实验室检验、稳定性试验以及质量部门不符合cGMP，FDA发出警告信。
WARNING LETTER
DSP Skin Care LLC
MARCS-CMS 622549 — JULY 19, 2022
July 19, 2022
Dear Mr. Alkadi:
The U.S. Food and Drug Administration (FDA) inspected your drug manufacturing facility, DSP Skin Care LLC, FEI 3013374118, at 1930 Wilshire Boulevard, Suite 507, Los Angeles, from September 7 to September 9, 2021.
美国食品和药物管理局(FDA)于2021年9月7日至9月9日检查了企业位于洛杉矶Wilshire Boulevard, Suite 507的生产设施DSP Skin Care LLC，FEI 3013374118。
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).
该警告信总结了产品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 (the FD&C Act), 21 U.S.C. 351(a)(2)(B).
由于企业生产、加工、包装或贮存方法、设施或控制不符合CGMP，企业的药品根据《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)规定的范围内掺假。
In addition, your Hongosan Anti-Fungal Set product is an unapproved new drug 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 is misbranded under sections 502(a), (c), and (ee) of the FD&C Act, 21 U.S.C. 352(a), (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，企业的Hongosan抗真菌套装产品是未经批准的新药，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(a)， (c)和(ee)条[21 U.S.C. 352(a)， (c)和(ee)]为错标。根据《FD&C法案》第301(d)条和(a)条[21 U.S.C. 331(d)条和(a)条]，禁止州际贸易中引入或交付此类产品。这些违规行为将在下文详细描述。
In addition, DSP Skin Care LLC is not duly registered with FDA as required by section 510 of the FD&C Act and 21 CFR Part 207. With some limited exceptions, firms that manufacture, prepare, propagate, compound, or process drugs in the United States, or that are offered for import into the United States, must be registered with the FDA. Sections 510(b), (c), (d), and (i) of the FD&C Act, 21 U.S.C. 360(b), (c), (d), and (i).
此外， DSP Skin Care LLC 没有按照FD&C法案第510条和21 CFR Part 207的要求正式在FDA注册。除了一些有限的例外，在美国生产、制备、繁殖、合成或加工药物，或提供进口到美国的公司必须在FDA注册。FD＆C法案第510（b），（c），（d）和（i）节，21 U.S.C. 360(b), (c), (d), 和 (i)。
Hongosan Anti-Fungal Set product (tolnaftate 1%, undecylenic acid 0.1%, soap), Hongosan Anti-Fungal Cream (tolnaftate 1%), and Hongosan Premium Plus Spray (undecylenic acid 0.1%) are not duly listed with FDA as required by section 510(j) of the FD&C Act. Failure to properly list a drug product is prohibited under section 301(p) of the FD&C Act, 21 U.S.C. 331(p), and will render a drug misbranded under section 502(o) of the FD&C Act, 21 U.S.C. 352(o). Introduction or delivery for introduction of such products into interstate commerce is prohibited under section 301(a) of the FD&C Act, 21 U.S.C. 331(a). These violations are described in more detail below.
Hongosan Anti-Fungal Set product (甲苯1%，十一烯酸0.1%，肥皂)，Hongosan Anti-Fungal Cream(甲苯1%)Hongosan Premium Plus Spray(十一烯酸0.1%)未按照FD&C法案第510(j)条的要求正式在FDA登记。根据《FD&C法案》(21 U.S.C. 331(p))第301(p)条禁止未能正确登记药品，并将导致药品在《FD&C法案》(21 U.S.C. 352(o))第502(o)条下为错标。根据FD&C法案21 U.S.C. 331(a)第301(a)条，禁止在州际贸易中引入或交付此类产品。下面将更详细地描述这些违规行为。
We reviewed your September 17, 2021, response to our Form FDA 483 in detail.
FDA详细审查了企业于2021年9月17日对FDA 483表格的回复。
During our inspection, our investigators observed specific violations including, but not limited to, the following.
在FDA的检查过程中，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 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)).
1. 贵公司未能在放行前对每批药品进行适当的符合药品最终质量标准的实验室检验，包括每种活性成分的鉴别和规格(21 CFR 211.165(a))。
Your firm released Hongosan Premium Plus Spray and DSP Skin Care Hand Sanitization Gel over-the-counter (OTC) drug products without testing to ensure that they met their identity, purity, strength, and other appropriate quality attributes. While the label for Hongosan Premium Plus Spray drug product lists an active ingredient, you stated that your contract manufacturer did not test the product since it no longer contained an active ingredient, undecylenic acid. In addition, you stated to our investigators that your DSP Skin Care Hand Sanitization Gel drug product was not tested by your contract manufacturer because you failed to pay them to test the product.
