Hospira被发警告信

红茶.

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老外违起规来，一点不含糊，天朝群众表示情绪稳定——大家都一个样嘛

Warning Letter

CERTIFIED MAIL                                                                        
RETURN RECEIPT REQUESTED

WL: 320-15-08

March 31, 2015



Mr. Michael Ball
Chief Executive Officer
Hospira S.p.A.
275 N. Field Drive
Lake Forest, IL 60045
USA

Dear Mr. Ball:

During our May 5-9 and 12-13, 2014 inspection of your pharmaceutical manufacturing facility, Hospira S.p.A., located at Via Fosse Ardeatine 2, Liscate, Italy, investigators from the U.S. Food and Drug Administration (FDA) identified significant violations of current good manufacturing practice (CGMP) regulations for finished pharmaceuticals, Title 21, Code of Federal Regulations, Parts 210 and 211. These violations cause your drug products to be adulterated within the meaning of Section 501(a)(2)(B) of the Federal Food, Drug, and Cosmetic Act (the Act), 21 U.S.C. 351(a)(2)(B), in that the methods used in, or the facilities or controls used for, their manufacture, processing, packing, or holding do not conform to, or are not operated or administered in conformity with, CGMP.

We have conducted a detailed review of your firm’s response dated June 4, 2014 and note that it lacks sufficient corrective actions. We acknowledge receipt of your firm’s correspondence dated August 4, 2014, October 2, 2014, December 4, 2014, and February 9, 2015

Our investigators observed specific violations during the inspection, including, but not limited to, the following:

1.    Your firm failed to establish and follow appropriate written procedures that are designed to prevent microbiological contamination of drug products purporting to be sterile, and that include validation of all aseptic and sterilization processes (21 CFR 211.113(b)).

Your firm did not evaluate all critical operations during dynamic airflow studies to determine risk to product sterility.

a)    Your firm did not evaluate significant aseptic interventions during dynamic airflow studies (smoke studies) to determine how the movement of air and personnel during aseptic operations could pose risks to product sterility. For example,

i.    Your smoke studies did not evaluate the impact of operators pushing (b)(4) vials down a chute while simultaneously removing a (b)(4) located (b)(4) the chute to load vials in the designated (b)(4).  The inspection documented that (b)(4) from the vials during this (b)(4) vial transfer operation, potentially exposing the product in the vials to contaminants from personnel or the surrounding environment.  In addition, during our inspection, the investigator observed operators reaching over the (b)(4) vials during this operation, an action which could compromise product sterility by introducing microbiological contaminants.

Your investigation on February 18, 2013, documented that you were aware of problems caused by the (b)(4) vial loading operation. Exception report record, PR ID 119409, noted that the (b)(4) vial loading operation frequently results in rough aseptic transitions. However, our investigator observed operators continuing this practice over a year after you closed PR ID119409. It did not appear that you had acted on your findings to correct this problem or prevent its recurrence, and the sterility of your products may have been compromised in the meantime.  

ii.    You did not perform smoke studies to demonstrate unidirectional airflow for set-up activities of the aseptic fill line or for the (b)(4) transfer of (b)(4) vials from the vial holding area to the (b)(4).  Your smoke studies also did not show unidirectional airflow above the un-stoppered vials that pass (b)(4) the stopper loading chute. Without smoke study data to demonstrate that air flows unidirectionally over these critical operations and processing steps, you cannot show that your processes are designed to prevent microbiological contamination of your products or provide adequate assurance of product sterility.

iii.    We also note that your stopper (b)(4) creates air turbulence in the area around the stopper loading chute, which could lead to additional opportunities for microbiological contamination.

The examples listed above show how disruptions to the unidirectional flow of air could lead to the contamination of product in exposed vials. We acknowledge your response that you have performed smoke studies, and made limited modifications to the operation in an effort to reduce risks posed by the design deficiencies identified in our inspection. For example, we note that you made some minor changes to reduce rocking of the (b)(4) during the(b)(4) vial transfer operation described above in 1. a) 1. However, your response is inadequate because you have not committed to provide a thorough design assessment.  You also failed to provide a video of the new smoke studies you indicated that you performed.

