觸目驚心！FDA警告信揭露藥廠亂象：污染水制藥，原料不檢驗
審計對象： Naturich Cosmetique Labs 時間：2025.09.25
一、前言
這封發(fā)給Naturich Cosmetique Labs的警告信（編號320-25-115）指出，該公司在2025年4月至5月的FDA檢查中，其藥品生產(chǎn)存在嚴重違反CGMP規(guī)范的行為。
主要違規(guī)問題包括：
1. 生產(chǎn)控制與工藝驗證不足：
水系統(tǒng)不合格：用于生產(chǎn)藥品的純化水系統(tǒng)未經(jīng)充分驗證、維護和監(jiān)控，設(shè)計存在缺陷，并多次檢出包括腸道菌、洋蔥伯克霍爾德菌和假單胞菌在內(nèi)的有害微生物。
工藝未驗證：所有非處方（OTC）藥品的生產(chǎn)工藝均未經(jīng)驗證，關(guān)鍵步驟缺乏控制，導(dǎo)致批次內(nèi)產(chǎn)品含量不均，出現(xiàn)過效價不足或超標的批次。
2. 調(diào)查不充分：對水系統(tǒng)多次出現(xiàn)的微生物超標結(jié)果未進行充分調(diào)查，其糾正和預(yù)防措施（CAPA）無效，僅依賴所謂的“加熱步驟”來保證成品無微生物污染，缺乏科學(xué)依據(jù)。
3. 物料控制缺失：
未對每批進貨原料（如乙醇、甘油）進行鑒別檢驗，僅依賴供應(yīng)商報告。
尤其嚴重的是，未對高風(fēng)險的乙醇原料進行甲醇污染檢測，也未對甘油等原料進行二甘醇或乙二醇污染檢測，這些雜質(zhì)曾導(dǎo)致全球多起致死事件。
FDA認為公司的整改回應(yīng)不充分，要求其在15個工作日內(nèi)提供全面的根本原因分析、詳細的補救計劃，并對所有在效期內(nèi)的相關(guān)產(chǎn)品進行風(fēng)險評估和檢測。同時，強烈建議公司聘請獨立的CGMP顧問。若未能及時妥善解決，可能面臨法律行動、產(chǎn)品扣押、禁令等嚴重后果。
二、下面是警告信全文及翻譯內(nèi)容
Warning Letter 320-25-115
September 25, 2025
Dear Mr. Purohit:
The United States Food and Drug Administration (FDA) inspected your drug manufacturing facility, Naturich Cosmetique Labs, FEI 3008480436, at 2505 Merritt Drive, Garland, from April 28 to May 2, 2025.
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).
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).
警告信 320-25-115
2025年9月25日
尊敬的普羅希特先生：
美國食品藥品監(jiān)督管理局（FDA）于2025年4月28日至5月2日對貴司位于加蘭市梅里特大道2505號的藥品生產(chǎn)設(shè)施Naturich Cosmetique Labs（FEI編號：3008480436）進行了檢查。
本警告信概述了貴方在藥品成品生產(chǎn)過程中嚴重違反《現(xiàn)行藥品生產(chǎn)質(zhì)量管理規(guī)范》（CGMP）的行為。詳見《聯(lián)邦法規(guī)匯編》第21卷第210及211部分（21 CFR parts 210 and 211）。
由于貴公司生產(chǎn)、加工、包裝或儲存所采用的方法、設(shè)施或控制措施不符合CGMP要求，根據(jù)《聯(lián)邦食品、藥品和化妝品法案》（FD&C Act）第501(a)(2)(B)條（21 U.S.C. 351(a)(2)(B)）規(guī)定，貴公司藥品產(chǎn)品屬于摻假產(chǎn)品。
We reviewed your May 22, 2025, response to our Form FDA 483 in detail. Your response is inadequate because you failed to provide supportive documentation for evaluation or adequate evidence of corrective actions taken to bring your operations into compliance with CGMP.
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 (21 CFR 211.100(a)).
我們已詳細審查貴公司2025年5月22日對FDA 483表格的回復(fù)。貴方回復(fù)存在不足，未能提供支持性文件供評估，亦未提交充分證據(jù)證明已采取糾正措施使生產(chǎn)操作符合CGMP規(guī)范。
1. 貴公司未能建立充分的書面生產(chǎn)與工藝控制程序，以確保所生產(chǎn)藥品具備其宣稱或標示的身份、效力、質(zhì)量及純度（21 CFR 211.100(a)）。
Inadequate Water System
Your firm uses water as a component to manufacture topical over-the-counter (OTC) drug products including skin protectants applied to irritated and potentially broken skin of infants. You failed to adequately validate your water production process to ensure the system was consistently producing water of appropriate quality for its intended use. Additionally, your water system was not adequately maintained nor periodically sanitized. Furthermore, you failed to demonstrate that your water system was adequately monitored to ensure it consistently produced water that met appropriate chemical and microbial quality standards.
In your response, you commit to hiring a third-party laboratory to perform conductivity and total organic carbon testing of your water system. However, your response is inadequate because you did not include timeframes for completing microbiological testing, including appropriate microbial enumeration and identification of water system sample isolates.
