Findings citing 21 CFR 211.84

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), 211.84(d)(2) and 211.110(c)). You failed to perform adequate identity testing on each shipment of each lot of the incoming components (e.g., (b)(4) ) used in the manufacture of your OTC drug products. You also purchase (b)(4) multiple components used for manufacturing your drug products, some containing (b)(4) , and you do not test the in-process materials for identity, strength, quality, and purity as appropriate. For example, you did not ensure that each of the (b)(4) components met the relevant safety limits for (b)(4) . In both cases, you relied on your suppliers’ certificate of analysis without establishing the reliability of each of the suppliers’ test analyses at appropriate intervals. Identity testing for high-risk drug components (b)(4) includes a limit test in the United States Pharmacopeia (USP) to ensure the component meets the relevant safety limits for (b)(4) levels, respectively. Because you did not perform identity testing on each shipment of each lot using the USP identification test or an equivalent validated method that detects these hazardous impurities, you failed to assure the acceptability of these components for use in the manufacture of your drug products. (b)(4) You failed to adequately test each shipment of each lot of (b)(4) , used as an active pharmaceutical ingredient, for (b)(4) . The use of (b)(4) contaminated with (b)(4) has resulted in various lethal poisoning incidents in humans worldwide. See FDA’s guidance document (b)(4) . (b)(4) You failed to adequately test each shipment of each lot of (b)(4) , used as an inactive ingredient, for (b)(4) contamination. 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) In your response, you commit to updating the specification for every raw material used in US-bound OTC products to include at least one specific identity test. Your response is inadequate. You failed to specify the identity tests you intend to perform including limit tests to detect hazardous impurities as appropriate. Without adequate testing, you do not have appropriate assurance that components and purchased in process material (b)(4) , conform to appropriate specifications prior to use in the manufactured drug products. As a manufacturer, you have the responsibility to sample, test, and examine drug components and any purchased in-process material (b)(4) before use in production to assure adequate quality. In response to this letter, provide: A description of how you will test each component or purchased in-process material (b)(4) lot, for conformity with all appropriate specifications for identity, strength, quality, and purity. If you intend to accept any results from your supplier’s certificates of analysis (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 re-validation. In addition, include a commitment to always conduct at least one specific identity test for each incoming component lot. In the case of (b)(4) and certain additional high-risk components we note that this includes the performance of (b)(4) of the United States Pharmacopeia (USP) monograph. A commitment to provide (b)(4) 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 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 (b)(4) . A full risk assessment for drug products that are within expiry which contain any ingredient at risk for (b)(4) contamination (including, but not limited to, (b)(4) ). Take prompt and appropriate actions to determine the safety of all lots of the component(s) and any related drug product that could contain (b)(4) , including customer notifications and product recalls for any contaminated lots. 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. Detail these actions in your response to this letter. The chemical and microbiological quality control specifications you use to test each incoming lot of high-risk drug components to determine acceptability for use in manufacturing. A comprehensive assessment of your in-process monitoring and sampling operations, focusing on each upstream process step that can introduce variability. Provide your remediation plan to improve: (1) in-process detection of variation, (2) upstream controls, and (3) sampling plans. 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 results obtained from testing all components to evaluate the reliability of the COA from each component manufacturer. Include your SOP that describes this COA validation program. A summary of your program for qualifying and overseeing contract facilities that test the drug products you manufacture.

