工艺及水系统未验证、偏差调查不彻底和质量部门不符合cGMP要求，FDA发出警告信。
WARNING LETTER
Spartan Chemical Company, Inc.
MARCS-CMS 614450 — DECEMBER 15, 2021
WL # 614450
December 15, 2021
Dear Mr. Swigart:
The U.S. Food and Drug Administration (FDA) inspected your drug manufacturing facility, Spartan Chemical Company, Inc., FEI 3001451695, at 1110 Spartan Drive, Maumee, from March 1 to 26, 2021.
美国食品和药物管理局(FDA)于2021年3月1日至26日检查了企业位于莫米斯巴达大道1110号的药品生产设施斯巴达化学公司，编号FEI 3001451695。
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CGMP法规的情况。参见第21篇《联邦法规》(CFR)第210和211部分(第21篇《联邦法规》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要求，企业的药品根据《联邦食品、药品和化妆品法》(FD&C法)第501(a)(2)(B)条、21 U.S.C. 351(a)(2)(B)规定为掺假药品。
Furthermore, the FDA collected drug product samples during the inspection of your facility. FDA laboratory analysis revealed the presence of objectionable microbial contamination, including Burkholderia cepacia (B. cepacia) complex, in one of those drug products, Lite’n Foamy Lemon Blossom Hand Sanitizer (lot 538756, expiring January 2023). As such, drug products were prepared, packed, or held under insanitary conditions, whereby they may have become contaminated with filth or rendered injurious to health, causing your drug products to be adulterated under section 501(a)(2)(A) of the FDCA.
此外，FDA在检查贵工厂期间收集了药品样品。FDA实验室分析显示，在其中一种药品Lite 'n泡沫柠檬花洗手液(批次538756,2023年1月到期)中存在微生物污染，包括洋葱伯克霍尔德菌(B. cepacia)复合体。因此，药品是在不卫生的条件下制备、包装或保存的，因此它们可能被污染或对健康有害，根据FDCA第501(a)(2)(a)条规定企业的药品被定义为掺假。
In addition, this is to advise you that the United States Food and Drug Administration (FDA) reviewed your websites at the Internet address https://www.spartanchemical.com/ on October 8, 2021. In addition, the FDA has reviewed the labeling on your product packaging for the foamyiQ and Lite'n Foamy product lines that include the over-the-counter (OTC) drug products, foamyiQ™ Lemon Blossom Hand Sanitizer (4604), foamyiQ™ Eucalyptus Mint Sanitizing Handwash (4603), Lite'n Foamy® Lemon Blossom Hand Sanitizer (3338), Lite'n Foamy® Eucalyptus Mint Sanitizing Handwash (3337) foamyiQ™ Healthcare Personnel Handwash (4605), and Lite'n Foamy® Healthcare Personnel Handwash (3341).
此外，美国食品和药物管理局(FDA)于2021年10月8日审查了企业的网站，网址是https://www.spartanchemical.com/。此外，FDA已经审查了企业的foamyiQ和Lite'n泡沫产品线的产品包装上的标签，包括非处方药(OTC)药品，foamyiQ™柠檬花洗手液(4604)，foamyiQ™桉树薄荷消毒洗手液(4603)，Lite'n泡沫®柠檬花洗手液(3338)，Lite'n泡沫®桉树薄荷消毒洗手液(3337)泡沫yiq™医护人员洗手液(4605)和Lite'n泡沫®医护人员洗手液(3341)。
The FDA has observed that these consumer and health care antiseptic products1 are intended to mitigate, prevent, treat, diagnose, or cure COVID-192 in people and their labeling include statements that falsely indicates that they are registered and approved by the FDA. Based on our review, these products are unapproved new drugs sold in violation of section 505(a) of the Federal Food, Drug, and Cosmetic Act (FD&C Act), 21 U.S.C. 355(a). Furthermore, these products are misbranded drugs under sections 502(a) and (ee) of the FD&C Act, 21 U.S.C. 352(a) and (ee). The introduction or delivery for introduction of these products into interstate commerce is prohibited under sections 301(a) and (d) of the FD&C Act, 21 U.S.C. 331(a) and (d). These violations are described in more detail below.
FDA注意到，这些消费品和保健杀菌产品旨在减轻、预防、治疗、诊断或治愈人体中的COVID-192，它们的标签包括错误地表明它们已注册并获得FDA批准的声明。根据我们的审查，这些产品是未经批准的新药，违反了《联邦食品、药物和化妆品法》(FD&C法)第505(a)条，21 U.S.C. 355(a)。此外，根据FD&C法案第502(a)条和(ee)条，21 U.S.C. 352(a)和(ee)条，这些产品属于假药。根据《FD&C法案》第301(a)和(d)条、21 U.S.C. 331(a)和(d)条的规定，禁止将这些产品引入或交付于州际贸易。
There is currently a global outbreak of respiratory disease caused by a novel coronavirus that has been named “severe acute respiratory syndrome coronavirus 2” (SARS-CoV-2). The disease caused by the virus has been named “Coronavirus Disease 2019” (COVID-19). On January 31, 2020, the Department of Health and Human Services (HHS) issued a declaration of a public health emergency related to COVID-19 and mobilized the Operating Divisions of HHS.3 In addition, on March 13, 2020, there was a Presidential declaration of a national emergency in response to COVID-19 that has been extended.4 Therefore, FDA is taking measures to protect consumers from certain products that, without approval or authorization by FDA, claim to mitigate, prevent, treat, diagnose, or cure COVID-19 in people.
目前，由一种被命名为“严重急性呼吸综合征冠状病毒2型”(SARS-CoV-2)的新型冠状病毒引起的呼吸系统疾病在全球暴发。这种病毒引起的疾病被命名为“2019冠状病毒病”(COVID-19)。2020年1月31日，美国卫生与公众服务部(HHS)发布了与COVID-19相关的公共卫生紧急状态声明，并动员了HHS的各运营部门。此外，2020年3月13日，总统发布了针对COVID-19的全国紧急状态声明，该声明已被延长。因此，FDA正在采取措施保护消费者免受某些产品的影响，这些产品在未经FDA批准或授权的情况下，声称可以减轻、预防、治疗、诊断或治愈COVID-19。
We reviewed your April 5, 2021, response to our Form FDA 483 in detail and acknowledge receipt of your subsequent correspondence. Your response is inadequate, because it did not provide sufficient detail or evidence of corrective actions to bring your operations into compliance with CGMP.
我们详细审阅了企业2021年4月5日对我们FDA 483表格的回复，并确认收到了企业后续的信函。企业的回复是不充分的，因为它没有提供足够的细节或纠正措施的证据，使企业的操作符合CGMP。
During our inspection, our investigators observed specific violations including, but not limited to, the following.
在检查期间，FDA的调查人员观察到了具体的违规行为，包括但不限于以下内容。
CGMP Violations
CGMP违规
1. 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, and your firm’s quality control unit did not review and approve those procedures, including any changes (21 CFR 211.100(a)).
