供应商未确认，工艺规程未验证、稳定性计划不合理及QU职责不明确，FDA发出警告信。
WARNING LETTER
Custom Research Labs Inc.
MARCS-CMS 616184 — JULY 08, 2022
July 8, 2022
Dear Mr. Kim:
The U.S. Food and Drug Administration inspected your drug manufacturing facility, Custom Research Labs Inc., FEI: 3008268262, at 432 W. Alondra Blvd., Gardena, from June 1 to June 4, 2021.
2021年6月1日至6月4日,美国食品和药物管理局检查了企业位于432 W. Alondra Blvd., Gardena的药品生产设施，Custom Research Labs Inc.，FEI: 3008268262。
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).
本警告信总结了成品药严重违反现行良好生产规范(CGMP)规定的情况。参见《联邦法规法典》第21篇，第210和211部分(21 CFR第210和211部分)。
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).
由于生产、加工、包装或贮存方法、设施或控制不符合CGMP，企业的药品在《联邦食品、药品和化妆品法案》(FD&C法案)第501(a)(2)(B)条21 U.S.C. 351(a)(2)(B)节的含义范围内掺假。
In addition, “(b)(4),” “(b)(4) HAND SANITIZER” (8 oz and 16 oz), and “BAK-OFF Instant Hand Sanitizer” are unapproved new drugs introduced or delivered for introduction into interstate commerce in violation of section 505(a) of the FD&C Act, 21 U.S.C 355(a), and are misbranded under sections 502(c) and (ee) of the FD&C Act, 21 U.S.C. 352(c) and (ee). Introduction or delivery for introduction of such products into interstate commerce is prohibited under sections 301(d) and (a) of the FD&C Act, 21 U.S.C. 331(d) and (a). These violations are described in more detail below.
此外， “(b)(4),” “(b)(4) HAND SANITIZER” (8 oz and 16 oz), and “BAK-OFF Instant Hand Sanitizer”是未经批准的新药，违反了《FD&C法案》第505(a)条，21 U.S.C. 355(a)条，并根据《FD&C法案》第502(c)和(ee)条，21 U.S.C. 352(c)和(ee)条的规定而引入或交付到州际商业中。根据《FD&C法案》第301(d)和(a)条，21 U.S.C. 331(d)和(a)条，禁止将此类产品引入州际贸易。以下将详细描述这些违规行为。
We reviewed your June 10, 2021, response to our Form FDA 483 in detail.
FDA详细审查了企业在2021年6月10日对FDA 483表格的回复。
During our inspection, our investigators observed specific violations including, but not limited to, the following.
检查过程中，检查人员发现了具体的违规行为，包括但不限于以下几点。
1. 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)).
1.未能检验每一原辅料样品的成分并确定是否符合纯度、规格和质量的所有适当书面质量标准。也未能定期验证并建立对原辅料供应商检验分析的信任关系。(21 CFR 211.84(d)(1) 和 (2))
Your firm failed to test incoming active pharmaceutical ingredients (e.g., camphor and menthol) and other components (e.g., deionized (DI) water) used to manufacture over-the-counter drug products to determine their identity, purity, strength, and other appropriate quality attributes. For active pharmaceutical ingredients (API), you relied solely on certificates of analysis (COA) from suppliers where you have not established their reliability. In addition, you have not shown that your water system can consistently produce water suitable for drug manufacturing, and, at a minimum, meets the USP monograph for purified water and appropriate microbial limits.
企业未能检测原料的活性药物成分(如樟脑和薄荷醇)和其他用于生产非处方药的成分(如去离子水)，以确定其鉴别、纯度、规格和其他适当的质量属性。对于原料药(API)，企业仅依赖于来自供应商的分析证书(COA)，而尚未确定其可靠性。另外，企业没有证明水系统能够持续生产出符合药品生产的水，并且至少满足USP各论中关于纯化水和适当的微生物限度的要求。
For example,
例如
Inadequate API Testing
API检测不充分
Your firm relied on the COA from unqualified suppliers of camphor and menthol. These components are used in the manufacture of your (b)(4) drug product. The FDA requires identity testing for each component lot used in drug product manufacturing, and you can only rely on the COA for other component attributes by appropriately validating the supplier’s test results at appropriate intervals.
