During our August 24-28, 2009 inspection of your active pharmaceutical ingredient (API) manufacturing facility, Jilin Shulan Synthetic Pharmaceutical Co., Ltd. located at No. 2066 Peoples Main Road, Shulan City, Jilin Province, People’s Republic of China (PRC) 132600, an investigator from the Food and Drug Administration (FDA) identified significant deviations from Current Good Manufacturing Practice (CGMP) for the manufacture of APIs. The deviations cau your APIs to be adulterated within the meaning of ction 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 ud in, or the facilities or controls ud for, their manufacture, processing, packing, or holding do not conform to, or are not operated or administered in conformity with, CGMP. We have reviewed your firm’s respon of October 12, 2009, and note that it lacks sufficient corrective actions. Specific deviations obrved during the inspection include, but are not limited, to the following: 1. Production personnel fail to ensure that all production deviations are reported and evaluated, and that critical deviations are investigated and the conclusions are recorded. For example, during the (b)(4) of (b)(4) sub-batch (b)(4), our investigator obrved that the pressure and temperature of the (b)(4) equipment fell out of range (below (b)(4) mPa and (b)(4)°C). The investigator obrved no initiation of an investigation into this deviation and received no assurance that an investigation would take place. Any deviations from processing parameters should be documented and explained, whereas critical deviations should be thoroughly investigated. In addition, the investigator obrved a shift change while sub-batch (b)(4) was undergoing (b)(4), in which operators from the new shift had not reported to their duty stations for more than 30 minutes after their shift began. You should have adequate systems in place to ensure that critical operations are witnesd, or are subjected to another appropriate control. 2. Master production records do not include complete production instructions. Your master production records do not include all steps in the production of (b)(4) and your batch production records are not accurate reproductions of your master production records. The master production record does not include the (b)(4) stage of the (b)(4) production. Your October 12, 2009 respon states you will revi your DMF for (b)(4) USP to include the information regarding (b)(4) treatment and the manufacturing of (b)(4). However, you provide no evidence to show that the steps have been included in your master batch records. We are also concerned that you did not comprehensively evaluate the manufacturing process, for this and other drugs, in its entirety to ensure that all steps are included in your master batch records and your DMF. Adequate batch records are a critical part of a manufacturing operation becau they provide confidence that the established procedures were followed, process were controlled, and quality API was manufactured. In addition, there is no assurance that the (b)(4) obtained from the (b)(4) recovering steps included in your current process is of adequate quality. Plea provide information on studies performed to characterize the (b)(4) obtained from this part of the process. 