1.贵公司未能制定足够的书面生产和工艺控制程序，以确保贵公司生产的药品具有其声称或代表拥有的成分、规格、质量和纯度，且贵公司的质量部门未审查和批准这些程序，包括任何变更(21 CFR 211.100(a))。
The system used to provide water for drug product manufacturing operations at your facility was not adequately validated for its intended use. While you completed installation qualification of the water system, you failed to perform performance qualification of the system. Nevertheless, your firm used water from this system to manufacture aqueous-based drug products.
贵工厂用于为药品生产操作提供水的系统没有得到充分验证。虽然企业完成了水系统的安装确认，但没有进行系统的性能确认。尽管如此，贵公司用这个系统的水来生产药品。
Furthermore, you lacked long term monitoring data to evaluate the quality of water produced by your system. Your firm did not initiate a routine program to test water quality until July 2020 and presumed that finished product testing would provide assurance of the adequacy of the water used in the manufacture of your aqueous-based drug products. This practice was inappropriate, because it failed to directly monitor the quality of water produced by your firm’s water system. It is unacceptable to rely on drug product testing to monitor whether your water system is in a state of control.
此外，企业缺乏长期的监测数据来评估系统产生的水的质量。贵公司直到2020年7月才启动水质量测试的常规程序，并假定成品测试可以保证企业药品生产中使用的水的充分性。这种做法是不恰当的，因为它没有直接监测贵公司供水系统产生的水的质量。依靠药品测试来监测水系统是否处于控制状态是不可接受的。
Notably, following initiation of a monitoring program, significant deviations from microbial action limits were identified in your water system.
值得注意的是，在启动监测程序后，在企业的水系统中发现了微生物作用限度的重大偏差。
During the previous FDA inspection conducted in 2016, we had also observed that your original water system was not adequately validated for its intended use. This was discussed with your firm’s management at the conclusion of that inspection.
在2016年FDA进行的前一次检查中，我们也观察到企业原有的水系统没有充分验证其预期用途。在检查结束时，我们与贵公司管理层讨论了这个问题。
Assuring ongoing state of control of your water system is integral to support drug manufacturing operations. Water utilized for the manufacture of drug products must be suitable for its intended use and routinely tested to promptly detect any lapse in performance.
确保水系统的持续控制状态是支持药品生产运作的必要条件。用于生产药品的水必须适合其预期用途，并进行常规测试，以便及时发现任何性能缺陷。
In your response, your firm stated that significant changes have been made to your water system and you will complete (b)(4) of the system by (b)(4). However, your response failed to address the reason why your water system was not adequately designed and validated, although the need for a robust validated system was discussed during your previous FDA inspection conducted in 2016. Additionally, your response did not include any preventive actions put in place to ensure more vigilant and timely operational oversight in the future.
回复中，贵公司声明水系统已经做了重大的整改，企业将于 (b)(4)之前完成该系统的 (b)(4)。然而，企业的回复没有说明水系统没有充分设计和验证的原因，尽管企业在2016年进行的FDA检查中讨论了对稳健的验证系统的需求。此外，企业的答复没有包括采取任何预防措施，以确保在未来进行更加警惕和及时的操作监督。
In response to this letter, provide the following:
针对本函，请提供以下内容：
A remediation plan that better assures ongoing management oversight throughout the manufacturing lifecycle of all drug products. Provide a more data-driven and scientifically sound program that identifies sources of process variability and assures that manufacturing operations meet appropriate parameters and quality standards. This includes, but is not limited to, evaluating suitability of equipment for its intended use, ensuring quality of input materials, determining the capability and reliability of each manufacturing process step and its controls, and vigilant ongoing monitoring of process performance and product quality.
一项整改计划，以更好地确保在所有药品的整个生产生命周期中进行管理监督。一份数据驱动和科学合理的分析，识别工艺变化的来源，并确保生产操作符合适当的参数和质量标准。这包括但不限于，评估设备对其预期用途的适用性，确保投入原料的质量，确定每个制造工艺步骤及其控制的能力和可靠性，以及对工艺性能和产品质量的持续监测。
A comprehensive, independent assessment of your water system design, control, and maintenance.
对水系统的设计、控制和维护进行全面、独立的评估。
A thorough remediation plan to install and operate a suitable water system. Include a robust ongoing control, maintenance, and monitoring program to ensure the remediated system design consistently produces water adhering to Purified Water, USP monograph specifications, and appropriate microbial limits.
安装和运行合适的水系统的彻底整改计划。包括一个稳健的持续控制、维护和监控程序，以确保整改系统设计始终可以生产出符合纯化水、USP各论规范和适当的微生物限度的水。
Regarding the latter, ensure that your total microbial count limit for water is appropriate in view of the intended use of the products produced by your firm.
对于后者，鉴于贵公司生产的产品的预期用途，请确保企业的水中微生物总数限制是适当的。
Discuss your efforts toward systematic, comprehensive corrective action and preventive action (CAPA) to prevent recurrence of similar violations.
讨论企业为系统、全面的纠正措施和预防措施(CAPA)所做的努力，以防止类似违规事件再次发生。
2. Your firm failed to thoroughly investigate any unexplained discrepancy or failure of a batch or any of its components to meet any of its specifications, whether or not the batch has already been distributed (21 CFR 211.192).
2. 企业未能彻底调查批产品或其成分与质量标准的不明原因的差异或不符合其质量标准，不管这批是否放行销售(21 CFR 211.192)。
Your investigations into failing results were inadequate. Your investigations did not identify the root cause of failing results, lacked an evaluation of the impact of failing results on already distributed batches, and did not include appropriate CAPA.
企业对不合格结果的调查不够充分。企业的调查没有确定不合格结果的根本原因，缺乏对已分发批次不合格结果影响的评估，也没有包括适当的CAPA。
For example:
例如：
On September 15, 2020, your firm initiated an investigation (CAR 09152020QCU) in response to failing microbial enumeration results regarding several lots of hand sanitizer manufactured by your firm. The investigation into these failures was inadequate, including:
2020年9月15日，贵公司启动了一项调查(CAR 09152020QCU)，以回应贵公司生产的几批洗手液微生物计数结果不合格。对这些故障的调查不够充分，包括:
o Some of these lots were sent to your contract laboratory for microbial identification and revealed the presence of B. cepacia. Despite your firm’s knowledge that products were contaminated with B. cepacia, and unacceptable levels of yeast and mold, the associated investigation did not address the specific objectionable microorganisms or provide an adequate determination of the root cause of the failures.
o其中一些批次被送往企业的合同实验室进行微生物鉴定，发现存在B. cepacia。尽管贵公司知道产品被B. cepacia污染，以及不可接受的酵母菌和霉菌水平，但相关的调查没有解决具体的不良微生物，也没有充分确定故障的根本原因。
o Insufficient actions were identified to prevent recurrence of objectionable microbial contamination of your drug products.
o未采取足够的措施防止药品再次受到不良微生物的污染。
Since September 21, 2020, there have been recurring failing results observed during water system monitoring that exceeded appropriate microbial limits at dispensing ports used in the manufacture of drug products, but you routinely lacked investigations into these failing results.
自2020年9月21日以来，在用于药品生产的配药端口的水系统监测中，反复观察到超过适当微生物限度的不合格结果，但企业通常缺乏对这些不合格结果的调查。
Your procedure that governs corrective actions (SOP.002.011.001 Corrective Action Procedure) lacked adequate provisions for root cause determination or effectiveness checks. You also lacked adequate procedures addressing the need for preventive actions.