贵公司依赖不合格的樟脑和薄荷醇供应商的COA。这些原辅料用于企业xx药品的生产。FDA要求对药品生产中使用的每个原辅料进行鉴别，企业只能通过依赖供应商COA并定期验证供应商的测试结果来获得其他成分属性。
In addition, you did not ensure all specifications of your components were in conformance with USP. For example, the COA specification for impurity testing for halogens of camphor gum USP states “CONFORMS TO USP.” However, the USP monograph for camphor gum has a quantitative acceptance criterion for halogens and the quantitative result was not provided. Also, you provided the COA for menthol USP, which lacked impurity testing data for limit of nonvolatile residue and related compounds as required per the USP monograph.
另外，企业没有确保所有原料的规格都符合USP。例如，对樟脑胶卤素杂质检测的COA规定“符合USP”。然而，USP关于樟脑胶的各论对卤素有一个定量接受标准，并且没有提供定量结果。另外，企业提供了薄荷醇USP的COA，其中缺乏根据USP各论要求的非挥发性残留和相关化合物限度的杂质检测数据。
In your response, you stated that both camphor and menthol have been validated by a third-party laboratory “through assay.” Your response is inadequate because you failed to demonstrate that all appropriate tests for camphor and menthol were performed or that appropriate validation of the supplier’s test results was conducted. Further, you did not address the discrepancies between your third-party laboratory’s COA and USP specifications.
回复中，企业声称樟脑和薄荷醇都已由第三方实验室“通过检测含量”验证。企业的回复是不充分的，因为未能证明对樟脑和薄荷醇进行了所有适当的测试，或对供应商的测试结果进行了适当的验证。此外，没有说明企业第三方实验室COA和USP规范之间的差异。
Inadequate Component Water
成分水不足
Your firm has not shown that your DI water is suitable for aqueous-based dosage form drug product manufacturing, and, at a minimum, meets the USP purified water monograph and appropriate microbial limits. Further, your firm lacked sufficient testing of your DI water system. Inadequate water system design is a repeat observation from your 2016 FDA inspection. For example,
贵公司没有证明去离子水适用于水基剂型药品的生产，并且至少符合USP纯化水专论和适当的微生物限度。此外，贵公司缺乏DI水系统充分的检验。水系统设计不充分是企业2016年FDA检查中的重复观察项。例如,
• Your firm has no record of testing water for Total Organic Carbon (TOC). In your response you stated, "All products produced since March 2020, have passed micro testing ensuring there are no TOC issues." You committed to purchase a TOC meter but failed to provide a timeline for the purchase and validation of the equipment. Further, the vendor stated in the TOC meter proposal provided in your response that, based on the current design of the system, TOC will most likely not meet the specification and that a recirculation pump must be added to keep the TOC low. Your response lacked details on whether you will establish appropriate TOC specifications and ensure your water system is adequately designed to meet those specifications.
贵公司没有测试水的总有机碳(TOC)记录。在回复中，企业解释，“自2020年3月以来生产的所有产品都通过了微生物测试，确保没有TOC问题。”企业承诺购买TOC仪表，但未能提供购买和验证设备的时间表。此外，供应商在企业的回复中提供的TOC仪表建议中指出，基于系统的当前设计，TOC很可能无法满足规范，必须添加一个再循环泵以保持较低的TOC。企业的回复缺少关于是否将建立适当的TOC规范并确保企业的水系统充分设计以满足这些规范的细节。
• Since March 2020, your firm failed to monitor conductivity of your water used as a component in your drug products. You also failed to establish a specification for conductivity. Your response failed to address the lack of a conductivity specification.
•自2020年3月以来，贵公司未能监测药品生产所用水的电导率。也没有制定电导率规范。回复未能解决缺乏电导率规范的问题。
Furthermore, your firm’s water system point-of-use ports yielded elevated bioburden counts of 1.3 x 106 and 2.3 x 104 total plate count (TPC)/ml for water used as a component in your drug products. Your action limit was (b)(4) TPC/ml. Your associated investigations did not adequately determine potential root cause(s) to fully investigate product impact. Your response did not address bioburden failures that lacked adequate investigation. Also, in multiple instances, the pH of your water system Line (b)(4) was out of specification with results ranging between 3.59 and 4.73. Your pH specification was (b)(4). In your response, you stated that, batches manufactured during this period were reviewed and there was no evidence that batches were affected. However, you did not provide data to substantiate this claim.
