Bentley Laboratories LLC — FDA Warning Letter Findings

CFR 201.66(b)(2) defines “active ingredient” to mean “any component that is intended to furnish pharmacological activity or other direct effect in the diagnosis, cure, mitigation, treatment, or prevention of disease, or to affect the structure or any function of the body of humans.” Although the product label does not specifically list Glycolic Acid as an active ingredient in the Drug Facts labeling, your product labeling makes claims such as “1.5% Glycolic Acid…Clears Skin Fast…Prevents New Breakouts” which demonstrates that this is an “active ingredient” in your acne treatment product because it is intended to furnish pharmacological activity. Specifically, the ingredient for this product is not permitted or recognized as an acceptable active ingredient when used under M006. We note that while salicylic acid is a permitted active ingredient under M006, it is not permitted in combination with the above ingredient or other active ingredients. In addition, as labeled, "Perricone MD Acne Relief Maximum Strength Spot Gel" includes the active ingredients Lactic & Succinic Acids, Citrulline, and Tea Tree Oil, which are not permitted active ingredients under M006.10. Although the product label does not specifically list Lactic & Succinic Acids, Citrulline, and Tea Tree Oil as active ingredients in the Drug Facts panel. Label claims such as “KEY INGREDIENTS Lactic & Succinic Acids: Target Acne-Causing Bacteria…help minimize blemishes…Citrulline: Fight & Visibly Reduce Redness…Tea Tree Oil: helps soothe the skin & visibly reduce redness” demonstrate that these are “active ingredients” in your acne treatment product because they are intended to furnish pharmacological activity. Thus, the “Geologie Acne Control Body Wash” and “Perricone MD Acne Relief Maximum Strength Spot Gel” products do not comply with the applicable conditions specified in M006 and have not otherwise been found to be GRASE. 2 Accordingly, these products are new drugs within the meaning of section 201(p) of the FD&C Act, 21 U.S.C. 321(p), and there is no basis under section 505G of the FD&C Act under which these products would be legally marketed without an approved application. Because there are no applications in effect for these products, these products are unapproved new drugs. The introduction or delivery for introduction of these unapproved new drug products into interstate commerce violates sections 505(a) and 301(d) of the FD&C Act, 21 U.S.C. 355(a) and 331(d). Misbranded Drug Violations Your “Geologie Acne Control Body Wash” and “Perricone MD Acne Relief Maximum Strength Spot Gel” are misbranded under section 502(ee) of the FD&C Act, 21 U.S.C. 352(ee), because these products are nonprescription drugs subject to section 505G of the FD&C Act, 21 U.S.C. 355h, but do not comply with the requirements for marketing under that section and are not the subject of an application approved under section 505 of the FD&C Act, 21 U.S.C. 355. The introduction or delivery for introduction of a misbranded drug into interstate commerce violates section 301(a) of the FD&C Act, 21 U.S.C. 331(a). Cosmetics Manufactured for Distribution in the United States In addition, some of the products you manufacture may be regulated as cosmetics, as defined in section 201(i) of the FD&C Act [21 U.S.C. 321(i)]. Any cosmetics you manufacture must comply with applicable statutory and regulatory requirements, including the FD&C Act. We note that under section 301(a) of the FD&C Act [21 U.S.C. 331(a)], it is a prohibited act to introduce or deliver for introduction into interstate commerce a cosmetic that is adulterated or misbranded. We also note that the Modernization of Cosmetics Regulation Act of 2022 (MoCRA) provides new requirements with which facilities that manufacture cosmetic products must comply. You may find the FD&C Act, MoCRA, and FDA’s regulations through links on FDA’s website at www.fda.gov. Drug Production Suspended We acknowledge your commitment to suspend production of OTC drug products “that do not meet the required testing and systemic rigor” at this facility. If you plan to resume any manufacturing operations regulated under the FD&C Act, notify this office before resuming your drug manufacturing operations. 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 action and preventive action, 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 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)). 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 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 failed to adequately validate your manufacturing processes for OTC drug products. You did not revalidate your manufacturing processes after making major process changes, nor did you fully execute validation protocols through the completion of all batches. For example, you changed the manufacturing process for (b)(4) to rephase the formulation without revalidation and outside of your change management system. Also, for (b)(4) , your process validation execution deviated from your Validation Master Plan (VMP) which requires validating your manufacturing processes with three batches. Furthermore, you did not retain stability samples from any of the three batches. Your firm also failed to adequately validate your cleaning processes for non-dedicated equipment used to manufacture (b)(4) . For the two validation batches where cleaning validation swab samples were collected, OOS results for residual of active pharmaceutical ingredients were not adequately investigated. In your response, you state a change control will be conducted for the (b)(4) and, if required, a process validation will be performed for the revised process. You also state you will complete the validation for the (b)(4) and will update your VMP as well as applicable standard operating procedures (SOPs). Your response is inadequate because you do not commit to revalidating the (b)(4) process. Additionally, you do not evaluate the roles and responsibilities of your QU, including change management and document control, to ensure comprehensive oversight functions. Also, it appears that you used a maximum allowable carryover limit of (b)(4) ppm in your cleaning validation calculations without adequate scientific justification. Without adequate process validation that incorporates all manufacturing inputs and parameters that can affect product quality, your firm lacks basic assurance that you can reproducibly deliver products that meet specifications. 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 assure the quality of raw material inputs, in-process materials, and finished drugs. Process qualification studies include intensive monitoring and testing throughout each significant process stage to characterize intra-batch variation and evaluate batches to 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 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: 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. A timeline for performing appropriate process performance qualification for each of your marketed drug products. A risk assessment for the distributed drug products produced using inadequately validated processes. Appropriate improvements to your cleaning validation program, with special emphasis on incorporating conditions identified as worst case in your drug manufacturing operation. This should include, but not be limited to, identification and evaluation of all worst-case: o drugs with higher toxicities o drugs with higher drug potencies o drugs of lower solubility in their cleaning solvents o drugs with characteristics that make their manufacturing equipment difficult to clean o swabbing locations for areas that are most difficult to clean o maximum hold times before cleaning A description of the steps that will be taken in your change management system before introduction of new manufacturing equipment or a new product. A summary of updated SOPs that ensure an appropriate program is in place for verification and validation of cleaning procedures for products, processes, and equipment. A comprehensive, independent retrospective assessment of your cleaning effectiveness to evaluate the scope of cross-contamination hazards. Include the identity of residues, other manufacturing equipment that may have been improperly cleaned, and an assessment whether cross-contaminated products may have been released for distribution. The assessment should identify any inadequacies of cleaning procedures and practices, and encompass each piece of manufacturing equipment used to manufacture more than one product. Quality Systems Your firm’s quality systems are inadequate. For help implementing quality systems and risk management approaches to meet the requirements of CGMP regulations 21 CFR, parts 210 and 211, see FDA’s guidance documents Quality Systems Approach to Pharmaceutical CGMP Regulations at https://www.fda.gov/media/71023/download. Significant findings in this letter demonstrate that your firm does not operate an effective quality system in accord with CGMP. In addition to the lack of effective management oversight of your production and laboratory operations, we found your quality unit is not enabled to exercise proper authority and/or has insufficiently implemented its responsibilities.…