昨天，Celltrion宣布收到FDA针对其两种BLA申请产品(CT-P10和CT-P6)的完整回应信（Complete Response Letters），CT-P10和CT-P6分别是在研的针对利妥昔单抗(
Rituximab
)和曲妥珠单抗(
Trastuzumab
)的生物类似药。
根据Celltrion网站的声明，FDA要求提供关于两种产品的补充信息。Celltrion表示将与监管机构密切合作，解决导致收到完整回应信的问题，并希望在一年内获得FDA批准这两种药物。
没有无缘无故的爱，也没有无缘无故的恨。
美国FDA拒绝这两个生物类似药上市申请的决定，其实并不令人意外。这家韩国制药商去年收到了FDA的483表格，提到了违反cGMP的12个观察结果，包括记录不完整、设备设计不合理、环境监测不足，以及灭菌过程验证不充分等细节问题（
FDA警告信中英文翻译稿见文末
）。然后，2018年2月，Celltrion收到监管机构有关其制造工艺的警告信。虽然Celltrion向投资者保证，正在及时解决这些问题，但Celltrion的合作伙伴Teva表示，对生产设施问题的补救可能会导致对药物的“延迟批准”。Teva制药拥有在美国和加拿大市场商业化该两个生物类似药的独家权利。
不过尽管Celltrion工厂存在这些制造问题，CT-P6最近仍然获得了欧盟上市许可，Celltrion计划以Herzuma的名义在欧洲推出该产品。
CT-P10也在欧盟获得上市批准，以Blitzima，Ritemvia，Rituzena和Truxima等品牌名进行销售。该生物类似药（以及Sandoz的生物类似药Riximyo）在欧盟的上市已经开始对利妥昔单抗市场产生重大影响;罗氏在其2017年年度报告中向投资者表示，由于来自生物类似药挑战者的竞争，欧洲创新药利妥昔单抗的销售额下降11％。
来源: biopharma-reporter
2018-02-08
近期，FDA发布了关于韩国仁川的Celltrion的警告信（Warning Letter 320-18-28），FDA于2017年5月22日至6月2日对该公司进行了检查，发现其制剂生产存在严重违反CGMP的行为。
检查缺陷
1. Your firm failed to establish and follow appropriate written procedures that are designedto prevent microbiological contamination of drug products purporting to besterile, and that include validation of all aseptic and sterilization processes(21 CFR 211.113(b)). 你们公司未能建立并遵守适当的书面程序，设计用以防止理应无菌的药品受到微生物污染，其中包括对所有无菌和灭菌工艺的验证(21 CFR211.113(b))。
Poor Aseptic Behavior 无菌行为太差
On May 23, 2017, ourinvestigator observed multiple poor aseptic practices during the set-up andfilling of (b)(4) batch(b)(4).
2017年5月23日，我们调查人员在XX产品XX批装配和灌装时发现多个不良无菌做法。
For example, during theaseptic filling of vials, an operator used restricted access barrier system(RABS) (b)(4) to remove a jammed stopper by reaching over exposedsterile stoppers in the stopper bowl. The RABS (b)(4) disrupted theunidirectional airflow over the stopper bowl, creating a risk for microbialcontamination. After the operator removed the jammed stopper, the filling linewas restarted, but the affected stoppers were not cleared.
例如，在西林瓶无菌灌装中，一名操作员使用RABS XX越过装塞子的钵子里暴露的无菌塞子来移除卡住的塞子。该RABS XX里塞子钵上方单向流被中断，带来微生物污染风险。在操作员移除了卡住的塞子后，灌装线重新启动，但受影响的塞子并未清出。
In your response, you includedrevised aseptic technique procedures for set-up and filling. However, yourresponse was inadequate because you did not perform a retrospectiveinvestigation and thorough risk assessment of the effect on your product. Inaddition, your revised procedure FF21024 permits contamination ofproduct-contact surfaces during set-up, followed by wiping with a disinfectant,instead of preventing sterile equipment contamination by improved design andprocedures.
在你们的回复中，你们放进了一份修订后的装配和灌装无菌技术程序。但是，你们的回复是不充分的，因为你们并未执行回顾性调查，也未对其对你们产品的影响进行彻底风险评估。另外，你们修订后的程序FF21024可能会导致装配过程中产品表面接触污染，你们在之后采用消毒剂擦除，而不是通过改进设计和程序来防止无菌设备的污染。
Smoke Study Deficiencies 烟雾试验缺陷
Our investigator reviewed thesmoke studies for the RABS filling and (b)(4) loading areas, anddocumented deficiencies. The smoke studies conducted for these ISO 5 areaslacked sufficient evaluation of dynamic conditions, including set-up androutine aseptic manipulations. For example, you did not address criticalinterventions such as the removal of jammed stoppers, so it was not possible toevaluate the effects of such interventions on unidirectional airflow.
我们调查人员审核了RABS灌装和XX进料区烟雾试验并记录下了缺陷。这些ISO5级区所实施的烟雾试验缺乏对动态条件下的足够评估，包括装配和日常无菌控制。例如，你们并未解决关键的干扰问题如移除卡住的塞子，因此无法评估此类对单向流的干扰。
In your response, you statedthat you conducted two additional smoke studies. In response to this letter,provide a copy (e.g., an mpeg file) of your new smoke study recordings.
在你们的回复中，你们声称你们已执行了2次附加烟雾试验。在回复此函时，请提交一份你们新的烟雾试验录影的副本（例如，一份MPEG文件）。
Media Fill Deficiencies 培养基灌装缺陷
Our investigator observedmultiple deficiencies related to the validation of your aseptic processes.