此外，贵公司的水系统使用点端口产生了1.3 x 106和2.3 x 104总平板计数(TPC)/ml的微生物负荷计数升高，用于企业药品生产中使用的水。企业的行动限为xx TPC/ml。企业的相关调查未能充分确定潜在根本原因，无法全面调查产品影响。企业的回复没有提及缺乏充分调查的生物负荷不合格。此外，在多个情况下，企业的水系统(b)(4)线的pH值超出规格，结果范围在3.59 - 4.73之间。企业的pH值规格为xx。在回复中声称，在此期间生产的批次已经过审核，没有证据表明批次受到了影响。但是，企业没有提供数据来证实这一说法。
Without routine water monitoring of an appropriately designed system, you cannot ensure that your water meets minimum microbiological and chemical standards suitable for the manufacture of your drug products.
如果没有适当设计的系统进行常规水质监测，就无法确保企业的水质符合适合药品生产的最低微生物和化学标准。
In response to this letter, provide:
针对本函，请提供：
• 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.
描述企业将如何检验每一原辅料，以确保其符合所有适用的鉴别、规格、质量和纯度标准。如果企业打算接受供应商COA的检验结果，而不是检验每一原辅料的规格、质量和纯度，请说明企业将如何通过初始验证和定期重新验证来确认供应商检验结果的可靠性。此外，包括对每个进厂原辅料批次始终进行至少一次专属鉴别检验。
• The chemical and microbiological quality control specifications you use to test and release each incoming lot of component for use in manufacturing.
•检验和放行进厂原辅料的化学和微生物质量控制规范。
• 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.
•对物料系统进行全面、独立的审查，以确定所有原辅料、容器和密封件的供应商是否合格，并指定适当的有效或复验日期。审查还应确定进厂物料控制是否足以防止使用不合适的原辅料、容器和密封件。
• A procedure for your water system monitoring that specifies routine chemical and microbial testing of water to ensure its acceptability for use in each batch of drug products produced by your firm.
• 水系统监控程序，规定了水的常规化学和微生物检测，以确保其可用于贵公司生产的每批药品。
• A comprehensive, independent assessment of your water system design and maintenance including the sanitization process. In addition, provide a summary of the qualification protocol(s) for your component water system. Also, include a summary of any improvements made to your system design and program for routine control and maintenance.
•对企业的水系统设计和维护进行全面、独立的评估，包括消毒过程。另外，请提供一份水系统确认方案总结。此外，还应包括对系统设计和日常控制和维护程序所做改进的总结。
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)).
2. 未能制订充分的书面生产和工艺控制程序，以确保企业生产的药品具有其声称或表明拥有的鉴别、规格、质量和纯度(21 CFR 211.100(a))。
Your firm failed to validate the manufacturing process for (b)(4) drug product currently in distribution. This is a repeat observation from your 2016 FDA inspection.
贵公司未能验证当前在售的xx药品的生产工艺。这是2016年FDA检查的重复观察结果。
In your response, you stated that the validation of your (b)(4) drug product was not completed yet because you “require (b)(4) batches before we can validate a formula,” and only two batches have been completed. However, as observed during the inspection, there are at least (b)(4) batches manufactured using an unvalidated process and currently in distribution. Your response is inadequate because you failed to conduct an assessment or identify corrective actions to address unvalidated drug products currently in distribution.
回复中，企业声称xx药品的验证尚未完成，因为“需要xx批次，才能验证配方”，而目前只完成了两个批次。然而，正如在检查中观察到的，至少有xx批次使用未经验证的工艺生产，目前正在销售中。企业的回复是不充分的，因为未能进行评估或确定纠正措施来解决目前销售中的未验证药品的问题。
In response to this letter, provide:
针对本函，请提供：
• 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 monitoring of both intra-batch and inter-batch variation to ensure a continuing state of control.
