摘 要

FDA于2024年07月11日对Nowrez & Ismail Shukri Company签发了警告信，签发的警告信中的主要缺陷有：

1、在放行前未能对每一批药品进行适当的实验室测定，以确保其符合药品的最终标准，包括每种活性成分的鉴别和含量。

警告信中提到，根据提供的记录和信息，该公司未能证明对非处方药产品进行了充分的成品药测试。例如，提供的分析报告单(COA)没有包括适当的活性成分含量分析测试或微生物检测。

注：此类问题是OTC产品经常出现的问题。FDA按TOC管理很多产品，在中国并非按药品管理，如本警告信中提到的外用擦剂等，这类产品在国内往往按消毒剂管理。这也导致了这类的产品的质量管理相对薄弱，再加上GMP意识的薄弱，在FDA检查时往往出现很多重大的缺陷。此类产品在药品放行和分销前也需要进行全面的放行测试，包括活性成分的含量和鉴别测试。如果没有经过充分的测试，就没有足够的科学证据来确保药品在放行前符合适当的标准。

2、未能建立并遵循旨在评估药品稳定性特性的充分的书面检验程序。

警告信中提到，该公司最近被要求提供数据来支持每种药品配方的有效期时，该公司回复了 2017 年至 2020 年期间测试的相关批次的稳定性数据。其提供的稳定性数据未能表明该公司正在持续进行适当的化学和微生物检测，以支持 2017 年以后发货的 OTC 药品的有效期。

注：持续稳定性考察的目的是在有效期内监控已上市药品的质量，以发现药品与生产相关的稳定性问题（如杂质含量或溶出度特性的变化），并确定药品能够在标示的贮存条件下，符合质量标准的各项要求。所以稳定性计划需要包含长期的稳定性实验，以持续的检测药品的质量情况。一般情况下每年要选取代表性的批次加入稳定性研究。

3、未能对每种成分的样品进行鉴别测试和纯度、含量、质量的符合性测试。

警告信中提到，该公司未能证明其对非处方药产品生产过程中使用的进厂原材料进行了充分的检测。例如没有对活性成分异丙醇进行甲醇测试。同时提到仅依靠供应商分析报告单(COA) 列明的鉴别检测是不够的。如果没有经过充分的测试，你们就没有科学证据证明你们的原材料在用于生产药品之前符合适当的标准。

注：FDA 21 CFR 211.84(d)(1)中要求：应至少进行一项测试，以鉴定药品每种成分。FDA 21 CFR 211.84 (d)(2) 中要求：每个成分都应经过测试，以确保其纯度、含量和质量符合标准要求。无论是处方药还是非处方药都应该遵循这些要求。制定合适的成分、成品的质量标准，包括检测项目、方法、检测频次等信息。

【基础信息】

Posted Date：2024.08.13

Letter lssue Date：2024.07.11

FEI：3009721234

Firm name：Nowrez & Ismail Shukri Company

Type establishment inspected：Drug Manufacturing Facility

Investigator：N/A

警告信正文 

Your facility is registered with the United States Food and Drug Administration (FDA) as a manufacturer of over-the-counter (OTC) drug products.FDA has reviewed the records you submitted in response to our September 12, 2022, and February 26, 2024 requests for records and other information pursuant to section 704(a)(4) of the Federal Food, Drug, and Cosmetic Act (FD&C Act) for your facility, Nowrez & Ismail Shukri Company, FEI 3009721234, at Sahab, King Abdullah II Street, No 22, Amman, Jordan.

你工厂已在美国食品药品监督管理局 (FDA) 注册为非处方 (OTC) 药品制造商。FDA 已审查了你们根据我们于 2022 年 9 月 12 日和 2024 年 2 月 26 日依据《联邦食品、药品和化妆品法案》（FD&C 法案）第 704(a)(4) 节针对你们工厂 Nowrez & Ismail Shukri Company（FEI 3009721234，地址：Sahab, King Abdullah II Street, No 22, Amman, Jordan）提出的记录和其他信息要求而提交的记录。

This warning letter summarizes significant violations of Current Good Manufacturing Practice (CGMP) regulations for finished pharmaceuticals. See Title 21 Code of Federal Regulations, parts 210 and 211 (21 CFR, parts 210 and 211).

本警告信总结了成品药品现行生产质量管理规范 (CGMP) 规定的严重违规行为。参见《联邦法规》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 of drugs as described in your responses to our 704(a)(4) requests 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)).

