寧波澳门国际生物醫藥有限公司
行業動態
[GMP] FDA對"日本積水藥業"發布警告信
 
Mr. Hideo Tagashira
President
Sekisui Medical Co., Ltd.
3-13-5, Nihombashi, Chuo-ku
Tokyo 103-0027                                                  
Japan
 
Dear Mr. Tagashira:
 
The U.S. Food and Drug Administration (FDA) inspected your drug manufacturing facility, Sekisui Medical Co., Ltd., at 4-115 Matsuo, Hachimantai, Iwate, from June 13 to 17, 2016.
FDA在2016年6月13-17日檢查了你們在岩手的生產場所。
 
This warning letter summarizes significant deviations from current good manufacturing practice (CGMP) for active pharmaceutical ingredients (API).
本警告信總結了你們原料藥生產CGMP嚴重違規情況。
 
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).
由於你們生產、加工、包裝和保存的方法、設施和控製不符合CGMP要求,你們的藥品根據FDCA的定義被認為是摻假藥品。
 
We reviewed your July 8, 2016, response in detail and acknowledge receipt of your subsequent correspondence.
我們詳細審核了你們於2016年7月8日及隨後發來的回複。
 
During our inspection, our investigator observed specific deviations including, but not limited to, the following.
在我們檢查期間,我們的調查人員發現的違規情況包括但不僅限於以下:
 
1. Failure to maintain complete data derived from all laboratory tests conducted to ensure compliance with established API specifications and standards.
未能維護化驗室實施用以確保產品符合既定的原料藥質量標準的測試中所產生的完整數據。
 
Our investigator found that you failed to maintain complete data from all laboratory analyses, and that you relied on the incomplete information to determine whether your drugs met established specifications. For example:
我們的調查人員發現你們未能維護所有化驗室分析中產生的完整性數據,你們依賴這些不完整的信息決策你們的藥品是否符合既定的質量標準。例如:
 
a. Numerous data files were found in the recycle bin folder on the computer connected to gas chromatography instruments GC-4 andGC-6. Specifically, our investigator found deleted data for residual solvent testing for (b)(4) lot (b)(4) in the recycle bin. Your records show that you retested the lot without documented justification or an investigation. You retained only the final test result.
在與氣相色譜儀器GC-4和GC-6連接的計算機的回收站文件夾裏發現大量數據文件。具體情況是這樣的,我們的調查人員在回收站裏發現了被刪除的某某批號的殘留溶劑檢測數據。你們的記錄顯示你們重新檢測了這個批號,但沒有文件記錄的論證,也沒有調查。你們隻保存了最後的檢測結果。
 
b. During the inspection our investigator requested residual solvent release test data for two of your API, (b)(4) and (b)(4).You were unable to retrieve this data.
在檢查期間,我們的調查人員要求查看2批原料藥的殘留溶劑放行檢測數據。你們無法恢複這些數據。
 
Any data created as part of a CGMP record must be retained so that it can be evaluated by the quality unit as part of release criteria and maintained for CGMP purposes.
所有作為CGMP記錄創建的數據都必須保存,這樣才能由質量部門作為放行標準的一部分進行評估,並且為符合CGMP要求而進行保存。
 
We acknowledge that you commit to revising your SOP for archiving data. Your response is inadequate because it does not explain your failure to maintain complete records prior to the inspection. You also did not address validation of the systems you use to archive your data.
我們知曉你們承諾要修訂你們歸檔數據的SOP。你們的回複是不充分的,因為這並沒能解釋你們未能在檢查之前維護完整記錄的原因。你們也沒有說明你們用來歸檔數據的係統的驗證問題。
 
2. Failure to prevent unized access or changes to data, and failure to provide adequate controls to prevent omission of data.
未能防止未經授權的進入或更改數據,未能提供足夠的控製來防止數據刪除。
 