贵公司在没有进行检测以确保符合其鉴别、纯度、规格和其他适用质量属性的情况下，放行了Hongosan Premium Plus Spray and DSP Skin Care Hand Sanitization Gel非处方(OTC)药品。虽然Hongosan Premium Plus Spray药品的标签上列出了一种有效成分，但企业表示合同制造商没有检验该产品，因为它不再含有有效成分，即十一烯酸。另外，企业向FDA检查人员表示，企业的DSP Skin Care Hand Sanitization Gel药品没有经过合同生产商的检验，因为企业没有支付检验该产品的费用。
In your response, you stated the Hongosan Premium Plus Spray drug product (b)(4) and the packaging will be updated to reflect the removal of undecylenic acid. You also stated that you would further inquire about laboratory testing for your drug products and establish applicable procedures. Further, you stated that you do not intend to continue manufacturing your DSP Skin Care Hand Sanitization Gel drug product.
回复中，企业表示将更新 Hongosan Premium Plus Spray药品(b)(4)，其包装以反映十一烯酸的去除情况。企业还表示，将进一步检查实验室检验并制订适用的规程。此外，企业表示不打算继续生产DSP Skin Care Hand Sanitization Gel药品。
Your response is inadequate because you did not address how you will ensure appropriate laboratory determination of satisfactory conformance to final specifications, including identity and strength of each active ingredient in Hongosan Premium Plus Spray and DSP Skin Care Hand Sanitization Gel drug products prior to release. Further, you did not include sufficient information about your testing procedures, methods, or a detailed description of the tests you will conduct (for example, for identity, strength, and purity). Although you stated that you do not intend to continue manufacturing the DSP Skin Care Hand Sanitization Gel drug product, you failed to address the lack of testing of drug product on the market that is still within expiry.
企业的回复是不充分的，因为没有说明放行前将如何确保实验室检测符合药品的最终质量标准，包括Hongosan Premium Plus Spray and DSP Skin Care Hand Sanitization Gel 药品中每个活性成分的鉴别和规格。此外，企业没有详细描述关于检验规程、方法或将要执行的检验（例如，鉴别，规格和纯度）的充分信息。尽管企业表示不打算继续生产DSP护肤洗手液，但企业未解决市场上仍在效期内的药品缺少检验的问题。
Testing is essential to ensure that the drug products you manufacture meet established specifications.
检测对于确保企业生产的药品符合既定的质量标准是必不可少的。
In response to this letter, provide the following:
针对本函，请提供以下信息：
• A list of chemical and microbiological specifications, including test methods, used to analyze each lot of your drug products before a lot disposition decision.
•化学和微生物标准清单，包括在批次处置决定之前用于分析每批药品的检验方法。
o An action plan and timelines for conducting full chemical and microbiological testing of retain samples, to determine the quality of all batches of distributed drug products that are within expiry as of the date of this letter.
o对留样进行全面的化学和微生物检测的行动计划和时间表，以确定截止本函日期的所有已销售药品批次的质量。
o A summary of all results obtained from testing retain samples from each batch. If such testing reveals substandard-quality drug products, take rapid corrective actions, such as notifying customers and product recalls.
o每批留样的所有检验结果的总结。如果检测发现了不符合质量标准的药品，应迅速采取纠正措施，如通知客户和药品召回。
2. 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)).
2. 贵公司未能建立并遵循充分的书面检验规程，该规程旨在评估药品的稳定性特征，并使用稳定性试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 an adequate stability program to demonstrate that the chemical and microbiological properties of your Hongosan Anti-Fungal Set and Hongosan Premium Plus Spray drug products remain within specification throughout their labeled expiry period. You explained to our investigators that the contract manufacturer verbally informed you that a two-year expiration date is the appropriate shelf life for these products without conducting stability studies or providing any stability data. You proposed remediation of your stability program in your 2018 inspection.
贵公司缺乏足够的稳定性方案来证明Hongosan Anti-Fungal Set and Hongosan Premium Plus Spray 药品的化学和微生物特征在其标示的有效期内保持在质量标准范围内。企业向FDA检查人员解释说，合同生产商口头通知企业，这些产品的保质期为两年，但没有进行稳定性研究或提供任何稳定性数据。企业在2018年的检查中表示对稳定性计划进行整改。
In your response, similar to your response regarding finished product testing, you stated that you would further inquire about laboratory testing for your drug products and establish applicable procedures.
