近日，F(xiàn)DA發(fā)布了四川某生物科技有限公司的警告信，警告信所述缺陷透露著一個個“啪啪打臉”的故事：

在檢查之前通話中，該公司向FDA聲稱有多月未生產(chǎn)肝素鈉粗品了，只是在進行設備測試。

FDA在檢查過程中，在倉庫發(fā)現(xiàn)有個倉庫員工拿著一只纖維紙板桶離開倉庫，于是詢問桶里裝了什么。你公司說桶里裝的XX袋。但是對桶進行檢查時發(fā)現(xiàn)有2批在FDA檢查之前幾天剛剛生產(chǎn)的肝素粗品。

FDA隨后要求查看這2批肝素粗品的生產(chǎn)和檢測記錄，該公司稱沒有這2批肝素粗品的記錄。

在檢查期間，F(xiàn)DA檢查員在行政樓3樓的QA辦公室的地板上、桌子上和柜子里發(fā)現(xiàn)大量記錄。

一個員工說這些記錄是制作來支持政府基金申報的，但記錄中所寫的肝素粗品批次并未實際生產(chǎn)過。

隨后的檢查中，該公司又說QA辦公室的所有記錄實際上是真實的肝素粗品批次的。

FDA通過該公司的肝素鈉粗品庫存和銷售記錄發(fā)現(xiàn)該公司在2019年6月1日至2019年7月30日期間生產(chǎn)不止2批肝素鈉粗品，但只有2批肝素鈉粗品的完整批記錄。

在FDA檢查之前，歐美也曾發(fā)布了該公司的GMP不符合報告，包含24條GMP缺陷，其中7條為主要缺陷。

主要缺陷包括：1、污染風險；2、廠房和設施；3、設備；4、起始物料儲存；5、工藝；6、物料管理，起始物料的可追溯性；7、溶劑回收。

由于歐美GMP互認，警告信答復中“在‘官方批準’之前不會再向歐洲或美國市場銷售產(chǎn)品”。

企業(yè)最重要的就是誠信，包括之前GMP認證，也有不少企業(yè)弄虛作假。現(xiàn)在我國已經(jīng)取消GMP認證，這也就意味著企業(yè)即將面臨更加嚴格的飛檢。潔凈儀器：遼寧塵埃粒子計數(shù)器、遼寧浮游菌采樣器、遼寧SX-M潔凈度實時在線監(jiān)測系統(tǒng)等都是一個醫(yī)藥行業(yè)不可或缺的潔凈室小幫手。

警告信原文及翻譯

February 13, 2020

Warning Letter 320-20-24

Dear Mr. Tuo:

The U.S. Food and Drug Administration (FDA) conducted an inspection at Yibin Lihao Biotechnical Co., Ltd, FET 3008846564, at Number 5 Binjiang Road, Luolong Industrial Central Park. Yibin, Sichuan, from July 31 to August 6, 2019.

美國FDA于2019年7月31日至8月6日檢查了你們位于中國四川宜賓市南溪區(qū)羅龍工業(yè)園區(qū)濱江西路5號的宜賓市利豪生物科技有限公司生產(chǎn)場所。

This warning letter summarizes significant deviations from current good manufacturing practice (CGMP) for active pharmaceutical ingredients (API).

本警告信總結(jié)了原料藥生產(chǎn)嚴重違反CGMP的行為。

Because your methods, facilities, or controls for manufacturing, processing, packing, or holding do not conform to CGMP, your API 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).

由于你們的原料藥生產(chǎn)、加工、包裝或保存的方法、場所或控制不符合CGMP要求，你們的原料藥根據(jù)FDCA的501(a)(2)(B)以及21 U.S.C.351(a)(2)(B)被認為是摻假藥品。

We reviewed your August 26, 2019, response to our Form FDA 483 in detail.

我們已詳細審核了你公司2019年8月26日對FDA 483表格的回復。

During our inspection, our investigator observed specific deviations including. but not limited to, the following.

檢查期間，我們的調(diào)查人員發(fā)現(xiàn)的具體問題包括但不僅限于以下：

1. Failure to prepare and use production and control records for each intermediate and APT batch. 

未制訂和使用各中間體和APT批次的生產(chǎn)和檢驗報告。

Your site produces crude heparin for purification into finished API. During a pre-inspectional call on July 10, 2019, your firm stated to FDA that you had not manufactured any materials for months. At the start of the FDA inspection on July 31, 2019, your firm stated to the investigator that you were not manufacturing crude heparin and were only performing equipment testing.