•一份确保整个产品生命周期内受控状态的验证程序以及相关规程的详细总结。请描述企业的工艺性能确认程序，以及对批内和批间差异的持续监控，以确保持续受控状态。
• A timeline for performing appropriate process performance qualification for each of your marketed drug products, including how you will ensure proper validation prior to distribution of drugs.
对每一种上市药品进行适当工艺性能确认的时间表，包括企业将如何确保在药品销售前进行适当的验证。
3. Your firm failed to establish and follow an adequate written testing program designed to assess the stability characteristics of drug products and to use results of stability testing to determine appropriate storage conditions and expiration dates (21 CFR 211.166(a)).
3.贵公司未能建立并遵循充分的书面检验程序，该程序旨在评估药品的稳定性特征，并使用稳定性检验结果来确定适当的存储条件和有效期(21 CFR 211.166(a))。
Your firm lacked stability data to support the expiration dates for your (b)(4) drug product which is currently in distribution. This is a repeat observation from your 2016 FDA inspection. Instead, to support the two-year expiration date of your drug product, you provided data from a different formulation of (b)(4) that failed its long-term stability study and was stopped at the three-month time point because of changes in viscosity. The long-term stability test report determined the need for reformulation.
贵公司缺乏稳定性数据来支持目前正在销售中xx药品的有效期。这是2016年FDA检查的重复观察结果。相反，为了支持药品的两年有效期，企业提供了另一种xx配方的数据，该配方未能通过其长期稳定性研究，由于粘度变化在三个月时间点被停止。长期稳定性试验报告确定需要重新配制。
In your response, you explained that because a retain sample of (b)(4) drug product passed microbiology and assay testing, the two-year expiration date was justified for the drug product. However, the retain sample tested was the formulation that failed its long-term stability study for viscosity. Further, you did not provide testing to ensure the retain sample met all specifications required during your stability studies such as odor, pH, and viscosity. Your response is inadequate because you failed to provide a report that ensures adequate stability studies have been conducted for all drug products.
回复中，企业解释说由于xx药品的留样通过了微生物和含量检测，该药品的2年有效期是合理的。然而，被检验的保留样品是未通过粘度长期稳定性研究的配方。此外，企业没有提供检验结果以确保留样符合稳定性研究期间要求的所有标准，如气味、pH值和粘度。企业的回复是不充分的，因为未能提供一份报告，以确保对所有药品进行了充分的稳定性研究。
Without an adequate stability program, you cannot confirm that your drug products will meet established specifications and all pre-determined quality criteria throughout their shelf life.
没有充分的稳定性研究，企业不能确认药品在整个保质期内符合既定的标准和所有预先确定的质量标准。
In response to this letter, provide the following:
针对本函，请提供以下内容：
• A comprehensive, independent assessment and corrective action and preventive action (CAPA) plan to ensure the adequacy of your stability program. Your remediated program should include, but not be limited to:
•一份全面、独立的评估及纠正和预防措施(CAPA)计划，以确保企业的稳定性计划的充分性。整改措施应包括但不限于:
o Stability studies for each drug product in its marketed container-closure system before distribution is permitted.
o在允许销售前，对每种药品在其上市的容器封闭系统中的稳定性进行研究。
o Stability-indicating methods.
o稳定性指示方法。
o An ongoing program in which representative batches of each product are added each year to the program to determine if the shelf-life claim remains valid.
o一个持续的程序，每年将每种产品的代表性批次添加到程序中，以确定货架期声明是否有效。
o Detailed definition of the specific attributes to be tested at each station (timepoint).
o详细定义在每个点(时间点)检测的具体属性。
• All procedures that describe these and other elements of your remediated stability program.
• 描述整改稳定性计划的以上要素和其他要素的所有规程
4. 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).
4. 贵公司的质量部门未能履行其职责，以确保生产的药品符合CGMP，并符合鉴别、规格、质量和纯度标准(21 CFR 211.22)。
Your quality unit (QU) failed to review batch records before releasing drug product for distribution. Your QU procedure specifies that the Quality Assurance designee is responsible for reviewing all manufacturing, production, and quality records. However, during the inspection, one of your QU employees stated that the shipping and production department had released drug product batches before the batch record had been reviewed by the QU. It was also stated that your firm is trying to catch up on back logged batch record reviews. During the inspection, we observed that drug product batch records were incomplete at the time of release for (b)(4) Lot (b)(4), and (b)(4) and for (b)(4) Lot (b)(4).