In response to this letter, please describe further design modifications you will make to mitigate the contamination hazards in your operation, including, but not limited to, the examples discussed above in examples 1. a)1-3. Also, provide a copy of the video/DVD depicting smoke studies you performed to demonstrate unidirectional airflow during the manufacturing operations described above.

b)    Your firm rejected possible integral units (i.e., units with intact container/closure systems) from media fills without a written justification or explanation. For example, during media fill batch (b)(4) (June 2012), you rejected 5 vials as “tilted” and you also rejected 250 vials during the (b)(4) process without explanation or justification. Similarly, during media fill batch (b)(4) (December 2013), you rejected 21 vials as “tilted” and you also rejected 30 vials during the (b)(4) process without explanation or justification. During the inspection, your management told the investigator that the vials you rejected as “tilted” would likely be fully stoppered and integral. Your media fill batch records did not include any further rationale for rejecting these vials, although many of them were likely integral.

When you perform a final product inspection of units immediately following a media fill run, all integral units should proceed to incubation.  Units found to have defects not related to integrity (e.g., cosmetic defects) should be incubated; units that lack integrity should be rejected. Erroneously rejected units should be returned promptly for incubation with the media fill lot. After incubation is underway, any unit found to be damaged should be included in the data for the media fill run because the units might be representative of drug product released to the market. Any decision to exclude non-integral units from the final run tally should be fully justified and you should fully explain the deviation in your media fill report.  If a correlation emerges between difficult to detect damage and microbial contamination, you should conduct a thorough investigation to determine its cause.

We acknowledge that you completed a media fill performance qualification. However, your protocol, Shut Down Media Fill Qualification Protocol KC4103-PQ, is inadequate because it does not provide criteria that adequately defines when vials are to be rejected.  In your response to this letter, provide your categorization criteria and justification for rejection of vials from a media fill.

These violations are similar to those found during the October 2012 inspection of your Irugattukottai, Sriperumburdur, India manufacturing site. Dynamic airflow study and media fill deficiencies were noted in Warning Letter (WL: 320-13-18), issued May 28, 2013. Your response to that warning letter stated that you implemented your Global Quality Strategy and Global Quality Plan in February 2013for your manufacturing facilities. Provide evidence of the effectiveness of your implemented global corrective actions and preventive actions.

2.    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).

For example, your firm failed to conduct a thorough investigation for 103 complaints for (b)(4) injection related to discoloration of (b)(4) or (b)(4) solution between November 1, 2011 and October 31, 2013, and a more recent complaint on April 3, 2014. Many customer complaints have stated that the product changed to a (b)(4) color, rather than the normal “(b)(4)” appearance.  You concluded that the root cause for the discoloration was the (b)(4) of the product. Your investigation is inadequate because you failed to evaluate the impact that (b)(4) may have on the quality of the product and to correlate the level of (b)(4) degradant with the amount of discoloration observed. Your investigation also failed to consider that the discoloration might have been caused by the failure to perform a step in the manufacturing process in an (b)(4) environment. Specifically, you mention that some vials may have (b)(4) as a result of them (b)(4) shelf during the stoppering manufacturing phase. You state that the unloading of the vials from the (b)(4) to (b)(4) is not performed (b)(4) and that there is a potential for (b)(4)ingress.   

We acknowledge your commitment to continue the investigation of (b)(4) levels in (b)(4) vials per protocol KC3601-ENG. However, your response does not adequately address the impact of the effect of (b)(4) in that your medical assessment lacks an evaluation of whether the degradant poses a risk to patients.   

In addition, your firm has not adequately addressed vulnerabilities in your manufacturing process that can be addressed to prevent the potential ingress of (b)(4).

Please provide a protocol and timeline for the assessment of your manufacturing process to control the level of(b)(4) in the vial (b)(4). Also, include your scientific rationale that the level of the (b)(4) degradant has no meaningful impact on product quality.