3. The buildings and facilities ud in the manufacture of (b)(4) USP are not designed and constructed to facilitate cleaning, maintenance, and operations as appropriate to the stage of manufacture. Facilities are not designed to minimize potential contamination. Your facility consists of surfaces that are not easy to clean and can potentially lead to product contamination. In (b)(4) your “ Clean Room” our investigator obrved peeling foil-faced tape, which was ud to al wall and ceiling joints. Our investigator obrved accumulated debris within wall and floor joints throughout your (b)(4) USP production facility. You ud adhesive tape around hos in the (b)(4) and (b)(4) rooms that became covered in production material. The (b)(4) routinely spills onto the floor of the (b)(4) rooms, causing the undersurfaces of your (b)(4) to become rusty and caked with production materials. The investigator also obrved (b)(4) accumulation on the rusty stairs in the (b)(4) room. When your personnel cleaned the (b)(4) area in respon to our investigator’s comments regarding caked material on the underside of the (b)(4) your personnel ud mops soaked in dirty water. Your October 12, 2009 respon includes some corrective actions concerning the noted deficiencies that make your facility difficult to clean, but we are concerned that you have only addresd items specifically pointed out by our investigator during the inspection. We request that you fully evaluate your current cleaning procedures. You should also thoroughly asss the adequacy of your facility design to facilitate cleaning and minimize potential contamination, as well as the training provided to your employees on appropriate cleaning procedures and to ensure CGMP. You continued to u the (b)(4) in the (b)(4) area, although approximately 5% of the (b)(4) cover was peeling due to rust. You state in your October 12, 2009 respon that you repaired the deteriorated cover of this (b)(4) and that your corrective action plan includes a recheck of all production equipment, and the strengthening of the check and maintenance for equipment in the future. However, you provide no information regarding what other equipment was identified as needing repair, the repairs conducted, or supporting documentation to show that your preventive maintenance program was improved. Our investigator obrved (b)(4) uncovered carts containing approximately (b)(4) in the corridor adjoining production areas. You state in your October 12, 2009 respon that all in-process (b)(4) contained in the carts should be covered and stored in their dedicated room during their temporary storage period. However, you have not provided updated procedures implementing this new requirement, or training documentation to ensure all pertinent personnel were trained in this procedure. In addition, you provided no information regarding the disposition of the (b)(4), obrved uncovered in the corridor adjoining production areas during the inspection. The investigator also obrved that doors leading to corridors and adjoining rooms throughout the “(b)(4) Clean Room” building (including the (b)(4) room) failed to clo properly during production. You indicate in your October 12, 2009 respon that all doors would be checked and repaired if necessary. However, we are concerned that you have not addresd the failure of your personnel to identify this and other deficiencies, nor have you identified a mechanism through which future problems will be reported and addresd. 