供水系統(tǒng)存在缺陷
貴公司將水作為原料生產(chǎn)外用非處方藥產(chǎn)品，包括用于嬰兒受刺激及可能破損皮膚的皮膚保護劑。貴公司未能充分驗證供水生產(chǎn)流程，以確保該系統(tǒng)能持續(xù)生產(chǎn)符合預(yù)期用途的水質(zhì)。此外，貴公司的供水系統(tǒng)既未得到充分維護，也未定期進行消毒處理。此外，貴公司未能證明其水處理系統(tǒng)受到充分監(jiān)測，以確保持續(xù)產(chǎn)出符合化學(xué)及微生物質(zhì)量標準的水。
貴公司在回復(fù)中承諾聘請第三方實驗室對水處理系統(tǒng)進行電導(dǎo)率和總有機碳檢測。但該回復(fù)存在不足，因未包含完成微生物檢測的時間表，包括對水處理系統(tǒng)樣本分離物的適當微生物計數(shù)和鑒定。
Additionally, you failed to consider inadequate aspects of your water system design (e.g., ambient temperature not otherwise subjected to sanitization processes) to ensure it is suitable for producing water used in the formulation of your drug products. Further, you do not address the potential impact of a poorly designed water system to drug products distributed within the United States that are within expiry.
(b)(4) water must be suitable for its intended use and routinely tested. To achieve an ongoing state of control in your (b)(4) water system, you must conduct routine monitoring of microbial levels and identify any contamination in the system.
Inadequate Process Validation
此外，貴方未能充分考慮水系統(tǒng)設(shè)計中的不足之處（例如未對環(huán)境溫度實施消毒處理），以確保該系統(tǒng)適用于生產(chǎn)藥品制劑所需用水。更未評估設(shè)計缺陷的水系統(tǒng)對美國境內(nèi)流通且仍在有效期內(nèi)的藥品可能產(chǎn)生的影響。
(b)(4)水必須符合預(yù)期用途要求并接受常規(guī)檢測。為實現(xiàn)(b)(4)水系統(tǒng)的持續(xù)受控狀態(tài)，必須定期監(jiān)測微生物水平并識別系統(tǒng)中的任何污染。
工藝驗證不足
You have not validated the processes you use to manufacture your OTC drug products. You failed to ensure adequate documentation and control over critical processing steps (e.g., blend times, speeds, temperatures, durations, and specific equipment) used for your large-scale, weight-based manufacturing processes. You distributed drug products with intra-batch potency variability, which indicated inadequate controls for mixing to ensure uniformity. Examples included:
A lot of sub-potent Acne Moisturizing lotion that was re-tested and subsequently released without adequate justification for the initial failing result.
A lot of super-potent (b)(4) SPF 30 lotion that repeatedly failed in-process testing and finished product release testing. Additionally, this lot was released after attempts to reprocess the in-process material, including blending with additional inactive components.
In your response, you commit to developing a master validation plan and a standardized process validation protocol for each of your OTC topical drug products. Your response is inadequate because you did not describe interim controls while process validation is pending or consider a retrospective assessment of the potential impact to your products distributed within the United States that are within expiry.
貴公司未對非處方藥產(chǎn)品的生產(chǎn)工藝進行驗證。在采用基于重量的大規(guī)模生產(chǎn)工藝時，未能確保關(guān)鍵加工步驟（如混合時間、速度、溫度、持續(xù)時間及特定設(shè)備）具備充分的文件記錄與控制措施。貴公司分銷的藥品存在批內(nèi)效力波動現(xiàn)象，表明混合控制措施不足以確保產(chǎn)品均勻性。具體案例包括：
一批效力不足的痤瘡保濕乳液經(jīng)復(fù)檢后獲準放行，但未對初次不合格結(jié)果提供充分說明。
一批效力過高的(b)(4) SPF 30乳液多次未能通過過程檢測和成品放行檢測。該批次在嘗試重新處理中間物料（包括添加額外非活性成分混合）后仍獲準放行。
貴方在回復(fù)中承諾將為每款非處方外用藥品制定主驗證計劃及標準化工藝驗證方案。但該承諾存在缺陷：未說明工藝驗證期間的中期控制措施，亦未考慮對美國境內(nèi)已上市且仍在保質(zhì)期內(nèi)的產(chǎn)品進行潛在影響的追溯評估。
Process validation evaluates the soundness of design and state of control of a process throughout its lifecycle. Each significant stage of a manufacturing process must be designed appropriately and assure the quality of raw material inputs, in-process materials, and finished drugs.
Process qualification studies include intensive monitoring and testing throughout each significant process stage to characterize intra-batch variation and evaluates batches to determine whether an initial state of control has been established.
Successful process qualification studies are necessary before commercial distribution. Thereafter, ongoing vigilant oversight of process performance and product quality is necessary to ensure you maintain a stable manufacturing operation throughout the product lifecycle. See FDA’s guidance for industry, Process Validation: General Principles and Practices, for general principles and approaches that the FDA considers appropriate elements of process validation at
https://www.fda.gov/regulatory-information/search-fda-guidance-documents/process-validation-general-principles-and-practices.