Please also explain whether your firm will be identifying and quantifying the (b)(4) degradant, and any other major degradants, and if you have determined that appropriate specification limits should be established.

In your response, you indicate that your appearance specification ((b)(4)) is subjective. Please explain how you intend to qualify the appearance specification for the (b)(4) finished product.

3.    Your firm failed to exercise appropriate controls over computer or related systems to assure that only authorized personnel institute changes in master production and control records, or other records (21 CFR 211.68(b)).

Specifically, your high performance liquid chromatography (HPLC) and gas chromatography (GC) data acquisition software, TotalChrom®, did not have sufficient controls to prevent the deletion or alteration of raw data files. During the inspection, the investigator observed that the server that maintains electronic raw data for HPLC and GC analyses (the J drive) contains a folder named “Test,” and that chromatographic methods, sequences, and injection data saved into this folder can be deleted by analysts.  The investigator also found that data files initially created and stored in the “Test” folder had been deleted, and that back-up files are overwritten(b)(4).

In addition, because no audit trail function was enabled for the “Test” folder, your firm was unable to verify what types of injections were made, who made them, or the date or time of deletion. The use of audit trails for computerized analytical instrumentation is essential to ensure the integrity and reliability of the electronic data generated.

Your response indicates that you have added computer controls to prevent the deletion of folders and files in the J drive for electronic raw data. However, you provide no evidence demonstrating how your firm will prevent deletion of newly created folders and files in each of your computer systems. We acknowledge your commitment to hire a third party consultant to address the inadequacies of your data systems. However, your response is inadequate as it fails to address how you will enable and review audit trail functions for all of your analytical computer systems.

In response to this letter, provide specific details about the comprehensive controls in place to ensure the integrity of electronic raw data generated by all computer systems used to support the manufacture and testing of drug products. Your response should demonstrate an understanding of your processes and the appropriate controls needed for each stage of manufacture that generates electronic raw data, as well as for your laboratories.

We identified a similar inspectional finding during the December 2013 inspection of your Irugattukottai, Sriperumburdur, India, manufacturing facility and noted this finding in an Untitled Letter, issued April 16, 2014. Explain how your firm will implement global corrective actions and preventive actions concerning computer controls and provide a timeline for implementation.

4.    Your firm failed to ensure that laboratory records included complete data derived from all tests necessary to assure compliance with established specifications and standards (21CFR 211.194(a)).

a)    Our investigators identified your practice of performing trial sample injections for HPLC analyses. For example, trial injections of (b)(4) stability samples (lot (b)(4) and (b)(4)) were acquired in the “Test” folder prior to official testing. Immediately after the trial injections were completed, the official samples were analyzed. The trial injection raw data, captured in the back-up files, were deleted from the test folder.

b)    You retested analytical samples without reporting original results in laboratory records. Because of this practice, you are unable to assure that all raw data generated is included and evaluated when you review analytical test results to determine whether your products conform with their established specifications and standards.

For example, (b)(4) lot #(b)(4) failed the content uniformity test, where sample #8 of (b)(4) resulted with a value(b)(4)%. Your firm proceeded to retest the sample on a different instrument without initiating an out-of-specification (OOS) investigation, as required by your chemistry laboratory investigation standard operating procedure, SOP QAG-097. These injections were not reported as part of the original data or included in your laboratory investigation report. Subsequently, the electronic raw data files were deleted. Moreover, there is no procedure describing the use of re-injections for standards or samples on a different system to verify an original result.

Your response indicates that the “Test” folders were used to equilibrate the analytical columns and to determine when the system was ready for analysis. It is your responsibility to follow validated methods that include specific procedures to assess the suitability of your instruments. Neither the ICH document Q2R, "Validation of Analytical Procedure: Text and Methodology," nor the United States Pharmacopoeia (USP), General Chapter <1058>, "Analytical Instrument Qualification," provides for use of “trial” injections as part of a validated method. Your rationale that you retested failing samples on different analytical instrumentation to evaluate system suitability is inadequate. See USP General Chapter <621>, “Chromatography,” which discusses system suitability tests and the use of replicate injections of a standard preparation or other standards to determine if the requirements for precision are satisfied.