企业管理纠正措施的程序(SOP.002.011.001纠正措施程序)对根本原因确定或有效性检查缺乏充分的规定。企业也缺乏处理预防性行动需要的适当程序。
In your response, your firm provided clarification regarding your water system testing limits and indicated that you are updating relevant procedures and forms. However, your response does not address why investigations were not initiated in response to failing water system results. It also does not propose a retrospective analysis to further understand past investigation lapses to identify preventive measures and systemic remediations. Additionally, your response lacks substantial improvements to your quality system to ensure investigations identify root causes, evaluate full scope and impact, and implement appropriate CAPA in response to failures, adverse trends, and other deviations and discrepancies.
回复中，贵公司澄清了水系统测试受限，并表示正在更新相关程序和表格。然而，企业的回复没有说明为什么没有针对供水系统故障的结果展开调查。也没有提出回顾性分析，以进一步了解过去的调查失误，以确定预防措施和系统性补救措施。此外，企业的回复缺乏对质量体系的实质性改进，以确保调查出根本原因，评估全面范围和影响，并针对失效、不利趋势和其他偏差和差异实施适当的CAPA。
In response to this letter, provide the following:
针对本函，请提供以下信息：
A comprehensive, independent assessment of your overall system for investigating deviations, discrepancies, complaints, out-of-specification (OOS) results, and failures. Provide a detailed action plan to remediate this system. Your action plan should include, but not be limited to, significant improvements in investigation competencies, scope determination, root cause evaluation, CAPA effectiveness, quality assurance oversight, and written procedures. Address how your firm will ensure all phases of investigations are appropriately conducted.
对调查偏差、异常、投诉、OOS结果和不合格的整体系统的综合独立评估。请提供一份详细的行动计划以对该系统进行整改。 行动计划应包括但不限于，调查能力、范围确定、根本原因分析、CAPA有效性、质量部门监督及书面规程的显著改进。请说明将如何确保调查的所有阶段都得以适当执行。
An independent assessment and remediation plan for your CAPA program. Provide a report that evaluates if staff with proper investigation competencies effectively conduct root cause analysis, assure CAPA effectiveness, regularly review investigations trends, implement improvements to the CAPA program when needed, ensure appropriate quality assurance decision rights, and are fully supported by executive management.
一份独立的CAPA评估和整改计划。提供一份报告，评估具有适当调查能力的员工是否有效地进行根本原因分析，确保CAPA的有效性，定期审查调查趋势，在需要时对CAPA计划实施改进，确保适当的质量保证决策权，并得到执行管理层的充分支持。
A comprehensive review and remediation plan for your OOS result investigation systems. The CAPA should include, but not be limited to, addressing the following:
OOS结果调查系统的综合审查及整改计划。纠正措施和预防措施（CAPA）计划，包括但不限于:
o Quality assurance oversight of laboratory investigations
o质量部门对实验室调查的监督
o Identification of adverse laboratory control trends
o识别实验室控制的不良趋势
o Resolution of causes of laboratory variation
o解决实验室差错的原因
o Initiation of thorough investigations of potential manufacturing causes whenever a laboratory cause cannot be conclusively identified
o当无法最终确定实验室原因时，启动对潜在生产原因的彻底调查
o Adequate scoping of each investigation and its CAPA
o充分确定每个调查的范围及其CAPA。
o Revised OOS investigation procedures with these and other remediations
o修订后的OOS调查规程，包括这些及其它整改措施。
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. 质量管理部门没有履行其职责确保所生产的药品CGMP合规并且符合鉴别、规格、质量和纯度的既定标准（21 CFR 211.22）。
During the inspection, our investigators observed that your quality unit did not provide adequate oversight for the manufacture of your drug products and failed to adequately establish and adhere to written procedures to ensure the strength, quality, and purity of your drug products. For example:
在检查期间，我们的调查人员发现，企业的质量部门没有对药品的生产提供充分的监督，未能充分建立和遵守书面程序，以确保药品的规格、质量和纯度。例如:
Your firm lacks an adequate procedure and formal system to manage change control. You did not have an effective mechanism or written procedure to assess proposed and actual changes that may impact your drug manufacturing facilities, systems, equipment, or processes.
贵公司缺乏适当的程序和正式的系统来管理变更控制。没有有效的机制或书面程序来评估可能影响药品生产设施、系统、设备或工艺规程和实际变更。
Your firm has a procedure that governs (b)(4) drug product reviews that was established on March 22, 2010. However, since the inception of this procedure your firm has never performed (b)(4) reviews for any of the drug products you manufacture.
贵公司有一套管理xx药品评审的程序，该程序于2010年3月22日建立。然而，自本程序启动以来，贵公司从未对企业生产的任何药品进行xx评审。
During the inspection, training records were reviewed for (b)(4) of your employees and these records indicated that all (b)(4) employees failed to receive complete training.
在检查期间，审查了企业xx员工的培训记录，这些记录表明所有xx员工未能接受完整的培训。
Your firm began plate count testing on September 21, 2020, for both in-process water and finished drug products utilizing a contract laboratory. Your firm ordered suitability and validation testing for TAMC and TYMC testing via (b)(4). However, your firm failed to request that B. cepacia suitability testing be performed.
贵公司于2020年9月21日开始利用合同实验室对生产用水和成品进行平板计数检测。贵公司通过xx订购了TAMC和TYMC测试的适用性和验证测试。然而，贵公司未能要求进行B. cepacia适用性性测试。
Your firm did not perform Antimicrobial Effectiveness Testing (AET) for your drug products that contain chloroxylenol.
贵公司没有对含有氯羟甲酚的药品进行抗菌效果测试(AET)。
Research has shown that B. cepacia complex (Bcc) bacteria employ strategies to cope with environmental stressors, including in benzalkonium chloride drug products. Under these conditions, cells can be viable and maintain their integrity and pathogenic potential although they cannot be initially cultured. At a later point in the shelf life, Bcc may adjust to the conditions and proliferate in the preserved drug, despite the fact that Bcc was not recovered during initial testing. While initial release testing results provide critical quality control information, those test results may not provide a full understanding of the microbial quality of a given batch or be predictive of stability characteristics. As an example, while your release testing yielded passing results for hand sanitizer lot 538756, expiring January 2023, testing later in the shelf-life by both your contract laboratory and FDA revealed failing Bcc and total count results.
研究表明，在苯扎氯铵药物产品中，cepacia复合菌(Bcc)采用了策略应对环境压力。在这些条件下，细胞可以存活并保持其完整性和致病潜力，尽管它们不能最初培养。在货架期的后期，Bcc可能会根据条件进行调整，并在保存的药物中增殖，尽管在最初的测试中没有发现Bcc。虽然最初的放行测试结果提供了关键的质量控制信息，但这些测试结果可能不能提供对给定批次的微生物质量的充分理解或对稳定性特征的预测。例如，虽然企业的放行测试对2023年1月到期的538756号洗手液产生了合格的结果，但在货架期后期由企业的合同实验室和FDA进行的测试显示Bcc和总计数结果不合格。
Your firm’s response states, in part, that you are creating or revising procedures associated with this violation, enhancing your maintenance program, enhancing your training program, and addressing the laboratory deficiencies identified. However, your response is inadequate as it failed to address the fundamental deficiencies in your quality unit that led to these failures. Additionally, no evaluation was made to determine if your deficient quality unit impacted drug operations not covered during this inspection. You failed to review the scope of your quality unit deficiencies and provide evidence that you have taken systemic steps to ensure robust oversight and control over manufacturing operations.
