从来不写评论，不过这次这家印度工厂的回复实在让人笑喷了，特别是关于微生物化验室的缺陷中，警告信所用的词简直太神了，感觉中国药品出口超过印度是指日可待的了。
受检公司：Apotex Research Private Limited (ARPL)
受检地址：Plot #1 & 2, Bommasandra Ind. Area, 4th Phase, Jigani Link Road, Bangalore, India
检查日期：2014年6月23日至7月1日
首次回复日期：2014年7月22日
后续回复日期：2014年8月11、29日，9月30日，10月31日，12月5日，2015年1月9日
警告信所列缺陷主要有四大项：
1. 你公司未能保证化验室记录包括所有测试产生的完整数据，这些数据是保证产品符合质量标准所必须的
检查中记录下了多次进行样品“试测”、忽略测试结果及仅报告额外测试所获得的结果等事件。例如
A． 某批片剂正式放行数据未知杂质报告为符合质量标准，但是色谱数据显示该批“试测”进针数据的未知杂质不符合质量标准
B． 某批片剂25度3个月稳定性试验测试点的正式HPLC杂质数据只包括了多次测试中最好的结果，而没有任何论述。该批次所得的数据已提交给美国FDA作为申报批次。
除上述例子外，我们检查还发现某片剂溶出度试验HPLC测试中44643针进样里有2803针没有处理或在正式数据文件夹中报告。我们检查发现不同药品（美国和非美国市场产品）大量“试针”情况，这说明公司习以为常。
你们对“试针”的缺陷回复中试图解释复测的合理性。你们声明“未知杂质是由于电子干扰或压力波动对HPLC产生的影响”。之后你们对偏差的调查得到结论是“未知杂质不属于产品，在所有商业批次和申报批次中均未发现”。你们在商业批次和申报批次中未发现该峰并不能论证为什么可以忽略检测运行，或不遵守适当的纠正预防措施。
根据你们的回复，你们化验室主管确认他知道稳定性样品被重复测试，他允许化验员重复进行检测，而没有进行深入调查。你们的回复还声明“样品进针信息没有进行处理是因为化验员没有在化验室记录本上记录样品制备过程，没有对色谱信息进行积分和报告检验结果”。该解释没有解决药监局的担心，反而增加了更多的问题。
在你们的回复中指出，你们启动了对这些事件的调查，有些发生在2年多以前，但是，你们没有提供文件证据来支持你们关于重复检测和相关行为的立场。你们的回复是不充分的，因为你们未能延伸调查的范围至你们化验室使用的其它所有电子系统。作为你们纠正和预防计划的一部分，说明你们公司要如何来保证你们工厂产生的所有分析数据的可靠性和完整性。
2. 你公司未能对计算机或相关系统进行适当的控制以保证 只有经过授权的人才能对母版生产记录和检测记录或其它记录（21CFR211.68（b））进行修改。
QC人员在计算机系统上未经适当的监管即创建了未经授权的文件夹。我们对商业化QC实验室里的HPLC的EMPOWER III工作站里2013-2014年的数据审核时发现一个数据文件夹，名为“WASH”。根据你们的管理，文件夹是用来保存进样前后用空白溶剂进行柱清洁的信息，但你们没有标准操作规程（SOP）详细说明该程序。你们QC化验室的一个化验员说该文件夹并不包含有任何标准进校或样品进样结果。但是我们的检查员发现该文件中含有共3353针结果，有些显示为样品结果。
你们的化验员确认在“WASH”文件夹中有一针名为“19”，代表一份2013年12月某片剂在正式检验前的试针样品进样。从该名为“WASH”文件夹的色谱图中，我们检查员在某相对保留时间RRT记录了一个未鉴别的杂质，计算浓度为A，而质量标准中任意未鉴别杂质的限度为B。你们并没有进行调查，也没有报告该OOS结果。
你们公司知道化验员牵涉到进行单针进样，未能遵守SOP“化验室工作通则”中规定的优良化验室规范，进行前述的问题进针的化验员决定进行未经授权和批准的进样。你们的回复中说明，在事件发生后6个月对化验员进行了面谈，你们认为他可能是无意使用了一份从液相托盘中取用的一次性使用旧样品瓶，用于柱冲洗。我们质疑你们关于可能性原因的结论，它没有任何支持性文件或记录，仅仅是基于可能在6个月这前发生过的事情的记忆。
