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摘 要

 

FDA于2024年07月11日對Nowrez & Ismail Shukri Company簽發(fā)了警告信，簽發(fā)的警告信中的主要缺陷有：

 

1、在放行前未能對每一批藥品進行適當(dāng)?shù)膶嶒炇覝y定，以確保其符合藥品的最終標(biāo)準(zhǔn)，包括每種活性成分的鑒別和含量。

 

警告信中提到，根據(jù)提供的記錄和信息，該公司未能證明對非處方藥產(chǎn)品進行了充分的成品藥測試。例如，提供的分析報告單(COA)沒有包括適當(dāng)?shù)幕钚猿煞趾糠治鰷y試或微生物檢測。

 

注：此類問題是OTC產(chǎn)品經(jīng)常出現(xiàn)的問題。FDA按TOC管理很多產(chǎn)品，在中國并非按藥品管理，如本警告信中提到的外用擦劑等，這類產(chǎn)品在國內(nèi)往往按消毒劑管理。這也導(dǎo)致了這類的產(chǎn)品的質(zhì)量管理相對薄弱，再加上GMP意識的薄弱，在FDA檢查時往往出現(xiàn)很多重大的缺陷。此類產(chǎn)品在藥品放行和分銷前也需要進行全面的放行測試，包括活性成分的含量和鑒別測試。如果沒有經(jīng)過充分的測試，就沒有足夠的科學(xué)證據(jù)來確保藥品在放行前符合適當(dāng)?shù)臉?biāo)準(zhǔn)。

 

2、未能建立并遵循旨在評估藥品穩(wěn)定性特性的充分的書面檢驗程序。

 

警告信中提到，該公司最近被要求提供數(shù)據(jù)來支持每種藥品配方的有效期時，該公司回復(fù)了 2017 年至 2020 年期間測試的相關(guān)批次的穩(wěn)定性數(shù)據(jù)。其提供的穩(wěn)定性數(shù)據(jù)未能表明該公司正在持續(xù)進行適當(dāng)?shù)幕瘜W(xué)和微生物檢測，以支持 2017 年以后發(fā)貨的 OTC 藥品的有效期。

 

注：持續(xù)穩(wěn)定性考察的目的是在有效期內(nèi)監(jiān)控已上市藥品的質(zhì)量，以發(fā)現(xiàn)藥品與生產(chǎn)相關(guān)的穩(wěn)定性問題（如雜質(zhì)含量或溶出度特性的變化），并確定藥品能夠在標(biāo)示的貯存條件下，符合質(zhì)量標(biāo)準(zhǔn)的各項要求。所以穩(wěn)定性計劃需要包含長期的穩(wěn)定性實驗，以持續(xù)的檢測藥品的質(zhì)量情況。一般情況下每年要選取代表性的批次加入穩(wěn)定性研究。

 

3、未能對每種成分的樣品進行鑒別測試和純度、含量、質(zhì)量的符合性測試。

 

警告信中提到，該公司未能證明其對非處方藥產(chǎn)品生產(chǎn)過程中使用的進廠原材料進行了充分的檢測。例如沒有對活性成分異丙醇進行甲醇測試。同時提到僅依靠供應(yīng)商分析報告單(COA) 列明的鑒別檢測是不夠的。如果沒有經(jīng)過充分的測試，你們就沒有科學(xué)證據(jù)證明你們的原材料在用于生產(chǎn)藥品之前符合適當(dāng)?shù)臉?biāo)準(zhǔn)。

 

注：FDA 21 CFR 211.84(d)(1)中要求：應(yīng)至少進行一項測試，以鑒定藥品每種成分。FDA 21 CFR 211.84 (d)(2) 中要求：每個成分都應(yīng)經(jīng)過測試，以確保其純度、含量和質(zhì)量符合標(biāo)準(zhǔn)要求。無論是處方藥還是非處方藥都應(yīng)該遵循這些要求。制定合適的成分、成品的質(zhì)量標(biāo)準(zhǔn)，包括檢測項目、方法、檢測頻次等信息。

 

【基礎(chǔ)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.

你工廠已在美國食品藥品監(jiān)督管理局 (FDA) 注冊為非處方 (OTC) 藥品制造商。FDA 已審查了你們根據(jù)我們于 2022 年 9 月 12 日和 2024 年 2 月 26 日依據(jù)《聯(lián)邦食品、藥品和化妝品法案》（FD&C 法案）第 704(a)(4) 節(jié)針對你們工廠 Nowrez & Ismail Shukri Company（FEI 3009721234，地址：Sahab, King Abdullah II Street, No 22, Amman, Jordan）提出的記錄和其他信息要求而提交的記錄。

 

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).

本警告信總結(jié)了成品藥品現(xiàn)行生產(chǎn)質(zhì)量管理規(guī)范 (CGMP) 規(guī)定的嚴(yán)重違規(guī)行為。參見《聯(lián)邦法規(guī)》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)).

由于你們在對我們的 704(a)(4) 請求的回復(fù)中所描述的用于藥品生產(chǎn)、加工、包裝或保存的方法、設(shè)施或控制不符合 CGMP，所以你們的藥品根據(jù)《聯(lián)邦食品藥品和化妝品法案》（FD&C 法案）第 501(a)(2)(B) 節(jié)、（21 U.S.C.351(a)(2)(B)）的規(guī)定被認(rèn)定為摻假藥品。

 

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:

在審查根據(jù)《聯(lián)邦食品、藥品和化妝品法案》第 704(a)(4)節(jié)提供的記錄和其他信息后，發(fā)現(xiàn)嚴(yán)重違規(guī)行為，包括但不限于以下情況：

 

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對每一批藥品進行適當(dāng)?shù)膶嶒炇覝y定，以確保其符合藥品的最終標(biāo)準(zhǔn)，包括每種活性成分的鑒別和含量（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.