由于你们在对我们的 704(a)(4) 请求的回复中所描述的用于药品生产、加工、包装或保存的方法、设施或控制不符合 CGMP，所以你们的药品根据《联邦食品药品和化妆品法案》（FD&C 法案）第 501(a)(2)(B) 节、（21 U.S.C.351(a)(2)(B)）的规定被认定为掺假药品。

Following review of records and other information provided pursuant to section 704(a)(4) of the FD&C Act, significant violations were observed including, but not limited to, the following:

在审查根据《联邦食品、药品和化妆品法案》第 704(a)(4)节提供的记录和其他信息后，发现严重违规行为，包括但不限于以下情况：

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)).

你公司在放行前未能对每一批药品进行适当的实验室测定，以确保其符合药品的最终标准，包括每种活性成分的鉴别和含量（21 CFR 211.165(a)）。

Based on the records and information provided, you did not demonstrate that you conducted adequate finished drug product testing on your OTC drug products.For example, the certificates of analysis (COA) you provided, including your (b)(4)% Isopropyl Rubbing Alcohol, did not include an appropriate assay test for active ingredient content or microbiological testing.

根据提供的记录和信息，你们未能证明对非处方药产品进行了充分的成品药测试。例如，你们提供的分析报告单(COA)（包括您的(b)(4)% 异丙醇外用擦剂）没有包括适当的活性成分含量分析测试或微生物检测。

Full release testing, including strength and identity testing of the active ingredient, must be performed before drug product release and distribution. Without adequate testing, you do not have adequate scientific evidence to assure that your drug products conform to appropriate specifications before release.

药品放行和分销前必须进行全面的放行测试，包括活性成分的含量和鉴别测试。如果没有经过充分的测试，你们就没有足够的科学证据来确保你们的药品在放行前符合适当的标准。

2.Your firm failed to establish and follow an adequate written testing program designed to assess the stability characteristics of drug products (21 CFR 211.166(a)).

你公司未能建立并遵循旨在评估药品稳定性特性的充分的书面检验程序（21 CFR 211.166（a））。

The records and information you provided did not demonstrate that your firm has an adequate stability program for the OTC drug products that you manufacture. For example, your firm initially provided a stability test report which noted three years of stability data for(b)(4)batch of(b)(4)% Isopropyl Rubbing Alcohol that was tested between 2017 and 2020.When asked recently to provide data to support the expiry period for each drug product formula, your firm responded with stability data for(b)(4)batch of(b)(4)% Isopropyl Rubbing Alcohol that was tested between 2017 and 2020.The stability data you provided failed to show appropriate chemical and microbiological testing was being performed on an ongoing basis to support the(b)(4)expiry period for your OTC drug products shipped after 2017 to present.

你们提供的记录和信息并未证明你公司对其生产的非处方药产品有足够的稳定性计划。例如，你公司最初提供了一份稳定性测试报告，其中注明了 2017 年至 2020 年期间测试的(b)(4)%异丙醇外用擦剂的 (b)(4) 批次 三年稳定性数据。当最近被要求提供数据来支持每种药品配方的有效期时，你公司回复了 2017 年至 2020 年期间测试的(b)(4)%异丙醇外用擦剂(b)(4)批次的稳定性数据。你们提供的稳定性数据未能表明你公司正在持续进行适当的化学和微生物检测，以支持 2017 年以后发货的 OTC 药品的(b)(4)有效期。

3.Your firm failed to test samples of each component for identity and conformity with all appropriate written specifications for purity, strength, and quality (21 CFR 211.84(d)(1) and 211.84(d)(2)).

你公司未能对每种成分的样品进行鉴别测试和纯度、含量、质量的符合性测试。（21 CFR 211.84(d)(1) 和 211.84(d)(2)）。

Based on the records and information provided, you did not demonstrate that you are adequately testing the identity of incoming components used in the manufacture of your OTC drug products.Your response indicates that you do not test your active ingredient, isopropyl alcohol, for methanol.

根据提供的记录和信息，你们未能证明你们对非处方药产品生产过程中使用的进厂原材料进行了充分的检测。你们的回复表明你们没有对活性成分异丙醇进行甲醇测试。

Relying solely on supplier’s certificate of analysis (COA) for identity testing is insufficient. Without adequate testing you do not have scientific evidence that your raw materials conform to appropriate specifications prior to use in the manufacture of your drug products. As a manufacturer, you have a responsibility to sample, test, and examine drug components before use in production to assure adequate quality, including testing for the presence of methanol in isopropyl alcohol.