工藝驗證旨在評估工藝在整個生命周期內(nèi)設(shè)計合理性與受控狀態(tài)。制造工藝的每個關(guān)鍵階段均需合理設(shè)計，確保原料投入、在制品及成品藥的質(zhì)量。
工藝確認研究涵蓋對各關(guān)鍵工藝階段的密集監(jiān)測與測試，以表征批內(nèi)變異性，并評估批次是否已建立初始受控狀態(tài)。
在商業(yè)化生產(chǎn)前，必須完成成功的工藝確認研究。此后，需持續(xù)嚴格監(jiān)督工藝表現(xiàn)與產(chǎn)品質(zhì)量，以確保在產(chǎn)品生命周期內(nèi)維持穩(wěn)定的生產(chǎn)運營。有關(guān)FDA認為符合工藝驗證要求的一般原則和方法，請參閱FDA行業(yè)指南《工藝驗證：一般原則與實踐》：
https://www.fda.gov/regulatory-information/search-fda-guidance-documents/process-validation-general-principles-and-practices。
In response to this letter, provide:
A comprehensive, independent, assessment of your water system design, control, and maintenance.
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 (b)(4) Water, United States Pharmacopoeia (USP) monograph, specifications and appropriate microbial limits.
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.
針對此函，請?zhí)峁?/span>
對貴方供水系統(tǒng)設(shè)計、控制及維護的全面獨立評估。
一份詳盡的整改方案，用于安裝并運行適宜的水處理系統(tǒng)。方案須包含完善的持續(xù)控制、維護及監(jiān)測程序，確保整改后的系統(tǒng)設(shè)計能持續(xù)產(chǎn)出符合《美國藥典》(USP)水質(zhì)專論(b)(4)標準及相應(yīng)微生物限值要求的水質(zhì)。
關(guān)于后者，請確保貴公司產(chǎn)品用途所對應(yīng)的水體總微生物計數(shù)限值設(shè)定合理。
A detailed risk assessment addressing the potential effects of the observed water system failures on the quality of all drug product lots currently in U.S. distribution or within expiry. Specify actions that you will take in response to the risk assessment, such as customer notifications and product recalls.
A detailed summary of your validation program for ensuring a state of control throughout the product lifecycle, along with associated procedures. Describe your program for process performance qualification, and ongoing monitoring of both intra-batch and inter-batch variation to ensure a continuing state of control.
A timeline for performing process performance qualification for each of your marketed drug products.
Process performance protocol(s), and written procedures for qualification of equipment and facilities.
A detailed program for designing, validating, maintaining, controlling, and monitoring each of your manufacturing processes that includes vigilant monitoring of intra-batch and inter-batch variation to ensure an ongoing state of control. Also, include your program for qualification of your equipment and facility.
一份詳細的風(fēng)險評估報告，針對已觀察到的供水系統(tǒng)故障可能對當前在美國流通或在有效期內(nèi)的所有藥品批次質(zhì)量造成的影響進行分析。明確說明您將采取的應(yīng)對措施，例如客戶通知和產(chǎn)品召回。
詳細概述貴方驗證計劃，確保產(chǎn)品全生命周期處于受控狀態(tài)，并附相關(guān)操作規(guī)程。描述貴方工藝性能確認計劃，以及持續(xù)監(jiān)測批內(nèi)與批間變異以維持受控狀態(tài)的方案。
列明每款上市藥品實施工藝性能確認的時間表。
提供工藝性能確認方案及設(shè)備設(shè)施確認的書面規(guī)程。
詳細闡述貴司各生產(chǎn)工藝的設(shè)計、驗證、維護、控制及監(jiān)測方案，其中需包含對批內(nèi)及批間變異性的嚴密監(jiān)控以確保持續(xù)受控狀態(tài)。同時需包含設(shè)備與設(shè)施的確認方案。
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).
You failed to adequately investigate multiple microbiological out-of-limit (OOL) results from your (b)(4) water system used to manufacture topical drug products. For example, from May 2024 through April 2025, you did not adequately investigate several OOL testing results from your water system, including the recovery of objectionable microorganisms from multiple points of use. These microorganisms included, but were not limited to Enterobacter cloacae (a common fecal microbiota), Burkholderia cepacia, and multiple Pseudomonas sp. Your investigation did not include an adequate corrective action and preventive action plan (CAPA) to prevent the use of components with potentially objectionable microbial contamination from being used in the manufacture of your drug product.
2. 貴公司未能對任何無法解釋的批次差異或失效情況，或任何組件未能滿足其規(guī)格的情況進行徹底調(diào)查，無論該批次是否已分發(fā)（21 CFR 211.192）。
貴公司未能充分調(diào)查用于生產(chǎn)外用藥品的(b)(4)水系統(tǒng)中多次微生物超標（OOL）結(jié)果。例如，2024年5月至2025年4月期間，貴公司未充分調(diào)查該水系統(tǒng)多次超標檢測結(jié)果，包括在多個用水點檢出有害微生物。這些微生物包括但不限于糞腸桿菌（常見糞便微生物群）、洋蔥桿菌及多種假單胞菌屬。貴公司的調(diào)查未包含充分的糾正與預(yù)防措施計劃（CAPA），未能防止含有潛在可疑微生物污染的組分用于藥品生產(chǎn)。
Furthermore, your justification to release associated finished product relied on subjecting finished products to poorly documented processes you identified as a “(b)(4) step of mixing temperature above that which gram-negative bacteria can withstand.”
In your response, you fail to include an adequate CAPA for controlling microbial recoveries from your water system, stating you continue to rely on “(b)(4) step” processes of (b)(4) batches to (b)(4) to ensure they are free of any microbial contamination. You also fail to consider how fundamental flaws in design, control, and maintenance of your water system may contribute to the OOL results of water.