我们的调查人员发现与你们无菌工艺验证有关的多个缺陷。
a. Our review of yourmedia fill batch records found that your firm rejected integral vials. Forexample, during simulation of a power failure at the capping station, your firmrejected integral vials filled and stoppered prior to the power outage. Thepractice is inappropriate and contrary to your firm’s media fill procedure (b)(4)2205 Media Fill Plan for Sterile Injectable Products.
我们对你们的培养基灌装批记录检查发现你们公司拒收了完整的西林瓶。例如，在轧盖区断电模拟中，你们公司拒收了在断电之前已灌装并加塞的完整瓶。该做法是不恰当的，与你们产公司的培养基灌装程序XX2205无菌注射剂产品培养基灌装计划是相反的。
Clear and specific SOPs forline clearance (i.e., intervention type and quantity of units removed) enableconsistent production practices and assessment of these practices during mediafills. Where procedures lack specificity, there is insufficient justificationfor exclusion of units from the media fill batch. You should not remove moreunits during a media fill intervention than would be cleared during aproduction run. To ensure a valid assessment, it is critical that media fillstudies accurately simulate these and other worst-case conditions encounteredduring commercial production.
清楚具体的清场SOP（即，干扰类型和移除单元的数量）能让培养基灌装过程中生产做法和对这些做法的评估保持一致。如果程序不够具体，对培养基灌装批次中排除的单元论证就不够充分。你们不应该在培养基干扰中移除比生产批次中更多的单元。为了确保有效的评估，培养基灌装研究准确地模拟这些情形和其它在商业化生产中会遇到的最差情况是很关键的。
b. Your procedure (b)(4)2205 did not specify that all personnel authorized to enter the asepticprocessing rooms during manufacturing should participate in a media fill atleast once a year.
你们的程序XX2205并未指定在生产期间所有经授权进入无菌加工间的人员均应至少每年参与一次培养基灌装。
c. You lacked adequateprocedures for training and qualifying personnel to examine media filled unitsfollowing incubation, and you did not specify how they are to conduct thisinspection. Furthermore, you did not keep adequate records that document whichpersonnel performed the examinations.
你们缺乏足够的培训和人员资格认定程序用以检查培养之后的灌装培养基单元，你们也没有说明他们要如何执行此检查。另外，你们也没有保存足够的记录记下哪个人员执行了这些检查。
In your response, you includedrevised media fill procedures, and indicated that you performed an additionalmedia fill. However, you did not adequately address the vials that wereerroneously removed and the impact on the accuracy of past media fill results.You also failed to perform a full assessment of your media fill program. Forexample, you did not conduct a thorough assessment of the training andqualifications of personnel to determine whether they can reliably examinemedia fill units.
在你们的回复中，你们包括了修订后的培养基灌装程序，并说你们执行了另一次培养基灌装。但是你们并未充分解决错误移除西林瓶的问题，以及其对过去培养基灌装结果准确性的影响。你们也未对你们的培养基灌装程序执行全面评估。例如，你们并未对人员培训和资格认定执行彻底的评估以确定其是否能可靠地检查培养基灌装单元。
2. Your firmfailed to thoroughly investigate any unexplained discrepancy or failure of abatch or any of its components to meet any of its specifications, whether ornot the batch has already been distributed (21 CFR 211.192). 你们公司未能彻底调查已销售和未销售的所有产品及其成分未解释的与质量标准差异和不合格情况(21 CFR 211.192)。
Lack of (b)(4) in Vials西林瓶中缺少XX
Our investigator documentedthat, from October 2015 to May 2017, you received approximately 140 complaintsfor(b)(4) related to (b)(4) in the vials. A substantial numberof these critical complaints were for U.S. batches and were received after FDAapproved (b)(4) in (b)(4). Your investigation identified the rootcause as vial stoppers (b)(4) which caused (b)(4) stoppering.This allowed (b)(4) to replace the (b)(4) in the (b)(4).This defect can significantly affect multiple quality attributes of yourproduct over its shelf life.
我们调查人员记录下从2015年10月至2017年5月你们收到了约140份与西林瓶中XX有关的XX产品客户投诉。这些关键投诉中很多是销往美国的批次，是在FDA批准XX中XX后收到的。你们的调查识别出根本原因是瓶塞XX导致了XX密闭。这使得XX替代在XX中替代了XX。此缺陷可能对你们产品在其货架期多个质量属性产生重大影响。
Your SOP QA2002 Deviationand Corrective Action Preventive Action requires prompt investigation andresolution of deviations. However, you investigated recurring (b)(4) complaintswithout resolution for more than two years, as indicated from the firstdeviation report DE-P2-16-003 dated January 6, 2015, to the summary reportdated March 3, 2017.
你们的SOP QA2002偏差和纠正预防措施要求对偏差进行迅速调查和解决。但是，你们对重复发生的XX投诉调查超过2年都没有解决方案。首个偏差报告DE-P2-16-003日期为2015年1月6日，总结报告日期为2017年3月3日。
You failed to thoroughlyinvestigate the lack of (b)(4) in vials and to implement a timely andeffective CAPA.
你们未能彻底调查西林瓶中缺少XX并实施及时有效的CAPA。
In addition, you failed tosubmit a biological product deviation report for (b)(4) to FDA asrequired by 21 CFR 600.14(c).
另外，你们未按21 CFR 600.14(c)的要求提交一份XX的生物产品偏差报告给FDA。
In your response, you statedthat you applied (b)(4) on the surface of both of the (b)(4) andare now routinely using(b)(4) stoppers. You state that these changeshave reduced the (b)(4) between (b)(4) and stoppers. You havealso added a (b)(4) as a (b)(4) detector for in-process controltesting.
在你们的回复中，你们声称你们在XX表面使用了XX，现在常规使用XX塞子。你们声称这些变更已减少了XX和塞子之间的XX。你们还为中控检测增加了XX作为XX探测器。