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 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)). Your firm failed to ensure that components were suitable for use in manufacturing your OTC (b)(4) drug products. For example, you did not perform adequate identity testing on each shipment of each lot of incoming components (e.g., (b)(4) ). Additionally, you relied on your suppliers’ certificates of analysis (COA) without establishing the reliability of each of your component suppliers’ test analyses at appropriate intervals. Products Containing (b)(4) You manufacture multiple drugs that contain (b)(4) (e.g., (b)(4) ). You failed to adequately test your incoming (b)(4) for (b)(4) contamination. The use of (b)(4) contaminated with (b)(4) has resulted in various lethal poisoning incidents in humans worldwide. See FDA’s guidance document (b)(4) . In your response, you state that you initiated a change control request “to modify the system to ensure (b)(4) impurity testing is included” and tested raw materials for (b)(4) impurities. Your response is inadequate because you do not provide sufficient detail about your updated raw material specifications and how you will ensure performance of appropriate incoming testing for each component. Also, you failed to indicate whether you lack retain samples of any batches and are therefore unable to test them for impurities. Additionally, you failed to demonstrate that the (b)(4) you used as a component to manufacture your drug products met USP monograph specifications including those for impurities (e.g., (b)(4) ). Products Containing (b)(4) You also failed to adequately test your incoming components at high risk of (b)(4) contamination for identity before using them to manufacture your drug products. This includes, but is not limited to, testing of (b)(4) to determine its appropriate identity before using it in manufacturing your OTC (b)(4) drug products. Identity testing for glycerin and certain other high-risk drug components includes a limit test in the USP to ensure that the component meets the relevant safety limits for (b)(4) or (b)(4) levels. 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 ensure the acceptability of these components for use in the manufacture of your drug products. 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 the CGMP requirements when manufacturing drugs containing ingredients at high-risk for (b)(4) contamination at (b)(4) . In your response, you state that you initiated a change control request “to modify the test procedure to ensure the inclusion of (b)(4) ” and tested raw materials for (b)(4) . Your response is inadequate because you do not provide sufficient documentation of your updated raw material specifications and how you will ensure performance of appropriate testing on incoming components. Also, you failed to indicate whether you lack retain samples of any batches and are therefore unable to test them for hazardous impurities. Without adequate testing, you do not have scientific evidence that the components conform to the appropriate specifications before their use in the manufacture of your drug products. You are responsible for sampling, testing, and examining drug components before their use in production to ensure that acceptable quality parameters are met. 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 lot of component for use in manufacturing. 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 re-validation. In addition, include a commitment to always conduct at least one specific identity test for each incoming component lot. In the case of (b)(4) , and certain additional high-risk components, we note that this includes the performance of parts (b)(4) of the USP monograph. Based on a thorough review, provide a summary of your systems CAPA to remediate the vendor qualification program and prevent use of unsuitable components, containers and closures. A commitment to perform reconciliation of retains tested versus all lots used in production. If retain samples are unavailable, a commitment to test finished drug product batches for the presence of (b)(4) . Also include your analytical methods. A summary of your program for qualifying and overseeing contract facilities that test the components and drug products you manufacture. A full risk assessment for drug products that are within expiry which contain any ingredient at risk for (b)(4) contamination (including, but not limited to, (b)(4) ). Take prompt and appropriate actions to determine the safety of all lots of the component(s) and any related drug product that could contain (b)(4) , including customer notifications and product recalls for any contaminated lots.…