回复中，与关于成品检验的回复类似，企业表示将进一步检查药品的实验室检验，并制订适用的规程。
In your response, you failed to provide data to demonstrate that the chemical and microbiological properties of your drug products will remain within specification throughout their labeled expiry period of up to two years, or interim measures to address the products on the market that are lacking stability data.
回复中，企业未能提供数据来证明药品的化学和微生物特性在其标示的长达两年的有效期内仍在质量标准范围内，也未能提供临时措施来解决市场上缺乏稳定性数据的产品。
Without an adequate stability program, you cannot confirm that your drug products will meet established specifications and all predetermined quality criteria throughout their shelf life.
没有充分的稳定性程序，企业无法确保药品在整个保质期内符合所有既定的质量标准。
In response to this letter, provide the following:
针对本函，请提供以下信息：
• 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、独立的评估及纠正措施和预防措施(CAPA)计划，以确保企业的稳定性计划的充分性。整改计划应包括但不限于:
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 稳定指示性方法。
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一个持续的计划，每年将每种产品的代表性批次添加到计划中，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)检验的具体属性。
• 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和其他要素的所有规程。
• A detailed risk assessment addressing the hazards posed by distributing drug products that lack stability data. Specify actions you will take in response to the risk assessment, such as customer notifications and product recalls.
•一份详细的风险评估报告，说明分销缺乏稳定性数据的药品所造成的危害。具体说明针对风险评估采取的措施，例如客户通知和产品召回。
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).
3.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，并符合药品的鉴别、规格、质量和纯度的既定标准(21 CFR 211.22)。
Your firm lacked written procedures detailing the roles, responsibilities, and duties of the quality unit (QU) to ensure that QU functions are accurately performed and that drug products meet quality standards. For example, your firm lacks written quality procedures for investigations, CAPA, change control, CGMP training, drug product stability, and finished drug product release. In addition, your firm could not provide batch production records, including lot control numbers, for bulk drug products used in repacking or filling operations for approximately 20 batches of Hongosan Anti-Fungal Cream and Hongosan Premium Plus liquid drug products. During the 2018 inspection, you acknowledged the need for a quality unit to ensure that the manufacturing process of OTC drug products remains in control.
贵公司缺乏书面规程，详细说明质量部门(QU)的角色、职责和权限，以确保准确执行QU职能，并确保药品符合质量标准。例如，贵公司缺乏书面的质量规程用于调查、CAPA、变更控制、CGMP培训、药品稳定性和成品放行。此外，贵公司不能提供批量生产记录，包括批量控制号，用于大约20批Hongosan Anti-Fungal Cream and Hongosan Premium Plus liquid 药品的重新包装或灌装操作。在2018年的检查中，企业承认需要一个质量部门来确保OTC药品的生产过程保持受控状态。
In your response, you stated that once testing procedures are established, “they shall be used to create a document for quality control.” Your response is inadequate because you failed to include details about how you intend to address all necessary requirements to establish a QU. Regarding batch production records, you stated that after the contract manufacturer who completes filling operations includes the batch numbers on product containers, your firm will document the “item, lot number, number of cases, and date” in a log. Your response is inadequate because you failed to establish a procedure or provide specific details about how you will ensure that batch production records will include complete information relating to the production and control of each batch.
回复中，企业表示一旦建立了检验规程，“需要创建一个文件来进行质量控制。”企业的回复是不充分的，因为没有打算如何解决建立QU的所有必要要求的详细信息。关于批生产记录，企业表示，在完成灌装操作的合同生产商记录产品容器上的批号后，贵公司将在日志中记录“产品、批号、装箱单和日期”。企业的回复是不充分的，因为未能制订规程或提供具体细节，说明将如何确保批生产记录包括每批生产和控制相关的完整信息。
Your response demonstrated a lack of CGMP understanding and the lack of adequate quality oversight and control from incoming products to finished product. Your firm must provide the QU with the appropriate authority and sufficient resources to carry out its responsibilities and consistently ensure drug quality. The QU is responsible for approving manufacturing procedures impacting the identity, strength, quality, and purity of the drug products and for reviewing production records to assure that no errors have occurred.