仅依靠供应商分析报告单(COA) 列明的鉴别检测是不够的。如果没有经过充分的测试，你们就没有科学证据证明你们的原材料在用于生产药品之前符合适当的标准。作为制造商，你们有责任在生产前对药物成分进行取样、检验和检查，以确保足够的质量，包括测试异丙醇中是否存在甲醇。

The use of ethanol or isopropyl alcohol contaminated with methanol has resulted in lethal poisoning incidents nationally. See FDA’s guidance document, Policy for Testing of Alcohol (Ethanol) and Isopropyl Alcohol for Methanol, at https://www.fda.gov/media/173005/download

在全国范围内，使用受甲醇污染的乙醇或异丙醇已导致致命的中毒事件。请参阅 FDA 的指导文件《酒精（乙醇）和异丙醇中甲醇检测政策》，网址为https://www.fda.gov/media/173005/download

CGMP Consultant Recommended

CGMP 顾问推荐

If your firm intends to resume manufacturing drugs for the U.S. market, you should engage a consultant qualified as set forth in 21 CFR 211.34 to assist your firm in meeting CGMP requirements before resuming drug manufacturing operations. The qualified consultant should also perform a comprehensive six-system audit of your entire operation for CGMP compliance and evaluate the completion and efficacy of all CAPAs before you pursue resolution of your firm’s compliance status per FDA’s guidance document, Quality Systems Approach to Pharmaceutical CGMP Regulations at https://www.fda.gov/regulatory-information/search-fda-guidance-documents/quality-systems-approach-pharmaceutical-current-good-manufacturing-practice-regulations.

如果你公司打算恢复为美国市场生产药品，在恢复药品生产业务之前，应聘请符合 21 CFR 211.34 规定的合格顾问，以协助你公司满足 CGMP 要求。合格的顾问还应对你们的整个运营进行全面的六大系统审计，以确保其符合 CGMP，并在你们按照 FDA 的指导文件《药品 CGMP 法规之质量体系方法》

（网址为：https://www.fda.gov/regulatory-information/search-fda-guidance-documents/quality-systems-approach-pharmaceutical-current-good-manufacturing-practice-regulations）解决公司的合规状态之前评估所有 CAPA 的完成情况和有效性。

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.FDA placed your firm on Import Alert 66-40 on July 3, 2024.

本信中列举的违规行为并非你工厂存在的所有违规行为的详尽清单。你公司有责任调查并确定所有违规行为的原因，并防止其再次发生或发生其他违规行为。FDA于2024年7月3日将你公司列入进口警告 66-40。

Correct any violations promptly. 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 any violations.

及时纠正所有违规行为。FDA 可能会拒绝批准将你公司列为药品制造商的新申请或补充申请，直到所有违规行为得到彻底解决且我们确认贵公司符合 CGMP。我们可能会重新检查以核实你公司是否完成了所有违规行为的纠正措施。

Failure to address any violations may also result in the FDA continuing to refuse admission of articles manufactured at Nowrez & Ismail Shukri Company, FEI 3009721234, at Sahab, King Abdullah II Street, No 22, Amman, Jordan, into the United States under section 801(a)(3) of the FD&C Act, 21 U.S.C.381(a)(3).Articles under this authority that appear to be adulterated may be detained or refused admission.

未能解决所有违规行为可能还会导致 FDA依据《联邦食品、药品和化妆品法案》的第381(a)(3)条、21 U.S.C.801(a)(3)，继续拒绝将位于Sahab, King Abdullah II Street, No 22, Amman, Jordan的 Nowrez & Ismail Shukri（FEI 3009721234）生产的商品入境美国。根据该规定，如果物品被发现掺假，可能会被扣留或拒绝入境。

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.

这封信函告知你公司我们的调查结果并为你公司提供解决上述缺陷的机会。收到此信后，请在15个工作日内以书面形式回复本办公室。详细说明你公司为解决违规行为并防止其再次发生所采取的措施。在回复此信时，你公司可以提供更多信息供我们考虑，因为我们会继续评估你公司的活动和做法。如果你公司无法在15个工作日内完成纠正措施，请说明延迟的原因和完成计划。