Your CAPA is not sufficient to ensure the production of water, used as a component, is suitable for its intended use. Your investigations are limited in scope and lack comprehensive review for potentially affected products produced with inadequate water as well as root cause determination. You also did not provide any supporting documentation, including details of your corrective actions with your response. Well-documented, thorough, and scientifically sound investigations are necessary to identify the root cause and implement the appropriate and effective CAPA.
此外，貴方放行相關(guān)成品的依據(jù)是將成品置于記錄不全的工藝流程中，該流程被貴方認定為“混合步驟溫度超過革蘭氏陰性菌耐受閾值”（具體步驟及批次信息以(b)(4)標注）。
貴方回復(fù)中未提供充分的糾正預(yù)防措施（CAPA）來控制供水系統(tǒng)的微生物檢出率，僅聲明繼續(xù)依賴（b）（4）批次中（b）（4）步驟的工藝確保無微生物污染。同時未考量供水系統(tǒng)在設(shè)計、控制及維護方面的根本缺陷如何導(dǎo)致水質(zhì)超標結(jié)果。
貴方糾正措施不足以確保作為組分的水源符合預(yù)期用途。調(diào)查范圍有限，既未全面審查受劣質(zhì)水源影響的潛在產(chǎn)品，也未確定根本原因。回復(fù)中更未提供任何支持性文件，包括糾正措施的具體細節(jié)。必須通過記錄詳實、全面且科學(xué)嚴謹?shù)恼{(diào)查來查明根本原因，并實施恰當有效的糾正措施。
In response to this letter, provide:
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 unit (QU) oversight, and written procedures. Address how your firm will ensure all phases of investigations are appropriately conducted.
An independent assessment and remediation plan for your CAPA program. Provide a report that evaluates whether the program includes effective root cause analysis, ensures CAPA effectiveness, analyzes investigations trends, improves the CAPA program when needed, implements final QU decisions, and is fully supported by executive management.
A comprehensive, independent assessment of the design and control of your firm’s manufacturing operations, with a detailed and thorough review of all microbiological hazards.
針對此函，請?zhí)峁?/span>
對貴公司調(diào)查偏差、差異、投訴、超規(guī)格（OOS）結(jié)果及失效事件的整體體系進行全面、獨立的評估。提交詳細的整改行動計劃。行動計劃應(yīng)涵蓋但不限于以下方面：顯著提升調(diào)查能力、范圍界定、根本原因評估、糾正預(yù)防措施（CAPA）有效性、質(zhì)量單位（QU）監(jiān)督及書面程序。闡明貴公司如何確保調(diào)查各階段均按規(guī)范執(zhí)行。
針對糾正預(yù)防措施（CAPA）計劃的獨立評估與整改方案。提交評估報告，確認該計劃是否包含有效的根本原因分析、確保糾正預(yù)防措施的有效性、分析調(diào)查趨勢、在必要時改進糾正預(yù)防措施計劃、執(zhí)行質(zhì)量部門的最終決定，并獲得高層管理團隊的充分支持。
對貴公司生產(chǎn)操作的設(shè)計與控制進行全面獨立評估，并對所有微生物危害進行詳細徹底的審查。
Complete investigations into all batches with potential objectionable microbial contamination or an OOS microbiological result (whether or not later invalidated). The investigations should detail your findings regarding the root causes of the contamination.
Appropriate microbiological batch release specifications (i.e., total counts, identification of bioburden to detect objectionable microbes) for each of your drug products.
All chemical and microbial test methods used to analyze each of your drug products.
A summary of results from testing retained samples of all 365 (b)(4) Baby Diaper Cream drug product batches within expiry. You should test all appropriate quality attributes including, but not limited to, identity and strength of active ingredients and microbiological quality (total counts and identification of bioburden to detect any objectionable microbes) of each batch. If testing yields an OOS result, indicate the corrective actions you will take, including notifying customers and initiating recalls.
對所有存在潛在可疑微生物污染或微生物學(xué)結(jié)果超標（無論后續(xù)是否被判定無效）的批次進行徹底調(diào)查。調(diào)查應(yīng)詳細說明您對污染根本原因的發(fā)現(xiàn)。
每種藥品均應(yīng)具備適當?shù)奈⑸锱畏判袠藴剩纯偩鋽?shù)、可檢測可疑微生物的生物負荷鑒定）。
用于分析每種藥品的所有化學(xué)和微生物檢測方法。
對所有365(b)(4)嬰兒護臀霜藥品批次在有效期內(nèi)保留樣本的檢測結(jié)果摘要。應(yīng)檢測每批次所有適用的質(zhì)量屬性，包括但不限于活性成分的鑒別與含量，以及微生物質(zhì)量（總菌落數(shù)及生物負荷鑒定以檢出任何有害微生物）。若檢測結(jié)果超出規(guī)格（OOS），需說明擬采取的糾正措施，包括通知客戶及啟動召回程序。
3. Your firm failed to conduct at least one test to verify the identity of each component of a drug product. Your firm also failed to validate and establish the reliability of your component supplier’s test analyses at appropriate intervals (21 CFR 211.84(d)(1) and 211.84(d)(2)).