根據(jù)提供的記錄和信息，你們未能證明對非處方藥產(chǎn)品進行了充分的成品藥測試。例如，你們提供的分析報告單(COA)（包括您的(b)(4)% 異丙醇外用擦劑）沒有包括適當(dāng)?shù)幕钚猿煞趾糠治鰷y試或微生物檢測。

 

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.

藥品放行和分銷前必須進行全面的放行測試，包括活性成分的含量和鑒別測試。如果沒有經(jīng)過充分的測試，你們就沒有足夠的科學(xué)證據(jù)來確保你們的藥品在放行前符合適當(dāng)?shù)臉?biāo)準(zhǔn)。

 

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評估藥品穩(wěn)定性特性的充分的書面檢驗程序（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.

你們提供的記錄和信息并未證明你公司對其生產(chǎn)的非處方藥產(chǎn)品有足夠的穩(wěn)定性計劃。例如，你公司最初提供了一份穩(wěn)定性測試報告，其中注明了 2017 年至 2020 年期間測試的(b)(4)%異丙醇外用擦劑的 (b)(4) 批次 三年穩(wěn)定性數(shù)據(jù)。當(dāng)最近被要求提供數(shù)據(jù)來支持每種藥品配方的有效期時，你公司回復(fù)了 2017 年至 2020 年期間測試的(b)(4)%異丙醇外用擦劑(b)(4)批次的穩(wěn)定性數(shù)據(jù)。你們提供的穩(wěn)定性數(shù)據(jù)未能表明你公司正在持續(xù)進行適當(dāng)?shù)幕瘜W(xué)和微生物檢測，以支持 2017 年以后發(fā)貨的 OTC 藥品的(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)).

你公司未能對每種成分的樣品進行鑒別測試和純度、含量、質(zhì)量的符合性測試。（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.

根據(jù)提供的記錄和信息，你們未能證明你們對非處方藥產(chǎn)品生產(chǎn)過程中使用的進廠原材料進行了充分的檢測。你們的回復(fù)表明你們沒有對活性成分異丙醇進行甲醇測試。

 

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.

僅依靠供應(yīng)商分析報告單(COA) 列明的鑒別檢測是不夠的。如果沒有經(jīng)過充分的測試，你們就沒有科學(xué)證據(jù)證明你們的原材料在用于生產(chǎn)藥品之前符合適當(dāng)?shù)臉?biāo)準(zhǔn)。作為制造商，你們有責(zé)任在生產(chǎn)前對藥物成分進行取樣、檢驗和檢查，以確保足夠的質(zhì)量，包括測試異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

在全國范圍內(nèi)，使用受甲醇污染的乙醇或異丙醇已導(dǎo)致致命的中毒事件。請參閱 FDA 的指導(dǎo)文件《酒精（乙醇）和異丙醇中甲醇檢測政策》，網(wǎng)址為https://www.fda.gov/media/173005/download

 

CGMP Consultant Recommended

CGMP 顧問推薦

 

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.

如果你公司打算恢復(fù)為美國市場生產(chǎn)藥品，在恢復(fù)藥品生產(chǎn)業(yè)務(wù)之前，應(yīng)聘請符合 21 CFR 211.34 規(guī)定的合格顧問，以協(xié)助你公司滿足 CGMP 要求。合格的顧問還應(yīng)對你們的整個運營進行全面的六大系統(tǒng)審計，以確保其符合 CGMP，并在你們按照 FDA 的指導(dǎo)文件《藥品 CGMP 法規(guī)之質(zhì)量體系方法》

（網(wǎng)址為：https://www.fda.gov/regulatory-information/search-fda-guidance-documents/quality-systems-approach-pharmaceutical-current-good-manufacturing-practice-regulations）解決公司的合規(guī)狀態(tài)之前評估所有 CAPA 的完成情況和有效性。

 

Conclusion

結(jié)論

 

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.

本信中列舉的違規(guī)行為并非你工廠存在的所有違規(guī)行為的詳盡清單。你公司有責(zé)任調(diào)查并確定所有違規(guī)行為的原因，并防止其再次發(fā)生或發(fā)生其他違規(guī)行為。FDA于2024年7月3日將你公司列入進口警告 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.

及時糾正所有違規(guī)行為。FDA 可能會拒絕批準(zhǔn)將你公司列為藥品制造商的新申請或補充申請，直到所有違規(guī)行為得到徹底解決且我們確認(rèn)貴公司符合 CGMP。我們可能會重新檢查以核實你公司是否完成了所有違規(guī)行為的糾正措施。

 

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.

未能解決所有違規(guī)行為可能還會導(dǎo)致 FDA依據(jù)《聯(lián)邦食品、藥品和化妝品法案》的第381(a)(3)條、21 U.S.C.801(a)(3)，繼續(xù)拒絕將位于Sahab, King Abdullah II Street, No 22, Amman, Jordan的 Nowrez & Ismail Shukri（FEI 3009721234）生產(chǎn)的商品入境美國。根據(jù)該規(guī)定，如果物品被發(fā)現(xiàn)摻假，可能會被扣留或拒絕入境。

 

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.

這封信函告知你公司我們的調(diào)查結(jié)果并為你公司提供解決上述缺陷的機會。收到此信后，請在15個工作日內(nèi)以書面形式回復(fù)本辦公室。詳細說明你公司為解決違規(guī)行為并防止其再次發(fā)生所采取的措施。在回復(fù)此信時，你公司可以提供更多信息供我們考慮，因為我們會繼續(xù)評估你公司的活動和做法。如果你公司無法在15個工作日內(nèi)完成糾正措施，請說明延遲的原因和完成計劃。