你們的工廠生產(chǎn)肝素粗品用于最終API的精制。在檢查之前2019年7月10日的電話里，你公司向FDA聲稱你們有多月未進行生產(chǎn)了。在FDA于2019年7月31日檢查開始時，你公司向檢查員說你們沒在生產(chǎn)肝素粗品，只是在進行設備測試。

During a walkthrough of your warehouse, the investigator observed a warehouse employee leaving the warehouse with a fiber drum and inquired about the contents of the drum. Your firm stated that the drum contained (b)(4) bags. However. inspection of the drum revealed two batches of crude heparin manufactured just a few days before the FDA inspection (CU190726, (b)(4), manufacturing date July 26, 2019, and CU 190727, (b)(4), manufacturing date July 27, 2019). When asked about manufacturing and testing records pertaining to these two crude heparin batches, your firm told us that you do not have records for the two crude heparin batches.

在倉庫檢查時，檢查員發(fā)現(xiàn)有個倉庫員工拿著一只纖維紙板桶離開倉庫，于是詢問桶里裝了什么。你公司說桶里裝的XX袋。但是對桶進行檢查時發(fā)現(xiàn)有2批肝素粗品是FDA檢查之前幾天剛剛生產(chǎn)的（CU190726，XX，生產(chǎn)日期2019年7月26日，以及CU190727，XX，生產(chǎn)日期2019年7月27日）。在索取這2批肝素粗品的生產(chǎn)和檢測記錄時，你公司告訴我們你們沒有這2批肝素粗品的記錄。

In your response, you acknowledged the failure to provide timely and complete records for crude heparin batches CU190726 and CU190727 due to deficiencies in your record keeping practices. Additionally, your response indicated that your firm is providing training to warehouse employees and your firm would not sell to European or U.S. markets before "official approval". However, you did not adequately address how you would remediate your documentation practices, nor did you assess the impact of poor documentation practices for distributed drugs.

在你們的回復中，你們承認因你們記錄保存規(guī)范的缺陷，所以未能及時提供肝素粗品CU190726和CU190727的完整記錄。另外，你們的回復說你公司正在給倉庫員工進行培訓，你公司在“官方批準”之前不會再向歐洲或美國市場銷售產(chǎn)品了。但是，你們并未充分說明你們要如何彌補你們的文件規(guī)范，你們亦未評估不良文件規(guī)范對已銷售藥品的影響。

In response to this letter, you should provide:

在回復本函時請?zhí)峤灰韵聝?nèi)容：

?      A complete reconciliation of all drugs, including crude heparin, distributed from your facility. Include in the reconciliation:

?      你們公司銷售的所有藥品的全部數(shù)量平衡，包括肝素粗品。包括以下數(shù)據(jù)：

Batch number

批號

Batch quantity

批數(shù)量

Name of drug

藥品名稱

Date of release

放行日期

Date of shipment

發(fā)貨日期

Destination of shipment

發(fā)貨目的地

Destination market

目的市場

?      A complete assessment of documentation systems used throughout your manufacturing and laboratory operations to determine where documentation practices are insufficient. Include a detailed corrective action and preventive action (CAP A) plan that comprehensively remediates your firm's documentation practices to ensure you retain attributable, legible, complete, original, accurate, contemporaneous records throughout your operation.

?      對你們生產(chǎn)和實驗室操作所用文件系統(tǒng)的全面評估，以確定有哪些做法是有缺陷的。要包括一份詳細的CAPA計劃，全面補救你們公司的文件規(guī)范，確保你們會保存你們整個操作可追溯、清晰的、完整的、原始的、準確的同步記錄。

2. Failure to establish, document, and implement an effective system for managing quality that involves the active participation of management and appropriate manufacturing personnel. 

未建立、記錄和實施有效的質(zhì)量管理系統(tǒng)，包括管理人員主動參與和適當?shù)纳a(chǎn)人員配置。

During the inspection, the investigator observed your firm did not adequately control critical documentation pertinent to the traceability of crude heparin manufactured at your facility. During the walkthrough on July 31, 2019, our investigator observed numerous records on the floor, desks, and cabinets of the Quality Assurance (QA) Office on the third floor of the office building. Some of these records included batch production records for heparin.