Your firm manufactures OTC topical drug products, including but not limited to hand sanitizer and skin protectants. You failed to perform adequate identity testing on each shipment of each lot of incoming components (e.g., ethyl alcohol, glycerin) used in the manufacture of your OTC topical drug products. In addition, you relied on your suppliers’ certificate of analysis (COA) without establishing the reliability of your component suppliers’ test analyses at appropriate intervals.
3. 貴公司未能對藥品制劑的每種成分進行至少一項真?zhèn)舞b別試驗。貴公司亦未在適當間隔期內(nèi)對原料供應(yīng)商的檢測分析進行驗證并確認其可靠性（參見《聯(lián)邦法規(guī)》第21卷第211.84(d)(1)條及第211.84(d)(2)條）。
貴公司生產(chǎn)非處方外用藥品，包括但不限于洗手液和皮膚保護劑。貴公司未對用于生產(chǎn)非處方外用藥品的每批次進料組分（如乙醇、甘油）的每批次貨物進行充分的鑒別試驗。此外，貴公司依賴供應(yīng)商提供的分析證書（COA），卻未在適當間隔內(nèi)建立組分供應(yīng)商檢測分析的可靠性。
Products Containing Ethyl Alcohol
You failed to adequately test your incoming component ethyl alcohol (ethanol) at risk of methanol contamination for identity before using it as an active pharmaceutical ingredient (API) in manufacturing your OTC topical drug products. The use of ethanol contaminated with methanol has resulted in various lethal poisoning incidents in humans worldwide. See FDA’s guidance document Policy for Testing of Alcohol (Ethanol) and Isopropyl Alcohol for Methanol to help you meet the CGMP requirements when manufacturing drugs containing ethanol at https://www.fda.gov/regulatory-information/search-fda-guidance-documents/policy-testing-alcohol-ethanol-and-isopropyl-alcohol-methanol.
Furthermore, you failed to demonstrate that the component ethanol, used to manufacture your hand sanitizer drug products, meets USP monograph specifications or is of adequate quality for its intended use.
Products Containing Ingredients at Risk for Diethylene Glycol or Ethylene Glycol Contamination
含乙醇產(chǎn)品
貴公司在將乙醇（乙醇）作為活性藥物成分（API）用于非處方外用藥物生產(chǎn)前，未能充分檢測該原料成分是否存在甲醇污染風(fēng)險。全球范圍內(nèi)，使用含甲醇污染的乙醇已導(dǎo)致多起致命中毒事件。請參閱FDA指導(dǎo)文件《乙醇與異丙醇甲醇檢測政策》（https://www.fda.gov/regulatory-information/search-fda-guidance-documents/policy-testing-alcohol-ethanol-and-isopropyl-alcohol-methanol），該文件可協(xié)助您在生產(chǎn)含乙醇藥物時滿足CGMP要求。
此外，貴方未能證明用于生產(chǎn)手部消毒劑藥品的乙醇成分符合《美國藥典》專論規(guī)格，亦未證明其質(zhì)量足以滿足預(yù)期用途。
含二甘醇或乙二醇污染風(fēng)險成分的產(chǎn)品
You also failed to adequately test your incoming components at high risk of diethylene glycol (DEG) or ethylene glycol (EG) contamination for identity before using them to manufacture your drug products. This includes, but is not limited to, testing of glycerin to determine its appropriate identity, prior to use in manufacturing your OTC topical drug products.
Identity testing for glycerin and certain other high-risk drug components includes a limit test in the USP to ensure the component meets the relevant safety limits for DEG or EG levels. Because you did not perform identity testing on each shipment of each lot using the USP identification test that detects these hazardous impurities, you failed to assure the acceptability of these components for use in the manufacture of your drug products.
The use of ingredients contaminated with DEG or EG has resulted in various lethal poisoning incidents in humans worldwide. See FDA’s guidance document Testing of Glycerin, Propylene Glycol, Maltitol Solution, Hydrogenated Starch Hydrolysate, Sorbitol Solution, and Other High-Risk Drug Components for Diethylene Glycol and Ethylene Glycol to help you meet the CGMP requirements when manufacturing drugs containing ingredients at high-risk for DEG or EG contamination at https://www.fda.gov/regulatory-information/search-fda-guidance-documents/testing-glycerin-propylene-glycol-maltitol-solution-hydrogenated-starch-hydrolysate-sorbitol.
您還未能在使用高風(fēng)險二甘醇（DEG）或乙二醇（EG）污染的進料組分生產(chǎn)藥品前，對其進行充分的鑒別測試。這包括但不限于在生產(chǎn)非處方外用藥品前，對甘油進行鑒別測試以確認其正確成分。
甘油及其他高風(fēng)險藥用成分的鑒別檢測需包含《美國藥典》規(guī)定的限值測試，以確保其二甘醇或乙二醇含量符合安全標準。由于貴公司未對每批次每批次貨物采用《美國藥典》鑒別測試（可檢測此類有害雜質(zhì)）進行鑒別檢測，未能確保這些組分符合藥品生產(chǎn)使用要求。
使用受DEG或EG污染的原料已在全球引發(fā)多起致命中毒事件。請參閱FDA指導(dǎo)文件《甘油、丙二醇、 麥芽糖醇溶液、氫化淀粉水解物、山梨糖醇溶液及其他高風(fēng)險藥物成分的二甘醇和乙二醇檢測指南，以協(xié)助您在生產(chǎn)含高風(fēng)險DEG/EG污染成分的藥物時滿足CGMP要求：https://www.fda.gov/regulatory-information/search-fda-guidance-documents/testing-glycerin -丙二醇-麥芽糖醇溶液-氫化淀粉水解物-山梨糖醇。
In your response, you state that your vendors for glycerin and ethyl alcohol are qualified and their COAs are accurate. You also commit to implement additional tests for a few incoming glycerin and ethyl alcohol batches specifically used in your topical OTC drug products. Your response is inadequate because you do not provide sufficient details and supporting data to demonstrate that your components meet all compendial requirements.