贵公司的回复部分陈述了企业正在制订或修订与此违规相关的程序，加强企业的维护计划和培训计划，并解决发现的实验室缺陷。然而，企业的回复是不充分的，因为它没有解决导致这些失败的质量部门的根本缺陷。此外，没有进行评估以确定质量部门的缺陷是否影响了本次检查中未覆盖的药品操作。企业未能审查质量部门缺陷的范围，也未能提供证据证明已采取系统性措施，以确保对生产操作进行强有力的监督和控制。
Significant findings in this letter indicate that your quality unit is not fully exercising its authority or responsibility. Your firm must provide the quality unit with the appropriate authority and sufficient resources to carry out its responsibilities and consistently ensure drug quality.
这封信中的重要发现表明企业的质量部门没有充分行使其权力或责任。贵公司必须为质量部门提供适当的权限和足够的资源，以履行其职责并始终如一地确保药品质量。
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 quality unit 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，以确保质量部门得到有效运作的权力和资源。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 确定所用的规程是否稳健且适用
o Provisions for quality unit oversight throughout your operations to evaluate adherence to appropriate practices
o规定QU在整个操作过程进行监督以评估对适当规范的遵守情况
o A complete and final review of each batch and its related information before the quality unit disposition decision
o 在QU处置决定之前对每批次及其相关信息的完整和最终审核
o Oversight and approval of investigations and discharging of all other quality unit 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
Appropriate improvements to your cleaning validation program, with special emphasis on incorporating conditions identified as worst case in your drug manufacturing operation and ensuring acceptable sanitary systems for manufacture. This should include, but not be limited to, identification and evaluation of all worst-case:
适当改进企业的清洁验证程序，特别强调纳入药品生产操作中确定的最坏情况，并确保可接受的生产卫生系统。这应包括但不限于识别和评估所有最坏情况:
o Drugs with higher toxicities, drugs with higher drug potencies, and drugs of lower solubility in their cleaning solvents
o毒性较高的药物、药物效力较高的药物以及在清洗溶剂中溶解度较低的药物
o Drugs with characteristics that make them difficult to clean
o具有难以清洗特征的药物
o Swabbing locations for areas that are most difficult to clean
o最难清洁区域的擦拭位置
o Microbial risks related to equipment and cleaning procedures and maximum hold times before cleaning
o与设备和清洁程序相关的微生物风险以及清洁前的最大保持时间
o Change management provisions that ensure new products and equipment are appropriately addressed
o确保新产品和设备得到适当处理的变更管理规定
Additionally, provide your written procedures regarding cleaning validation and verification, and a status report of all related studies performed to date for all equipment used by your firm for manufacturing processes. For each piece of equipment, state whether it is multi-use or dedicated.
此外，请提供企业关于清洁确认和验证的书面程序，以及迄今为止对贵公司用于生产工艺的所有设备所进行的所有相关研究的状态报告。对于每一件设备，说明它是多用的还是专用的。
A comprehensive, independent assessment of your change management system. This assessment should include, but not be limited to, your procedure(s) to ensure changes are justified, reviewed, and approved by your QU. Your change management program should also include provisions for determining change effectiveness.
对变更管理系统的全面、独立的评估。此评估应包括但不限于企业的程序，以确保变更得到企业的质量部门的证明、评审和批准。企业的变更管理计划还应包括确定变更有效性的规定。
A commitment to perform AET on your drug products utilizing USP<51> (or equivalent or superior method) during both development and on a batch at the end of shelf-life for preserved products (see ICH Q1A). The testing should be performed at a range of preservative concentrations (at or below the lowest preservative concentration according to the label claim) with no additional ingredients not included in the drug product formulation. In addition, provide an evaluation of the ability of slow growing microbes to survive in your drug formulations and proliferate later in the product shelf-life.
承诺在开发期间和在保存产品的货架期结束的批次上，使用USP<51>(或同等或更高的方法)对企业的药品进行AET(见ICH Q1A)。测试应在一定的防腐剂浓度范围内进行(根据标签声明，等于或低于最低的防腐剂浓度)，且不添加不包含在药品配方中的其他成分。此外，请对生长缓慢的微生物在制剂中存活和在产品货架期后期增殖的能力进行评估。
Microbiological contamination
微生物污染
During the course of your inspection, FDA investigators collected drug product samples, including FDA Sample number 1148361, which consisted of 3 sub-samples of one-gallon containers of Lite’n Foamy Lemon Blossom Hand Sanitizer (lot 538756, expiring January 2023). FDA’s laboratory analysis identified B. cepacia complex in this lot. In addition, high levels of microbes were recovered from total aerobic microbial count (TAMC) and total yeast and mold count (TYMC) testing of all 3 sub samples. These results significantly exceeded your finished product specification of (b)(4) colony forming units (CFU)/mL and (b)(4) CFU/mL, respectively. For example, TAMC counts were as follows: sub-sample 1 contained (b)(4) TAMC/mL, sub-sample 2 contained (b)(4) TAMC/mL, and sub-sample 3 contained (b)(4) TAMC/mL. TYMC counts were as follows: sub sample 1 contained (b)(4) TYMC/mL, sub sample 2 contained (b)(4) TYMC/mL, and sub sample 3 contained (b)(4) TYMC/mL. Your firm collected samples in tandem with our investigators and your contract laboratory obtained similar results. These sample results demonstrate that the drug products produced at your facility are manufactured under insanitary conditions, causing them to be adulterated under section 501(a)(2)(A) of the FDCA.
在检查过程中，FDA调查人员收集了药品样品，包括FDA样品编号1148361，其中包括3个一加仑装的低脂泡沫柠檬花洗手液(批次538756,2023年1月到期)的子样品。FDA的实验室分析在这个批次中发现了B. cepacia复合体。此外，从所有3个子样品的总需氧微生物计数(TAMC)和总酵母菌和霉菌计数(TYMC)测试中恢复了高水平的微生物。这些结果分别显著超过了企业的成品规格xx菌落形成单位(CFU)/毫升和xx CFU/毫升。例如，TAMC计数如下:子样品1含有(b)(4) TAMC/mL，子样品2含有(b)(4) TAMC/mL，子样品3含有(b)(4) TAMC/mL。TYMC计数如下:子样品1含有(b)(4) TYMC/mL，子样品2含有(b)(4) TYMC/mL，子样品3含有(b)(4) TYMC/mL。贵公司与我们的调查人员一起收集了样品，企业的合同实验室也得到了类似的结果。这些样品结果表明，贵工厂生产的药品是在不卫生的条件下生产的，根据FDCA第501(a)(2)(a)条规定为掺假药品。
We acknowledge your firm initiated a recall of 8 batches of drug products on March 29, 2021. However, the FDA did not agree with the scope of your proposed recall. On May 12, 2021, the FDA held a teleconference with your firm and recommended that your firm recall all aqueous-based drug products within expiry. Your firm expanded the recall on May 24, 2021.