企业的回复显示缺乏对CGMP的理解，从进厂原料到成品缺乏足够的质量监督和控制。你们公司必须向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。QU负责批准影响药品鉴别、规格、质量和纯度的生产规程，并审核生产记录，以确保没有发生错误。
In response to this letter, provide the following:
针对本函，请提供以下信息：
• 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，以确保赋予QU足够的权限和资源来有效地履行其职能。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健全和适用。
o Provisions for QU oversight throughout your operations to evaluate adherence to appropriate practices.
o 规定QU监督整个生产过程，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做出处理决定之前，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 Violations
未经批准的新药违规
Your Hongosan Premiun [sic] Plus product, which consists of your Hongosan Anti-Fungal Cream, Hongosan Anti-Fungal Drops, and Hongosan Soap co-packaged and marketed as a three-component set (hereinafter "Hongosan Anti-Fungal Set"), is a “drug” as defined by section 201(g)(1)(B) of the FD&C Act, 21 U.S.C. 321(g)(1)(B), because it is 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 it is intended to affect the structure or any function of the body. Specifically, this product is intended for use as a topical antifungal.
企业的Hongosan Premiun [sic] Plus产品，由 Hongosan Anti-Fungal Cream, Hongosan Anti-Fungal Drops, 和 Hongosan Soap 组成，作为三成分一起包装和销售（以下简称“Hongosan Anti-Fungal Set”），是根据FD&C法案201(g)(1)(B)，[21 U.S.C. 321(g)(1)(B)]定义的“药物”，因为其旨在用于疾病的诊断、治愈、缓解、治疗或预防，和/或根据FD&C法案201(g)(1)(C)[21 U.S.C. 321(g)(1)(C)]，因为其旨在影响身体的结构或任何功能。具体来说，本产品作用为外部抗真菌。
Examples of claims from your product labeling, including your website labeling (at dspskincareproducts.com, where this product is available for purchase), that provide evidence of the intended uses (as defined in 21 CFR 201.128) of the product include, but may not be limited to, the following:
产品标签，包括网站标签(dspskincareproducts.com，该产品可在该网站购买)提供产品预期用途(如21 CFR 201.128中定义)声明示例包括但不限于以下内容:
“Description . . . The Hongosan Anti Fungal Set is a specialized three piece solution that fights fungal skin infections commonly found on the skin. This combo set helps relieve itching, burning, cracking, irritation, scaling, and fungal rash that are commonly associated with fungal infections. In addition, Hongosan alleviates many common fungal infections on the skin, and promotes the healing of skin affected by fungal infections. . . . This 3-piece non-prescription antifungal solution contains the following items: One Hongosan Soap, one Hongosan Anti-Fungal Cream containing Tolnaftate, and one Hongosan Anti-Fungal Drop.” [description of products within the kit, from your website https://dspskincareproducts.com/product/hongosan-anti-fungal-set/]
描述……“本草山抗真菌套装”是一款专门用于治疗皮肤真菌感染的三件套产品。这一组合有助于缓解瘙痒，灼伤，开裂，刺激，脱屑，和真菌皮疹。此外，本草散还能缓解皮肤上常见的真菌感染，并促进真菌感染皮肤的愈合. . . .这款三份的非处方抗真菌溶液包含以下物品:One Hongosan Soap, one Hongosan Anti-Fungal Cream containing Tolnaftate, and one Hongosan Anti-Fungal Drop。"[套件内产品描述，来自企业网站https://dspskincareproducts.com/product/hongosan-anti-fungal-set/]
......
As explained below, your “Hongosan Anti-Fungal Set” is a new drug within the meaning of section 201(p) of the FD&C Act, 21 U.S.C. 321(p). A new drug may not be introduced or delivered for introduction into interstate commerce without an approved application from FDA in effect, as described in section 505(a) of the FD&C Act, 21 U.S.C. 355(a), unless it is a nonprescription drug governed by and lawfully marketed under section 505G of the FD&C Act (which is not the case for this product, as described below) or under other exceptions not applicable here. No FDA-approved application pursuant to section 505 of the FD&C Act, 21 U.S.C. 355, is in effect for this drug product.
