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昨夜，F(xiàn)DA官網(wǎng)掛出對全球仿制藥巨頭邁蘭（Mylan）制藥的警告信，缺陷主要涉及數(shù)據(jù)可靠性問題，包括：

• 無效OOS率約72%，但沒有充分的調(diào)查來確定根本原因

• 未能監(jiān)測和調(diào)查計算機(jī)化系統(tǒng)所產(chǎn)生的錯誤信號

• 刪除檢驗(yàn)數(shù)據(jù)、進(jìn)針結(jié)果、色譜圖等

• 多個OOS（數(shù)據(jù)丟失）歸咎為供電中斷、連接問題（網(wǎng)線或電源線中斷）、和儀器失靈。一周有7次因數(shù)據(jù)采集中斷導(dǎo)致原始結(jié)果丟失。

具體如下：

Mr. Rajiv Malik

President

Mylan Pharmaceuticals, Inc.

邁蘭制藥有限公司

1000 Mylan Boulevard

Canonsburg, PA 15317

Dear Mr. Malik:

The U.S. Food and Drug Administration (FDA) inspected your drug manufacturing facility, Mylan Laboratories Limited at F-4 & F-12, MIDC, Malegaon Taluka, Sinnar District, Nashik 422 113, Maharashtra, India, from September 5 to 14, 2016.

FDA與2016年9月5~14日檢查了你們位于印度馬哈拉施特拉邦納克西422113西納爾街馬萊岡的邁蘭實(shí)驗(yàn)室有限公司。

This warning letter summarizes significant violations of current good manufacturing practice (CGMP) regulations for finished pharmaceuticals. See 21 CFR, parts 210 and 211.

本警告信概況了成品CGMP條款重大違規(guī)。見21CFR第210部分和211部分。

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).

因?yàn)槟銈兊姆椒?，設(shè)施，或者生產(chǎn)、加工、包裝或者保存的控制不符合CGMP，你們的藥品被認(rèn)定為摻假。

We reviewed your October 5, 2016, response in detail and acknowledge receipt of your subsequent correspondence.

我們詳細(xì)審閱了你們于2016年10月5日及之后的回復(fù)。

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

檢查期間，我們的檢查員發(fā)現(xiàn)的具體違規(guī)包括但不限于，如下：

1.    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).

未能徹底調(diào)查批產(chǎn)品或其組分與其既定標(biāo)準(zhǔn)的任何不明原因的差異或不符，不管該批是否已經(jīng)被放行。 

From January 1 to June 30, 2016, your firm invalidated 101 out of 139 (about 72 percent) initial out-of-specification (OOS) assay results without sufficient investigation to determine the root cause of the initial failure.

從2016年6月1日到30日，貴司判定139個含量結(jié)果OOS里面有101個為無效OOS（約72%），但是沒有充分的調(diào)查來確定最初失敗的根本原因。

For example, you opened laboratory investigation report PR 908027 for an initial OOS six-month stability assay result of (b)(4) percent (specification (b)(4)–(b)(4) percent) for (b)(4) mg tablets, lot (b)(4). You invalidated the initial failing result without adequate investigation, performed re-testing, and then reported the (b)(4) results of these replicate re-tests ((b)(4) percent). Your investigation did not reach an assignable cause, nor did you take appropriate corrective actions and preventive actions to ensure that the significant “analytical bias” to which you ultimately attributed the initial failure would not affect other analytical work in your laboratory.

例如，你們對XX mg片劑，批次XX六個月穩(wěn)定性含量結(jié)果XX%（標(biāo)準(zhǔn)：XX~XX%）的初始OOS結(jié)果開展實(shí)驗(yàn)室調(diào)查報告PR908027。你們判定原來的不合格結(jié)果無效，沒有進(jìn)行充分的調(diào)查，而是重復(fù)檢驗(yàn)，并報告了重復(fù)檢驗(yàn)的XX%的XX結(jié)果。你們的調(diào)查沒有確定原因，也沒有采取適當(dāng)?shù)募m正和預(yù)防措施來確保你們最終確定的導(dǎo)致原先不合格結(jié)果的“分析偏差”不會影響其他你們實(shí)驗(yàn)室的其他分析工作。

In your response, you state that laboratory decisions are to be made on the basis of scientific evaluation, and that they are to determine whether OOS laboratory results are the result of the laboratory process or the manufacturing process. However, in the example above, your investigation assumed “analytical bias” in your laboratory process but failed to determine how this apparently significant error in your analyses could be eliminated or mitigated in the future.