我们确认贵公司于2021年3月29日开始召回8批药品。然而，FDA不同意企业提出的召回范围。2021年5月12日，FDA与贵公司举行了电话会议，建议贵公司召回所有在有效期内的药品。贵公司在2021年5月24日扩大了召回范围。
In addition, your firm had previously recalled 10 batches of drug products on July 1, 2020, after your contract laboratory found that some of your drug products were contaminated with B. cepacia complex, as well as yeast and mold. On August 3, 2020, FDA notified the public of the microbial contamination of your hand sanitize drug products at the following website https://www.fda.gov/drugs/drug-safety-and-availability/fda-updates-hand-sanitizers-consumers-should-not-use
此外，在企业的合同实验室发现的一些药品被B. cepacia复合物以及酵母和霉菌污染后，贵公司此前已于2020年7月1日召回了10批药品。2020年8月3日，FDA在以下网站https://www.fda.gov/drugs/drug-safety-and-availability/fda-updates-hand-sanitizers-consumers-should-not-use上通知公众，企业的消毒药品存在微生物污染
Burkholderia cepacia complex contamination in non-sterile, water-based drug products can pose a significant consumer hazard. For further information regarding the significance of B. cepacia complex contamination in drug products, see FDA’s July 7, 2021 advisory, at https://www.fda.gov/drugs/drug-safety-and-availability/fda-advises-drug-manufacturers-burkholderia-cepacia-complex-poses-contamination-risk-non-sterile#_edn4
非无菌的水基药品中的洋葱伯克霍尔德菌复合污染可对消费者构成重大危害。有关cepacia B.复合物污染在药品中的重要性的进一步信息，请参见FDA 2021年7月7日的咨询，网址为https://www.fda.gov/drugs/drug-safety-and-availability/fda-advises-drug-manufacturers-burkholderia-cepacia-complex-poses-contamination-risk-non-sterile#_edn4
Unapproved New Drug and Misbranding Violations
未经批准的新药和错标违规
foamyiQ™ Lemon Blossom Hand Sanitizer (4604), Lite'n Foamy® Lemon Blossom Hand Sanitizer (3338), foamyiQ™ Eucalyptus Mint Sanitizing Handwash (4603), Lite'n Foamy® Eucalyptus Mint Sanitizing Handwash (3337), foamyiQ™ Healthcare Personnel Handwash (4605), and Lite'n Foamy® Healthcare Personnel Handwash (3341) 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, foamyiQ™ Lemon Blossom Hand Sanitizer (4604), Lite'n Foamy® Lemon Blossom Hand Sanitizer (3338), foamyiQ™ Eucalyptus Mint Sanitizing Handwash (4603), and Lite'n Foamy® Eucalyptus Mint Sanitizing Handwash (3337) are intended for use as consumer antiseptics products and foamyiQ™ Healthcare Personnel Handwash (4605), and Lite'n Foamy® Healthcare Personnel Handwash (3341) are intended for use as health care antiseptics.
foamyiQ™柠檬花洗手液(4604)、低脂泡沫®柠檬花洗手液(3338)、foamyiQ™桉树薄荷洗手液(4603)、低脂泡沫®桉树薄荷洗手液(3337)、foamyiQ™医护人员洗手液(4605)和低脂泡沫®医护人员洗手液(3341)是《FD&C法案》第201(g)(1)(B)条定义的“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》第201(g)(1)(C)条，21 U.S.C. 321(g)(1)(C)条的规定，因为它们旨在影响身体的结构或任何功能。具体来说，foamyiQ™柠檬花洗手液(4604)、Lite'n泡沫®柠檬花洗手液(3338)、foamyiQ™桉树薄荷消毒洗手液(4603)和Lite'n泡沫®桉树薄荷消毒洗手液(3337)用于作为消费杀菌产品使用，foamyiQ™医疗保健人员洗手液(4605)和Lite'n泡沫®医疗保健人员洗手液(3341)用于作为医疗保健消毒剂使用。
Some examples of the claims on your websites that establish the intended use (as defined in 21 CFR 201.128) of foamyiQ™ Lemon Blossom Hand Sanitizer (4604), Lite'n Foamy® Lemon Blossom Hand Sanitizer (3338), foamyiQ™ Eucalyptus Mint Sanitizing Handwash (4603), Lite'n Foamy® Eucalyptus Mint Sanitizing Handwash (3337), foamyiQ™ Healthcare Personnel Handwash (4605), and Lite'n Foamy® Healthcare Personnel Handwash (3341) and misleadingly represent them as safe and/or effective for the treatment or prevention of COVID-19 include, but may not be limited to, the following:
企业网站上关于确定foamyiQ™柠檬花洗手液(4604)、低脂泡沫®柠檬花洗手液(3338)、foamyiQ™桉树薄荷洗手液(4603)、低脂泡沫®桉树薄荷洗手液(3337)、foamyiQ™医护人员洗手液(4605)的预期用途(定义见21 CFR 201.128)的一些权利要求举例，和Lite'n foam®医护人员洗手液(3341)，并误导性地表示它们对治疗或预防COVID-19是安全和/或有效的，包括但不限于:
“COVID-19…foamyiQ® E2 Sanitizing Foaming Handwash (4606)…COVID-19…foamyiQ® Eucalyptus Mint Sanitizing Handwash (4603)…COVID-19…foamyiQ® Healthcare Personnel Handwash (4605)…COVID-19…foamyiQ® Lemon Blossom Foaming Hand Sanitizer (4604)…COVID-19…Lite’n Foamy® Lemon Blossom Hand Sanitizer (3338)” [From spartanchemical.com]5
“COVID-19…泡沫yiq®E2消毒泡沫洗手液(4606)…COVID-19…泡沫yiq®桉树薄荷消毒洗手液(4603)…COVID-19…泡沫yiq®柠檬花泡沫洗手液(4605)…COVID-19…泡沫yiq®柠檬花泡沫洗手液(4604)…COVID-19…低脂泡沫®柠檬花洗手液(3338)”(来自spartanchemical.com）
“IMPORTANT FACTS: COVID-19…SARS-COV-2: THE CAUSE OF COVID-19…Which Spartan products are registered and approved by the FDA for antimicrobial activity?... foamyiQ Lemon Blossom Hand Sanitizer (4604)…foamyiQ Eucalyptus Mint Sanitizing Handwash (4603)…foamyiQ Healthcare Personnel Handwash (4605)…foamyiQ E2 Sanitizing Handwash (4606)…Lite'n Foamy Lemon Blossom Hand Sanitizer (3338)…Lite'n Foamy Eucalyptus Mint Sanitizing Handwash (3337)…Lite'n Foamy Healthcare Personnel Handwash (3341) [From spartanchemical.com]6
“重要事实:COVID-19……SARS-COV-2: COVID-19的原因……哪些斯巴达产品已被FDA注册和批准具有抗菌活性?”泡沫柠檬花洗手液(4604)…泡沫桉树薄荷洗手液(4603)…泡沫柠檬花洗手液(4605)…泡沫柠檬花洗手液(4606)…泡沫柠檬花洗手液(3338)…泡沫桉树薄荷洗手液(3337)…泡沫柠檬花洗手液(3341)[来自spartanchemical.com]
“Technical Bulletin…To: All Distributors…How to position this to your customers:…Educate – While hand hygiene is the first line of defense against the spread of harmful bacteria such as 2019 Novel Coronavirus (2019-nCoV), disinfection of high touch surfaces helps reduce the risk of personnel coming in contact with a contaminated surface.