在檢查期間，檢查員發(fā)現(xiàn)你公司并未充分控制你工廠所生產(chǎn)的肝素粗品追溯性有關的關鍵文件。在2019年7月31日檢查現(xiàn)場時，我們檢查員在行政樓3樓的QA辦公室的地板上、桌子上和柜子里發(fā)現(xiàn)大量記錄。其中一些記錄是肝素批生產(chǎn)記錄。

During the inspection, one of your employees stated that these records were generated to support an application for govern mentfunding, but the crude heparin batches specified in the records had not actually been manufactured. However, later during the inspection, on August 2, 2019, your firm stated that all the records in the QA Office were in fact associated with genuine crude heparin batches.

在檢查期間，你們一個員工說這些記錄是制作來支持政府基金申報的，但記錄中所寫的肝素粗品批次并未實際生產(chǎn)過。后來在2019年8月2日的檢查期間，你公司又說QA辦公室的所有記錄實際上是真實的肝素粗品批次的。

Additionally, even though your Crude Heparin Sodium Inventory and Distribution Record indicated your firm manufactured (b)(4) batches of crude heparin (CU190601 to CU190730) fromJune 1, 2019, to July 30, 2019, your firm was only able to provide complete batch records for two batches, CU190728 and CU190730.

另外，雖然你們的肝素鈉粗品庫存和銷售記錄顯示你公司在2019年6月1日至2019年7月30日期間生產(chǎn)了XX批次肝素粗品（CU190601至CU190730），但你公司只能提供2批（CU190728 和CU190730）的完整批記錄。

Traceability of crude heparin is a critical part of managing quality. You must ensure that a complete contemporaneous record of each batch of drug manufactured is retained for CGMP purposes. Your system for managing quality is inadequate and calls into question the traceability of all drugs, including crude heparin. manufactured at your facility.

肝素粗品的可追溯性是質(zhì)量管理的一個關鍵部分。你們必須確保所生產(chǎn)的每批藥品的完整同步記錄均得到保存，以符合GMP要求。你們的質(zhì)量管理體系是不充分的，導致在你工廠所生產(chǎn)的所有藥品，包括肝素粗品有追溯問題。

For further reference regarding heparin. see the guidance for industry Heparin for Drug and Medical Device Use: Monitoring Crude Heparin for Quality available online at http://www.fda.gov/downloads/Drugs/GuidanceComplianccRegulatorylnformation/Guidances/UCM291390.pdf.

關于肝素的更多參考資料，參見行業(yè)指南“藥品和醫(yī)療器械用肝素：監(jiān)測肝素粗品的質(zhì)量”。

Your response is inadequate because it does not holistically address systemic Quality Unit (QU) deficiencies.

你們的回復是不充分的，因為它并未全面解決QU的系統(tǒng)性缺陷。

In response to this letter, you should provide a comprehensive assessment and remediation plan to ensure your firm will establish, document, implement, and maintain a robust system for managing quaIity involving the active participation of management and appropriate manufacturing personnel. The assessment should also include, but not be limitedto:

在回復本函時，你們應提交一份全面評估和補救計劃，以確保你公司會制訂、記錄、實施和保存穩(wěn)健的質(zhì)量管理系統(tǒng)，包括管理人員主動參與和適當?shù)纳a(chǎn)人員配置。評估還應包括但不僅限于：

?      A determination of whether procedures used by your firm are robust and appropriate.

?      確定你公司所用程序是否穩(wěn)健和恰當

?      Provisions for oversight throughout your operations to evaluate adherence to appropriate practices.

?      對你們整個操作進行監(jiān)管以評估是否遵守恰當規(guī)范的條款

?      A complete and final review of each batch and its related information before the QU disposition decision.

?      在QU批處理決策之前對每個批次及其信息的完整和最終審核

?      Oversight and approval of investigations and discharging of all other QU duties to ensure identity, strength, quality, andpurity of all products.

?      監(jiān)管和批準調(diào)查，履行所有其它QU職責以確保所有藥品的鑒定、含量、質(zhì)量和純度

Data Integrity Remediation

數(shù)據(jù)完整性補救措施

Your quality system does not adequately ensure the accuracy and integrity of data to support the safety, effectiveness, and quality of the drugs you manufacture. See FDA's guidance document Data lntegrily and Compliance with Drug CGMP for guidance on establishing and following CGMP compliant data integrity practices at https://www.fda.gov/media/97005/download.

