FDA警告信：日本協和Kyowa Hakko Bio Co.，Ltd

最新 08-22

Warning Letter: 320-18-70August 10, 2018

Mr. Yasuo Morita,Regulatory Office Manager

Kyowa Hakko Bio Co., Ltd.

1-1 Kyowa-cho, Hofu-shi,Yamaguchi, Japan 747-8522

Dear Mr. Morita:

The U.S. Food and Drug Administration (FDA) inspected your drug manufacturing facility, Kyowa Hakko Bio Co., Ltd. at 1-1 Kyowa-cho,Hofu-shi, Yamaguchi, from September 4 to 8, 2017.

美國FDA於2017年9月4-8日檢查了你們位於日本山口的Kyowa Hakko Bio Co., Ltd.生產場所。

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

本警告信總結了原料葯生產嚴重違反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).

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

We reviewed your September 26, 2017, response in detail and acknowledge receipt of your subsequent correspondence.

我們已詳細審核了你公司2017年9月26日的回復，並此告知已收到後續通信。

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

檢查期間，我們的調查人員發現的具體問題包括但不僅限於以下：

1. Failure of your quality unit to exercise its responsibility to ensure the API manufactured at your facility are in compliance with CGMP.你們質量部門未能履行其職責確保在你們工廠生產的API符合CGMP。

Your firm performed retesting or manipulated data after obtaining out-of-specification (OOS) or other unacceptable results. For example, investigation 2016-C-023 stated that the system suitability test (SST) was nonconforming and that 「some data were manipulated to meet SST specification」 for the high-performance liquid chromatography (HPLC) an alysisof your raw material(b)(4). You attributed the root cause to your firm』s 「lack of awareness of the seriousness」 of CGMP deviations, and to an 「environment where test data could be easily manipulated.」 Your investigation stated that you reanalyzed the crude sample and concluded that it met the specification. You provided no further details on the root causes and on the effect of using a system that failed SST to test your raw material.

你公司在得到OOS或其它不可接受的結果之後進行了複測或捏造數據。例如，調查2016-C-023說你們原料XX的HPLC分析的系統適用性測試（SST）不合格，「一些數據是捏造出來以符合SST標準」。你們將根本原因歸因於你們公司「缺乏明白CGMP偏差嚴重性的意識」，以及「易於捏造數據的環境」。你們的調查說你們重複分析了精品樣品並得出結論說其符合質量標準。你們未提供更多根本原因以及使用不合格SST系統檢測原料的影響的詳細內容。

Your response stated that no product in distribution was found to be OOS, but you included no data to support this conclusion. Your response is inadequate. You identified additional data integrity issues, but failed to provide details regarding the corrective measures your firm has implemented.

你們的回復說未發現銷售中的產品為OOS，但你們沒有放入數據來支持此結論。你們的回復是不充分的。你們發現了更多的數據完整性問題，但未提交關於你們公司已實施的糾正措施的詳細信息。

In response to this letter, provide a thorough assessment of your overall system for investigating deviations, discrepancies, OOS results, complaints, and other failures. In addition, provide a retrospective review of all distributed lots within expiry to determine whether your firm released lots not conforming to established specifications or appropriate manufacturing standards.

在回復此函時，請提交一份對你們偏差、差異、OOS結果、投訴和其它失敗調查的整體系統的徹底評估。另外，請提供一份對所有已銷售且仍在效期內的批准的回顧性審核，確定你們公司是否有放行不符合既定標準或適當生產標準的批次。

For more information about handling failing, OOS,out-of-trend, or other unexpected results and documentation of your investigations, see FDA』s guidance document,Investigating Out-of-Specification (OOS) Test Results for Pharmaceutical Production, athttps://www.fda.gov/downloads/drugs/guidances/ucm070287.pdf.

更多OOS處理信息請參見官網指南。

2. Failure to exercise sufficient controls over computerized systems to prevent unauthorized access or changes to data, and failure to have adequate controls to prevent omission of data.未能對計算機化系統進行充分控制以防止未經授權的訪問或對數據的修改，且沒有足夠的控制防止數據遺漏。

Your firm』s controls over your HPLC systems are inadequate. Some HPLC systems did not have audit trail capability or audit trails enabled. In addition, unique user names and passwords were not required to perform HPLC activities. You stated that you did not create unique user names and passwords sothat operators in different(b)(4)could continue what previous operators had initiated.

你公司對你們HPLC系統的控制是不充分的。一些HPLC系統並無審計追蹤能力或審計追蹤未激活。另外，未要求有唯一用戶名和密碼來執行HPLC活動。你們聲稱你們並未創建唯一用戶名和密碼，因此不同XX的操作員可以繼續之前的操作員已開始的工作。

In your annual product reviews, you used unprotected Excel worksheets to perform calculations and statistical evaluations of production data, such as standard deviation and process capability. These electronic files were not secured to prevent unauthorized changes, and have no change history.