Furthermore, your response does not address testing each shipment of each lot, including each container, of your high-risk drug components for DEG or EG contamination and ethanol for the presence of methanol contamination. Also, you do not commit to retrospective testing of retained components or finished products, and you do not address potential impact on drug products in the U.S. market within expiry.
Without adequate testing, you do not have scientific evidence that the components conform to appropriate specifications before use in the manufacture of your drug products. You have a responsibility to sample, test, and examine drug components before use in production to ensure acceptable quality parameters are met.
在您的回復(fù)中，您聲明甘油和乙醇供應(yīng)商均符合資質(zhì)要求，且其合格證明（COA）準確無誤。您還承諾將對用于外用非處方藥產(chǎn)品的若干批次甘油和乙醇進貨實施額外檢測。但您的回復(fù)存在不足，未能提供充分細節(jié)和支持性數(shù)據(jù)以證明所用組分完全符合藥典要求。
此外，貴方回復(fù)未提及對高風(fēng)險藥用成分每批次每批貨（包括每個容器）進行二甘醇/乙二醇污染及乙醇中甲醇污染的檢測。同時，貴方既未承諾對留存組分或成品進行追溯性檢測，也未說明對美國市場在有效期內(nèi)藥品的潛在影響。
在缺乏充分檢測的情況下，貴方無法提供科學(xué)證據(jù)證明原料在用于藥品生產(chǎn)前符合相應(yīng)規(guī)格。貴方有責(zé)任在生產(chǎn)使用前對藥品原料進行取樣、檢測和檢驗，以確保其滿足可接受的質(zhì)量參數(shù)。
In response to this letter, provide:
A comprehensive, independent review of your material system to determine whether all suppliers of components, containers, and closures are each qualified and the materials are assigned appropriate expiration or retest dates. The review should also determine whether incoming material controls are adequate to prevent use of unsuitable components, containers, and closures.
The chemical and microbiological quality control specifications you use to test and release each incoming lot of components for use in manufacturing.
A description of how you will test each component lot for conformity with all appropriate specifications for identity, strength, quality, and purity. If you intend to accept any results from your supplier’s COA instead of testing each component lot for strength, quality, and purity, specify how you will robustly establish the reliability of your supplier’s results through initial validation as well as periodic re-validation. In addition, include a commitment to always conduct at least one specific identity test for each incoming component lot. In the case of alcohol, isopropyl alcohol, glycerin, and certain additional high-risk components, we note that this includes the performance of parts A, B, and C of the USP monograph.
針對此函，請?zhí)峁?/span>
對貴方物料體系進行全面獨立的審查，以確定所有組件、容器及封蓋供應(yīng)商是否均具備資質(zhì)，且物料是否被賦予適當?shù)挠行诨驈?fù)檢日期。該審查還應(yīng)確認進料控制措施是否充分，足以防止使用不合格的組件、容器及封蓋。
貴方用于檢測并放行每批進廠組件（用于生產(chǎn)制造）的化學(xué)及微生物質(zhì)量控制規(guī)范。
說明如何對每批組件進行測試，以確保符合所有適用的鑒別、效力、質(zhì)量和純度規(guī)范。若計劃采用供應(yīng)商提供的合格證明（COA）替代對每批組件進行效力、質(zhì)量和純度測試，需明確說明如何通過初始驗證及定期重新驗證，切實建立供應(yīng)商結(jié)果的可靠性。此外，需承諾對每批進廠組分至少實施一項特定鑒別試驗。針對乙醇、異丙醇、甘油及特定高風(fēng)險組分，需執(zhí)行《美國藥典》專論A、B、C部分的檢測要求。
A summary of results obtained from testing all components to evaluate the reliability of the COA from each component manufacturer. Include your SOP that describes this COA validation program.
A summary of your program for qualifying and overseeing contract facilities that test the drug products you manufacture.
A commitment to provide methanol test results, no later than 30 calendar days from the date of this letter, for retains for all lots of components of manufactured drug products within expiry. Alternatively, if a retain of a component lot is unavailable, perform retain sample testing of all implicated finished drug product batches for the presence of methanol.
對所有組件進行測試以評估各組件制造商提供的COA可靠性的結(jié)果摘要。請附上描述此COA驗證程序的標準操作規(guī)程（SOP）。
對您所制造的藥品進行測試的合同設(shè)施進行資格認證和監(jiān)督的程序摘要。
承諾自本函發(fā)出之日起30個日歷日內(nèi)，提供所有在有效期內(nèi)成品藥生產(chǎn)組分批次的留樣甲醇檢測結(jié)果。若某批次組分留樣不可用，則需對所有相關(guān)成品藥批次進行留樣檢測以確認甲醇含量。
A commitment to provide DEG and EG test results, no later than 30 calendar days from the date of this letter, from testing retains for all lots of high-risk drug components used in the manufacture of drug products. Alternatively, if a retain of a component lot is unavailable, perform retain sample testing of all implicated finished drug product batches for the presence of DEG and EG.