在与官方的通信中，你们指出没有发现恶意篡改数据完整性的工作方式和行为，还声明没有故意使用合格的数据来掩盖、替代、错误代表不合格的数据，没有发现删除文件或捏造数据的证据。你们的回复和意见都只是关注于意图，却没有充分说明检查中发现的违反CGMP的严重性。另外，FDA的检查缺陷并没有包括对特定文件的删除，不管是故意的或是其它情况。相反，FDA关注的是丢弃不合格结果的行为，进行试针的行为，以及未经任何调查即进行复测的行为。我们还关注你们没有文件记录来支持你们对有关批次样品首次检测不合格，而进行复测的决定，以及你们允许在没有质量部门监督的情况下进行生产活动。
作为你们综合评估和风险评估的一部分，你们包括了一份对你们工厂测试药品用的计算机系统的详细描述。该描述应包括过去5年中每个未根据有效SOP规定所建立的电子文件夹的信息，以及对每个这样的文件夹中的每份文件的描述，包括关于样品（产品）信息、测试日期、批号和原始检测结果。还要提供在这个时间段内关于所有复测的特定信息，你们没有经过调查即丢弃初始OOS结果或OOT结果的情况，以及你们明白该信息被丢弃的信息的具体日期。另外，对每个批次，要提供所进针数，以及所审核的图谱，以及用于报告结果的数据。还有，要提供一份更新过的评估，对你们公司的行为可能对你们已生产的和计划要生产的药品质量、安全性和有效性产生的影响，包括已批准的药品和在审评中的药品。
在你们的CAPA计划中，详细描述了你们已修订的控制计划，用以保证复测批次只有在调查实施后方可放行。还描述了你们将要如何防止这种情况再次发生，你们如何衡量纠正措施的有效性。还描述了所建立的关于管理和保留所有计算机数据的程序。
3. 你们公司未能建立和遵守适当的书面程序，用以防止在不需要无菌的药品中出现致病菌
在2014年6月23日，在对QC微生物化验室的检查中，我们的检查员发现很多不同药品、中控样品、水样和培养基促生产试验样品的微生物测试碟失踪了，例如：
A. 某片剂批次微生物样品碟/管在LIMS计算机系统中记录为2014年6月19-20日放入培养箱，根据你们的程序，该碟要培养N天，而在2014年6月23日，在所有培养箱中均未发现该批次的样品碟/管。
B. 某片剂的报批批次样品微生物测试在2014年6月13日进行。你们公司未能向FDA检查员提供记录培养时长和所用培养基的原始记录。你们化验员说该批次整个微生物测试已经在前一周完成，但化验员“忘记”了在记录上记下这些详细信息。
FDA检查员注意到其它一些中控药品、饮用水和促生长试验样品碟/管失踪的事件，即使是这样，记录仍显示这些样品碟还在培养箱里。
在你们的回复中，你们进行了一个调查，说“2个化验员立即就很恐慌（因为（1）知道FDA检查员将要进入微生物化验室（2）看见周末用过的碟散落在化验室里），让化验室的技术人员立即从微生物化验室移走了培养碟，极端错误并拙劣地竭力在FDA检查开始前清理干净微生物化验室。
你们的回复缺乏对于未能遵守程序、不充分的文件记录体系及不充分的关于微生物检测的行为规范的综合性风险评估。你们的回复未能对这些违规行为对产品质量造成的影响进行评估，未包括是否有其它产品受到影响的评估。
ARPL没有能力防止和发现不好的记录保存行为，这让当局对检查时没有适当的质量体系很担心。为保证用于作出决定的信息是可信的、准确的和可靠，适当的控制是必须的。
Public Health Service
Food and Drug Administration
Silver Spring, MD 20993
Warning Letter
WL: 320-15-06
CERTIFIED MAIL
RETURN RECEIPT REQUESTED
January 30, 2015
Jeremy B. Desai, PhD
President and Chief Operating Officer
Apotex, Inc.