4. Your Quality Unit failed to reject APIs contaminated with foreign material. For example, (b)(4) lot numbers were reprocesd after the breakage of an overhead light. The lots were retested and renumbered as (b)(4), respectively. We are concerned that you did not reject the two lots once they became contaminated with glass and other material associated with the broken overhead light. Plea provide your rationale for reprocessing the batches and explain what steps you took to ensure the final API lots, and other lots produced in the same equipment, were not contaminated with foreign material from the broken light. In addition, we request that you provide a detailed description of the corrective actions you implemented to prevent future recurrence of this type of incident. We note that your firm performs maintenance operations at the same time that production activities are occurring. Plea be advid that this is an inappropriate practice. You also identified black spots in the (b)(4) API lot number (b)(4). Your deviation states, “Operators shake off the floating material on the (b)(4) into the materials.” Plea provide an explanation for what is meant by this statement. It is unclear if you have identified the source of the “black spots,” but you reprocesd this lot and identified it as (b)(4). Plea provide your investigation regarding the identity of this contamination and your rationale for reprocessing this batch. Also, plea provide us with your procedures for placing reprocesd batches on stability and inform us if your firm placed the and other batches on stability. 5. You lack scientifically sound and appropriate test procedures to ensure APIs conform to established standards of quality and/or purity. For example, you routinely failed to utilize a suitable standard for the spectral comparison during the FTIR testing of (b)(4) Instead, you compared sample spectra with the spectrum of (b)(4) in the Chine Pharmacopeia. The (b)(4) USP requires that you compare the spectrum of your test sample with that of your reference standard. Your October 12, 2009 respon states that you have strengthened laboratory management and made it a requirement to compare the spectrum from every batch to the spectrum obtained from the reference substance in routine testing. However, you provide no details as to how you strengthened laboratory management, and you include no updated procedures requiring the comparison of the sample spectrum to that of the reference standard. You also provide no documentation to show adequate training of your personnel in the new testing procedures. You failed to include testing for method precision and ruggedness in your HPLC Assay Method Validation SHY1110-004-00-2 for (b)(4) USP. We are concerned that you have not established the degree of reproducibility or repeatability of the analytical procedure under normal operating conditions. In addition, you failed to establish adequate system suitability parameters to ensure that the complete testing system (including instrument, reagents, columns, and analysts) continues to operate suitably for the intended application. You currently only u one standard injection for system suitability, which is unacceptable. In addition, you