Our investigator observed that your laboratory systems lacked controls to prevent deletion of and alterations to electronic raw data. You do not have adequate controls for seven of (b)(4) high performance liquid chromatography (HPLC) systems and one of (b)(4) gas chromatography systems. For example, the audit trail on HPLC 15 did not record the (b)(4)batch (b)(4) assay. Your records indicate that the assay was performed on March 3, 2014, but your audit trail shows no assays performed between February 28 and March 4, 2014. Moreover, your analyst demonstrated to our investigator that he could change the data, including injection time and date, without the changes being captured in the audit trail, prior to printing the results.
我們的調查人員發現你們化驗室係統缺乏控製,不能防止對電子原始數據的刪除和修改。你們的9台HPLC係統和1台GC係統都沒有充分的控製。例如,HPLC15的審計追蹤沒有記錄某批次的含量。你們的記錄顯示含量是在2014年3月3日檢測的,但你們的審計追蹤顯示在2014年2月28日至3月4日之間都沒有檢測過含量。還有,你們的化驗員向我們的調查人員證實他可以在結果打印之前更改數據,包括進樣時間和日期,並且其操作是審計追蹤無法捕獲的。We acknowledge that you have committed to upgrading your analytical systems to be compliant with CGMP requirements. However, procuring new instruments, installing new and upgraded data acquisition software, and enabling various features on software are not sufficient alone. These steps will be effective only if you implement appropriate procedures and systems to ensure that your quality unit reviews all production and control data and associated audit trails as part of the batch release process.
我們知曉你們已承諾要更新你們的分析係統,以符合CGMP要求。但是,采購新的儀器、安裝新的和升級過的數據采集軟件、激活不同的軟件屬性本身並不充分。隻有當你們實施適當的程序和係統來確保你們的質量部門會審核所有生產和分析數據以及相關的審計追蹤,作為批放行過程的一部分時才是有效的。

3. Failure to ensure that your analytical methods used to test API are appropriately validated and verified.
未能確保你們用於檢測原料藥的分析方法經過適當的驗證和確認。

Our investigator found that your microbiological test methods were not adequately verified and that stability test methods were inadequately validated. For example:
我們的調查人員發現你們的微生物檢驗方法沒有經過適當的確認,穩定性測試方法的驗證不充分。例如:

a. (b)(4) of your nonsterile API are intended foruse in the manufacture of sterile finished dosage forms for U.S. distribution. You did not appropriately verify your test methods for total aerobic microbial count and total combined yeasts and molds. Specifically, you did not show that these methods are capable of recovering microorganisms in the presence of the API.
你們的非無菌原料藥某個批次要用於美國市場的無菌製劑生產,但你們沒有恰當地確認你們的TAMC和TCYM檢驗方法。具體情況是這樣的,你們沒有展示出這些方法有能力在有原料藥存在的情況下具有回收微生物的能力。

b. You did not demonstrate that your stability test methods are capable of detecting and resolving degradants from the main component as well as other (b)(4) components. Specifically, you did not perform forced degradation studies for the related-substance test methods for (b)(4),(b)(4), and (b)(4).
你們沒有證明你們的穩定性檢測方法有能力從主成分及其它成分中檢出和分離降解產物。具體情況是,你們沒有實施某相關物質檢驗方法的強降解試驗。

We acknowledge that you have committed to verifying and validating your test methods, but you did not include a plan to evaluate API within expiry that were distributed to the United States.
我們知曉你們已承諾要確認和驗證你們的檢驗方法,但你們沒有包括一份評估已銷往美國且仍在有效期內的原料藥的計劃。

Data Integrity Remediation  數據完整性彌補措施

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. We acknowledge that you are using a consultant to audit your operation and assist in meeting FDA requirements. In response to this letter, provide the following.
你們的質量體係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。我們知道你們聘請了顧問來審計你們的操作,協助符合FDA要求。在回複此函時,提供以下資料:

A.  A comprehensive investigation into the extent of the inaccuracies in data records and reporting. Your investigation should include: 
一份對數據記錄和報告不準確性程度的全麵調查。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、生產操作和係統的總結,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麵談,找出數據不準確的表現、範圍、根本原因。我們建議這些麵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 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麵回顧性評估。我們建議由一個有資質的第三方裏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 on the quality of your drugs. Your assessment should include analyses of the risks to patients caused by the release of drugs affected by alapse of data integrity, 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 firm that includes the details of your global corrective action and preventive action 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 of 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.
臨時描述,描述你們已采取的行動,或即將采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、控製、係統、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。
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