近日（rì），FDA發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（gōng）司向FDA聲稱有多月未生產肝素（sù）鈉粗品了，隻（zhī）是在進行設備測（cè）試。
FDA在檢（jiǎn）查過程中，在倉庫發現有個倉庫員工拿著一隻纖維紙板（bǎn）桶離開倉（cāng）庫，於是詢問桶裏裝了什麽。你公司說桶裏（lǐ）裝的XX袋。但是對（duì）桶進行（háng）檢（jiǎn）查時發（fā）現有2批在FDA檢查之前幾天剛剛生產的肝素粗品。
FDA隨後要求查看這2批肝（gān）素（sù）粗品的（de）生產和檢測記錄，該公司稱沒有（yǒu）這2批（pī）肝（gān）素粗品的記錄。
在檢查期間（jiān），FDA檢查員在行（háng）政樓3樓的QA辦公（gōng）室的地板上、桌子上和櫃子裏發現大量記錄（lù）。
一（yī）個（gè）員工說這些記錄是製作來支持政府基金申報（bào）的，但記錄中所寫的肝素粗品批（pī）次並未實際生產過。
隨後的檢查（chá）中（zhōng），該公司又說QA辦公室的所有記錄實際上是真（zhēn）實（shí）的肝素粗品批次的。
FDA通過（guò）該公司的肝素鈉粗品庫存和銷售記錄發現該公司在2019年6月1日至（zhì）2019年7月30日期間生產不止2批肝素鈉粗品，但隻有2批肝素鈉粗品的完整批記錄（lù）。
在（zài）FDA檢查（chá）之前，歐美也曾發布了該公司的GMP不符合（hé）報告，包含24條GMP缺（quē）陷，其中7條為主要缺陷。
主要缺陷包括：1、汙染風險；2、廠房和設施；3、設備（bèi）；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。
由於歐美GMP互認，警告信答複中（zhōng）“在‘官方批準’之前不（bú）會再向（xiàng）歐洲或美國市場銷售產品（pǐn）”。
企業（yè）最重要的就是誠信，包括（kuò）之前GMP認證，也有不少企業弄虛作假。現在我國已經取消GMP認證，這也就意味著企業即將麵臨更加嚴格（gé）的飛檢。潔淨儀器：遼寧塵埃粒子計數器（qì）、遼寧（níng）浮遊菌采樣器、遼寧SX-M潔淨度實時在線監測係統等（děng）都是一個醫藥行（háng）業（yè）不可（kě）或缺（quē）的潔淨室小幫手。
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於2019年7月31日至8月6日（rì）檢查了你們位於中國四川宜賓市南溪區羅龍工業園區（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).
本警告信總結了原料藥生產嚴重違反（fǎn）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).
由於你們的（de）原料藥生產（chǎn）、加工、包裝或保存的（de）方法、場所或控製不符合CGMP要求，你們的原料藥根據FDCA的501(a)(2)(B)以及21 U.S.C.351(a)(2)(B)被認為（wéi）是摻假藥品。
We reviewed your August 26, 2019, response to our Form FDA 483 in detail.
九幺免费版已詳（xiáng）細審核了你公司2019年8月（yuè）26日對FDA 483表格的回複。
During our inspection, our investigator observed specific deviations including. but not limited to, the following.
檢（jiǎn）查（chá）期間（jiān），九幺免费版的調查人員發現的具體問題（tí）包括但不僅限於以下：
1. Failure to prepare and use production and control records for each intermediate and APT batch.
未（wèi）製訂和使用各中間體和APT批次的生（shēng）產和檢驗報告。
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.
你們的工廠生產肝素粗品用於最終API的精製。在檢查之前2019年7月10日的電話裏，你公司向FDA聲稱你們有多（duō）月（yuè）未進行生產了。在FDA於2019年7月31日檢查開（kāi）始時，你公司向檢查員說你們沒在生產肝素粗（cū）品，隻是在進行設備測試。
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（kù）檢查時（shí），檢查員發現有個（gè）倉庫員工拿著一隻纖維紙（zhǐ）板桶（tǒng）離開倉庫，於是詢問桶（tǒng）裏裝了什麽。你公（gōng）司說桶裏裝的XX袋。但是對桶進（jìn）行檢查時發現有2批肝素（sù）粗品是FDA檢查之前幾天剛剛生產的（CU190726，XX，生產日期2019年7月26日，以及CU190727，XX，生產日期2019年7月27日）。在索取（qǔ）這2批（pī）肝素粗（cū）品的生產和檢測記錄時，你公（gōng）司告訴九幺免费版你們沒有這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.
在你們的回複中，你們承認因你們記錄保存規範的缺陷，所以未能及時提供肝素粗品CU190726和CU190727的完整記錄。另外，你們的回複說你公司（sī）正在給倉庫（kù）員工進行培訓，你公司在“官方批準”之前不會再向歐（ōu）洲或美國（guó）市場銷（xiāo）售產品了（le）。但是，你們並（bìng）未充分說明你們要如何彌補你們的文件規（guī）範，你（nǐ）們亦未評估不（bú）良文件規範對已銷（xiāo）售藥品的影響。
In response to this letter, you should provide:
在回複本函時請提交以下內容：
• A complete reconciliation of all drugs, including crude heparin, distributed from your facility. Include in the reconciliation:
• 你們（men）公司銷售的所有藥品的（de）全（quán）部數量平衡，包括肝素粗品。包括以下數據：
Batch number
批號（hào）
Batch quantity
批數量
Name of drug
藥品名稱（chēng）
Date of release
放行日期
Date of shipment
發貨日期
Destination of shipment
發貨目的地
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.