150 Signet Drive
Toronto, ON, Canada M9L 1 T9
Dear Dr. Desai:
During our June 23, 2014 through July 1, 2014, inspection of your pharmaceutical manufacturing facility, Apotex Research Private Limited (ARPL) located at Plot #1 & 2, Bommasandra Ind. Area, 4th Phase, Jigani Link Road, Bangalore, India, 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 July 22, 2014 and note that it lacks sufficient corrective actions. We also acknowledge receipt of your firm's additional correspondence dated August 11, 2014, August 29, 2014, September 30, 2014, October 31, 2014, December 5, 2014 and January 9, 2015.
Our investigators observed specific violations during the inspection, including, but not limited to, the following:
1. Your firm failed to ensure that laboratory records included complete data derived from all tests necessary to assure compliance with established specifications and standards (21 CFR 211.194(a)).
The inspection of your facility documented multiple incidents of performing "trial" testing of samples, disregarding test results, and reporting only those results from additional tests conducted. For example,
a. The official release data for (b)(4) and (b)(4) Tablets (b)(4) mg batch (b)(4) for unknown impurities was reported to be within specification (NMT (b)(4)%). However, the chromatographic data showed that the "trial" injection data for this batch failed the unknown impurities specification with a result of (b)(4)%.
b. The official High Performance Liquid Chromatography (HPLC) impurity data for (b)(4) mg Tablets batch(b)(4) ((b)(4)), 3-month stability time-point @ 25oC/60% RH only included the most favorable result obtained from multiple test results without any justification. The data from this batch was submitted to the U.S. FDA as an exhibit batch.
In addition to the examples above, our inspection found that 2,803 of 44,643 injection results were not processed or reported in the official data folder for dissolution analysis via HPLC for (b)(4) Tablets. Our inspection identified numerous examples of “trial” injections for various drug products (U.S. and non-U.S. markets), which suggests that this is a common practice.
Your response to our findings of “trial” injections attempts to explain the rationale for retesting (b)(4) and (b)(4)(1a above). You state that “the unknown were intermittent spikes resulting in aberrant chromatography caused by electronic disturbance or pressure fluctuation.” Your subsequent investigation into the observation concluded that “the unknown impurity peak…is not characteristic of the product and was not observed in the analysis of all commercial and exhibit batches.” The fact that you did not observe the peak in commercial and exhibit batches does not justify disregarding the test run or failing to follow up with appropriate corrective actions and preventive actions.
According to your response, your laboratory supervisor confirmed that he was aware of the repeated testing of the (b)(4) stability samples (1b above) and that he allowed the analyst to repeat the analysis without conducting further investigation. Your response also states the following: “sample injections were not processed as the analyst failed to record the sample preparations in the analytical laboratory notebook and did not integrate the chromatograms for reporting.” This explanation does not resolve the Agency’s concerns, but instead raises further issues.
You indicate in your response that you initiated investigations for these incidents, some of which occurred over two (2) years ago; however, you did not provide documentary evidence to support your assertions about the repeat testing and related activities. Your response is inadequate because you did not extend the scope of the investigation to the other electronic systems used in each of your laboratories. As part of your corrective action and preventive action plan, address how your firm intends to ensure the reliability and completeness of all analytical data generated at your facility.
2. 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)).
QC personnel created unauthorized folders on laboratory computerized systems without appropriate oversight. Our review of the HPLC Empower III data collected in 2013-2014 in the commercial QC laboratory found a data folder entitled “WASH.” According to your management, the folder was intended for column wash injections using blank solvent prior to and following sample runs, although you have no standard operating procedure (SOP) detailing this process. One of your laboratory analysts stated that this folder does not contain any standard or sample injection results. However, our investigator found that this folder contained a total of 3,353 injection results, some of which appeared to be samples.