evaluate the HPLC signal to noi ratio and analyze the baline for drift annually. Your October 12, 2009 respon indicates that you revid the Standard Operating Procedure (SOP) for calibration of the HPLC to increa the frequency of the determinations to every (b)(4) months. Our concern is that you may not be evaluating the signal to noi ratio during system suitability. Evaluation of the signal to noi ratio during system suitability is a normal laboratory practice when testing low level impurities or degradant content by HPLC. Furthermore, you only compare the working standards to the (b)(4) USP reference standard annually. Plea provide your scientific rationale and stability asssment of the working standard solution to justify performing the verification of the suitability of the working standard annually. 6. Personnel fail to wear clothing suitable for the manufacturing activity with which they are involved to protect (b)(4) USP from contamination. During this inspection, the investigator obrved individuals in the “ (b)(4) Clean Area” (including (b) (4) areas) with open toe or open foot sandals, torn plastic booties, wearing no masks, and wearing no gloves. We are concerned that you have not assd the adequacy of the practices during drug manufacturing operations, particularly during the latter steps of (b)(4) USP manufacturing. Your October 12, 2009 respon states that the Standard Operating Procedure (SOP) for “Clean area management Procedures for Personnel Passing In and Out” was updated to stipulate that all visitors and personnel operating in the clean area should wear gloves, masks, and white shoes, instead of slippers. However, you have not provided this SOP in your respon, nor have you provided any documentation indicating that the appropriate personnel have been trained on this updated SOP. 7. Your Quality Unit fails to ensure that new and modified equipment ud in the manufacture of (b)(4) USP are qualified and suitable for their intended u. During the inspection, our investigator obrved (b)(4), ud in the production of (b)(4) USP, operated by low, high, stop, and ret buttons. Your practice of listening to the (b)(4) in order to detect problems while in operation is not adequate. Also, you failed to perform equipment calibration for this equipment. Your October 12, 2009 respon states that you installed calibrated display devices for the rotational speed of the (b)(4) but you failed to demonstrate that the (b)(4) and the designated rotational speeds are suitable for their intended u. Plea provide the qualification documentation for your (b)(4) in your respon. You have not qualified the (b)(4) ud in your (b)(4) process. There is no description of the detectable (b)(4) sizes, or feed speed in your procedures. Furthermore, your (b)(4) procedures in SOP 1308-062 “ (b)(4) Finished Product Finished Position SOP” state: “When (b)(4) rings, operator should stop feeding material and check the material once again. If no abnormal situation is found, the material can pass, but if the (b)(4) rings again, the questioned material will be kept alone and treat as unqualified product.” This practice is unacceptable. Material that caus your (b)(4) to sound should not be deemed acceptable material once it is pasd through the (b)(4) a cond time. Plea indicate how you intend to address