Master Paints & Chemicals Corp. - 672462 - 03/13/2024

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DATE: 3/13/2024

Case #: 672462

WARNING LETTER

Dear Mr. Cardona:

The U.S. Food and Drug Administration (FDA) inspected your drug manufacturing facility, Master Paints & Chemicals Corp, FEI 3016668136, at Road 127, Km. 12.7, Guayanilla, Puerto Rico, from October 11 to 17, 2023.

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 November 3, 2023, 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 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 (21 CFR
211.165(a)).

You manufacture over-the-counter (OTC) drug products including alcohol-based hand sanitizer, anti-bacterial hand soap, isopropyl alcohol, and hydrogen peroxide. Your firm failed to adequately test your OTC drugs prior to release for distribution. For example, you failed to perform adequate potency and microbiological testing on your hand sanitizer and isopropyl alcohol. You only used a density meter to perform finished product strength testing.

Adequate testing is essential to ensure that the drug products you manufacture conform to all pre-determined quality attributes that are appropriate for their intended use, including microbiological specifications.

In your response, you note that you have followed FDA’s temporary guidances for hand sanitizers, which have been withdrawn, effective December 31, 2021,¹ and that you will review “alcohol-based products technical data sheets and labels to ensure that the information written in the document complies with quality control (QC) testing carried out in the laboratories.” Furthermore, you state that you hold hand sanitizer batches for release until testing is performed with the repaired density meter. Your response is inadequate because you did not provide information to establish that your testing complies with the applicable United States Pharmacopeia (USP) compendial methods.

In response to this letter, provide the following:

􀁸 A list of chemical and microbiological specifications, including test methods, used to analyze each batch of your drug products before batch disposition decisions.
    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 retain samples from each batch. If such testing reveals substandard quality drug products, take rapid corrective actions, such as notifying customers and product recalls.

􀁸 A comprehensive independent third-party assessment of your laboratory practices, procedures, methods, equipment, documentation, and analyst competencies. This assessment should include, but not be limited to, a review of method suitability criteria, and validation (or verification, for USP compendial methods) to determine whether they are fit for their intended use. Based on this review, provide a detailed plan to remediate and evaluate the effectiveness of your laboratory system.

2. Your firm failed to conduct at least one test to verify the identity of each component of a drug product (21 CFR 211.84(d)(1)).

Your firm manufactures OTC drug products without adequate assurance of the quality of raw materials. For example, you did not test incoming raw materials, including identity testing of each component lot used in the manufacture of your OTC drug products.

Without adequate testing, you do not have scientific evidence that the components conform to appropriate specifications prior to use in the manufacture of your drug products.

In your response, you commit to sending raw material samples to third-party laboratories for identification testing. Your response is inadequate because you failed to provide sufficient details regarding how you will ensure at least one identity test for each lot of each shipment of incoming raw materials is performed, and how you will qualify external laboratories to conduct testing on raw materials. You also did not address how you will assess the quality of your components used in your distributed drug products that are within expiry.

You manufacture drugs that contain ethanol. The use of ethanol contaminated with methanol has resulted in various lethal poisoning incidents in humans worldwide. See FDA’s guidance document Policy for Testing of Alcohol (Ethanol) and Isopropyl Alcohol for Methanol at: https://www.fda.gov/media/173005/download.

You also manufacture drugs that contain glycerin. The use of ingredients contaminated with diethylene glycol (DEG) or ethylene glycol (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 response to this letter, provide:

􀁸 A commitment to provide DEG and EG test results, no later than 30 calendar days from the date of this letter, from testing retains for all lots of high-risk drug components used in the manufacture of your drug products. Alternatively, if a retain of a component lot is unavailable, perform retain sample testing of all implicated finished drug product batches for the presence of DEG and EG.

􀁸 A full risk assessment for drug products that are within expiry which contain any ingredient at risk for DEG or EG contamination (including, but not limited to, glycerin). Take prompt and appropriate actions to determine the safety of all lots of the component(s) and any related drug product that could contain DEG or EG, including customer notifications and product recalls for any contaminated lots. Identify additional appropriate corrective action and preventive action (CAPA) that secure supply chains in the future, including, but not limited to, ensuring that all incoming raw material lots are from fully qualified manufacturers and free from unsafe impurities. Detail these actions in your response to this letter.

􀁸 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 suppliers’ COA instead of testing each component lot for strength, quality, and purity, specify how you will robustly establish the reliability of your suppliers’ 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 and microbiological quality control specifications you use to test and release each incoming lot of components 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 reassigned 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 incoming components and finished drug products you manufacture.

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) did not provide adequate oversight for the manufacture of your drug products. For example, your QU failed to ensure the following:

􀁸 Adequate written procedures for production and process controls (21 CFR 211.100(a)).

􀁸 Establishment of an adequate ongoing stability program (21 CFR 211.166(a)).

􀁸 Manufacturing equipment for OTC drug products is cleaned at appropriate intervals (21 CFR 211.67(a)).

Significant findings in this letter demonstrate that your firm does not operate an effective quality system in accordance with CGMP. In addition to the lack of effective management oversight of your production operations, we found that your QU is not enabled to exercise proper authority and/or has insufficiently implemented its responsibilities. Executive management should immediately and comprehensively assess your company’s global manufacturing operations to ensure that your systems, processes, and products conform to FDA requirements.

An adequate QU overseeing all manufacturing operations is necessary to consistently ensure drug quality. 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 response to this letter, provide:

􀁸 A comprehensive assessment and remediation plan to ensure your QU is given the authority and resources to function effectively. The assessment should also include, but not be limited to:
    o A determination of whether procedures used by your firm are robust and appropriate.
    o Provisions for QU oversight throughout your operations to evaluate adherence to appropriate practices.
    o A complete and final review of each batch and its related information before the QU disposition decision.
    o Oversight and approval of investigations and discharging of all other QU duties to ensure identity, strength, quality, and purity of all drug 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 audit² 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.

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.

Please electronically submit your reply on company letterhead to Mark W. Rivero, Compliance Officer, at ORAPHARM2_RESPONSES@fda.hhs.gov. In addition, please submit a signed copy of your response to mark.rivero@fda.hhs.gov.

If you have questions regarding any issues in this letter, please contact Mr. Mark Rivero by email or by phone at (954) 759 - 7718.

Sincerely,
/S/

Monica R. Maxwell
Program Division Director
Office of Pharmaceutical Quality Operations,
Division II

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1 Due to an increased demand for alcohol-based hand sanitizers during the COVID-19 pandemic, the FDA published three guidances outlining the Agency’s temporary policies for manufacturers to help meet the increased demand for alcohol-based hand sanitizers (ABHS). These guidances have now been withdrawn. Companies manufacturing ABHS consistent with the temporary policies must have ceased production of these products by December 31, 2021. By March 31, 2022, manufacturers must have stopped distribution of any remaining ABHS produced under the temporary policies. For more information see: https://www.fda.gov/news-events/press-announcements/fda-brief-fdawithdrawing-temporary-guidances-alcohol-based-hand-sanitizers

2 i.e., Quality System, Facilities & Equipment System, Materials System, Production System, Packaging & Labeling System, and Laboratory Control System per FDA’s guidance document Quality Systems Approach to Pharmaceutical CGMP Regulations.