Warning Letter 320-17-02
Via UPS
Return Receipt Requested
October 18, 2016
Mr. Yuke Maki
CEO
Interpharm Praha A.S.
Komoranska 955
Praha 4
Modrany, Czech Republic
Dear Mr. Maki:
The U.S. Food and Drug Administration (FDA) inspected your drug manufacturing facility, Interpharm Praha A.S., at Komoranska 955, Praha, Modrany, from October 12 to 16, 2015.
美國FDA于2015年10月12-16檢查了你們位于捷克的生產(chǎn)工廠。
This warning letter summarizes significant deviations from current good manufacturing practice (CGMP) for active pharmaceutical ingredients (API) and significant violations of CGMP regulations for finished pharmaceuticals, 21 CFR parts 210 and 211.
本警告信總結(jié)了你工廠原料藥和制劑生產(chǎn)嚴(yán)重違背CGMP要求的情況，21CFR第210和211部分。
Because your methods, facilities, or controls for manufacturing, processing, packing, or holding do not conform to CGMP, your drugs are adulterated within the meaning of section 501(a)(2)(B) of the Federal Food, Drug, and Cosmetics Act (the FD&C Act), 21 U.S.C. 351(a)(2)(B).
由于你們生產(chǎn)、加工、包裝和保存的方法、設(shè)施和控制不符合CGMP要求，你們的藥品根據(jù)FDCA的定義被認(rèn)為是摻假藥品。
We reviewed your November 6, 2015, response in detail.
我們?cè)敿?xì)審核了你們于2015年11月6日發(fā)來的回復(fù)。
During our inspection, our investigator observed specific violations and deviations including, but not limited to, the following.
在我們檢查期間，我們的調(diào)查人員發(fā)現(xiàn)的違規(guī)情況包括但不僅限于以下：
API Deviations 原料藥偏差
1. Failure to prevent unauthorized access or changes to da
未能防止未經(jīng)授權(quán)進(jìn)入或改變數(shù)據(jù)，未能提供充分控制來防止對(duì)數(shù)據(jù)的篡改和刪除。
Your quality control unit did not have basic controls to prevent changes to your electronically-stored laboratory da
貴公司的質(zhì)量控制部門沒有基本的控制來防止對(duì)你們電子存貯的實(shí)驗(yàn)室數(shù)據(jù)進(jìn)行變更。你們的化驗(yàn)員具有EMPOWER-2系統(tǒng)的用戶權(quán)限，可以生成和分析色譜數(shù)據(jù)，能夠刪除不合格、異常和不滿意的結(jié)果，而不需要通知；可以刪除峰；可以增加和刪除序列中的樣品，不需要批準(zhǔn)。
During the inspection, we reviewed an audit trail from your Empower-2 system that stored 8,906 entries. Of these, well over half indicated some form of da
在檢查期間，我們審核了你們EMPOWER-2系統(tǒng)里的審計(jì)追蹤，其中存貯了8906條記錄。這些記錄里，有超過一半顯示出數(shù)據(jù)刪除和篡改，包括至少1441次結(jié)果刪除，至少3643次手動(dòng)積分，至少194次對(duì)運(yùn)行樣品序列的修改。你們的員工確認(rèn)這些動(dòng)作在色譜數(shù)據(jù)處理中是很常見的。我們發(fā)現(xiàn)你們沒有制訂程序，對(duì)自動(dòng)化系統(tǒng)用戶的受限層次和要求進(jìn)行規(guī)定。
Your quality unit must review all pertinent analytical da
你們的質(zhì)量部門在做出批放行決定時(shí)必須審核所有分析相關(guān)數(shù)據(jù)，而你們的自動(dòng)化系統(tǒng)允許化驗(yàn)員刪除和篡改檢驗(yàn)結(jié)果，但不需要批準(zhǔn)。在這種情況下，你們的質(zhì)量部門對(duì)你們藥品的質(zhì)量的信息是不完整和不準(zhǔn)確的。
According to your response, you restricted access and permissions in the Empower 2 automated da
根據(jù)你們的回復(fù)，你們限制了EMPOWER-2自動(dòng)化數(shù)據(jù)系統(tǒng)里的進(jìn)入和權(quán)限。但是，你們的回復(fù)沒有證據(jù)說明你們所實(shí)施的具體控制是如何防止數(shù)據(jù)刪除和篡改的，也沒有展示你們要如何確保記錄、實(shí)施和遵守這些許可流程。最后，你們沒有展示出這些控制是如何確保這些批放行和其它質(zhì)量審核決策所依賴的記錄是完整和準(zhǔn)確的。
2. Failure to ensure that test procedures are scientifically sound and appropriate to ensure that your API conform to established standards of quality and/or purity.