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)). Your firm did not adequately test your incoming component, (b)(4) , for identity prior to use in manufacturing. (b)(4) is a component that is at high risk for (b)(4) contamination. Your firm also accepted the (b)(4) raw material based on the supplier’s certificate of analysis (COA), without establishing the reliability of each of your component suppliers’ analyses at appropriate intervals. Additionally, the (b)(4) lot you utilized for drug product production had expired. In your response, you state that you opened a CAPA, performed a risk assessment, and sent all remaining drums of (b)(4) out for testing. In addition, you state that your firm is evaluating the (b)(4) of your (b)(4) products to a lower-risk excipient, to eliminate supply chain risk in all future productions. Your response is inadequate. Your risk assessment is theoretical. You conclude that the risk is low based on (b)(4) and (b)(4) application. You did not correlate the assessment to the actual test results for all affected lots. Additionally, your firm acknowledges that identity testing based on supplier COA plus FTIR was inadequate for high-risk materials like (b)(4) , yet you still reference past acceptance decisions as part of your justification. Acknowledging the gap does not mitigate the fact that your product was released under a flawed system, without appropriate controls in place at the time. Further, while you describe retrospective testing of remaining drums, there is no clear discussion of drug product that had already been manufactured and potentially distributed using untested (b)(4) . There is no mention of an impact assessment or of any market action. While your response states that you will reformulate your finished drug products to remove (b)(4) , it lacks a retrospective assessment with supporting analytical testing for products containing materials at high risk for (b)(4) contamination that are still on the market and within expiry. Furthermore, your response did not include an assessment of your drug products to identify other components at risk for (b)(4) contamination and proposed corrective actions. Your response also lacks your interim plans, controls, or risk-mitigation strategies until you reformulate your finished drug products. Identity testing for (b)(4) and certain other high-risk drug components includes a limit test in the United States Pharmacopeia (USP) to ensure that the component meets the relevant safety limits for (b)(4) levels. 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 ensure the acceptability of these components for use in the manufacture of your drug products. 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 the CGMP requirements when manufacturing drugs containing ingredients at high risk for (b)(4) contamination at (b)(4) In your response to this letter, provide: A commitment to provide (b)(4) 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 drug products. Alternatively, if a retain of a component lot is unavailable, perform retain of a component lot is unavailable, perform retain sample testing of all implicated finished drug product batches for the presence of (b)(4) . A full risk assessment for drug products that are within expiry which contain any ingredient at risk for (b)(4) contamination (including, but not limited to, (b)(4) ). Take prompt and appropriate actions to determine the safety of all lots of the component(s) and any related drug product that could contain (b)(4) , including customer notifications and product recalls for any contaminated lots. Identify additional appropriate 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’ COAs 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 and 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 (b)(4) , 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 their 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 components you use to manufacture your drugs. A summary of results obtained from testing all components to evaluate the reliability of the COA from each component manufacturer.…

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) & 211.84(d)(2)). Your firm manufactures OTC drug products, including (b)(4) , intended for the U.S. market. Your response to our request for records and information under section 704(a)(4) indicated that you do not test the identity of each incoming component, (b)(4) , used in the manufacture of your drug products prior to manufacturing. Your response also indicated that you accept your suppliers’ certificates of analyses without verifying the test results at appropriate intervals. You also did not provide evidence that (b)(4) , the active ingredients in your drug products, meet USP limits for (b)(4) . See FDA’s guidance document (b)(4) . Without adequate testing and verification of supplier results, you do not have scientific evidence that your incoming components conform to appropriate specifications prior to use in the manufacture of your drugs. As a manufacturer, you have a responsibility to sample, test, and examine incoming materials before use in production to assure adequate quality.

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)). Your firm failed to perform identification testing on raw materials and components including APIs prior to use in your OTC drug products. For example, your firm did not perform any testing on the raw material (b)(4) , lot# (b)(4) . In addition, you relied on your suppliers’ certificates of analysis (COAs) in lieu of testing each component lot for purity, strength, identity, and quality. You also did not establish a supplier qualification program to assess (i.e., initially and periodically) the reliability of your suppliers’ test results for these attributes. In your response, you acknowledge the failure to conduct identity testing on incoming raw materials. You commit to confirming that the bulk lot was fully tested for identity and quantification by a third party before further processing. You also commit to performing identity testing for all API lots currently in inventory and retain samples. Your response is inadequate. Your response provides no assurance that all incoming materials will be tested for identity as required. In addition, you did not provide any procedures or testing methods for review. Your test report for incoming raw material is unclear on who performs the identification test or whether the results recorded are from the supplier’s COA. Also, you did not provide a plan for your supplier qualification program. 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 lot of components for use in manufacturing. 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 re-validation. In addition, include a commitment to always conduct at least one specific identity test for each incoming component lot. A summary of results obtained from testing all components to evaluate the reliability of the COA from each component manufacturer. Include your SOP that describes this COA validation program.