“技术通报……致:所有发行商……如何向您的客户定位:……教育——虽然手部卫生是防止有害细菌传播的第一道防线，如2019新型冠状病毒(2019- ncov)，但对高接触表面进行消毒有助于降低人员接触受污染表面的风险。
Recommend - This is a perfect opportunity to talk to your distributors about the NEW foamylQ™ Antibacterial Hand Wash and Hand Sanitizers • Eucalyptus Mint (4603), Lemon Blossom (4604), and Healthcare Personnel Hand Wash (4605). Adding waterless sanitizer products leads to an increase in the frequency of hand hygiene practiced. Combined with a managed cleaning program, featuring the Spartan disinfectant of their choice, they will have a good program to prevent the spread of 2019 Novel Coronavirus (2019-nCoV) and other viruses.” [From spartanchemical.com]7
推荐—这是与您的经销商讨论新泡沫q™抗菌洗手液和洗手液•桉树薄荷(4603)、柠檬花(4604)和医护人员洗手液(4605)的绝佳机会。添加无水消毒剂产品可以增加手部卫生实践的频率。结合他们选择的斯巴达消毒剂的管理清洁计划，他们将有一个很好的计划来防止2019新型冠状病毒(2019- ncov)和其他病毒的传播。“[spartanchemical.com] 7
Spartan Lemon Blossom Hand Sanitizer with 0.1% benzalkonium chloride complies with the FDA Final Rule on hand sanitizers. View Approval” [From spartanchemical.com]8
斯巴达柠檬花洗手液含有0.1%苯扎氯铵，符合FDA洗手液最终规则。查看批准”[来自spartanchemical.com]
Based on the claims above, these consumer and health care products are “new drugs” within the meaning of section 201(p) of the FD&C Act, 21 U.S.C. 321(p), because they are not generally recognized as safe and effective (GRASE) for use under the conditions prescribed, recommended, or suggested in their labeling. New drugs may not be introduced or delivered for introduction into interstate commerce without prior approval from FDA, as described in section 505(a) of the FD&C Act, 21 U.S.C. 355(a), unless they are lawfully marketed under section 505G of the FD&C Act (which is not the case for these products, as further described below) or under other exceptions not applicable here. No FDA approved applications pursuant to section 505 of the FD&C Act, 21 U.S.C. 355, is in effect for these drug products, nor are we aware of any adequate and well-controlled clinical studies in the published literature that support a determination that your foamyiQ™ and Lite'n Foamy® drug products are GRASE for use under the conditions suggested, recommended, or prescribed in their labeling. Accordingly, these drug products are unapproved new drugs marketed in violation of sections 505(a) and 301(d) of the FD&C Act, 21 U.S.C 355(a) and 331(d).
根据上述声明，这些消费品和保健产品属于FD&C法案21 U.S.C. 321(p)第201(p)条所指的“新药”，因为它们在其标签中规定、推荐或建议的条件下，通常不被认为是安全有效的(GRASE)。如《FD&C法案》第505(a)条、21 U.S.C. 355(a)条所述，未经FDA事先批准，新药不得引入或交付州际贸易，除非它们是根据《FD&C法案》第505G条合法上市的(这些产品并非如此，下文将进一步说明)或在其他不适用于此的例外情况下。FDA没有根据FD&C法案第505条(21 U.S.C. 355)批准这些药品的申请，我们也不知道在已发表的文献中有任何充分和良好对照的临床研究支持确定企业的foamyiQ™和Lite'n Foamy®药品在其标签中建议、推荐或规定的条件下使用GRASE。因此，这些药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)条。
We note that over-the-counter (OTC) topical antiseptic products had been the subject of rulemaking under the Agency’s OTC Drug Review. In particular, consumer antiseptics were addressed in a tentative final monograph (TFM) entitled “Topical Antimicrobial Drug Products for Over-the-Counter Human Use; Tentative Final Monograph for Health-Care Antiseptic Drug Products,” Proposed Rule, 59 FR 31402 (June 17, 1994) (1994 TFM), as further amended by “Safety and Effectiveness of Consumer Antiseptics; Topical Antimicrobial Drug Products for Over-the-Counter Human Use; Proposed Amendment of the Tentative Final Monograph; Reopening of Administrative Record,” Proposed Rule, 81 FR 42912 (June 30, 2016) (Consumer Antiseptic Rubs Proposed Rule). Over the course of these rulemakings, three active ingredients (benzalkonium chloride, ethyl alcohol (ethanol), and isopropyl alcohol) were classified as Category III for use in consumer antiseptic rub products, meaning that additional safety and effectiveness data are needed to support a determination that a drug product containing one of these active ingredients would be GRASE for use as a consumer antiseptic rub. Additionally, OTC consumer antiseptic washes were addressed in the “Safety and Effectiveness of Consumer Antiseptics; Topical Antimicrobial Drug Products for Over-the-Counter Human Use,” Proposed Rule, 78 FR 76444 (December 17, 2013) (Consumer Antiseptic Washes Proposed Rule) and “OTC Safety and Effectiveness of Topical Antimicrobial Drug Products for Over-the-Counter Human Use,” Final Rule, 81 FR 61106 (September 6, 2016). Over the course of these rulemakings benzalkonium chloride, benzethonium chloride, and chloroxylenol were classified as Category III for use in consumer antiseptic wash products, meaning that additional safety and effectiveness data are needed to support a determination that a drug product containing one of these active ingredients would be GRASE for use as a consumer antiseptic wash.