未能確保檢驗(yàn)程序是科學(xué)合理的，適合于確保你們的原料藥符合既定的質(zhì)量和/或純度標(biāo)準(zhǔn)。
Your laboratory procedures allowed analysts to modify chromatographic sequences and delete results with no justification.
你們的化驗(yàn)室程序允許化驗(yàn)員修改色譜序列和刪除結(jié)果，不需要論證。
During our review of chromatograms generated during impurities testing for (b)(4), we observed that your analysts conducted many manual integrations. We also found discrepancies in peak integrations, including inconsistent integrations, and peaks that were not integrated at all. Such peaks could represent impurities: they were not included in da
在我們審核你們對(duì)某產(chǎn)品純度檢驗(yàn)所生成的色譜圖時(shí)，我我們發(fā)現(xiàn)你們的化驗(yàn)員做了許多手動(dòng)積分。我們還發(fā)現(xiàn)峰積分差異，包括積分不一玩笑，有的峰完全沒有積分。這些峰可能代表的是雜質(zhì)，但沒有包括在呈交給你們的質(zhì)量部門批放行單曲循環(huán)所用的數(shù)據(jù)包里。因此，你們的質(zhì)量審核和產(chǎn)品放行決策是依據(jù)不完整的藥品質(zhì)量數(shù)據(jù)的。
According to your response, you scheduled training on manual integration for all analysts who use Empower-2 software. You have not shown how you will ensure that your test methods are appropriate to determine whether your API conform to established standards and specifications.
根據(jù)你們的回復(fù)，你們計(jì)劃對(duì)所有使用EMPOWER-2軟件的化驗(yàn)員進(jìn)行手動(dòng)積分培訓(xùn)。你們沒有說明你們要如何確保你們的檢驗(yàn)方法適合于決定你們的原料藥是否符合既定的標(biāo)準(zhǔn)和質(zhì)量。
In response to this letter, provide your act
在回復(fù)此函時(shí)，請(qǐng)?zhí)峤荒銈兘?、?yàn)證和實(shí)施你們藥品質(zhì)量屬性分析的色譜分析方法的行動(dòng)計(jì)劃。寫明你們要實(shí)施用以處理你們的與所有檢驗(yàn)結(jié)果和審計(jì)追蹤功能的色譜數(shù)據(jù)的程序。詳細(xì)說明你們要如何審核作為批放行程序和文件的一部分的色譜結(jié)果。寫明你們將要實(shí)施用以確保所有手動(dòng)積分步驟只有在預(yù)定的有限情形下根據(jù)質(zhì)量部門批準(zhǔn)和監(jiān)管下操作的程序。
Finished Product Violations 制劑違規(guī)
1. Your firm failed to exercise appropriate controls over computer or related systems to assure that on
你們公司未能對(duì)計(jì)算機(jī)和相關(guān)系統(tǒng)進(jìn)行適當(dāng)控制以確保只有經(jīng)過授權(quán)的人員才能對(duì)主生產(chǎn)和檢驗(yàn)記錄或其它記錄進(jìn)行修改(21 CFR 211.68(b))。
For example, our investigator reviewed an audit trail for impurities testing conducted on (b)(4) validation lot (b)(4), number(b)(4) vial # (b)(4), Injections 1 and 2. The audit trail revealed many deleted results and manual integrations.
例如，我們的調(diào)查人員審核了某產(chǎn)品驗(yàn)證批的雜質(zhì)檢驗(yàn)審計(jì)追蹤，進(jìn)樣瓶XX進(jìn)樣序列1和2。審計(jì)追蹤顯示有許多記錄被刪除，有手動(dòng)積分。
As discussed above, deleted and altered analytical test results mean that your quality unit is presented with incomplete and inaccurate information about the quality of your drugs.
如上所討論，檢驗(yàn)結(jié)果刪除和篡改意味著你們的質(zhì)量部門收到的是不完整不準(zhǔn)確的藥品質(zhì)量信息。
2. Your firm failed to establish laboratory controls that include scientifically sound and appropriate specifications, standards, sampling plans, and test procedures designed to assure that components, drug product containers, closures, in-process materials, labeling, and drug products conform to appropriate standards of identity, strength, quality, and purity (21 CFR 211.160(b)).
