TCI Co., Ltd BioCosme PABP BRANCH — FDA Warning Letter Findings

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) lacked adequate control over your OTC drug product manufacturing operations and failed to ensure that you had adequate procedures. Your firm made changes to your manufacturing process parameters in the batch manufacturing instructions without following your Procedure for Change Management and Operational Procedures for Handling of Abnormal Situations . For example: During the manufacture of your product (b)(4) , batch (b)(4) , you changed your (b)(4) without documented justification. During the manufacture of your product (b)(4) , batches (b)(4) , you changed a (b)(4) without documented justification. Your response states that a retrospective investigation revealed that your research and development team made on-site adjustments to process parameters without following the established change procedure. In your response you commit to following the required change procedure. Your response is inadequate because your retrospective review did not include a comprehensive assessment of other possible incidents of the change procedure not being followed. Additionally, the following are examples of poor QU oversight: The batch production and control records are deficient in that they do not include documentation of the accomplishment of each significant step in manufacturing. 21 CFR 211.188(b) There is no written testing program designed to assess the stability characteristics of drug products. 21 CFR 211.166(a) 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 at https://www.fda.gov/downloads/drugs/guidances/ucm353925.pdf for help implementing quality systems and risk management approaches to meet the requirements of CGMP regulations 21 CFR parts 210 and 211 . In response to this letter, provide the following: A copy of your revised SOP, Operational Procedures for Handling of Abnormal Situations 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 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 products. Procedures to ensure if your manufacturing process parameters change your quality approves before all commercial manufacturing. Training records to confirm that all relevant personnel, including research and development staff have been trained in the change management requirements. Drug Production Suspended During the inspection you communicated your decision to allow your drug registration with the FDA to expire. Your firm stated that you will renew the drug registration if a U.S. (b)(4) order is received. If you plan to resume any manufacturing operations regulated under the FD&C Act, notify this office before resuming your drug manufacturing operations. If you resume CGMP activities, you are responsible for resolving all deficiencies and systemic flaws to ensure your firm is capable of ongoing CGMP compliance. In addition, 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 all 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. In your notification to the Agency, provide a summary of your remediations to demonstrate that you have appropriately completed all corrective action and preventive action (CAPA).

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 manufactured over-the-counter (OTC) drug products without adequate identity testing of incoming active pharmaceutical ingredients (APIs) and raw materials including, but not limited to, (b)(4) before use in your OTC drug products. Additionally, you relied on your suppliers’ certificates of analysis (COA) for these components without verifying your suppliers’ test results at appropriate intervals. Your firm failed to ensure components met United States Pharmacopeia (USP) monograph identity requirements and were suitable for use in manufacturing your (b)(4) drug products. For example: You did not perform all identity testing on components you used to manufacture (b)(4) , batches (b)(4) , including (b)(4) . You did not perform all identity testing on components you used to manufacture (b)(4) , batch (b)(4) , including (b)(4) . You failed to test incoming lots of (b)(4) used in the manufacturing of the drug products intended for the US market for (b)(4) and (b)(4) in each shipment of each lot of (b)(4) before determining acceptability for use. The identity testing of (b)(4) includes a limit test per the USP monograph to ensure it meets the relevant safety limits for the levels of (b)(4) . The use of ingredients contaminated with (b)(4) has resulted in various lethal poisoning incidents in humans worldwide. See FDA’s guidance document (b)(4) , to help you meet CGMP requirements when manufacturing drugs containing ingredients at high-risk for (b)(4) contamination. Your quality control laboratory failed to perform all identity testing of (b)(4) per USP monograph requirements. Additionally, your Ingredients and Raw Material Standard Guidelines do not require these raw materials be tested for identity. Our investigator documented that you do not test your components in conformance with the USP monograph. For example, your supplier’s COA for (b)(4) lacks Identification Test A, Impurities - Lead test, Iron and Other Heavy Metals test, Alkalinity test, and Carbonate and Color of Solution test. In addition, for (b)(4) the supplier COA lacks Identification Test A, Residue on Ignition test, Limit of Lead test, and Limit of Organic Impurities test; for (b)(4) the supplier’s COA lacks Identification Test A, Composition of Fatty Acid test, Residue on Ignition test, and Limit of (b)(4) test. You failed to provide records indicating that you established the reliability of your supplier’s analyses through appropriate validation of the supplier’s test results. Although 21 CFR 211.84(d)(2) provides for some reliance on a COA from the supplier of the component, such reliance is permissible only if the drug product manufacturer establishes the reliability of the supplier’s test results through appropriate validation of the test results at appropriate intervals. In your response you state, your laboratory has not performed identification testing for certain raw materials due to the lack of appropriate instrumentation. Further, you state for certain raw materials, you did not perform identity testing because the USP methods do not specify such tests. It is your responsibility to ensure that the appropriate USP monographs are used for the testing of all ingredients used in the manufacture of your drug products. We acknowledge that you commit to outsourcing testing for certain raw materials for which USP does not specify an identity testing method. Without adequate testing, you do not have scientific evidence that components conform to appropriate specifications prior to use in the manufacture of your drug products. As a manufacturer, you have a responsibility to adequately sample, test, and examine drug components before use in production to assure quality. In response to this letter, provide the following: Identify additional appropriate corrective actions and preventive actions (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. 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 qualification as well as periodic requalification.