我们注意到，非处方(OTC)局部抗菌产品一直是FDA OTC药品审查的规则制定对象。特别地，在题为“非处方人类用外用抗菌药物产品;卫生保健防腐药品初步最终专论”，拟议规则59 FR 31402(1994年6月17日)(1994 TFM)，经“消费用防腐剂的安全性和有效性;非处方人用外用抗菌药物产品;对专著暂定终稿的修改建议;重新开放行政记录”，建议规则，81 FR 42912(2016年6月30日)(消费者防腐摩擦建议规则)。在制定这些规则的过程中，三种活性成分(苯扎氯铵、酒精(乙醇)和异丙醇)被归类为用于消费者消毒搓揉产品的III类，这意味着需要更多的安全性和有效性数据来支持确定含有其中一种活性成分的药品将是用于消费者消毒搓揉的GRASE。此外，在“消费者防腐剂的安全性和有效性;非处方人用外用抗菌药物产品”，提案规则78 FR 76444(2013年12月17日)(消费者抗菌洗涤剂提案规则)和“非处方人用外用抗菌药物产品的OTC安全和有效性”，最终规则81 FR 61106(2016年9月6日)。在制定这些规则的过程中，苯扎氯铵、苯甲铵和氯羟甲酚被归类为用于消费杀菌洗涤产品的III类，这意味着需要更多的安全和有效性数据来支持含有这些活性成分之一的药品将作为消费杀菌洗涤产品使用的GRASE。
OTC healthcare antiseptics products were addressed in the Effectiveness of Health Care Antiseptics; Topical Antimicrobial Drug Products for Over-the-Counter Human Use; Proposed Amendment of the Tentative Final Monograph; Reopening of Administrative Record,” Proposed Rule, 80 FR 25166 (May 1, 2015) (Health Care Antiseptics Proposed Rule), and “Safety and Effectiveness of Health Care Antiseptics; Topical Antimicrobial Drug Products for Over-the-Counter Human Use,” Final Rule, 82 FR 60474 (December 20, 2017). Over the course of these rulemakings, six active ingredients (benzalkonium chloride, benzethonium chloride, chloroxylenol, ethyl alcohol, isopropyl alcohol, and povidone-iodine) were classified as Category III for use in health care antiseptic products, meaning that additional safety and effectiveness data are needed to support a determination that a drug product containing one of these active ingredients would be GRASE for use as health care antiseptics including rubs and washes.
OTC保健用防腐剂产品在《保健用防腐剂的有效性》中进行了论述;非处方人外用抗菌药物产品;对专著暂定终稿的修改建议;重新开放行政记录”，拟议规则，80 FR 25166(2015年5月1日)(卫生保健防腐剂拟议规则)，以及“卫生保健防腐剂的安全性和有效性;非处方人用外用抗菌药物产品”，最终规则82 FR 60474(2017年12月20日)。在制定这些规则的过程中，六种活性成分(苯扎氯铵、苯甲氯铵、氯羟甲酚、乙醇、异丙醇和聚维酮碘)被归类为III类用于卫生保健杀菌产品，这意味着需要额外的安全和有效性数据来支持确定含有其中一种活性成分的药品将作为卫生保健杀菌产品(包括摩擦和洗涤)使用的GRASE。
Section 505G of the FD&C Act addresses nonprescription drugs marketed without an approved application. Under section 505G(a)(3) of the FD&C Act, drugs that were classified as Category III for safety or effectiveness in a TFM that is the most recently applicable proposal or determination for such drugs issued under 21 CFR Part 330 – and that were not classified as Category II for safety or effectiveness – are not required to have an approved application under section 505 in order to be marketed, as long as they meet the relevant conditions of use outlined in the applicable TFM, including the active ingredient, and comply with all other applicable requirements.
FD&C法案第505G条涉及未经批准申请而上市的非处方药。下节505 g (a)(3)的使用行为,药物被列为三级安全性或有效性的TFM最近适用的建议或决定发行这类药物在21 CFR 330——这部分不属于第二类安全性或有效性——不需要有一个根据第505条批准的申请即可上市,只要它们符合适用TFM中概述的相关使用条件,包括活性成分，并符合所有其他适用的要求。
However, your consumer and health care topical antiseptic products do not conform to the 1994 TFM, nor any other TFM, proposed rule, or final rule and do not meet the conditions under section 505G(a)(3) of the FD&C Act for marketing without an approved application under section 505G.
然而，企业的消费和卫生保健专用杀菌产品不符合1994 TFM，也不符合任何其他TFM、拟议规则或最终规则，不符合FD&C法案第505G(a)(3)条规定的条件，在没有根据第505G条批准申请的情况下进行营销。
Specifically, your labeling claims, suggesting that your consumer, and health care topical antiseptic products are effective in shortening the duration of infection and preventing infection or disease from the novel coronavirus that causes COVID-19, go beyond merely describing the general intended use of an antiseptic as set forth in the 1994 TFM.9
具体来说，企业的标签声明表明，企业的消费者和卫生保健局部抗菌产品在缩短感染时间和预防导致COVID-19的新型冠状病毒的感染或疾病方面是有效的，而不仅仅是描述1994年tft .9中规定的一种防腐剂的一般预期用途
We are unaware of any adequate and well-controlled clinical studies in the published literature that support a determination that your consumer, and health care topical antiseptic products are GRASE for the above-described intended uses. Accordingly, your consumer, and health care topical antiseptic products are new drugs under section 201(p) of the FD&C Act. In addition, there are no FDA-approved applications in effect for your consumer, and health care topical antiseptic products and, accordingly, they are unapproved new drugs sold in violation of sections 505(a) and 301(d) of the FD&C Act, 21 U.S.C §§ 355(a) and 331(d). We note that your consumer, and health care topical antiseptic products also do not conform to any temporary policy FDA has implemented during the public health emergency.10
在已发表的文献中，我们不知道有任何充分和良好对照的临床研究支持确定企业的消费者和卫生保健局部抗菌产品是用于上述预期用途的GRASE。因此，根据FD&C法案第201(p)条，企业的消费者和卫生保健局部抗菌产品是新药。此外，没有FDA批准的适用于企业的消费者的申请，因此，它们是未经批准的新药，违反了FD&C法案第505(a)和301(d)条，21 U.S.C§355(a)和331(d)条出售。我们注意到，企业的消费者和卫生保健局部杀菌产品也不符合FDA在公共卫生紧急事件期间实施的任何临时政策
In addition, these consumer and health care topical antiseptic products are misbranded under section 502(a) of the FD&C Act, 21 U.S.C 352(a), because their labeling is false or misleading. Specifically, labeling for these products falsely indicates that they are registered and approved by the FDA. However, as previously noted, your products are not the subject of an FDA-approved application. Further, under 21 CFR Part 207, domestic and foreign establishments that manufacture, repack, relabel, or salvage a drug are required to be registered with the FDA and drug products from such firms must be listed with the FDA. Therefore, a labeling representation suggesting that your products are FDA-approved and registered is false or misleading.
此外，根据FD&C法案第502(a)条，21 U.S.C 352(a)条，这些消费和卫生保健局部抗菌产品被错误地贴上了标签，因为它们的标签是虚假的或具有误导性的。具体来说，这些产品的标签错误地表明它们已经FDA注册和批准。然而，如前所述，企业的产品不是FDA批准申请的对象。此外，根据21 CFR第207部分，国内和国外生产、重新包装、重新标记或回收药品的企业必须在FDA注册，这些企业的药品必须在美国上市。因此，暗示企业的产品经过FDA批准和注册的标签陈述是错误的或具有误导性的。
These consumer and health care topical antiseptic products are also misbranded under section 502(ee) of the FD&C Act, 21 U.S.C. 352(ee), because they 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 these products into interstate commerce is prohibited under sections 301(a) of the FD&C Act, 21 U.S.C. 331(a).
根据FD&C法案第502(ee)条，21 U.S.C. 352(ee)条，这些消费者和卫生保健局部抗菌产品也被贴错标签，因为它们是非处方药，受FD&C法案第505G条，21 U.S.C. 355h的约束，但不符合该章节下的营销要求，并不是根据FD&C法案第505条，21 U.S.C. 355批准的申请的内容。根据《FD&C法案》第301(a)条，21 U.S.C. 331(a)条，禁止将这些产品引入或交付于州际贸易。
Ineffective Quality System
无效的质量体系
These violations demonstrate a failure of your executive management to exercise proper oversight and control over the manufacture of drugs. You should immediately and comprehensively assess your company’s manufacturing operations to ensure that systems, processes, and ultimately, products conform to FDA requirements.