在你們的年度產品回顧中，你們使得了未經保護的EXCEL表格對生產數據進行計算和統計評估，如標準偏差和工藝能力。這些電子文件並未受到保護以防止未經授權的修改，亦無修改歷史。

Your firm』s lack of data control calls the reliability of your data into question.

你們公司對數據缺乏控制，導致你們公司數據的可靠性存在問題。

Your response stated that you stopped operating these HPLC systems without audit trail capability. Your response also stated that you will create a procedure for control of your electronic worksheets. Your response is inadequate because you have not assessed the effects of using data from uncontrolled HPLC systems or unsecured worksheets on your products.

你們的回復聲稱你們已停止使用這些沒有審計追蹤能力的HPLC系統。你們的回復亦聲稱你們將建立程序對電子工作表進行控制。你們的回復是不充分的，因為你們並未評估使用不受控制HPLC系統的數據或沒有安全保護的工作表對你們產品的影響性。

In response to this letter, provide a comprehensive,independent review of controls and procedures for electronic data generated from all of your laboratory equipment. Based on this review, provide a detailed corrective action and preventive action (CAPA) plan to remediate laboratory systems, including but not limited to data creation, modification, maintenance, retention, and system security. Your plan should also include the process you will use to evaluate CAPA effectiveness.

在回復此函時，請提交一份對你們化驗室儀器獲得的電子數據的控制和程序的獨立全面審核。基於此審核，請提交一份詳細的CAPA計劃用以補救化驗室系統，包括但不僅限於數據創建、修改、維護、保存和系統安全。你們的計劃亦應包括你們將用於評估CAPA有效性的流程。

Also see additional requests under the Data Integrity Remediation section below.

亦請參見以下數據完整性補救措施部分里的其它要求。

Repeat observations at multiple sites多個工廠重複缺陷

In a previous warning letter (WL 320-10-009), FDA cited similar CGMP deviations related to your quality unit』s failure to thoroughly investigate and document OOS events. FDA also cited similar CGMP observations at your Ube site during our September 2017 inspection. These repeated failures at multiple sites demonstrate that executive management oversight and controlover the manufacture of drugs is inadequate.

Your executive management remains responsible for fully resolving all deficiencies, and ensuring ongoing CGMP compliance. You shouldimmediately and comprehensively assess your company』s global manufacturingoperations to ensure that systems and processes, and ultimately, the products manufactured, conform to FDA requirements.

你們的執行管理人員負有解決所有缺陷以及確保持續CGMP合規的義務。你們應立即對你公司的全球生產運作進行全面評估，以確保系統和工藝，以及最終，所生產的產品符合FDA要求。

Data Integrity Remediation數據完整性補救措施

Your quality system does not adequately ensure the accuracyand integrity of data to support the safety, effectiveness, and quality of thedrugs you manufacture. We acknowledge that you are using a consultant to audit your operation and assist in meeting FDA requirements. Each third party consultant used by your firm must be qualified for their specific assigned function, including data integrity remediation.

你們的質量體系不能充分確保數據的準確性和完整性，無法支持你們生產的藥品的安全性、有效性和質量。我們被告知你們正在使用一個顧問審計你們的運作情況，協助符合FDA要求。你們公司所用的每個第三方顧問均必須具備其指定領域的資質，包括數據完整性補救。

In response to this letter, provide the following.

在回復此函時請提交以下資料：

A. A comprehensive investigation into theextent of the inaccuracies in data records and reporting. Your investigationshould include:一份對數據記錄和報告不準確性程度的全面調查。你們的調查應包括

A detailed investigation protocol and methodology; a summary of all laboratories, manufacturing operations, and systems to be covered by the assessment; and a justification for any part of your operation that you propose to exclude.

詳細的調查方案和方法學；對評估所覆蓋的所有化驗室、生產操作和系統的總結，以及對你們意在排除的操作中所有部分的論證。

Interviews of current and former employees to identify the nature, scope, and root cause of data inaccuracies. We recommend that these interviews be conducted by a qualified third party.

與現有的和已離職的員工進行面談，找出數據不準確的表現、範圍、根本原因。我們建議這些面談由一個有資質的第三方來實施。

An assessment of the extent of data integrity deficiencies at your facility. Identify omissions, alterations, deletions, record destruction, non-contemporaneous record completion, and other deficiencies. Describe all parts of your facility』s operations in which you discovered data integrity lapses.

你們工廠數據完整性缺陷的程度的評估。識別出省略、修改、刪除、記錄銷毀、不同步記錄填寫和其它缺陷。描述你們工廠操作中發現數據完整性問題的所有部分。

A comprehensive retrospective evaluation of the nature of the testing, manufacturing, and other data integrity deficiencies. We recommend that a qualified third party with specific expertise in the area where potential breaches were identified should evaluate all data integrity lapses.

一份對數據完整性缺陷狀況的全面回顧性評估。我們建議由一個有資質的第三方里具有該領域專業水平的專家評估所有數據完整性問題。

B. A current risk assessment of the potential effects of the observed failures onthe quality of your drugs. Your assessment should include analysesof the risksto patients caused by the release of drugs affected by a lapse of dataintegrity, and risks posed by ongoing operations.