A full risk assessment for drug products that are within expiry which contain any ingredient at risk for DEG or EG contamination, including, but not limited to, glycerin. Take prompt and appropriate actions to determine the safety of all lots of the component(s) and any related drug product that could contain DEG or EG, including customer notifications and product recalls for any contaminated lots. Identify additional appropriate CAPA that secure supply chains in the future, including, but not limited to, ensuring that all incoming raw material lots are from fully qualified manufacturers and free from unsafe impurities. Detail these actions in your response to this letter.
承諾在收到本函之日起30個日歷日內(nèi)，提供所有用于藥品生產(chǎn)的高風(fēng)險藥用成分批次的DEG和EG檢測結(jié)果。若某成分批次的留樣不可用，則應(yīng)對所有相關(guān)成品藥批次進行留樣檢測，以確認是否存在DEG和EG。
對有效期內(nèi)含有DEG或EG污染風(fēng)險成分（包括但不限于甘油）的藥品進行全面風(fēng)險評估。采取及時適當?shù)拇胧┐_認所有可能含有DEG或EG的原料藥批次及相關(guān)藥品的安全性，包括對受污染批次實施客戶通知和產(chǎn)品召回。制定額外適當?shù)募m正預(yù)防措施以保障未來供應(yīng)鏈安全，包括但不限于確保所有進料原料批次均來自完全合格的生產(chǎn)商且不含不安全雜質(zhì)。請在對本函的回復(fù)中詳細說明這些措施。
Quality Systems
Your firm’s quality systems are inadequate. For guidance on establishing and maintaining CGMP-compliant quality systems, see these FDA guidance documents:
Q8(R2) Pharmaceutical Development at https://www.fda.gov/regulatory-information/search-fda-guidance-documents/q8r2-pharmaceutical-development
Q9 Quality Risk Management at https://www.fda.gov/regulatory-information/search-fda-guidance-documents/q9r1-quality-risk-management
Q10 Pharmaceutical Quality System at https://www.fda.gov/regulatory-information/search-fda-guidance-documents/q10-pharmaceutical-quality-system
CGMP Consultant Recommended
質(zhì)量體系
貴公司的質(zhì)量體系存在不足。有關(guān)建立和維護符合CGMP要求的質(zhì)量體系的指導(dǎo)，請參閱以下FDA指導(dǎo)文件：
Q8(R2) 藥品開發(fā)指南，網(wǎng)址：https://www.fda.gov/regulatory-information/search-fda-guidance-documents/q8r2-pharmaceutical-development
Q9《藥品質(zhì)量風(fēng)險管理指南》詳見：https://www.fda.gov/regulatory-information/search-fda-guidance-documents/q9r1-quality-risk-management
Q10《藥品質(zhì)量體系指南》詳見：https://www.fda.gov/regulatory-information/search-fda-guidance-documents/q10-pharmaceutical-quality-system
CGMP顧問推薦
Q9 質(zhì)量風(fēng)險管理（網(wǎng)址：https://www.fda.gov/regulatory-information/search-fda-guidance-documents/q9r1-quality-risk-management）Q10 藥品質(zhì)量體系（網(wǎng)址：https://www.fda.gov/regulatory-information/search-fda-guidance-documents/q10-pharmaceutical-quality-system）CGMP顧問推薦
Based upon the nature of the violations we identified at your firm, you should engage a consultant qualified as set forth in 21 CFR 211.34 to evaluate your operations and to assist your firm in meeting CGMP requirements. 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 your corrective actions and preventive actions before you pursue resolution of your firm’s compliance status with FDA. See 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.
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.
鑒于貴公司存在違規(guī)行為的性質(zhì)，應(yīng)聘請符合《聯(lián)邦法規(guī)》第21卷第211.34條規(guī)定的合格顧問，對貴公司運營進行評估，協(xié)助貴公司滿足CGMP要求。該合格顧問還應(yīng)在貴公司尋求解決與FDA合規(guī)問題之前，對貴公司整體運營進行涵蓋六個系統(tǒng)的全面CGMP合規(guī)性審計，并評估貴公司糾正措施和預(yù)防措施的完成情況及有效性。詳見FDA指導(dǎo)文件《藥品CGMP法規(guī)的質(zhì)量體系方法》：https://www.fda.gov/regulatory-information/search-fda-guidance-documents/quality-systems-approach-pharmaceutical-current-good-manufacturing-practice-regulations。
聘請顧問并不能免除貴公司遵守CGMP的義務(wù)。貴公司高管層仍需承擔(dān)解決所有缺陷和系統(tǒng)性缺陷的責(zé)任，以確保持續(xù)符合CGMP要求。
Responsibilities as a Contractor
Drugs must be manufactured in conformance with CGMP. FDA is aware that many drug manufacturers use independent contractors such as production facilities, testing laboratories, packagers, and labelers. FDA regards contractors as extensions of the manufacturer.