在你們的回復(fù)中，你們說實(shí)驗(yàn)室決策將基于科學(xué)評價，并說將確定實(shí)驗(yàn)室OOS結(jié)果是實(shí)驗(yàn)室過程引起還是生產(chǎn)過程引起。但是，在以上的例子中，你們的調(diào)查認(rèn)定為實(shí)驗(yàn)室過程引起的“分析偏差”而沒有確定在實(shí)驗(yàn)室過程中如此明顯的重大錯誤在將來將如何被消除或減少。 

Your response is inadequate because you failed to implement a corrective action and preventive action (CAPA) plan to mitigate errors that you attribute to laboratory process. Further, you did not include these improperly invalidated OOS results in your analysis of laboratory investigation trends. According to your Laboratory Investigation Report procedure MLLNSK-SOP-QA-GMP-0138, version 6, only “confirmed” root causes are to be identified and trended in laboratory investigation reports. Because your laboratory investigations frequently invalidate initial failures without cause, your laboratory trending excludes a large proportion of data that would otherwise alert you to problems in your laboratory system. Failure to identify trends in OOS investigations is a repeat observation from the previous FDA inspection, March 19 to 26, 2015.

你們的回復(fù)是不充分的，因?yàn)槟銈儧]有實(shí)施糾正措施和預(yù)防措施計劃來減少你們所歸咎為實(shí)驗(yàn)室過程引起的錯誤。而且，在你們的實(shí)驗(yàn)室調(diào)查趨勢分析中沒有包括這些被誤判為無效的OOS結(jié)果。根據(jù)你們的實(shí)驗(yàn)室調(diào)查報告規(guī)程，MLLNSK-SOP-QA-GMP-0138，第六版，只有“確定的根本原因”才會在實(shí)驗(yàn)室調(diào)查報告中被認(rèn)定和趨勢分析。因?yàn)槟銈兊膶?shí)驗(yàn)室調(diào)查經(jīng)常判定一開始的不合格結(jié)果無效而沒有原因，你們的實(shí)驗(yàn)趨勢分析將一大部分本可能警戒實(shí)驗(yàn)室系統(tǒng)問題的數(shù)據(jù)排除在外。未能分析OOS調(diào)查的趨勢是2015年3月19~26日上次FDA檢查發(fā)現(xiàn)的重復(fù)缺陷。

2.    Your firm failed to establish an adequate quality control unit with the authority to review production records to assure that no errors have occurred or, if errors have occurred, that they have been fully investigated (21 CFR 211.22(a)).

貴司未能建立一個充分的質(zhì)量控制部門，使其有權(quán)審核生產(chǎn)記錄以確保沒有錯誤發(fā)生，或者在發(fā)生錯誤后，能夠被充分調(diào)查。 

Your quality unit failed to monitor and investigate error signals generated by the computerized systems that you use for high performance liquid chromatography and gas chromatography. These signals indicated the loss or deletion of original CGMP analytical data. However, your quality unit did not comprehensively address the error signals or determine the scope or impact of lost or deleted data until after these problems were reviewed during our inspection.

你們的質(zhì)量部門未能監(jiān)測和調(diào)查由高效液相（HPLC）和氣相（GC）所用的計算機(jī)化系統(tǒng)所產(chǎn)生的錯誤信號。這些信號顯示了原始CGMP分析數(shù)據(jù)的丟失或刪除。然而，你們的質(zhì)量部門沒有徹底處理這些錯誤信號，或確定所丟失或刪除的數(shù)據(jù)的范圍和影響，直到這些問題在我們檢查期間被發(fā)現(xiàn)。

For example, our investigator reviewed audit trails from August 2016 assay testing on (b)(4) batch (b)(4) and dissolution testing for (b)(4) tablets batch (b)(4). The audit trail for these tests included the message, “deleted result set,” but neither of these two incidents were recorded in the analytical packages for these batches of drug products, nor were they reviewed or investigated by the quality unit.