质量部门(QU)在放行药品供销售前未审核批记录。企业的QU规程规定质量保证指定人员负责审查所有生产和质量记录。然而，在检查过程中，企业的一名QU员工表示，在QU审核批记录之前，销售和生产部门就已经放行了药品批次。他还表示，贵公司正在努力审核积压的批记录。在检查中，FDA发现xx批号、xx批号和xx批号放行时药品批号记录不完整。
In your response, you stated that all pending batch record reviews have been completed and that you revised your record review procedure to include batch sheet approval and other controls. However, your response failed to provide details of the outcome of that review. Your response is inadequate because you failed to identify appropriate corrective actions when the QU released drug products before batch record completion to ensure that drug products met established specifications for identity, strength, quality, and purity.
回复中，企业声明所有待处理的批记录审核已经完成，企业修改了记录审核规程，包括批单审批和其他控制。但是，企业的答复未能提供审查结果的细节。企业的回复是不充分的，因为未能在批记录完成及药品放行时之前确定适当的纠正措施，以确保药品符合既定的鉴别、规格、质量和纯度标准。
Your response demonstrated a lack of CGMP understanding and the lack of adequate quality oversight and control from incoming products to finished product.
企业的回复表明缺乏对CGMP的理解，从进厂原料到成品缺乏充分的质量监督和控制。
Your inspectional history indicates that your quality unit is not fully exercising its authority and responsibilities. Your firm must provide the QU with the appropriate authority and sufficient resources to carry out its responsibilities and consistently ensure drug quality.
企业的检查历史表明质量部门没有充分履行其权力和职责。贵公司必须向QU提供适当的权限和足够的资源，以履行其职责并持续确保药品质量。
In response to this letter, provide:
针对本函，请提供：
• 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:
•一份全面的评估和整改计划，以确保企业的QU得到有效运作的授权和资源。评估还应包括但不限于:
o A determination of whether procedures used by your firm are robust and appropriate
o确定贵公司使用的规程是否稳健和适用
o Provisions for QU oversight throughout your operations to evaluate adherence to appropriate practices
o规定QU对整个生产过程进行监督，以评估对适当做法的遵守情况
o A complete and final review of each batch and its related information before the QU disposition decision
o在QU处理决定之前，对每批产品及其相关信息进行完整和最终的审核
o Oversight and approval of investigations and discharging of all other QU duties to ensure identity, strength, quality, and purity of all products
o监督和批准调查以及履行所有其他QU职责，以确保所有产品的鉴别、规格、质量和纯度
Unapproved New Drug and Misbranding Violations
未经批准的新药和错标违规
Unapproved New Drug Violations
未经批准的新药违规
“(b)(4) HAND SANITIZER” (8 oz and 16 oz), and “BAK-OFF Instant Hand Sanitizer” are “drugs” as defined by section 201(g)(1)(B) of the FD&C Act, 21 U.S.C. 321(g)(1)(B), because they are intended for use in the diagnosis, cure, mitigation, treatment, or prevention of disease, and/or under section 201(g)(1)(C) of the FD&C Act, 21, U.S.C. 321(g)(1)(C), because they are intended to affect the structure or any function of the body. Specifically, “(b)(4),” and “(b)(4) are topical products intended for use as external analgesics. “(b)(4) HAND SANITIZER” (8 oz and 16 oz) and “BAK-OFF Instant Hand Sanitizer” are topical products intended for use as consumer topical antiseptics. Examples of claims from the products’ labeling, including websites listed on product labels, that provide evidence of the intended uses (as defined by 21 CFR 201.128) of these products include, but may not be limited to, the following: From your website (b)(4):
“(b)(4) HAND SANITIZER” (8 oz and 16 oz), and “BAK-OFF Instant Hand Sanitizer”是根据FD&C法案第201(g)(1)(b)(21 U.S.C. 321(g)(1)(b)定义的“药物”，因为它们旨在用于诊断、治愈、缓解、治疗或预防疾病，和/或根据FD&C法案第201(g)(1)(C) (21 U.S.C. 321(g)(1)(C)，因为它们旨在影响身体的结构或任何功能。具体来说，“(b)(4)”和“(b)(4)”是打算用作外部镇痛的产品。“(b)(4) HAND SANITIZER” (8 oz and 16 oz) and “BAK-OFF Instant Hand Sanitizer”是外用产品，用作消费者外用抗菌剂。产品标签(包括产品标签上列出的网站)提供了这些产品预期用途(按照21 CFR 201.128的定义)的证据，包括但不限于以下内容:
On your website homepage:
(b)(4)
在网站主页上：
(b)(4)
On your website for “HOW IT WORKS”:
(b)(4)
在“如何工作”网站上：
(b)(4)
“(b)(4) HAND SANITIZER” (8 oz and 16 oz)
“Easy To Use Spray + Surface Disinfectant . . . Uses1 ● for handwashing to decrease microbial contamination on the skin ● may be reapplied during the day as required ● for disinfecting surfaces” [from your product label]
“易于使用的喷雾剂+表面消毒剂。..用途1●洗手以减少皮肤上的微生物污染●可在白天重复使用●表面消毒”[来自产品标签]
......