Your analyst confirmed that the single injection titled “19” in the “WASH” folder represented a trial sample injection performed prior to the official analysis of (b)(4) Tablets on December 19, 2013. From this chromatogram in the “WASH” folder, our investigator documented an unidentified impurity at relative retention time (RRT) (b)(4) calculated at a concentration of (b)(4)%. However, the specification for any unidentified impurity is (b)(4)%. You neither investigated nor reported this out-of-specification (OOS) result.
Your firm acknowledged that the analysts involved in performing single injections failed to follow good laboratory practices described in the SOP “General Laboratory Working,” and that the analysts conducting the injections in question made decisions to perform unauthorized, unapproved injections. Your response indicates that, during an interview of the laboratory analyst conducted approximately six months after the incident, you determined that he may inadvertently have used an old sample vial from the LC tray for the single injection made for the purpose of a column wash. We question your conclusion about the likely cause without having any supporting documentation or record, and based only on memory of what may have happened six months earlier.
In correspondence with the Agency, you indicate that no malicious data integrity patterns and practices were found. Also, you state that no intentional activity to disguise, misrepresent or replace failing data with passing data was identified and no evidence of file deletion or manipulation was found. Your response and comments focus primarily on the issue of intent, and do not adequately address the seriousness of the CGMP violations found during the inspection. In addition, FDA’s inspection did not include observations related to deletion of specific files, intentionally or otherwise. Rather, FDA’s concern pertains to the practice of disregarding failing results, conducting trial injections and retesting products without any investigation. We are also concerned that you do not have documentation to support your decision to retest samples of lots that had initially failed to meet specifications, and you allowed manufacturing activities to occur without the oversight of your quality unit.
As part of your comprehensive evaluation and risk assessment, include a detailed description of all computerized systems in your facility used for testing drugs. This description should include information on each electronic folder that was not created pursuant to a valid SOP and an assessment of every file in each such folder, including information about the sample (product), date of test, lot number and original test result over the last five (5) years, except for data relating to exhibit batches, in which case there is no time limitation. Also provide specific information about all retests during these time frames, where an initial out-of-specification or out-of-trend result was disregarded without an investigation and the date on which you became aware such information had been disregarded. In addition, for each batch, provide the number of injections performed and chromatograms reviewed, and of those, the number that were used to generate a reported result. Furthermore, provide an updated assessment on the possible effects of your firm’s practices on the quality, safety, and efficacy of the drugs you manufacture or plan to manufacture, including drugs covered by approved or pending applications.
In your corrective action and preventive action plan, describe in detail your revised control process for ensuring that batches with retest results are not released until a thorough investigation is conducted. Also describe how you intend to prevent these failures from recurring in the future, and how you will measure the effectiveness of your corrections. Also describe the procedures established to manage and retain all computerized data.
3. Your firm failed to establish and follow appropriate written procedures, designed to prevent objectionable microorganisms in drug products not required to be sterile (21 CFR 211.113(a)).
On June 23, 2014, during the inspection of the QC Microbiology Laboratory, our investigators observed missing in-progress microbiological test plates for various finished drug products, in-process products, water, and media growth promotion samples. For example:
a. Finished drug product (b)(4) Tablets (b)(4)mg batches (b)(4) and (b)(4) microbial sample plates/tubes were placed in the incubators on June 19-20, 2014, as documented in your LIMS computer system. The plates should have been incubated for (b)(4) days, per your procedures. On June 23, 2014, no plates/tubes for this batch were observed in any of the incubation chambers.
b. Finished drug product (b)(4) Tablets (b)(4) mg Exhibit Batch (b)(4) sample for microbial testing was prepared on June 13, 2014. Your firm failed to provide the FDA investigator with the worksheet to document the incubation times and media used for the analysis. Your analyst described that the entire microbial test for this batch had already been completed the previous week but that the analyst had "forgotten" to document the details on the worksheet.