• 對你們生產和（hé）實驗室操作所用文件係統的全麵評估，以確（què）定有哪些做法是有缺陷（xiàn）的。要包括一份詳細的CAPA計劃，全麵補救你們公司（sī）的文（wén）件規範（fàn），確保（bǎo）你們會（huì）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（de）質量管理係統（tǒng），包括管理人員（yuán）主動參與和（hé）適當的生產人員配置。
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，檢查員發現你公司（sī）並未充分控製你（nǐ）工（gōng）廠所生產的肝素（sù）粗品追溯（sù）性有關的關（guān）鍵文件。在2019年7月（yuè）31日檢查現場（chǎng）時，九幺免费版檢查員在行（háng）政樓3樓的（de）QA辦公室的地板上、桌子上（shàng）和櫃子裏發現大（dà）量記錄（lù）。其（qí）中一（yī）些（xiē）記錄是肝素（sù）批生產記錄（lù）。
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（jiān），你們（men）一個員工說這些記（jì）錄是製作來支持政府基金申報的，但記錄（lù）中所寫的肝素粗品批次並未實際生產過（guò）。後來在2019年8月2日（rì）的檢查期間，你公司又說QA辦（bàn）公室的所有記錄實際上是真（zhēn）實的肝素（sù）粗品批次的（de）。
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（jì）錄顯示你公（gōng）司在2019年6月1日至2019年7月30日期間生產了XX批次肝素粗品（CU190601至CU190730），但你公司隻能提（tí）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（zhuī）溯性是質（zhì）量管理的一個（gè）關鍵部分。你們必須確保所生產的每批藥品的完整同步記錄均得（dé）到保存，以符合GMP要求。你們的（de）質量（liàng）管（guǎn）理體係是不充分的，導致在你工廠所生產的所有藥品，包（bāo）括肝素粗（cū）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.
關於肝素的更多參（cān）考資料，參見行業指南“藥品和醫療器械用肝素：監測肝素（sù）粗品的質量”。
Your response is inadequate because it does not holistically address systemic Quality Unit (QU) deficiencies.
你們的回複是不充分的，因為它並未全（quán）麵解決QU的係統性缺陷。
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:
在回複（fù）本函時，你們應提交一份全麵評估和補救計劃，以確保你公司會（huì）製訂、記錄、實施和保存穩健的（de）質量管理係統，包（bāo）括管理人員主動參與（yǔ）和適當的生產人員配置。評估還應包括但（dàn）不僅限於：
• A determination of whether procedures used by your firm are robust and appropriate.
• 確定你公司所用程序是（shì）否（fǒu）穩健和恰當
• Provisions for oversight throughout your operations to evalsuate adherence to appropriate practices.
• 對你們整個操作進行監管以評估是否遵守恰當規範的條款
• 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.
• 監管和批準調查，履行所（suǒ）有其（qí）它QU職責以確保所（suǒ）有藥品的鑒定、含量、質量和純度
Data Integrity Remediation
數據完整性補救措施
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.
你們的質量體係不能充分確（què）保數據的準確性和完整（zhěng）性（xìng），無法支持你們生產的藥品的（de）安全性、有效性和質量。參見FDA指南文件（jiàn）“數據完整性和（hé）藥品GMP合格”指導建立和遵守CGMP合格數（shù）據完整性規範。
We strongly recommend that you retain a qualified consultant to assist in your remediation.
九幺免费版強烈建議你們聘請一位具（jù）備資質的顧問協助你們進行（háng）補救。
In response to this letter, you should provide the following:
在回（huí）複此函時請提交以下信息：
• 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.
• 一份對數據記錄和報（bào）告（gào）不準確性程度的全麵（miàn）調查（chá）。在其中詳細寫明你們數據完整性問題的範圍和根本原因。
• 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.
• 你們藥品質量中所發（fā）現的（de）不合格情況的（de）潛在影（yǐng）響的當前風險評估。你們的評估（gū）應包括由於受到（dào）數據完整性問題影響（xiǎng）的藥（yào）品放行（háng）導致的（de）患者風險的分析，以及持續運營所具有的風險。
• 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，包括你們全球CAPA計（jì）劃詳細情況。詳細的（de）糾正計劃應寫明你們準備如何確保你公司生成的所有數據的（de）可靠性和完整性，包括微生物和分析數據、生產記錄和提交給FDA的所有數據。
Conclusion
結論
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並不是全部。你們有責任對這些偏差（chà）進行（háng）調查，確定（dìng）原因，防止其再次發生，防止你們設施內其它偏差（chà）的發生。
FDA placed your firm on Import Alert 66-40 and 55-03 on January 15, 2020.
FDA已於2020年1月15日將你公司置（zhì）於進口禁令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並且由我（wǒ）們確認你們符合CGMP之前，FDA可能會擱置所有將你（nǐ）公司列為藥（yào）品生產的新申報（bào）和增補申報的（de）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（zhì）FDA依（yī）據FDCA第（dì）801(a)(3)條和21 U.S.C. 381(a)(3)拒絕接（jiē）受（shòu）在上述地址生產的產品進入美國。
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.
在收到此函後，請在15個（gè）工（gōng）作日內回複至本辦公室。在回複中說明自從檢查後，你們做了哪些工（gōng）作來糾正你們的偏差，防止其再次發生。如果不能在15個（gè）工作日內完成糾正措施，說明（míng）延（yán）遲的原因以及（jí）完成計劃。
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