如下所述，你们的“Hongosan Anti-Fungal Set”是FD&C法案21 U.S.C. 321(p)第201(p)条定义的新药，。如21 U.S.C. 355(A)《FD&C法案》第505(A)条所述，未经FDA批准，新药不得引入或交付用于州际贸易，除非其是受《FD&C法案》第505G条约束并合法销售的非处方药(本产品不属于这种情况，如下所述)或在这里不适用其他例外情况。FDA根据FD&C法案第505条(21 U.S.C. 355)批准的申请对该药品无效。
Your Hongosan Anti-Fungal Set product is a drug subject to section 505G of the FD&C Act, 21 U.S.C. 355h, which governs nonprescription drugs marketed without an approved application. Under section 505G of the FD&C Act, certain nonprescription drugs marketed without an approved application —commonly referred to as "OTC monograph drugs"—may be legally marketed if they meet applicable requirements. With respect to OTC topical antifungal drug products, such products are deemed to be generally recognized as safe and effective (GRASE) and not a new drug if, among other things, they conform to the conditions of use set forth in the Over-the-Counter (OTC) Monograph M005: Topical Antifungal Drug Products for Over-the-Counter Human Use (henceforth “M005”).1 Your “Hongosan Anti-Fungal Set” product is an OTC topical antifungal drug product based on the claims noted above and thus, it is subject to the requirements of Over-the-Counter (OTC) Monograph M005. However, the “Hongosan Anti-Fungal Set” does not conform to the conditions of use specified in M005; in particular, the product is neither formulated nor labeled in conformance with M005.
企业的Hongosan Anti-Fungal Set产品是需要遵守21 U.S.C. 355h ，FD&C Act 505G条的药物，该条管理未经批准申请而上市的非处方药。根据FD&C法案第505G条，某些未经批准申请销售的非处方药——通常称为“OTC专论药物”——如果符合适用要求，可以合法销售。对于非处方外部抗真菌药物产品，如果符合《非处方(OTC)专论M005:人非处方外部抗真菌药物(以下简称“M005”)》规定的使用条件，则被普遍认为是安全有效的(GRASE)，而不是新药。1企业的“Hongosan Anti-Fungal Set”产品是基于上述声明的OTC外用抗真菌药物产品，因此，它受非处方(OTC)专论M005的要求。但“Hongosan Anti-Fungal Set”不符合M005规定的使用条件;特别是，该产品的配方和标签都不符合M005。
Tolnaftate 1%, as a sole active ingredient, is permitted for use as an antifungal under M005 and is the active ingredient in your Hongosan Anti-Fungal Cream. However, the directions for use on the labeling of your Hongosan Anti-Fungal Set, noted above, convey to the consumer that the components of this product, including the Hongosan Anti-Fungal Drops containing undecylenic acid 0.1% and the Hongosan Soap, are intended to be used in conjunction with each other as an antifungal treatment. M005 does not allow for such a combination of components as a nonprescription antifungal drug, nor does it allow for more than one active ingredient in a nonprescription antifungal drug. In addition, the labeling of your Hongosan Anti-Fungal Set product makes claims that the product “Treats most external fungal infections” and “Treats most dermic infections”, which are not claims permitted by M005.
1%的Tolnaftate，作为唯一的有效成分，在M005下被允许作为抗真菌药物使用，并且是Hongosan Anti-Fungal中的有效成分。然而，上述Hongosan Anti-Fungal Set标签上的使用说明告诉消费者，本产品的成分，包括含有0.1%十一烯酸的Anti-Fungal Drops和Hongosan Soap，是用来联合使用用于抗真菌治疗的。M005不允许将这种成分组合作为非处方抗真菌药物，也不允许在非处方抗真菌药物中含有一种以上的活性成分。另外，Hongosan Anti-Fungal Set产品的标签上写着“治疗大多数的外部真菌感染”和“治疗大多数的皮肤感染”，这不是M005所允许的。
Therefore, your Hongosan Anti-Fungal Set product does not meet the requirements of section 505G under which a product is deemed to be GRASE and not a new drug.
因此，企业的Hongosan Anti-Fungal Set产品不符合第505G条款的要求，该产品被视为GRASE而不是新药。
Further, as noted above, no FDA-approved application pursuant to section 505 of the FD&C Act, 21 U.S.C. 355, is in effect for Hongosan Anti-Fungal Set topical antifungal drug product. Additionally, we are not aware of any adequate and well-controlled clinical studies in the published literature that support a determination that your “Hongosan Anti-Fungal Set” drug product is GRASE for use under the conditions prescribed, recommended, or suggested in its labeling. Accordingly, this topical antifungal drug product is an unapproved new drug marketed in violation of section 505(a) and 301(d) of the FD&C Act, 21 U.S.C 355(a) and 331(d).