對你們藥品質量中所發現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於受到數據完整性問題影響的藥品放行導致的患者風險的分析，以及持續運營所具有的風險。

C. A management strategy for your firmthat includes the details of your global corrective action and preventiveaction plan. Your strategy should include:

你們公司的管理策略，包括你們全球CAPA計劃詳細情況。你們的策略應包括：

A detailed corrective action plan that describes how you intend to ensure the reliability and completeness of all the data you generate, including analytical data, manufacturing records, and all data submitted to FDA.

詳細的CA計劃，描述你們如何確保你們生成的所有數據的可靠性和完整性，包括分析數據、生產記錄和所有提交給FDA的數據。

A comprehensive description of the root causes of your data integrity lapses, including evidence that the scope and depth of the current action plan is commensurate with the findings of the investigation and risk assessment. Indicate whether individuals responsible for data integrity lapses remain able to influence CGMP-related or drug application data at your firm.

一份完整的描述你們數據完整性問題的根本原因的描述，包括認定當前行動計劃的範圍和深度與調查和風險評估發現相稱的證據。說明是否對數據完整性問題承擔責任的個人仍有能力對你公司對CGMP相關或藥物應用數據產生影響。

Interim measures describing the actions you have taken or will take to protect patients and to ensure the quality of your drugs, such as notifying your customers, recalling product, conducting additional testing, adding lots to your stability programs to assure stability, drug application actions, and enhanced complaint monitoring.

臨時措施，描述你們已採取的行動，或即將採取用以保護患者確保你們藥品質量的努力，例如通知你們的客戶、召回產品、實施額外測試、向穩定性試驗計劃中增加批次以確保穩定性、藥品申報行動以及加強投訴監測。

Long-term measures describing any remediation efforts and enhancements to procedures, processes, methods, controls, systems, management oversight, and human resources (e.g., training, staffing improvements) designed to ensure the integrity of your company』s data.

長期措施，其中描述所有對用以確保你們公司數據完整性的程序、流程、方法、控制、系統、管理監管和人力資源（例如培訓、員工提高）的彌補和提升。

A status report for any of the above activities already underway or completed.

對上述活動已開展或已經完成的狀態報告。

Conclusion結論

Deviations cited in this letter are not intended as anall-inclusive list. You are responsible for investigating these deviations, for determining the causes, for preventing their recurrence, and for preventing other deviations in all your facilities.

此函中所引用的違規並不是全部。你們有責任對這些偏差進行調查，確定原因，防止其再次發生，防止其它偏差的發生。

If you are considering an action that is likely to lead to a disruption in the supply of drugs produced at your facility, FDA requests thatyou contact CDER』s Drug Shortages Staff immediately, at drugshortages@fda.hhs.gov, so that FDA can work with you on the most effectiveway to bring your operations into compliance with the law. Contacting the Drug Shortages Staff also allows you to meet any obligations you may have to report discontinuances or interruptions in your drug manufacture under 21 U.S.C.356C(b) and allows FDA to consider, as soon as possible, what actions, if any,may be needed to avoid shortages and protect the health of patients who depend on your products.

如果你們在考慮要採取的措施可能會導致你們工廠所生產的藥品供應中斷，FDA要求你立即聯繫CDER藥品短缺負責人員，這樣FDA可以與你們一起採用最為高效的方式引導你們的操作符合法規要求。聯繫藥品短缺負責人員還能讓你滿足依據21 U.S.C. 356C(b)你可能必須報告你們藥品中止或中斷的義務，讓FDA儘快考慮是否需要採取何種措施來避免短缺，保護依賴於你們藥品的患者健康。

Until you correct all deviations completely and we confirm your compliance with CGMP, FDA may withhold approval of any new 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們確認你們符合CGMP之前，FDA可能會擱置所有將你公司列為藥品生產的新申報和增補申報的批准。

Failure to correct these deviations may also result in FDA refusing admission of articles manufactured at Kyowa Hakko Bio Co., Ltd. at 1-1Kyowa-cho, Hofu-shi, Yamaguchi, into the United States under section 801(a)(3)of the FD&C Act, 21 U.S.C. 381(a)(3). Under the same authority, articlesmay be subject to refusal of admission, in that the methods and controls usedin their manufacture do not appear to conform to CGMP within the meaning ofsection 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的產品進入美國。

After you receive this letter, respond to this office inwriting within 15 working days. Specify what you have done since our inspectionto correct your deviations and to prevent their recurrence. If you cannotcomplete corrective actions within 15 working days, state your reasons fordelay and your schedule for completion.

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

Towanda Terrell

Compliance Officer

U.S. Food and Drug Administration

White Oak Building 51, Room 4359

10903 New Hampshire Avenue

Silver Spring, MD 20993

USA

Sincerely,

/S/

Francis Godwin

Acting Director