this issue. During the inspection, the investigator obrved a rusted balance and counterweight in the (b)(4) area that appeared to be unusable. The pieces of equipment are ud to weigh reagents, including (b)(4). During the inspection, you painted over the rust on both the balance and the counterweight, but there continues to be no assurance that either is suitable for u in its current condition. In addition, the operational range of the scale is (b)(4), whereas your production records indicate that the balance is ud to weigh (b)(4) of (b)(4). Production equipment should only be ud within its qualified operating range. 8. Your Quality Unit does not maintain revision histories and, therefore, fails to control the issuance, revision, and withdrawal of all documents. For example, standard operating procedures (SOPs) and batch records do not include version numbers or effective dates. Your lack of document control can lead to the u of outdated procedures or work instructions. Your October 12, 2009 respon states that you have revid all your SOPs to provide version control numbers, but we are concerned with the APIs that were previously manufactured under uncontrolled procedures. You provide no information regarding which SOPs and batch records were not previously identified with version control numbers, nor did you provide an example of your master batch records for (b)(4) USP, including the version control number. In addition, you fail to address your general approach to document control. Plea provide the procedures and associated training you have in place to ensure that revision histories will be maintained, and that only the most current documents will be available for u. During this inspection, you indicated to our investigator that your firm has only shipped (b)(4) to the United States for u in (b)(4), and that you have not shipped product to the United States for u in pharmaceutical products. However, our records indicate that you have distributed (b)(4) USP, as well as (b)(4) USP and (b)(4) USP, to the United States for u in pharmaceutical products. In future correspondence plea include clarification on this issue. The deviations detailed in this letter are not intended to be an all-inclusive statement of deviations that exist at your facility. You are responsible for investigating and determining the caus of the deviations identified above and for preventing their recurrence and the occurrence of other deviations. If you wish to ship APIs to the United States, it is the responsibility of your firm to ensure compliance with all U.S. standards for CGMP and all applicable U.S. laws and regulations. Until all corrections have been completed and FDA has confirmed corrections of the deviations and your firm’s compliance with CGMP, this office will recommend withholding approval of any new applications or supplements listing your firm as an API manufacturer. In addition, failure to correct the deviations may result in FDA denying entry of articles manufactured at Jilin Shulan Synthetic Pharmaceutical Co., Ltd. located at No. 2066 Peoples Main Road, Shulan City, Jilin Province, People’s Republic of China (PRC) 132600, into the United States. The articles could be subject to refusal of admission pursuant to ction 801(a)(3) of the Act [21 U.S.C. § 381(a)(3)] in that the methods