, which can potentially cause patient harm depending on the organism.

In your response, you committed to performing a new cleaning validation based on “worst-case” scenarios, including a toxicological and microbiological risk assessment of all raw materials using in manufacturing.

Your response is inadequate in that the test methods appear to be incomplete.

In response to this letter, provide:

• Your total microbial count limits to monitor whether this system is producing water suitable for the intended uses for each of your drug products.
• A summary of updated SOPs that ensure an appropriate program is in place for verification and validation of cleaning procedures for products, processes, and equipment.

4. Your firm failed to establish an adequate quality control unit with the responsibility and authority to approve or reject all components, drug product containers, closures, in-process materials, packaging materials, labeling, and drug products (21 CFR 211.22(a)).

Your quality unit (QU) failed to ensure the chemical and microbial testing methods performed by your contract laboratory for finished drug product release testing and water system monitoring were not adequately validated or verified as appropriate.

In your response, you state that you sent drug product and (b)(4) water samples to your contract laboratory to complete method verification for your chemical and microbial tests. You also updated your procedure to require that method validations and verifications be performed on required test methods.

Your response is inadequate. It did not provide assurance that the analytical test methods used to test your components and finished drug products are suitable for the intended purpose. Further, you did not provide an evaluation of potential impact to drug products currently on the U.S. market.

An adequate QU overseeing all elements of CGMP is necessary to consistently ensure drug product quality. Your firm’s quality systems are inadequate. See FDA’s guidance document Quality Systems Approach to Pharmaceutical CGMP Regulations at https://www.fda.gov/media/71023/download for help in implementing quality systems and risk management approaches.

In response to this letter, provide:

• A comprehensive assessment and remediation plan to ensure your QU is given the authority and resources to effectively function. The assessment should also include, but not be limited to:
  o A determination of whether procedures used by your firm to ensure you have an adequate contract testing facility are robust and appropriate.
  o Provisions for QU oversight throughout your laboratory operations to evaluate adherence to appropriate practices.
  o Oversight and approval of investigations and discharging of all other QU duties to ensure identity, strength, quality, and purity of all products.

CGMP Consultant Recommended

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.

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.

Cosmetics Manufactured for Distribution in the United States

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. Any cosmetics you manufacture must comply with applicable statutory and regulatory requirements, including the FD&C Act. A cosmetic is deemed adulterated under section 601(c) of the FD&C Act [21 U.S.C. 361(c)] if it has been prepared, packed, or held under insanitary conditions whereby it may have become contaminated with filth or whereby it may have been rendered injurious to health.

Some conditions that cause the drug products you manufacture to be adulterated may also cause any cosmetics you manufacture to be adulterated. We note that 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. Further, your facility may be subject to requirements under the Modernization of Cosmetics Regulations Act of 2022 (MoCRA). Information on MoCRA requirements may be found at https://www.fda.gov/cosmetics/cosmetics-laws-regulations/modernization-cosmetics-regulation-act-2022-mocra.

Conclusion

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 3000205837 and ATTN: Philip Kreiter.

Sincerely,
/S/

Francis Godwin
Director
Office of Manufacturing Quality
Office of Compliance
Center for Drug Evaluation and Research

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1 Components with higher risk of DEG or EG contamination compared to other drug components.