Colgin, Inc.

The U.S. Food and Drug Administration (FDA) inspected your drug manufacturing facility, Colgin, Inc., FEI 1610391, at 4111 Mint Way, Dallas, from September 18 to September 21, 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 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 September 28, 2023, 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 failed to conduct at least one test to verify the identity of each component of a drug product. 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 manufacture an over-the-counter (OTC) drug product, ChigaRid External Analgesic. You failed to adequately test your incoming components for identity before using the components to manufacture your OTC drug product. You also relied on your suppliers’ certificate of analysis (COA) without establishing the reliability of your component suppliers’ test analyses at appropriate intervals. Additionally, your firm approved the use of expired raw materials during the production of your ChigaRid External Analgesic drug product.

Your response includes actions that will be taken to improve your component controls. Your response is inadequate because you did not provide supportive documentation, did not consider a retrospective evaluation of potential impact to product currently on the market, and your completion timelines are unclear.

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. As a manufacturer, you have a responsibility to sample, test, and examine drug components before use in production to assure adequate quality.

In response to this letter, provide:

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.

The chemical and microbiological quality control specifications you use to test and release each incoming batch of components for use in manufacturing.

A description of how you will test each component batch 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 batch 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 re-validation. In addition, include a commitment to always conduct at least one specific identity test for each incoming component batch.

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 that describes this COA validation program.

A summary of your program for qualifying and overseeing contract facilities that test the drug products you manufacture.

A detailed risk assessment addressing the hazards posed by distributing drug products manufactured with expired components. The risk assessment should include a summary of all results obtained from testing retain samples from each batch of impacted product. If such testing reveals substandard quality drug products, take rapid corrective actions, such as notifying customers and product recalls.

2. Your firm failed to establish 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 has not established that your processes used to manufacture ChigaRid External Analgesic drug product are validated.

In your response, you commit to validating your manufacturing process. Your response is inadequate because you did not provide supportive documentation, did not consider a retrospective impact assessment, it lacks completion timelines, and your interim production plans are unclear.

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 ensure 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 that you maintain a stable manufacturing operation throughout the product lifecycle.

See FDA’s guidance document 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.

In response to this letter, provide the following:

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.

Include your process performance protocol(s), and written procedures for qualification of equipment and facilities.

Provide 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.

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 microbiological testing and appropriate specifications for your finished drug products (21 CFR 211.165(b)).

Any unexplained discrepancy or failure of a batch or any of its components to meet any of its specifications are thoroughly investigated, whether or not the batch has already been distributed (21 CFR 211.192).

Adequate cleaning and maintenance procedures for the firm’s dedicated manufacturing equipment (21 CFR 211.67(a))

Establishment of an adequate stability program (21 CFR 211.137(a)).

Performance of periodic (i.e., at least annually) product reviews (21 CFR 211.180(e)).

Adequate training for employees engaged in the manufacture, processing, packing, or holding of drug products (21 CFR 211.25(a)).

In your response, you commit to improving oversight of your QU. However, your response is inadequate because you did not provide supportive documentation, did not consider a retrospective impact assessment, and your interim production plans as well as your completion timeframes are unclear.

Your firm’s quality systems are inadequate. See FDA’s guidance document Quality Systems Approach to Pharmaceutical CGMP Regulations for help in 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 that your QU is given the authority and resources to effectively function. The assessment should also include, but not be limited to:

A determination of whether procedures used by your firm are robust and appropriate.

Provisions for QU oversight throughout your operations to evaluate adherence to appropriate practices.

A complete and final review of each batch and its related information before the QU disposition decision.

Oversight and approval of investigations and discharging of all other QU duties to ensure identity, strength, quality, and purity of all drug products.

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 (b)(4)-system audit1 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.

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 e-mail or by phone at (954) 759 - 7718.