You are responsible for the quality of drugs you produce as a contract facility regardless of agreements in place with product owners. You are required to ensure that drugs are made in accordance with section 501(a)(2)(B) of the FD&C Act for safety, identity, strength, quality, and purity. See FDA’s guidance document Contract Manufacturing Arrangements for Drugs: Quality Agreements at https://www.fda.gov/regulatory-information/search-fda-guidance-documents/contract-manufacturing-arrangements-drugs-quality-agreements-guidance-industry.
Cosmetics Manufactured for Distribution in the United States
承包商的責(zé)任
藥品必須符合CGMP規(guī)范生產(chǎn)。FDA知悉許多制藥企業(yè)會使用獨立承包商，例如生產(chǎn)設(shè)施、檢測實驗室、包裝商和貼標商。FDA將承包商視為生產(chǎn)企業(yè)的延伸。
作為合同生產(chǎn)設(shè)施，您需對所生產(chǎn)藥品的質(zhì)量負責(zé)，無論與產(chǎn)品所有者簽訂何種協(xié)議。您必須確保藥品符合《聯(lián)邦食品、藥品和化妝品法案》第501(a)(2)(B)條規(guī)定的安全性、真?zhèn)涡浴⑿ЯΑ①|(zhì)量及純度要求。詳見FDA指導(dǎo)文件《藥品合同生產(chǎn)安排：質(zhì)量協(xié)議》https://www.fda.gov/regulatory-information/search-fda-guidance-documents/contract-manufacturing-arrangements-drugs-quality-agreements-guidance-industry。
供美國境內(nèi)分銷的化妝品生產(chǎn)
In addition, we note that some of the products you manufacture may be regulated as cosmetics, as defined in section 201(i) of the FD&C Act [21 U.S.C. 321(i)]. Any cosmetics you manufacture must comply with applicable statutory and regulatory requirements, including the FD&C Act. Under section 301(a) of the FD&C Act [21 U.S.C. 331(a)], it is a prohibited act to introduce or deliver for introduction into interstate commerce a cosmetic that is adulterated or misbranded.
Further, your facility may be subject to requirements of the Modernization of Cosmetics Regulation Act of 2022 (MoCRA). Information on MoCRA requirements may be found at https://www.fda.gov/cosmetics/cosmetics-laws-regulations/modernization-cosmetics-regulation-act-2022-mocra.
此外，我們注意到貴公司生產(chǎn)的部分產(chǎn)品可能屬于《聯(lián)邦食品、藥品和化妝品法案》第201(i)條[21 U.S.C. 321(i)]定義的化妝品范疇。貴公司生產(chǎn)的任何化妝品均須符合適用法律法規(guī)要求，包括《聯(lián)邦食品、藥品和化妝品法案》。根據(jù)該法案第301(a)條[21 U.S.C. 331(a)]規(guī)定，將摻假或標簽不實化妝品投入或交付投入州際貿(mào)易屬違法行為。
此外，貴設(shè)施可能需遵守《2022年化妝品監(jiān)管現(xiàn)代化法案》（MoCRA）的要求。有關(guān)MoCRA要求的詳細信息可查閱：https://www.fda.gov/cosmetics/cosmetics-laws-regulations/modernization-cosmetics-regulation-act-2022-mocra。
Conclusion
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.
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.
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.
結(jié)論
本函所述違規(guī)行為并非貴機構(gòu)現(xiàn)有違規(guī)行為的完整清單。貴機構(gòu)有責(zé)任調(diào)查并確定任何違規(guī)行為的根源，防止其再次發(fā)生或引發(fā)其他違規(guī)行為。
請立即糾正所有違規(guī)行為。若未能及時妥善處理此事，F(xiàn)DA可能在不另行通知的情況下采取監(jiān)管或法律行動，包括但不限于扣押和禁令。未解決的違規(guī)行為還可能導(dǎo)致其他聯(lián)邦機構(gòu)拒絕授予合同。
若未處理違規(guī)行為，F(xiàn)DA可能暫停簽發(fā)出口證書。在完全解決所有違規(guī)問題并確認貴公司符合CGMP規(guī)范前，F(xiàn)DA可能暫緩批準將貴公司列為藥品生產(chǎn)商的新申請或補充申請。我們可能進行復(fù)查以核實貴公司是否已完成糾正措施。
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.
Send your electronic reply to CDER-OC-OMQ-Communications@fda.hhs.gov. Identify your response with FEI 3008480436 and ATTN: Matthew R Dionne, Compliance Officer.
Sincerely,
Francis Godwin
Director
Office of Manufacturing Quality
Office of Compliance
Center for Drug Evaluation and Research
本函旨在告知貴方我方調(diào)查結(jié)果，并提供整改上述缺陷的機會。收到函件后，請于15個工作日內(nèi)以書面形式回復(fù)本辦公室，具體說明已采取的整改措施及預(yù)防措施。在回復(fù)函件時，可提供補充材料供我方在持續(xù)評估貴方活動與實踐時參考。若無法在15個工作日內(nèi)完成整改，請說明延遲原因及預(yù)計完成時間表。
電子回復(fù)請發(fā)送至CDER-OC-OMQ-Communications@fda.hhs.gov，郵件標注FEI 3008480436并注明收件人：合規(guī)官Matthew R Dionne。
此致
弗朗西斯·戈德溫
主任
生產(chǎn)質(zhì)量辦公室
合規(guī)辦公室
藥品評價與研究中心