此外，如上所述，FDA根据FD&C法案第505条(21 U.S.C. 355)批准的申请对Hongosan Anti-Fungal Set产品无效。此外，FDA尚未得知在已发表的文献中有任何充分的、控制良好的临床研究支持企业的“Hongosan Anti-Fungal Set”药品是GRASE，可以在其标签中规定的、推荐的或建议的条件下使用。因此，该外用抗真菌药物产品是未经批准的新药，违反了FD&C法案第505(a)和301(d)条[21 U.S.C 355(a)和331(d)]。
Please note that we attribute the antifungal claims on the package labeling of your Hongosan Anti-Fungal Set product to each of its components (i.e., Hongosan Anti-Fungal Cream, Hongosan Anti-Fungal Drops, and Hongosan Soap), which are intended to be used in conjunction with each other as a topical antifungal treatment. Under section 201(g) of the FD&C Act, the definition of "drug" includes "articles intended for use as a component" of any product otherwise meeting the definition of "drug" (such as your Hongosan Anti-Fungal Set product). Therefore, the Hongosan Anti-Fungal Cream, Hongosan Anti-Fungal Drops, and Hongosan Soap are drugs based on their intended use and are themselves subject to applicable requirements under the FD&C Act, including the requirements of M005. Because these three components of your Hongosan Anti-Fungal Set are intended to be used together as an integrated treatment regimen, but lack an FDA approval for such use, these components are also unapproved new drugs. In addition, these components of your Hongosan Anti-Fungal Set would not be compliant with M005 even if marketed separately for their intended use, because their individual labeling does not comply with the requirements of M005.
请注意，我们将Hongosan Anti-Fungal Set产品包装标签上的抗真菌声明归因于其每一种成分(即Hongosan Anti-Fungal Cream, Hongosan Anti-Fungal Drops, and Hongosan Soap)，这些成分将相互配合使用，作为局部抗真菌治疗。根据FD&C法案第201(g)条，“药品”的定义包括“预期用作任何符合“药品”定义的产品（例如企业的Hongosan Anti-Fungal Set产品）的“原辅料”。因此，he Hongosan Anti-Fungal Cream, Hongosan Anti-Fungal Drops, and Hongosan Soap根据其预期用途是药物，本身符合FD&C法案的适用要求，包括M005的要求。由于企业的 Hongosan Anti-Fungal Set的这三种成分是打算作为一个综合治疗方案一起使用，但缺乏FDA对此用途的批准，这些成分也是未经批准的新药。此外，即使企业针对其预期用途进行单独销售，企业Hongosan Anti-Fungal Set的这些成分也不符合M005，因为其个别标签不符合M005的要求。
Misbranded Drug Violations
错标药物违规
Your Hongosan Anti-Fungal set product is also misbranded under section 502(a) of the FD&C Act, under which a drug is deemed misbranded if its labeling is false or misleading in any particular. Under section 201(n) of the FD&C Act, "in determining whether the labeling or advertising is misleading there shall be taken into account (among other things) not only representations made or suggested by statement, word, design, device, or any combination thereof, but also the extent to which the labeling or advertising fails to reveal facts material in the light of such representations." In particular, the Drug Facts panel on the product’s labeling does not declare all active ingredients present in the Hongosan Anti-Fungal Set, as required under 21 CFR 201.66(c)(2), because the Drug Facts panel omits reference to the active ingredient undecylenic acid contained in the product's constituent Hongosan Anti-Fungal Drops.
根据FD&C法案第502(a)条，企业的Hongosan Anti-Fungal set产品也是错标，根据该条款，如果药物的标签在任何特定情况下是错误的或具有误导性的，则该药物被视为错标。根据FD&C法案第201(n)条，“在确定标签或广告是否具有误导性时，不仅要考虑到声明、文字、设计、装置或其任何组合所做的陈述或建议，还要考虑到标签或广告未能根据此类陈述揭示真实情况的程度。”特别是，产品标签上的药物事实版面没有按照21 CFR 201.66(c)(2)的要求声明Hongosan Anti-Fungal Set中存在的所有活性成分，因为药物事实版面省略了产品成分Hongosan Anti-Fungal Drops中包含的活性成分十一烯酸。
The Hongosan Anti-Fungal Set also fails to conform to the Drug Facts labeling requirements under 21 CFR 201.66(c)(8), which requires use of the term “Inactive ingredients” for listing all inactive ingredients. Consequently, your Hongosan Anti-Fungal Set product is also misbranded under section 502(c) of the FD&C Act, 21 U.S.C. 352(c) because the Drug Facts panel does not contain all information that is required under 21 CFR 201.66.