These are serious CGMP violations that demonstrate that your quality system does not adequately ensure the accuracy and integrity of the data you generate to support the safety, effectiveness, and quality of the drug products you manufacture. We acknowledge your commitment to work with a third party consultant to conduct a comprehensive assessment of your firm’s manufacturing, laboratory, and quality operations. However, it is your responsibility to ensure that the third party audit includes a full evaluation of sophisticated electronic systems and the potential for manipulation of such systems. In response to this letter, provide the following to the Agency:

1.    A comprehensive evaluation of the extent of the inaccuracy of the reported data. As part of your comprehensive evaluation, provide a detailed action plan to investigate the extent of the deficient documentation practices noted above;


2.    A risk assessment regarding the potential effect on the quality of drug products. As part of your risk assessment, determine the effects of your deficient documentation practices on the quality of the drug product released for distribution; and

3.    A management strategy for your firm that includes the details of your global corrective action and preventive action plan.

a)    As part of your corrective action and preventive action plan, describe the actions you have taken or will take, such as contacting your customers, recalling product, conducting additional testing and/or adding lots to your stability programs to assure stability, monitoring of complaints, or other steps to assure the quality of the product manufactured under the violative conditions discussed above.

b)    In addition, as part of your corrective action and preventive action plan, describe the actions you have taken or will take, such as revising procedures, implementing new controls, training or re-training personnel, or other steps to prevent the recurrence of CGMP violations, including breaches of data integrity.

The violations cited in this letter are not intended to be an all-inclusive list of violations that exist at your facility. You are responsible for investigating and determining the causes of the violations identified above and for preventing their recurrence and the occurrence of other violations.

If, as a result of receiving this warning letter or for other reasons, you are considering a decision that could reduce the number of finished drug products produced by your manufacturing facility, FDA requests that you contact CDER's Drug Shortages Program immediately, as you begin your internal discussions, at drugshortages@fda.hhs.gov so that we can work with you on the most effective way to bring your operations into compliance with the law. Contacting the Drug Shortages Program also allows you to meet any obligations you may have to report discontinuances in the manufacture of your drug under 21 U.S.C. 356C(a)(1), 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. In appropriate cases, you may be able to take corrective action without interrupting supply, or to shorten any interruption, thereby avoiding or limiting drug shortages.

Until all corrections have been completed and FDA has confirmed corrections of the violations and your firm’s compliance with CGMP, FDA may withhold approval of any new applications or supplements listing your firm as a drug product manufacturer. In addition, your failure to correct these violations may result in FDA refusing admission of articles manufactured at Hospira S.p.A located at Via Fosse Ardeatine 2, Liscate, Italy  into the United States under Section 801(a)(3) of the Act, 21 U.S.C. 381(a)(3). The articles may be subject to refusal of admission pursuant to Section 801(a)(3) of the Act, 21 U.S.C. 381(a)(3), 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 Act, 21 U.S.C. 351(a)(2)(B).

Within fifteen working days of receipt of this letter, please notify this office in writing of the specific steps that you have taken to correct and prevent the recurrence of violations, and provide copies of supporting documentation. If you cannot complete corrective actions within fifteen working days, state the reason for the delay and the date by which you will have completed the corrections. Additionally, if you no longer manufacture or distribute the drug products at issue, provide the date(s) and reason(s) you ceased production. Please identify your response with FEI # 3004640070.

Please send your reply to:

Christina Alemu-Cruickshank
Compliance Officer
U.S. Food and Drug Administration
Center for Drug Evaluation and Research
Office of Manufacturing Quality
Division of Drug Quality I
White Oak, Building 51 room 4233
10903 New Hampshire Ave.
Silver Spring, MD 20993

小兵

看不懂啊

红茶.