貴公司未能建立對(duì)化驗(yàn)室的控制，包括科學(xué)合理和適當(dāng)?shù)馁|(zhì)量標(biāo)準(zhǔn)、取樣計(jì)劃和檢驗(yàn)方法，用以確保藥品組份、藥品容器、密閉器、在制品、標(biāo)簽和藥品符合既定的鑒別、劑量、質(zhì)量和純度標(biāo)準(zhǔn)(21 CFR 211.160(b)).
Your laboratory procedures allowed analysts to modify and delete chromatographic results without adequate justification, and to use manual integration in uncontrolled circumstances.
你們的化驗(yàn)室程序讓化驗(yàn)員可以修改和刪除色譜結(jié)果，而沒有充分的論證，并且在不受控的情況下使用手動(dòng)積分。
For example, our investigator found results deleted after repeated manual integrations for (b)(4) stability lots (b)(4). Unjustified, repeated manual integrations and deletions indicate that your laboratory controls are not scientifically sound and appropriate to test your products.
例如，我們的調(diào)查人員發(fā)現(xiàn)某穩(wěn)定性樣品的色譜數(shù)據(jù)在反復(fù)手動(dòng)積分之后又刪除了結(jié)果。沒有論證、重復(fù)手動(dòng)積分和刪除顯示你們化驗(yàn)室的控制是不科學(xué)不合理的，不適合于檢測(cè)你們的產(chǎn)品。
In your response to this letter, describe all steps you will take to ensure that appropriate laboratory controls have been implemented to support product quality review and batch release decisions. Include the controls you will implement for the modification, deletion, and manual integration of chromatographic test results.
在你們對(duì)此函的回復(fù)中，請(qǐng)描述你們將要采取的所有用以確保實(shí)施適當(dāng)?shù)幕?yàn)室控制來支持產(chǎn)品質(zhì)量審核和批放行決策的措施。包括你們將要實(shí)施用以控制色譜檢驗(yàn)結(jié)果修改、刪除和手動(dòng)積分的程序。
Da
Your quality system does not adequately ensure the adequacy and integrity of da
In response to this letter, provide the following.
A. A comprehensive investigation into the extent of the inaccuracies in da
A detailed investigation protocol and methodology; a summary of all laboratories, manufacturing operations, and systems to be covered by the assessment; and justification for any part of your operation that you propose to exclude.
Interviews of current and former employees to identify the nature, scope, and root cause of da
ta inaccuracies. We recommend that these interviews be conducted by a qualified third party.
An assessment of the extent of da
ta 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 da
ta integrity lapses.
A comprehensive retrospective evaluation of the nature of your da
ta integrity deficiencies.
We recommend that a qualified third party with specific expertise in the area where potential lapses were identified should evaluate all da
ta integrity lapses.
B. A current risk assessment of the potential effect 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 in da
C. A management strategy that includes the details of your global corrective act
The detailed corrective act
ion plan that describes how you intend to ensure the reliability and completeness of all of the da
ta you generate, including analytical da
ta, manufacturing records, and all da
ta submitted to the FDA.
A comprehensive description of the root causes of your da
ta integrity lapses, including evidence that the scope and depth of the current act
ion plan is commensurate with the findings of the investigation and risk assessment. Indicate whether individuals responsible for da
ta integrity lapses remain able to influence CGMP-related or drug application da
ta at your firm.
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.
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 da
ta.
A status report for any of the above activities already underway or completed.
Conclusion
Violations and deviations cited in this letter are not intended as an all-inclusive list. You are responsible for investigating these violations and deviations, for determining the causes, for preventing their recurrence, and for preventing other violations and deviations in all your facilities.
If you are considering an act
Until you correct all violations and 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.
Failure to correct these violations and deviations may also result in FDA refusing admission of articles manufactured at Interpharm Praha A.S., Komoranska 955, Praha 4, Modrany, 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, 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).
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 violations and 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.
Send your electronic reply to CDER-OC-OMQ-Communications@fda.hhs.gov or mail your reply to:
Carlos Gonzalez, Compliance Officer
U.S. Food and Drug Administration
White Oak Building 51, Room 4359
10903 New Hampshire Avenue
Silver Spring, MD 20993
USA
Please identify your response with FEI 3002807299.
Sincerely,
/S/
Francis Godwin
Acting Director
Office of Manufacturing Quality
Office of Compliance
Center for Drug Evaluation and Research
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