The FDA investigator noted other instances of missing samples/plates for in-process drug products, potable water, and growth promotion, even though records indicated that they were in the incubator.
As a result of the above observation, your firm initiated an investigation and reported that 290 (b)(4) plates and 36 media tubes under testing were missing, affecting 45 product sample batches, 12 growth promotion test batches, and 37 negative control plates. Your firm also found discrepancies between the documentation and location of samples/plates and you indicated that the majority of the missing plates were found in the decontamination area for disposal.
In your response, you refer to an investigation and indicate that “…two analysts momentarily panicked (upon (1) learning that FDA Investigators were approaching the microbiology Lab and (2) seeing used petri plates from the weekend scattered throughout the laboratory)[sic] and directed the lab technician to immediately remove the petri plates from the microbiology lab … in an utterly misguided and ill-conceived attempt to clean up the microbiology lab prior to the start of the FDA inspection.”
Your response lacks a comprehensive risk assessment of your failure to follow procedures, your inadequate documentation system and your inadequate practices related to microbiological control. Your response failed to evaluate the effect of these violations on product quality, and did not include an assessment as to whether any other batches have been compromised.
ARPL’s inability to prevent and detect poor recordkeeping practices raises serious concerns regarding the quality system in place at the time of the inspection. Appropriate controls are essential to assure that the information used for making decisions is trustworthy, accurate, and reliable.
4. Your firm failed to follow written procedures applicable to the quality control unit (21 CFR 211.22(d)) and your quality control unit failed to review and approve all drug product production and control records to determine compliance with all established, approved written procedures before a batch is released or distributed (21 CFR 211.192).
For example:
a. Your procedure titled “Quality Unit Responsibility” (#GPOL-004 dated 07/09/2013) states that “any deviation shall be investigated to discover possible causes and prevent possible reoccurrence.” Although your written procedure clearly describes the protocols for handling deviations, your quality unit management indicated to our investigator that there were no deviation reports, no OOS investigations, nor any evaluations to address the possible root cause(s) of the deviations/OOSs. Among other failures, your quality unit did not follow your procedures for conducting investigations into the examples listed in citation #1 of this letter.
4. 你们公司未能遵守书面的质量控制部门程序(21 CFR 211.22(d))，你们质量控制部门在对产品批次放行或销售前，未能对所有药品生产和检测记录进行审核和批准，来决定是否符合所有已建立并批准的书面程序(21 CFR 211.192).
例如
A. 你们的程序题为“质量部门职责”（#GPOL-004,日期为07/09/2013）说“所有偏差应进行调查，发现可能的原因，防止再次发生的可能性”。尽管你们的书面程序清楚描述了处理偏差的方案，你们的质量部门管理人员告诉我们检查官没有偏差报告，没有OOS调查，也没有任何评估来说明偏差/OOS可能的根本原因，在其它不符合性情况中，你们质量部门没有遵守你们的程序对本警告信第1项中所列的例子进行调查。
B. 你们公司对全球方针“审计计划”（文件编号#GPOL-015日期2013年9月7日）中描述的审计计划的实施不够充分，它未能防止药品在对正式样品进行非正式样品测试，并处理要报告的结果的操作再次发生。
C. 另外，检查发现不合格或非典型结果没有进行调查，也没有按照21CFR211.192的要求包括在正式化验室控制记录中。我们重申对于所有的OOS事件均需要进行调查。参见FDA关于OOS调查的指南“行业指南，OOS调查，药品生产检测结果”。
你们质量部门负责保证你们公司对所有在你们工厂生产的药品整个生产和生命周期进行处于持续控制状态。你们质量部门负有全部的职责对质量相关活动进行监管和批准。作为你们CAPA计划的一部分，请描述你们质量部门将如何对调查和生产批记录提供持续的、充分的审核和批准。
我们在2014年1月对你们公司另一厂址进行的检查已发现关于试针的问题，这次检查表明纠正措施并未能在全球范围内实施。另外，你们公司工厂质量部门监督缺失是2010年3月检查中的重复缺陷。关于需要进行适当的全球质量监督已在2009年9月11日、2010年3月31日和2014年4月11日与APOTEX高层管理召开的法规会议中进行了沟通。
b. Your firm’s implementation of the audit program described in the Global Policy "Audit Program" document #GPOL-015 dated September 7, 2013 is inadequate in that it failed to prevent the recurrence of testing unofficial samples of drug product prior to testing the official sample and generating only those results to be reported.