小兵 发表于 2015-4-9 08:03
看不懂啊

谷歌翻译，有道翻译，百度翻译。。。。。。七七八八了。

中华骏捷

不明白呀。

呼吸

红茶. 发表于 2015-4-9 08:05
谷歌翻译，有道翻译，百度翻译。。。。。。七七八八了。

敢不敢弄点法语、德语、火星语反正是那种越看不懂越好的语言

淡莣

警告信


挂号信

收条交回



王:320-15-08



2015年3月31日




迈克尔先生球

首席执行官

Hospira公司。

275 n .字段驱动器

森林湖,IL 60045

美国


亲爱的先生:


2014年5月5 - 9和12 - 13,在我们检查你的制药生产设施,Hospira公司。Liscate,位于通过壕Ardeatine 2日,意大利,调查人员从美国食品和药物管理局(FDA)确定重大违反现行良好生产规范(CGMP)规定完成制药、标题21日的联邦法规,210年和211年。这些违规导致药物产品中掺假的意义Section 501(a)(2)(B)联邦食品、药物和化妆品法案(该法案),21事项351(a)(2)(B),在这种方法中使用,或使用的设施或控制他们的制造、加工、包装、或不符合,或不操作或管理符合CGMP。


我们已经进行了详细的审查,贵公司的反应6月4日,2014年,注意,它缺乏足够的纠正措施。我们已收到贵公司的信件日期为8月4日,2014年10月2日,2014年,2014年12月4日和2015年2月9日


我们的调查人员在检查观察特定的违反,包括,但不限于,如下:


1。贵公司未能建立并遵守适当的书面程序,目的是防止微生物污染的药物产品声称是无菌的,而且包括验证的无菌和灭菌过程(21 CFR 211.113(b))。


贵公司没有评估所有关键操作期间动态气流研究来确定产品不育的风险。


贵公司没有评估重大无菌干预期间动态气流研究(烟研究)来确定空气的流动和人员在无菌产品无菌操作可能会带来风险。例如,


我。你的烟没有评价经营者的影响研究推动(b)(4)瓶一滑槽,同时删除(b)(4)(b)(4)指定的槽加载瓶(b)(4)。检验证明,(b)(4)从瓶在这个(b)(4)瓶转移操作,可能暴露产品在瓶从人员或周围的环境污染物。此外,在我们检查,研究者观察到运营商达成的(b)(4)瓶在这个操作,一个操作可以妥协产品不育通过引入微生物污染物。


你的调查于2013年2月18日,记录引起你注意的问题(b)(4)瓶加载操作。异常报告记录,119409年公关ID,指出,(b)(4)瓶装载作业经常导致粗糙无菌转换。然而,我们的研究者观察到运营商持续这一实践一年之后你公关ID119409关闭。它没有出现,你发现这个问题纠正或预防其复发,和你的产品可能是不育同时受损。


二世。你没有执行烟研究证明单向气流设置活动的无菌填充行或(b)(4)(b)(4)转让的瓶瓶等候区(b)(4)。你的烟也没有研究显示单向气流un-stoppered瓶以上,(b)(4)制动器加载槽。没有烟的研究数据表明,单向地将空气流动对这些关键的操作和处理步骤,你不能显示你的流程是为了防止微生物污染产品无菌的产品或提供足够的保证。


三世。我们还要注意,你塞(b)(4)创建空气扰动在制动器加载槽周围的区域,这可能导致额外的微生物污染的机会。


上面列出的例子展示了中断的单向流动空气可能导致产品污染的暴露瓶。我们承认你的回应,你表现研究,吸烟,使有限的修改操作,以降低风险造成的设计缺陷确定在我们的检查。例如,我们注意到您做了一些微小的变化,减少摇摆期间(b)(4)(b)(4)瓶转移操作在1上面描述。一)1。然而,你的反应是不够的,因为你没有致力于提供全面的设计评估。你还没能提供一个视频的新执行的研究表明,你抽烟。