Hongosan Anti-Fungal Set 也不符合21 CFR 201.66(c)(8)项下的药物实情标签要求，该要求使用术语“非活性成分”来列出所有非活性成分。因此，企业的Hongosan Anti-Fungal Set产品根据FD&C法案21 U.S.C. 352(c)第502(c)条定义为错标，因为药品实情面板没有包含21 CFR 201.66要求的所有信息。
Further, your Hongosan Anti-Fungal Set product is misbranded under section 502(ee) of the FD&C Act, 21 U.S.C. 352(ee), because this product is a nonprescription drug subject to section 505G of the FD&C Act, 21 U.S.C. 355h, is not the subject of an application approved under section 505 of the FD&C Act, 21 U.S.C. 355, and does not comply with the requirements under section 505G of the FD&C Act, 21 U.S.C. 355h.
此外，企业的Hongosan Anti-Fungal Set产品根据FD&C法案(21 U.S.C. 352(ee))第502(ee)条为错标，因为该产品是受FD&C法案(21 U.S.C. 355h)第505G条约束的非处方药，不是根据FD&C法案(21 U.S.C. 355)第505条批准的申请的主题，不符合FD&C法案(21 U.S.C. 355h)第505G条的要求。
Moreover, based on their labeling for joint use as an integrated treatment regimen, the Hongosan Anti-Fungal Cream, Hongosan Anti-Fungal Drops, and Hongosan Soap are themselves misbranded drugs in the same manner as your Hongosan Anti-Fungal Set product considered as a whole. In addition, these components of your Hongosan Anti-Fungal Set would be misbranded under section 502 of the FD&C Act even if marketed separately for their intended use, because their individual labeling would be deemed misbranded under section 502(c) for failing to meet applicable labeling requirements, and these components would also be deemed misbranded under section 502(ee) on the same basis as described above for your Hongosan Anti-Fungal set product.
此外，根据作为综合治疗方案联合使用的标签，the Hongosan Anti-Fungal Cream, Hongosan Anti-Fungal Drops, and Hongosan Soap是错标，与被认为是无效的Hongosan Anti-Fungal Set产品相同。此外，企业的Hongosan Anti-Fungal Set产品的这些成分根据FD&C法案第502条为错标，即使是按照其预期用途单独销售，因为它们的个别标签将根据第502(c)条被视为不符合适用的标签要求，这些成分也将根据第502(ee)条被视为与上述Hongosan Anti-Fungal Set产品相同的错标行为。
Introduction or delivery for introduction of misbranded products into interstate commerce is prohibited under section 502 and 301(a) of the FD&C Act, 21 U.S.C. 352 and 331(a).
根据FD&C法案第502和301(a)条，21 U.S.C. 352和331(a)条，禁止将错标产品引入州际商业。
Establishment Registration and Drug Listing Violations
违反设施注册和药品上市规定
DSP Skin Care LLC manufactures drug products as detailed in an FDA inspection conducted September 7 through 9, 2021. Under section 510(b) of the FD&C Act, 21 U.S.C. 360(b), and 21 CFR 207.17(a), all manufacturers must register each domestic establishment. Additionally, firms must review and update registration information annually or certify that there are no changes. 21 CFR 207.29. Our query of FDA’s drug registration and listing database determined that the DSP Skin Care LLC’s (FEI 3013374118) establishment registration expired on December 31, 2017. DSP Skin Care LLC is required to submit registration information annually by electronic means for each establishment it owns or operates that is engaged in the manufacture, preparation, propagation, compounding, or processing of a drug that is in commercial distribution in the United States. DSP Skin Care LLC has not fulfilled its registration requirement. As a result, all drugs manufactured in this establishment are misbranded under Section 502(o) of the FD&C Act [21 U.S.C. 352(o)].