Quality Systems
质量体系
Your firm’s quality systems are inadequate. See the 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/regulatory-information/search-fda-guidance-documents/quality-systems-approach-pharmaceutical-current-good-manufacturing-practice-regulations.
贵公司的质量体系不充分。参见FDA的指导文件《药品CGMP法规质量体系方法》，帮助实施质量体系和风险管理方法，以满足CGMP法规21 CFR, 210和211部分的要求，网址是https://www.fda.gov/regulatory-information/search-fda-guidance-documents/quality-systems-approach-pharmaceutical-current-good-manufacturing-practice-regulations。
CGMP Consultant Recommended
建议聘请CGMP顾问
Based upon the nature of the violations we identified at your firm, we strongly recommend engaging a consultant qualified as set forth in 21 CFR 211.34 to assist your firm in meeting CGMP requirements. 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.
基于FDA发现的违规性质，FDA强烈建议聘请一位符合21 CFR 211.34中规定的合格顾问来帮助你公司满足CGMP要求。使用顾问并不能免除遵守CGMP的义务。贵公司的执行管理层仍有责任全面解决所有缺陷，以确保持续的CGMP符合性。
Additionally, we note that you manufacture several OTC drug products, “(b)(4)” and “(b)(4)” that are labeled with a Drug Facts panel in which the purpose identifies these products as a “Pain Reliever.” While we acknowledge that neither product currently appears to be available for purchase or distribution in the US, we want to advise you of their regulatory status under 505G of the FD&C Act, 21 U.S.C. 355G. “(b)(4)” and “(b)(4)” are considered to be drugs as defined under section 201(g)(1)(C) of the FD&C Act, 21 U.S.C. 321(g)(1)(C) because they are intended for use as external analgesics. Section 505G of the FD&C Act, 21 U.S.C. 355h governs nonprescription drugs marketed without an approved application. These products prominently feature cannabidiol (CBD) on the principal display panel and include statements such as, “(b)(4) CBD.” Although CBD is labeled as an inactive ingredient in the labels of “(b)(4)” and “(b)(4),” the labeling for these products clearly represents CBD as an active ingredient.6 Currently, a nonprescription drug product containing CBD cannot be legally marketed without an approved new drug application, regardless of whether the CBD is represented on the labeling as an active ingredient or an inactive ingredient. To date, no CBD-containing drug has met applicable FDA requirements to be legally marketed for nonprescription use. Nonprescription drug products that include CBD as an active ingredient are not generally recognized as safe and effective and are new drugs which require an approved application to be legally marketed.
