Wittman Pharma, Inc.

The U.S. Food and Drug Administration (FDA) inspected your drug manufacturing facility, Wittman Pharma, Inc., FEI 3005350897, at 15431 Flight Path Drive, Brooksville, from February 6 to March 15, 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 March 20, 2024 response to our Form FDA 483 in detail.

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

1. 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 firm manufactures over-the-counter (OTC) drug products, such as cough, cold, and allergy medications. Your firm failed to establish an adequate quality unit (QU) to adequately oversee the manufacture of your drug products. For example, your QU approved drug products for release without complete finished product testing. Your firm shipped multiple units of a batch of (b)(4) to your customer on July 19, 2023. However, finished product samples for microbial testing for that batch were not taken until August 10, 2023, and QU approval of the finished product test specification sheet was not until August 23, 2023. This practice also deviates from your own procedures which prohibited release of finished drug products prior to passing all acceptance criteria. Complete testing of each batch of drug product before release is required to determine if the drug products you manufacture meet appropriate specifications.

Furthermore, your QU lacked adequate authority to perform their duties. For example, your firm’s senior management circumvented QU authority and changed the deviation classification from “moderate” to “minor” during an investigation into discoloration of finished drug product tablets. The downgrade in classification, under your procedures, would no longer require an investigation. Your firm subsequently disposed of the discolored tablets and the investigation was closed without identifying a root cause.

Your QU also failed to ensure:

Thorough investigations into deviations and other discrepant results are performed (21 CFR 211.192).

Adequate finished product testing to ensure each batch of drug is free of objectionable microorganisms (21 CFR 211.165(b)).

Scientifically sound and appropriate sampling plans and test procedures were designed to assure that finished drug products conform to appropriate standards of identity, strength, quality, and purity (21 CFR 211.160(b)).

Appropriate procedures are established and followed for cleaning and maintenance of equipment (21 CFR 211.67(b)).

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.

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)).

Your firm uses water as a component in your drug products. However, you failed to adequately qualify your water system to ensure that the system is operating properly and continuously producing water suitable for its intended use. For example, during qualification of your water system, you detected the presence of objectionable microorganisms, including Burkholderia cepacia. You failed to conduct adequate investigations into the presence of these objectionable microorganisms. In addition, you failed to conduct adequate investigations into other excursions, including exceeding specification limits for total aerobic microbial counts, and conductivity. Your water system qualification also failed to establish adequate corrective actions in response to contamination in your (b)(4) water system; on several occasions, you detected objectionable microorganisms in your (b)(4) water shortly after system sanitization.

As a result of several qualification failures, your (b)(4) water system was not in a state of control. Yet, your firm manufactured several drug products and released them for distribution during your qualification studies when the presence of objectionable microorganisms was detected, and other excursions occurred in your component water.

In your response you state that your drug products “have no risk with objectionable organisms due to the formulation of the product” and its “robust” preservative system. Your response is inadequate because antimicrobial preservatives should not be used as a substitute for good manufacturing practices. This concern is heightened because multiple water system sample failures for objectionable microbiological contamination were noted in your water system qualification protocol, with some occurring even shortly after sanitization.

Water for pharmaceutical purposes must be suitable for its intended use and routinely tested to ensure ongoing conformance with appropriate chemical and microbiological attributes. The lack of adequate validation provides no assurance the system performs as intended, and subsequent use of inadequately (b)(4) water in pharmaceutical manufacturing can adversely affect drug product quality and patient safety.

You failed to adequately test each shipment of each lot of propylene glycol for identity, a component at higher risk for diethylene glycol (DEG) and ethylene glycol (EG) contamination. We note that propylene glycol is an ingredient used in your drug products. Identity testing for propylene glycol and certain other high-risk drug components include a DEG/EG limit test in the United States Pharmacopeia (USP) to ensure that the component meets the relevant safety limits. Because you did not perform full 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 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 there is “no compulsory mandate for the routine execution of exhaustive identification testing” on raw materials. Your response is inadequate because identity testing for components is a requirement per 21 CFR 211.84.

Based on information submitted to FDA, it appears you may be selling your facility. In response to this letter, clarify whether you intend to continue manufacturing drugs at this or any other facility.

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 at this or any other facility where you manufacture drugs. 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.

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.

Your written notification should refer to case # 683081.

Please electronically submit your reply, on company letterhead, to Dayna I. Martinez, Compliance Officer, at ORAPHARM2_RESPONSES@fda.hhs.gov and dayna.martinez@fda.hhs.gov, and copy ronda.loyd-jones@fda.hhs.gov.

If you have questions regarding the contents of this letter, you may contact Dayna I. Martinez via phone at 787-729-8608 or email at dayna.martinez@fda.hhs.gov