为了应对这封信,请描述进一步设计修改你将减轻污染危害操作,包括,但不限于,在例子1上面讨论的例子。1 - 3。同时,提供一份视频/ DVD描绘吸烟研究你执行演示单向气流在上面描述的制造业务。


b)贵公司拒绝可能积分单元(即。单位与完整的容器/关闭系统)培养基灌装没有书面理由或解释。例如,在媒体填补批(b)(4)(2012年6月),你拒绝了5瓶“倾斜”,你也拒绝了250瓶(b)(4)过程中没有解释或理由。同样地,在媒体填补批(b)(4)(2013年12月),你拒绝了21瓶“倾斜”,你也拒绝30瓶(b)(4)过程中没有解释或理由。在检验期间,你的管理告诉调查员,瓶你拒绝“倾斜”可能会完全密封而积分。你的媒体填补批记录不包括任何进一步的理由拒绝这些瓶,尽管他们中很多人可能积分。


当您执行单位的最终产品检验后立即媒体运行,所有积分单元应该进行孵化。单位发现有缺陷与完整性(例如应该孵化、化妆品缺陷);单位,缺乏完整性应被拒绝。错误地拒绝单位应及时返回孵化与媒体填补很多。正在孵化后,任何单位发现损坏应包括媒体数据填补来看,因为单位可能发布的药品市场的代表。任何决定排除非整体单位从最终统计应充分合理的运行,你在媒体应充分解释偏差报告。如果很难发现之间的关系出现损伤和微生物污染,应该进行彻底调查,以确定其原因。


我们承认,你完成了一个媒体填充性能资格。然而,你的协议,关闭媒体填补KC4103-PQ资格协议,是不够的,因为它不提供标准,充分定义当瓶被拒绝。在你的这封信,提供您的分类标准和理由拒绝瓶从媒体填补。


这些违反类似Irugattukottai,2012年10月进行检查时发现Sriperumburdur,印度制造业的网站。动态气流研究和媒体填补缺陷被发现在一封警告(王:320-13-18),2013年5月28日发布。你的回应,一封警告说你实现全球质量战略和全球质量计划在2013年2月的生产设施。提供的证据的有效性实施全球纠正措施和预防措施。


2。贵公司未能彻底调查任何无法解释的偏差或失败的一批或它的任何组件来满足任何的规格,是否批已经分布(21 CFR 211.192)。


例如,贵公司没有进行彻底调查103投诉(b)(4)注射相关变色(b)(4)或(b)(4)解决方案在11月1日,2011年10月31日,2013年,和最近的一个投诉4月3日,2014年。许多客户投诉说,产品改变(b)(4)的颜色,而不是正常的”(b)(4)”外观。你得出的结论是,变色的根源(b)(4)的产品。你的调查是不够的,因为你没有评价的影响(b)(4)可能会对产品的质量和相关的水平(b)(4)降解的变色。你的调查也未能考虑到变色可能造成未能执行生产过程的一个步骤(b)(4)环境。具体地说,你提到一些瓶可能(b)(4)由于他们(b)(4)货架在加塞制造阶段。你国家的卸瓶从(b)(4)(b)(4)(b)(4)不执行,是一个潜在的(b)(4)入口。


我们承认你的承诺继续的调查(b)(4)水平(b)(4)每个协议KC3601-ENG瓶。然而,你的反应不充分解决的影响(b)(4)的影响,你的医疗评估缺乏评价降解是否对病人造成威胁。


此外,贵公司还没有充分解决漏洞可以解决制造过程中防止潜在的(b)(4)入口。


请提供一个协议和时间表的评估生产过程控制的(b)(4)瓶(b)(4)。同时,包括你的科学原理的水平(b)(4)降解没有有意义的对产品质量的影响。


也请解释贵公司是否会被识别并量化(b)(4)降解,和任何其他主要降解,如果你已经确定,应该建立相应的规范限制。


在你的回应,你表明你的外表规范((b)(4))是主观的。请解释你打算如何符合外观规范(b)(4)成品。


3。贵公司未能适当运动控制计算机或相关系统,以确保只有经过授权的人员研究所主生产和控制记录的变化,或其他记录(21 CFR 211.68(b))。


具体地说,你的高效液相色谱,气相色谱法(GC)数据采集软件,TotalChrom&reg;,没有足够的控制,以防止删除或更改原始数据文件。在查验中,研究者观察到的服务器维护电子HPLC和GC分析原始数据(J驱动器)包含一个文件夹命名为“测试”,色谱方法、序列和注入数据保存到这个文件夹,分析师可以删除。研究者还发现,数据文件最初创建并存储在“测试”文件夹被删除,而备份文件被覆盖(b)(4)。