你們的質(zhì)量體系不能充分確保數(shù)據(jù)的準確性和完整性，無法支持你們生產(chǎn)的藥品的安全性、有效性和質(zhì)量。參見FDA指南文件“數(shù)據(jù)完整性和藥品GMP合格”指導建立和遵守CGMP合格數(shù)據(jù)完整性規(guī)范。

We strongly recommend that you retain a qualified consultant to assist in your remediation.

我們強烈建議你們聘請一位具備資質(zhì)的顧問協(xié)助你們進行補救。

In response to this letter, you should provide the following:

在回復此函時請?zhí)峤灰韵滦畔ⅲ?

?      A comprehensive investigation into the extent of inaccuracies in data records and reporting, including results of the data review for drugs distributed to the United States. Describe the scope and root causes of your data integrity lapses in detail.

?      一份對數(shù)據(jù)記錄和報告不準確性程度的全面調(diào)查。在其中詳細寫明你們數(shù)據(jù)完整性問題的范圍和根本原因。

?      A current risk assessment of the potential effects of the observed failures on the quality of your drugs. Your assessment should include analyses of the risks to patients caused by the release of drugs affected by a lapse of data integrity and analyses of the risks posed by ongoing operations.

?      你們藥品質(zhì)量中所發(fā)現(xiàn)的不合格情況的潛在影響的當前風險評估。你們的評估應包括由于受到數(shù)據(jù)完整性問題影響的藥品放行導致的患者風險的分析，以及持續(xù)運營所具有的風險。

?      A management strategy for your firm that includes the details of your global CAPA plan. The detailed corrective action plan should describe how you intend to ensure the reliability and completeness of all data generated by your firm, including microbiological and analytical data, manufacturing records, and all data submitted to FDA.

?      你們公司的管理策略，包括你們?nèi)駽APA計劃詳細情況。詳細的糾正計劃應寫明你們準備如何確保你公司生成的所有數(shù)據(jù)的可靠性和完整性，包括微生物和分析數(shù)據(jù)、生產(chǎn)記錄和提交給FDA的所有數(shù)據(jù)。

Conclusion 

結(jié)論

The deviations cited in this letter are not intended to be an all-inclusive list of deviations that exist at your facility/in connection with your products. You are responsible for investigating and determining the causes of these deviations and for preventing their recurrence or the occurrence of other deviations.

此函中所引用的違規(guī)并不是全部。你們有責任對這些偏差進行調(diào)查，確定原因，防止其再次發(fā)生，防止你們設施內(nèi)其它偏差的發(fā)生。

FDA placed your firm on Import Alert 66-40 and 55-03 on January 15, 2020.

FDA已于2020年1月15日將你公司置于進口禁令66-40和55-03中。

Until you correct all deviations completely and we confirm your compliance with CGMP, FDA may withhold approval of any new drug applications or supplements listing your firm as a drug manufacturer.

在貴公司未能完成所有偏差糾正并且由我們確認你們符合CGMP之前，F(xiàn)DA可能會擱置所有將你公司列為藥品生產(chǎn)的新申報和增補申報的批準。

Failure to correct these deviations may also result in the FDA continuing to refuse admission of articles manufactured at Yibin Lihao Bio-technical Co., Ltd at Number 5 Binjiang Road, Luolong Industrial Central Park, Yibin, Sichuan, into the United States under section 801 (a)(3) of the FD&C Act, 21 U.S.C. 381(a)(3). Under this authority, articles may be subject to refusal of admission, in that the methods and controls used in their manufacture do not appear to conform to CGMP within the meaning of section 501(a)(2)(B) of the FD&C Act, 21 U.S.C. 351(a)(2)(B).

未能糾正這些偏差可能還會導致FDA依據(jù)FDCA第801(a)(3)條和21 U.S.C. 381(a)(3)拒絕接受在上述地址生產(chǎn)的產(chǎn)品進入美國。

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 deviations and to prevent their recurrence. If you cannot complete corrective actions within 15 working days, state your reasons for delay and your schedule for completion.

在收到此函后，請在15個工作日內(nèi)回復至本辦公室。在回復中說明自從檢查后，你們做了哪些工作來糾正你們的偏差，防止其再次發(fā)生。如果不能在15個工作日內(nèi)完成糾正措施，說明延遲的原因以及完成計劃。