c. In addition the inspection revealed that failing or otherwise atypical results were not investigated, nor included in the official laboratory control records as required by 21 CFR 211.192. We reiterate that an investigation is necessary for any out-of-specification (OOS) event. Refer to the FDA's guidance on OOS investigations Guidance for Industry, Investigating Out-of-Specification (OOS), Test Results for Pharmaceutical Production.
Your quality unit is responsible for assuring that your firm is operating in a sustainable state of control throughout the manufacture and lifecycle of all drugs produced at your facility. Your quality unit has the overall responsibility for oversight and approval of quality related activities. As part of your corrective action and preventive action plan, please describe how your quality unit will provide consistent, adequate review and approval of investigations and production batch records.
Be aware that Apotex was notified of our concerns with the practice of “trial” injections during FDA’s January 2014 inspection at your Apotex Pharmachem India Pvt. Ltd. located at Plot # 1A Bommasandra Ind. Area, 4th Phase, Jigani Link Road, Bangalore, India. However, our findings during this inspection suggest that corrective actions were not implemented globally. Furthermore, inadequate oversight by your firm’s site-specific quality units is a repeat finding from WL: 320-10-003 dated March 29, 2010. The need for appropriate and global quality oversight was communicated to Apotex senior management during the regulatory meetings held September 11, 2009, March 31, 2010, and April 11, 2014.
Conclusion
The foregoing examples are of serious CGMP violations demonstrating that your quality system does not adequately ensure the accuracy and integrity of the data generated at your facility to ensure the safety, effectiveness, and quality of the drug products you manufacture. We found that your quality system failed to ensure the adequate investigation and resolution of quality failures. ARPL failed to investigate OOS results, failed to contemporaneously document failures and report failures, and selected only passing results without the oversight of a quality unit. In your response and in subsequent communications with the agency, you indicated that you interviewed employees and found no evidence of data manipulation or deletion. In focusing on the issues of deletion and alteration of data, you have not sufficiently addressed or resolved other substantial CGMP issues as discussed above. In response to this letter and including the specific requests noted above, provide the following to the Agency:
1. A comprehensive evaluation of the extent of the inaccuracy of recorded and 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 of the potential effect of the observed failures 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. We acknowledge that you are working with a third party consultant already to conduct a compressive audit of your systems and data integrity.
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 continuing to refuse admission of articles manufactured at Apotex Research Private Limited located at Plot #1 & 2, Bommasandra Ind. Area, 4th Phase, Jigani Link Road, Bangalore, India 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 # 3006076314.
We also recommend that you contact Araceli Rey at Araceli.rey@fda.hhs.gov, or 301-796-3284, within five days of receipt of this letter to schedule a regulatory meeting with Apotex Research Private Limited and Apotex Inc.
Please send your reply to:
Maan Abduldayem
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 4212
10903 New Hampshire Ave.
Silver Spring, MD 20993
Sincerely,
/S/
Thomas Cosgrove, J.D.
Director
Office of Manufacturing Quality
Office of Compliance
Center for Drug Evaluation and Research
CC:
Dr. Parizad Elchidana
Managing Director
Apotex Research Private Limited
Plot #1 & 2, Bommasandra Ind. Area
4th Phase, Jigani Link Road
Bangalore, India – 560 099
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