DSP Skin Care LLC生产的药品详细信息在2021年9月7日至9日进行的FDA检查中可以查到。根据FD&C法案第510(b)条、21 U.S.C. 360(b)条和21 CFR 207.17(a)条，所有生产商必须注册每个国内设施。此外，公司必须每年审查和更新注册信息或确保没有变更。21 CFR 207.29。我们查询了FDA的药品注册和上市数据库，确定DSP Skin Care LLC(FEI 3013374118)的注册已于2017年12月31日到期。要求DSP Skin Care LLC每年通过电子方式提交其拥有或运营的、在美国商业分销的药物的生产、制备、繁殖、合成或加工的每个设施的注册信息。DSP Skin Care LLC未满足其注册要求。因此，根据FD&C法案(21 U.S.C. 352(o))第502(o)条，在该工厂生产的所有药品都为错标。
Under section 510(j)(1) of the FD&C Act, 21 U.S.C. 360(j)(1), and 21 CFR 207.41, all drugs manufactured, prepared, propagated, compounded, or processed for U.S. commercial distribution must be listed with FDA Hongosan Anti-Fungal Set (NDC 70826-576) drug listing with FDA was not certified as required by 21 CFR 207.57 and has therefore been inactivated. Hongosan Anti-Fungal Cream (tolnaftate 1%), and Hongosan Premium Plus Spray (undecylenic acid 0.1%) were never listed with FDA. Failure to properly list a drug product is prohibited under section 301(p) of the FD&C Act, 21 U.S.C. 331(p), and will render a drug misbranded under section 502(o) of the FD&C Act, 21 U.S.C. 352(o).
根据FD&C法案第510(j)(1)条、21 U.S.C. 360(j)(1)条和21 CFR 207.41条，所有用于美国商业销售的生产、制备、繁殖、合成或加工的药物必须被FDA列入 Hongosan Anti-furgium Set (NDC 70826-576)药物清单。未按21 CFR 207.57的要求认证，因此已被停用。Hongosan Anti-Fungal Cream (1% toolnaftate), 和 Hongosan Premium Plus Spray (0.1%) 从未在FDA登记过。根据《FD&C法案》(21 U.S.C. 331(p))第301(p)条禁止未能正确登记的药品，并将导致药品在《FD&C法案》(21 U.S.C. 352(o))第502(o)条下为错标。
The introduction or delivery for introduction of a misbranded drug into interstate commerce is prohibited under section 301(a) of the FD&C Act, 21 U.S.C. 331(a).
根据《FD&C法案》(21 U.S.C. 331(a))第301(a)条的规定，禁止在州际贸易中引入或交付错标药品。
Quality Systems
质量体系
Your firm’s quality systems are inadequate. See 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: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, and because you failed to correct repeat violations, 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检查员发现的违规行为的性质，并且由于企业未能纠正重复的违规行为，FDA强烈建议聘请一位符合21 CFR 211.34所述资格的顾问来帮助贵公司满足CGMP要求。使用顾问并不能减轻遵守CGMP的责任。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。
Repeat Observations at Facility
工厂重复违规项
In a previous inspection, dated September 17, 2018, to September 26, 2018, FDA cited similar CGMP observations. Your failure to implement appropriate remediations for the observations documented during the 2018 and 2021 inspections demonstrates that your executive management oversight and control over the manufacture of drug products is inadequate.
在之前2018年9月17日至2018年9月26日的检查中，FDA引用了类似的CGMP观察结果。企业未能对2018年和2021年检查期间记录的观察结果实施适当的整改，这表明企业执行管理层对药品生产的监督和控制是不充分的。
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.
本函信中引用的违规行为并不是企业设施中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.
请及时纠正违规行为。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 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.
未能解决违规问题还可能导致FDA暂停签发出口证书。FDA可能会拒绝批准将贵公司列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，以核实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.
这封信通知企业FDA的检查结果，并为供解决上述缺陷的机会。收到本函后，请于15个工作日内回复本办公室。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，企业可以提供额外的信息供FDA考虑，FDA将继续评估企业的活动和做法。如果企业不能在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 send your electronic reply to ORAPHARM4_Responses@FDA.HHS.GOV or mail your reply 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
Please identify your responses with the unique identifier: CMS 622549.
If there is any question about the released information, please contact Mariza Jafary, compliance officer, at 949-608-2977, or at Mariza.Jafary@fda.hhs.gov.
Sincerely,
/S/
CDR Steven E. Porter, Jr.
Director, Division of Pharmaceutical Quality Operations IV
____________________
1 Section 505G(a)(1) of the FD&C Act specifies criteria under which certain nonprescription drugs without an approved application are deemed GRASE and not "new drugs", notably conformance with conditions detailed in applicable OTC monograph documents issued by FDA under 21 CFR 330 prior to enactment of the CARES Act. In the case of OTC antifungal drug products, relevant documents were deemed under section 505G to be a final administrative order, Over-the-Counter Monograph M005: Topical Antifungal Drug Products for Over-the-Counter Human Use. (See Order ID OTC000017, available at FDA’s website OTC Monographs@FDA, https://www.accessdata.fda.gov/scripts/cder/omuf/.)