and controls ud in their manufacture do not appear to conform to Current Good Manufacturing Practice within the meaning of ction 501(a)(2)(B) of the Act [21 U.S.C. § 351(a)(2)(B)]. Within fifteen working days of receipt of this letter, plea notify this office in writing of the specific steps that you have taken to correct deviations. Include an explanation of each step being taken to prevent the recurrence of deviations and copies of supporting documentation. If you cannot complete corrective action within fifteen working days, state the reason for the delay and the date by which you will have completed the correction. Additionally, your respon should state if you no longer manufacture or distribute (b)(4) USP, and provide the date and reasons you cead production. Plea identify your respon with FEI #3003091092. If you have questions or concerns regarding this letter, contact Kristy A. Zielny, Compliance Officer, at the below address and telephone number. U.S. Food and Drug Administration Center for Drug Evaluation and Rearch Division of Manufacturing and Product Quality International Compliance Branch White Oak, Building 51 10903 New Hampshire Ave Silver Spring, MD 20993 Tel: (301) 796-3120 Fax: (301) 847-8741 | 在2009年8月24到28日，针对中华人民共和国吉林省舒兰市人民路2066号的吉林舒兰药物合成有限公司的原料药生产设施的检查中，FDA检察官发现其与现行药品生产质量规范存在显著偏差。根据《食品，药品和化妆品法案》第501（a）（2）（B）项，该公司用于其生产，工艺，包装和储存所采用的方法，或是设施设备，以及监控措施，不符合CGMP标准，这些偏差将导致你们的原料药掺杂。 我们审阅了贵公司在2009年10月12日的回复，发现其缺乏足够的纠正措施。 检查过程中发现的具体偏差包括但不仅限于下列部分： 1. 生产人员未能对所有的生产偏差进行报告和评估，也未对关键偏差进行调查并记录结论。 例如我们的检察官发现在（b）（4）分批次（b）（4）过程中，设备的温度和压力超出范围（低于（b）（4）温度和（b）（4）压力限）。检察官没有发现针对该项偏差展开的调查，也没有收到将会展开该项调查的承诺。工艺参数产生的任何偏差都应该有记录和解释，关键偏差应被彻底调查。 此外，检察官发现, 换班过程中, （b）（4）亚批在生产，新的值班人员到岗30多分钟后都没有向值班地点报告。你们应该有充分的体系确保关键操作处于人为的监控状态或受到其他适当的控制。 2.主生产记录没有包括完整的生产指令。 你们的主生产记录没有包括（b）（4）生产的所有步骤，而且批生产记录没有精确复述主生产记录的内容。主生产记录没有记录（b）（4）生产的（b）（4）阶段。 你们在2009年10月12日的回复声明提到将修订DMF文件包括关于（b）（4）的处理和（b）（4）的生产信息。但是你们没有提供证据表明这些措施已经记录在你们的主批记录中。我们还关注到你们没有为该药物和其他药物的生产过程进行全面评估，以全面保证所有的步骤都被记录在你们的主批记录和DMF文件中。完整的批生产记录是生产制造的关键部分，因为它能保证规定的程序被遵循，工艺被控制，以及保证生产的原料药质量。 此外，在你们现行程序中，从（b）（4）生产过程回收得到的（b）（4）的质量没有保障。请提供该过程中得到的（b）（4）的特征研究信息。 3. 用于生产（b）（4）的厂房和设施并未按照生产设施的清洁、维护和操作要求设计和建造。设施没有按照尽量减少潜在污染的原则来设计。 你们的设施表面难以清洁并可能导致产品污染。在（b）（4），你们的“洁净室”内，我们的检察官发现用于密封墙壁和天花板交界处的箔表面胶带脱落。我们的检察官注意到积累的碎屑遍及你们的（b）（4）USP生产设施中的墙壁和地板交接处。在被生产原料覆盖的（b）（4）和（b）（4）房间内的软管附近你们使用了粘合胶带。（b）（4）日常溢出到（b）（4）房间的地板上，导致你们（b）（4）的底部表面生锈，并且生产原料结块。检察官还发现在（b）（4）房间生锈的阶梯上累积有（b）（4）。对于我们检察官评价的（b）（4）区域有（b）（4）下面结块的原料，你们的职员用吸了脏水的拖把清理该区域。在2009年10月12日你们的回复中包含了对那些使得你们的设施难以清洁的显著的缺陷采取的纠正措施，但是我们担心你们仅仅处理了我们检察官在视察期间特别指出的事项。我们要求你们充分评估现在的清洁程序。你们也应该彻底评估你们的设施设计是否方便清洁和可以尽量减少潜在污染，并且充分评估对适当的清洁程序中给员工的培训，并确保符合CGMP。 你们依旧在使用（b）（4）区域内的（b）（4），尽管大约5%的（b）（4）表皮因为生锈而脱落。你们在2009年10月12日的回复中声称你们修复了该（b）（4）腐蚀的表面，并且在你们的纠正措施计划里包括了复查所有的生产设备以及以后加强对设备的检查和维护。然而，你们并未提供关于还有什么其他设备确定为需要修理以及所实施的修理的信息，也未提供表明你们的改进预防性维修程序的辅助文件。 我们的检察官注意到在连接生产区域的走廊上的装着大约是 （b）（4）的手推车未遮蔽。在你们2009年10月12日的回复中声明所有的手推车内（b）（4）在暂存期间都应遮盖并储存在专用房间内。但是，你们并没有提供执行这项新要求的最新规程，或者是提供保障所有相关人员都受过改规程培训的培训文件。 此外，你们并未提及关于如何处理检查期间发现的在临接生产区域的走廊上的未遮盖的（b）（4）。 检察官还发现“（b）（4）洁净室”大楼（包括（b）（4）房）的通向走廊和相邻房间的门在生产期间没有关严。你们在2009年10月12日的回复中指出所有的门都要检查和并对有需要修理的门进行修理。然而，我们关心的是你们既没有处理职员没有识别这个和其他缺陷的问题，也没有确定一个报告和处理未来问题的机制。 4. 你们的质量部门未能拒收被异物点污染的原料药。 例如，（b）（4）批在顶灯坏掉之后被再加工过。这些批次分别被重新检测和重新编号为（b）（4）。 我们担心你们没有拒收因为坏掉的顶灯而被玻璃和其他材料污染的两批产品。请提供你们重新处理这些批原料药的基本原因，并解释你们采取了哪些步骤保证这些批次的最终原料药以及其他用同样设备生产的批次没有被坏掉的灯的材料污染。