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)). Your firm failed to adequately test your OTC drug products prior to release and distribution to the U.S. market. For example, your firm did not perform assay testing of the API as part of finished product release testing of your (b)(4) product (b)(4) batches (b)(4) . These batches were released and distributed to the U.S. market without appropriate testing. Without adequate testing, you do not have adequate scientific evidence to assure that drug product batches conform to appropriate specifications before release. In your response you state you will confirm the definitions of raw material and product specification standards with your customer and explicitly verify whether the assay test is included. Your response is inadequate. Your firm’s quality system does not ensure that all required tests are identified, documented, and performed before product is released to your customers. You do not have a written procedure or a quality agreement describing the roles and responsibilities between you, as the contract manufacturing organization, and your customer regarding testing requirements and established product specifications. You are responsible for the quality of drugs you produce as a contract facility regardless of agreements in place with product owners. You are required to ensure that drugs are made in accordance with section 501(a)(2)(B) of the FD&C Act for safety, identity, strength, quality, and purity. See FDA’s guidance document Contract Manufacturing Arrangements for Drugs: Quality Agreements at https://www.fda.gov/downloads/drugs/guidances/ucm353925.pdf. In response to this letter, provide the following: A comprehensive quality agreement describing the responsibilities of each party regarding drug products testing and release, establishing drug product specifications, initiating investigations, and batch disposition. The quality agreement should define the manufacturing responsibilities and communication processes for quality related activities. A list of chemical and microbial test methods and specifications used to analyze each lot of your drug product before making a lot disposition decisions.

Your firm failed to establish adequate written procedures for production and process controls designed to assure that the drug products have the identity, strength, purity, and quality that they are purported or represented to possess (21 CFR 211.100(a)). Inadequate Process Validation for Drugs Your firm did not adequately validate the manufacturing processes you used to manufacture your (b)(4) drug products to demonstrate that your processes are reproducible and controlled to consistently yield drugs of uniform character and quality. Your Process Validation for Cosmetic Products document indicates that you use it to validate your manufacturing process for your OTC (b)(4) mL bottle. During the inspection, your firm confirmed that this process validation is intended to support the manufacture of (b)(4) . However, our investigator confirmed that the (b)(4) is not manufactured in accordance with the validated process. For example, the process validation includes a (b)(4) step that is absent from the (b)(4) batch record. Furthermore, you failed to conduct process validation for your (b)(4) . Your firm confirmed during the inspection that your firm relies on the process validation performed for (b)(4) to support the manufacturing of (b)(4) . However, the manufacturing processes for these products differ. We acknowledge your commitment to perform process validation for all your products moving forward. It remains your responsibility to maintain all supporting documentation, including your defined critical manufacturing process parameters. 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 to ensure the quality of raw material inputs, in-process materials, and finished drugs. Your validation program should identify sources of process variability and assure that manufacturing operations meet appropriate parameters and quality standards. This includes, but is not limited to, evaluating suitability of equipment for its intended use, ensuring quality of input materials, determining the capability and reliability of each manufacturing process step with ongoing monitoring of process performance and product quality. Inadequate Validation of (b)(4) You used (b)(4) as a component to manufacture multiple batches of OTC (b)(4) drug products and distributed these batches to the U.S. market. However, your firm failed to adequately qualify your (b)(4) to ensure it produces (b)(4) that meets appropriate chemical and microbial attributes and meets the (b)(4) monograph. Specifically, your (b)(4) qualification protocol and report lacked total organic carbon (TOC) testing, conductivity, or microbial content to ensure the (b)(4) is fit for its intended use. Additionally, you use this (b)(4) for cleaning drug manufacturing equipment. (b)(4) is an ingredient in your drug products. (b)(4) must be suitable for its intended use and routinely tested to ensure ongoing conformance with appropriate chemical and microbiological attributes. In your response, you state you increased microbial sampling frequency to (b)(4) , revised the (b)(4) facility inspection record form to include TOC for routine monitoring, and established a trend analysis mechanism. Your response is inadequate because it fails to include the current action and alert limits for total counts and objectionable microorganisms used for your (b)(4) . Without defined limits, increased sampling frequency alone does not constitute a robust monitoring mechanism. See FDA's guidance for industry, Process Validation: General Principles and Practices at https://www.fda.gov/downloads/drugs/guidances/ucm070336.pdf for general principles and approaches that FDA considers appropriate elements of process validation. 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 and ongoing vigilant monitoring of both intra-batch and inter-batch variation to ensure a continuing state of control. Also, describe your equipment and facility qualification program. A procedure for your (b)(4) 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. The current action/alert limits for total counts and objectionable organisms used for your (b)(4) . Ensure that the total count limits for your (b)(4) are appropriately stringent in view of the intended use of each of the 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) specifications and appropriate microbial limits.