例如，我們的檢查員審閱了2016年8月XX產(chǎn)品XX批次的含量檢測和XX片劑XX批次的溶出檢測的審計追蹤。這些檢驗(yàn)的審計追蹤均提示“刪除結(jié)果集”，但是這兩個事件均沒有在他們的藥品批次分析包中記錄，也沒有被質(zhì)量部門審核或調(diào)查。

In addition, during the inspection, our investigator observed that your Empower 3 system audit trail displayed many instances of a “Project Integrity Failed” message, which indicates that injections were missing from the results of analytical testing. For example, in (b)(4) analysis for (b)(4) tablets batch (b)(4) conducted on June 20, 2016, no chromatogram was rendered for the initial run of testing. The data package for this testing clearly shows that the initial run is missing, but your quality unit did not investigate the incident.

另外，在檢查期間，我們的檢查員發(fā)現(xiàn)你們的Empower 3系統(tǒng)審計追蹤顯示有很多“項(xiàng)目完整性失敗”的提示，這些提示表示分析檢驗(yàn)結(jié)果中的進(jìn)針缺失。例如，在2016年6月20日所進(jìn)行的XX片劑XX批次的XX分析中， 沒有繪制一開始檢驗(yàn)的色譜圖。該次檢驗(yàn)的數(shù)據(jù)包清楚顯示一開始的檢驗(yàn)已經(jīng)缺失，但是你們的質(zhì)量部門沒有調(diào)查該事件。

Although you showed our investigator isolated examples of interrupted, missing, deleted, and lost data for which you had opened investigations, you reached similar conclusions in many of these investigations regarding the root cause of your loss of data integrity but failed to take appropriate corrective action and preventive action in response. Our investigator observed that you attributed numerous incidents to power interruptions, connectivity problems (disconnection of the Ethernet or power cord), and instrument malfunctions. You could not explain why these events occurred with frequency in your laboratory, nor had you undertaken a comprehensive investigation into the problem or sought to correct it and prevent its recurrence.

盡管你們給我們的檢查員展示了你們已經(jīng)開展調(diào)查的中斷、缺失、刪除，和丟失數(shù)據(jù)的個例，在這些調(diào)查中有很多你們就數(shù)據(jù)可靠性問題的根本原因得出了相似的結(jié)論，但是沒有采取適當(dāng)?shù)募m正和預(yù)防措施。我們的檢查員發(fā)現(xiàn)你們將很多問題歸咎為供電中斷、連接問題（網(wǎng)線或電源線中斷）、和儀器失靈。你們未能解釋為什么這些問題在你們的實(shí)驗(yàn)室頻繁出現(xiàn)，也沒有對問題采取全面的調(diào)查或力求糾正它并預(yù)防再次發(fā)生。

In your written response dated February 17, 2017, you identified seven samples from a single week of testing for which original results were lost following data acquisition interruptions at the time of initial analysis. Instead of uniformly initiating an investigation into the root cause of each interruption when it occurred or even documenting it for later review and investigation by the quality unit, you explained in your response that you retested the samples immediately after the interruptions.

在你們?nèi)掌跒?017年2月17日的書面回復(fù)中，你們在一周的檢驗(yàn)里面確定了7個在一開始分析時由于數(shù)據(jù)采集中斷導(dǎo)致原始結(jié)果丟失的例子 。你們在你們的回復(fù)中解釋說你們在中斷后立即重新測試了樣品，而不是對每一次中斷在其發(fā)生時都進(jìn)行一個根本原因調(diào)查，或至少記錄它們以進(jìn)行后續(xù)審核并由質(zhì)量部門調(diào)查。

Your response is inadequate because you have not identified and investigated each instance in which data acquisition was interrupted. While you assessed a limited number of error codes from a seven day period, you did not evaluate the effects of other error codes identified in your simulation exercise report on the reliability, accuracy, or completeness of the data you use to evaluate the quality of your drugs. 

你們的回復(fù)是不充分的，因?yàn)槟銈儧]有確定和調(diào)查每一個數(shù)據(jù)采集中斷的情況。在你們評估了為期一周的有限數(shù)量的錯誤代碼之后，你們沒有在你們的模擬演練報告中評價你們所確定的其他錯誤代碼對你們用于評價你們藥品質(zhì)量的數(shù)據(jù)的可靠性、準(zhǔn)確性、或完整性的影響。