我们还要求你们提供详细的防止类似的事故再次发生的纠正措施。 我们注意到贵公司在生产进行的过程中执行维护操作。现谨通知你们这是不恰当的做法。 你们也确认了（b）（4）批（b）（4）原料药中的黑点。你们的偏差声称：“操作人员将（b）（4）上的非固定的材料抖落到物料中。”请解释这个声明是什么意思。你们尚不清楚是否已经确认了这些黑点的来源，你们就重加工了这批原料并将它标记为（b）（4）。请提供你们确认该杂质的调查报告以及再加工这批料的基本原因。 同时，请提供给我们你们用再加工批次原料药做稳定性试验的规程以及告知我们贵公司是否将这些和其他批次做了稳定性试验。 5. 你们缺乏科学可靠和适当的检测程序以保障原料药符合制定的质量和纯度标准。 例如，你们在对（b）（4）红外测试期间未能利用一个合适的对照品。相反，你们采用中国药典上的（b）（4）光谱数据来与样品光谱进行对照。（b）（4）USP专论规定你们须将测试样品的光谱与你们的对照品进行对照。你们在2009年10月12日的回复中声明你们已经加强了实验室的管理并且规定每一批的对照品光谱都与常规实验中对照品的光谱对照。但是，你们并未提供如何加强实验室管理的细节，也没有提供要求样品光谱与参比标准对照的更新的规程。也没有提供表明你们的员工接受新的检测规程培训的文档。 在你们(b)(4) USP的HPLC测定方法验证SHY1110-004-00-2中，你们没有对测试方法的精密度和重现性进行验证。我们担心你们还没有建立在正常操作条件下分析方法的再现性和可重复性。而且，你们也没有建立适当的系统适用性参数以保障整个测试系统（包括仪器，试剂，柱子和分析员）能够符合预期的应用持续运行下去。你们当前仅进一针标准品做系统适用性是不可接受的。此外，你们每年一次评估HPLC信号的信噪比和分析基线的漂移。你们在2009年10月12日的回复中表明已经修订了HPLC校准的标准操作规程（SOP）：增加测试频率到每(b)(4)个月。我们关心的是在系统适用期你们可能没有评估信号的信噪比。当用HPLC测试低浓度杂质和降解物含量时，在系统适用期评估信号的信噪比是一项常规的实验室操作。此外，工作标准与(b)(4) USP参比标准的对照工作你们每年仅进行一次。请提供你们论证每年用于确认工作标准品适用性的工作标准品溶液的稳定性评估和科学原理。 6. 员工没有穿着适合其所从事生产操作以免(b)(4) USP受到污染的服装。 在这次检查期间，检察官发现在“(b)(4)洁净区”（包括(b)(4)区）有多个人穿着露脚指或脚的拖鞋，裂开的塑料脚套，不戴口罩，不戴手套。我们担心的是你们没有对药品生产过程特别是(b)(4) USP生产的后面几步中这些行为是否妥当进行评估。在你们2009年10月12日的回复中声明“洁净区进出人员管理规程”的SOP已经更新，规定所有访问人员和操作人员在洁净区必须穿戴手套，口罩和白鞋，不得穿拖鞋。但是，你们并未在你们的回复中提供这份SOP，也没有提供能够表明相关员工已经接受过这份更新的SOP的培训。 7. 你们的质量部不能保障在生产(b)(4) USP中使用的新的和改进过的设备是合格的并适合其预期用途。 在检查期间，我们的检察官注意到在(b)(4) USP生产中使用的(b)(4)仪器，是通过 低，高，停止和重启键操作。在操作过程中，你们通过听(b)(4)的声音来检测问题的操作是不适当的。同样，你们也未能对这台设备进行校验。你们在2009年10月12日的回复中声明你们为(b)(4)旋转速度安装了校验装备，却没有证明(b)(4) 和指定的旋转速度适用于其预期用途。请在你们的回复中提供(b)(4)的确认文件。 你们没有对在(b)(4)过程中使用的(b)(4)进行质量论证。没有对可检测的(b)(4)的尺寸描述，也没有描述其在你们程序的进料速度。此外，你们在SOP1308-062中的(b)(4)规程“(b)(4)成品生产完毕的SOP”中声称：“当(b)(4)响起来，操作者应该停止进料并重新检查一遍物料。假如没发现异常情况，物料还可以进入，该程序可以继续进行。但是如果(b)(4)再一次响起来，那么这批问题物料就要被单独放置并当作不合格产品处置。”这个操作是不可接受的，导致(b)(4)响起来的物料不应该在第二次通过(b)(4)时被认为是合格的。请表明你们打算如何处理该问题。 在检查期间，我们的检察官注意到了一台生锈的天平，而且(b)(4)位置的砝码看上去不能使用了。而这些设备还被用来称量试剂包括(b)(4)。在检查期间，你们给腐蚀了的砝码天平上了油漆，但是这依旧不能保证两者在现在条件下适合使用。此外，其操作使用范围是(b)(4)，然而你们的生产记录表明这台天平用于称量(b)(4)的(b)(4)。生产设备仅能在其允许的操作范围内使用。 8. 你们的质量部门没有保存修订历史，因此不能控制所有文档的发布，修订和回收。 例如SOPs和批记录中没有版本号码和有效日期。缺乏文档控制会导致你们使用过期的操作规程或工作指令。你们在2009年10月12日的回复中声称你们已经修订了所有的SOPs提供了版本控制号码，但是我们关注的是在以前在无控制的规程下生产的原料药。你们没有提供有关哪些SOPs和批记录不是以前与版本控制号码一致的信息，也没有提供(b)(4)USP生产需要的主批记录示例包括版本控制号。此外，你们没有注明文件控制的常规方法。请提供相关规程和相关培训以确保修订历史被保存和仅有最新版本的文档才能使用有效。 在这次检查期间，你们向我们的检察官提到贵公司的仅向US出口用于(b)(4)用途的(b)(4)而没有向US出口用于药剂用途的产品。然而我们的记录表明你们曾向US经销用于药剂用途的(b)(4)USP以及(b)(4)USP和(b)(4)USP。在下次通信中请解释这个问题。 这封信件中的偏差并没有详细说明将你们工厂存在的所有偏差都包括在内。你们应该对调查和决定导致上述偏差的起因负责，防止其再次发生，并防止其他偏差的产生。如果你们希望向美国出口原料药，那么贵公司有责任保证遵守所有的CGMP美国标准和适用于所有的美国法律法规。 直到所有整改已经完成并且经FDA确认这些偏差的整改及贵公司符合CGMP，否则审批办公室将建议拒绝批准任何将贵公司列为原料药生产商的新药申请或补充。此外，整改偏差失败可能会导致美国FDA拒绝来源于中华人民共和国吉林省舒兰市人民路2066号，邮编132600的吉林舒兰药物合成有限公司的物品进口美国。按照法令801（a）（3）【21 U.S.C§381(a)(3)】部分，在生产过程中使用的方法和控制不符合CGMP法令的501（a）（2）（B）【21 U.S.C§351(a)(2)（B）】部分，这些产品可以被拒绝进入。 在收到该信件15个工作日内，请以书面形式向审批办公室详细说明你们采取的整改偏差的步骤。包括预防偏差再次发生所采取的每一步的解释和辅助文件的副本。如果你们在15个工作日内无法完成整改措施，请陈述延期原因以及完成整改的期限。此外，你们的回复需要表明你们是否不再制造或者经销(b)(4)USP并提供你们终止生产的日期和原因。请将你们的答复标志为：FEI#3003091092. 如果你们对该信有问题或关注的地方，请与官员Kristy A. Zielny联系，地址和电话号码如下： 美国食品和药物管理局 药品评价与研究中心 生产和产品质量分部 国际法规分部 White Oak，51栋 10903 新罕布尔大街 银泉，MD：20993 电话：(301)796-3120 传真：（301）847-8741 |
本文发布于:2023-05-07 23:09:15，感谢您对本站的认可！
本文链接：https://www.wtabcd.cn/fanwen/fan/90/99854.html
版权声明：本站内容均来自互联网，仅供演示用，请勿用于商业和其他非法用途。如果侵犯了您的权益请与我们联系，我们将在24小时内删除。
| 留言与评论（共有 0 条评论） |