这些违规行为表明企业的行政管理部门未能对药品生产进行适当的监督和控制。企业应该立即全面评估贵公司的生产操作，以确保系统、流程和最终的产品符合FDA的要求。
In your response, describe how top management will support quality assurance and reliable operations, including but not limited to, timely provision of resources to proactively address emerging manufacturing and quality issues and to assure a continuing state of control.
回复中，请描述最高管理层将如何支持质量保证和可靠的运营，包括但不限于及时提供资源，主动解决新出现的生产造和质量问题，并确保持续的受控状态。
Drug Production Suspended
暂停药品生产
We acknowledge your commitment to temporarily suspend production of drugs at this facility. If you plan to resume drug manufacturing operations, contact the agency before resuming your operations to schedule a meeting to discuss your remediation status. Your meeting request should include a written confirmation of full remediation, and detailed supporting documents of your systemic CGMP corrections.
我们了解到企业承诺暂时停止该工厂的药品生产。如果企业计划恢复药品生产操作，请在恢复操作前与该机构联系，安排会议讨论企业的整改状态。企业的会议要求应包括全面整改的书面确认，以及企业系统性CGMP纠正的详细证明文件。
CGMP Consultant Recommended
CGMP顾问推荐
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.
基于我们在贵公司发现的违规性质，我们强烈建议聘请一名符合21 CFR 211.34规定的资质顾问，协助企业公司满足CGMP要求。企业使用顾问并不减轻贵公司遵守CGMP的义务。贵公司的执行管理层仍有责任解决所有缺陷，以确保持续的CGMP符合性。
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.
本函中所列举的违规行为并不包括贵工厂存在的所有违规行为。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.
请及时纠正任何违规行为。未能及时和充分地解决此问题可能会导致无需进一步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阻止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.
未能解决违规也可能导致FDA扣留出口证书的发放。FDA可能会拒绝批准将贵公司列为药品制造商的新申请或补充申请，直到完全解决任何违规问题并确认贵公司符合CGMP。我们可能会重新检查，以确认企业已完成纠正措施，以解决任何违规行为。
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 since our inspection to correct your 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.
这封信通知企业我们的发现，并为企业提供了一个解决上述缺陷的机会。收到本函后，请于15个工作日内以书面方式回复本办公室。说明自我们检查以来，企业为纠正违规行为和防止违规行为再次发生所做的工作。在回复本函时，企业可以提供额外的信息供我们考虑，因为我们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，请说明延误的原因和完成的时间表。
Your written notification should refer to the Warning Letter Number above (614450). Please address your reply via email to: ORAPHARM3_RESPONSES@fda.hhs.gov
Attention: Eric Mueller, Compliance Officer
U.S. Food and Drug Administration
Division of Pharmaceutical Quality Operations Division III
If you have questions regarding the contents of this letter, please contact Eric Mueller, Compliance Officer at (402) 331-8536, ext. 101.
Sincerely,
/S/
Jeffrey D. Meng
Acting Program Division Director
Division of Pharmaceutical Quality Operations Division III
___________________________
1 Consumer antiseptics: foamyiQ™ Lemon Blossom Hand Sanitizer (4604), Lite'n Foamy® Lemon Blossom Hand Sanitizer (3338), foamyiQ™ Eucalyptus Mint Sanitizing Handwash (4603), Lite'n Foamy® Eucalyptus Mint Sanitizing Handwash (3337). Health care antiseptics: foamyiQ™ Healthcare Personnel Handwash (4605) and Lite'n Foamy® Healthcare Personnel Handwash (3341).
1 .家用消毒液:泡沫yiq™柠檬花洗手液(4604)，Lite'n泡沫®柠檬花洗手液(3338)，泡沫yiq™桉树薄荷消毒洗手液(4603)，泡沫Lite'n桉树薄荷消毒洗手液(3337)。医疗保健消毒剂:泡沫yiq™医疗保健人员洗手液(4605)和Lite'n泡沫®医疗保健人员洗手液(3341)。
2 As explained in the next paragraph, there is currently an outbreak of a respiratory disease named “Coronavirus Disease 2019” (COVID-19).
2如下一段所述，目前有一种名为“2019冠状病毒病”(COVID-19)的呼吸道疾病暴发。
3 Secretary of Health and Human Services, Determination that a Public Health Emergency Exists. (originally issued on Jan. 31, 2020., and subsequently renewed) available at https://www.phe.gov/emergency/news/healthactions/phe/Pages/2019-nCoV.aspx).
3卫生与公众服务部部长，确定存在突发公共卫生事件。(最初发布于2020年1月31日。，并随后更新)可在https://www.phe.gov/emergency/news/healthactions/phe/Pages/2019-nCoV.aspx)。
4 Proclamation on Declaring a National Emergency Concerning the Novel Coronavirus Disease (COVID-19) Outbreak (originally issued Mar. 13, 2020., and subsequently renewed) ), available at https://www.whitehouse.gov/briefingroom/presidential-actions/2021/02/24/notice-on-the-continuation-of-the-national-emergency-concerning-the-coronavirusdisease-2019-covid-19-pandemic/.
4关于新型冠状病毒病(COVID-19)爆发全国进入紧急状态的公告(原于2020年3月13日发布)。，并随后更新))，可在https://www.whitehouse.gov/briefingroom/presidential-actions/2021/02/24/notice-on-the-continuation-of-the-national-emergency-concerning-the-coronavirusdisease-2019-covid-19-pandemic/下载。
5 https://www.spartanchemical.com/products/category/wcovid/
6 spartanchemical.com/solutions/covid-19/faq-page/ (page 2)
7 spartanchemical.com/globalassets/solutions/covid-19/2019-novel-coronavirus-2019-ncov-in-the-news.pdf
8 spartanchemical.com/globalassets/solutions/covid-19/hand sanitizer-efficacy-infographic.pdf
9 The 1994 TFM covers health care antiseptics that are indicated for use to help reduce bacteria that potentially can cause disease and health care and consumer antiseptics that are indicated for use to decrease bacteria on the skin. 59 FR at 31443.
9 1994年TFM规定了用于帮助减少可能导致疾病的细菌的保健用防腐剂和用于减少皮肤上细菌的保健用和消费用防腐剂。FR 59, 31443。
10 See, e.g., Temporary Policy for Preparation of Certain Alcohol-Based Hand Sanitizer Products During the Public Health Emergency (COVID-19). Because your non-alcohol-based consumer antiseptic products are not consistent with the formulations described in these guidances, they do not fall within any temporary Agency policy not to take action against firms manufacturing hand sanitizer products for violations of section 505 of the FD&C Act.
10参见《突发公共卫生事件(COVID-19)期间制备某些含酒精洗手液产品的临时政策》。因为企业的不含酒精的消毒液产品不符合本指南中描述的配方，它们不属于任何临时机构政策的范围，不对违反FD&C法案第505条的生产洗手液产品的公司采取行动。