另外，FDA注意到企业生产几种OTC药品，“xx”和“xx”标有药品事实说明，目的是将这些产品标识为“止痛药”。虽然FDA知晓目前这两种产品似乎都无法在美国购买或分销，但根据FD&C法案505G (21 U.S.C. 355G)，FDA希望通知企业其监管状态。“(b)(4)”和“(b)(4)”被认为是根据《FD&C法案》21 U.S.C. 321(g)(1)(C)第201(g)(1)(C)条定义的药物，因为其预期用途是外用镇痛剂。FD&C Act, 21 U.S.C. 355h第505G条管理未经批准申请上市的非处方药。这些产品在主要展示面板上显著地标明了大麻二酚(CBD)，并包括诸如“(b)(4) CBD”之类的声明。虽然在“(b)(4)”和“(b)(4)”标签中，CBD被标记为非活性成分，但这些产品的标签上明确表示CBD是一种活性成分，含有CBD的非处方药产品如果没有获得批准的新药申请，就不能合法销售，无论CBD在标签上是作为有效成分还是非活性成分。到目前为止，还没有含有CBD的药物符合FDA的要求，可以合法地用于非处方用途。包括CBD作为活性成分的非处方药产品通常不被认为是安全有效的，而且是需要批准申请才能合法销售的新药。
Furthermore, even if CBD could be considered an inactive ingredient in a nonprescription drug product, that product would still need an approved new drug application to be legally marketed, because the product would not meet the general requirements for nonprescription drug products under section 505G of the FD&C Act. In particular, such product would not meet the general requirement with respect to the safety and suitability of inactive ingredients under 21 CFR 330.1(e)7. Additionally, an inactive ingredient should not exert pharmacological effect8 and must be safe when used at the intended dosage.9
此外，即使CBD可以被视为非处方药产品中的非活性成分，该产品仍需要获得批准的新药申请才能合法销售，因为该产品不符合FD&C法案第505G条对非处方药产品的一般要求。特别是，该产品将不符合21 CFR 330.1(e)7关于非活性成分的安全性和适用性的一般要求。此外，非活性成分不应发挥药理作用，并且在规定剂量时必须是安全的
We note that CBD also cannot legally be sold in a conventional food or dietary supplement product. Please see the following for more information: FDA Regulation of Cannabis and Cannabis-Derived Products, Including Cannabidiol (CBD) and Warning Letters and Test Results for Cannabidiol-Related Products.
我们注意到CBD也不能在传统食品或膳食补充剂产品中合法销售。请参阅以下信息:FDA对大麻和大麻衍生产品的监管，包括大麻二酚(CBD)和对大麻二酚相关产品的警告信和检验结果。
Conclusion
结论
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.
在这封信中引用的违规行为并不是企业存在的所有违规行为的清单。企业有责任调查和确定任何违规行为的原因，并防止其再次发生或其他违规行为的发生。
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.
及时纠正违规行为。未能及时并充分地解决该问题可能会导致无需另行通知的监管或法律行动，包括但不限于扣押和禁令。未解决的违规行为也可能妨碍其他联邦机构授予合同。
Failure to address violations may also cause the FDA to withhold issuance of Export Certificates. The 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.
未能解决违规问题还可能导致FDA暂停签发出口证书。FDA可能会拒绝批准贵公司作为药品生产商的新申请或补充申请，直到完全解决任何违规行为，并且FDA确认企业符合CGMP。FDA可能会重新检查，以确认企业是否完成了针对任何违规行为的纠正措施。
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.
本函通知企业FDA的调查结果，并为企业提供解决上述缺陷的机会。收到此信后，请在15个工作日内书面回复本办公室。请说明已经做了哪些工作来解决任何违规并防止其再次发生。在回复这封信时，可以提供额外的信息供我们考虑，FDA将继续评估企业的活动和做法。如果不能在15个工作日内完成纠正措施，说明延迟的原因和完成计划。
Please identify your response with the unique identifier: CMS# 616184
Send your electronic response to ORAPHARM4_Responses@FDA.HHS.GOV with ATTN: CDR Steven E. Porter, Jr. or mail your written response to:
CDR Steven E. Porter, Jr.
Director, Division of Pharmaceutical Quality Operations IV
U.S. Food & Drug Administration
19701 Fairchild Road
Irvine, California 92612-2506
If you have questions regarding this letter, please contact LCDR Rumany Penn, Compliance Officer, at (949) 608-4409, or by email at Rumany.Penn@fda.hhs.gov.
Sincerely,
/S/
Lance M. De Souza
Acting Director, Division of Pharmaceutical Quality Operations IV
Cc:
David V. Ward
President
Custom Research Labs Inc.
432 W. Alondra Blvd.
Gardena, CA 90248-2425
david@customresearchlabs.com