此外,由于没有启用审计跟踪功能的“测试”文件夹中,贵公司无法核实什么类型的注射,谁让他们,或删除的日期或时间。审计跟踪的使用计算机分析仪器是必要的,以确保生成的电子数据的完整性和可靠性。


你的反应表明,添加计算机控制防止删除文件夹和文件的J推动电子原始数据。然而,您提供任何证据证明贵公司将如何防止删除新创建的文件夹和文件在您的计算机系统。我们承认你的承诺,雇佣第三方咨询解决数据系统的不足。然而,你的反应是不够的,因为它未能解决如何启用和审查审计跟踪所有的分析计算机系统的功能。


为了应对这封信,提供全面控制的具体细节以保证电子原始数据的完整性产生的所有计算机系统用于支持药物产品的制造和测试。你的反应应该展示你的理解过程和适当的控制每个阶段所需的制造产生电子原始数据,以及为您的实验室。


我们发现了一个类似目测发现在2013年12月检查Irugattukottai,Sriperumburdur,印度制造工厂,这一发现在一个无标题的信,2014年4月16日发布。说明贵公司将实现全球有关计算机控制和纠正措施和预防措施提供一个时间表执行。


4。贵公司未能确保实验室记录包含完整的数据来自所有必要的测试,以确保符合规范和标准建立(21 cfr 211.194(a))。


)我们的调查人员发现你的实践执行注射试验样品的高效液相色谱分析。例如,试验注射(b)(4)稳定性样品(很多(b)(4)和(b)(4))中获得的“测试”文件夹之前官方测试。试验后立即注射完成后,官方的样本进行了分析。俘获的注射试验原始数据,备份文件,从测试文件夹中删除。


b)测试分析样品没有报告原始结果在实验室记录。因为这种做法,你不能确保包括所有原始数据生成和评估当你回顾分析测试结果来确定产品符合他们的规范和标准。


例如,(b)(4)很多#(b)(4)含量均匀度测试失败,在示例# 8(b)(4)导致的一个值(b)(4)%。贵公司开始重新测试样品在不同的仪器没有启动超标(OOS)调查,根据你的化学实验室调查标准操作程序,SOP qag - 097。这些注射不报道作为原始数据的一部分或包含在你的实验室调查报告。随后,电子原始数据文件删除。此外,没有过程描述re-injections的使用标准或样品在一个不同的系统来验证一个原始的结果。


你的反应表明,“测试”文件夹是用来平衡分析列和确定当系统已经准备好了进行分析。你有责任遵守验证方法,包括特定的程序来评估工具的适用性。无论是我文档Q2R”,验证分析方法:文本和方法论”,也不是美国药典(USP),一般章< 1058 >,“分析仪器的资格,”提供了使用“审判”注射的方法进行验证。你的理由,你测试失败的样品在不同的分析仪器评估系统适用性是不够的。见USP一般章< 621 >,“色谱法”,讨论了系统适用性测试和使用复制注射准备一个标准或其他标准来确定满足精度的要求。


这些是严重违反CGMP充分证明你的质量体系不保证数据的准确性和完整性生成支持安全、效率和质量的药物你所制造的产品。我们承认你的承诺与第三方顾问进行全面评估贵公司的制造、实验室和质量操作。然而,这是你的责任,以确保第三方审计包括一个完整的复杂的电子系统和评估潜在的这种系统的操纵。为了应对这封信,提供以下机构:


1。综合评价的准确程度的报告数据。作为综合评价的一部分,提供一个详细的行动计划调查实践缺乏文档上面所提到的程度;



2。风险评估有关的潜在影响药品的质量。作为风险评估的一部分,确定的影响缺乏文档实践对发布的药品的质量分布;和


3。贵公司的管理策略,包括全球纠正措施和预防措施的细节计划。


)作为你的纠正措施和预防措施计划的一部分,描述你已采取或将采取的行动,比如联系你的客户,召回产品,进行额外的测试和/或添加很多稳定程序来保证稳定,监测投诉,或其他措施来保证产品的质量上面讨论违犯的条件下生产。


b)此外,作为你的纠正措施和预防措施计划的一部分,描述你已采取或将采取的行动,比如修改程序,实施新的管制,培训或部门人员,或其他措施来防止侵犯CGMP的复发,包括违反数据完整性。


引用的违反这封信不是为了存在的违反你的全面列表。你是负责调查,确定上述违规行为的原因和防止复发和其他违法行为的发生。


如果由于收到这一封警告或其他原因,你正在考虑一个决定,可以减少药物成品的数量由你的制造工厂,FDA要求你立即联系CDER的药品短缺的计划,当你开始你的内部讨论,在drugshortages@fda.hhs。政府,这样我们可以与你最有效的方法把你的操作符合法律要求。接触药品短缺程序还允许您以满足任何义务报告中止生产药物的21岁以下事项356 c(a)(1),并允许FDA考虑,尽快采取什么行动,如果有的话,可能需要避免短缺和保护病人的健康取决于你的产品。在适当的情况下,你可以采取纠正措施而不中断供应,或缩短任何中断,从而避免或限制药品短缺。


直到所有修改已经完成,FDA已确认纠正违规和贵公司符合CGMP,FDA可能停止批准任何新的应用程序或补充清单贵公司作为药物产品制造商。此外,你未能纠正这些问题可能导致FDA拒绝承认文章制造Hospira S.p。Liscate位于通过壕Ardeatine 2日,意大利到美国在801条款(A)(3),21个事项381(A)(3)。文章可能会拒绝承认依照第801条(a)(3),21事项381(a)(3),在生产过程中使用的方法和控制不出现符合CGMP的意义在第501条(a)(2)(B),21事项351(a)(2)(B)。


15个工作日内收到这封信,请书面通知这个办公室的具体步骤,你采取了纠正和预防复发的违规行为,并提供支持文档的副本。如果你不能在十五个工作日内完成纠正措施,国家延迟的原因和日期,你将完成修正。Additionally, if you no longer manufacture or distribute the drug products at issue, provide the date(s) and reason(s) you ceased production. Please identify your response with FEI # 3004640070.


Please send your reply to:


Christina Alemu-Cruickshank

Compliance Officer

U.S. Food and Drug Administration

Center for Drug Evaluation and Research

Office of Manufacturing Quality

Division of Drug Quality I

White Oak, Building 51 room 4233

10903 New Hampshire Ave.

Silver Spring, MD 20993

淡莣

用翻译软件翻译完了之后，也不行啊，各种翻译错误。

blueriver

看来老外的工厂也不强呀

赢者无悔

总不能老从洋媚外吧。

红茶.

淡莣 发表于 2015-4-9 08:18
用翻译软件翻译完了之后，也不行啊，各种翻译错误。

差不多就行了，要是没个翻译错误的，你让那些英语专业的都失业咩。。。。。。

xqliu

学习一下啦，谢谢提供分享。

一沙一叶

淡莣 发表于 2015-4-9 08:15
警告信

这个东西没法看啊

冷血无情

http://fanyi.youdao.com/WebpageT ... 1&keyfrom=360ce

淡莣

一沙一叶 发表于 2015-4-9 08:38
这个东西没法看啊

没法看就对了，因为我都看不下去，还是先学学英语去！~

cph2345

淡莣 发表于 2015-4-9 15:46
没法看就对了，因为我都看不下去，还是先学学英语去！~

还不如自己一边看着一边猜。