2017年9月6日，FDA对韩国生物类似药巨头Celltrion发布483报告，该份报告是针对今年5月22-26日及5月29日-6月2日对位于韩国仁川（Incheon）的工厂现场核查做出的。这份长达10页的483报告含有12项调查结果，涉及多种生产缺陷。
▲ Celltrion收到的FDA 483报告
FDA 483报告，也称现场检查报告，是美国FDA检查人员根据美国现行法律法规，对企业进行现场检查，对不符合cGMP的地方进行报告总结并发给企业。企业需立即针对不符合项进行整改，并在收到483报告后15个工作日内向FDA相关部门回复483中不符合项的整改情况。若FDA认定企业的答复妥当，并符合现行法律法规的要求，那么企业就避免收到FDA警告信。
此次Celltrion收到FDA 483报告的仁川工厂，目前拥有4*12500L和6*15000L的共14万升的产能，涉及Truxima和Inflectra/Remsima等多个生物类似药的全球生产，此次现场核查或对Celltrion多个类似药的市场渗透产生影响。
自2015年第四季度以来，Celltrion共遭受了140项关于西林瓶胶塞相关的投诉。但Celltrion尚未采取足够的纠正和预防措施来解决这些问题，也没有确保在批次放行之前将受影响的药瓶移除。此外，对原液和成品中检测到的异物并没有进行及时的调查。包含颗粒的药物的批次仍被放行进行进一步的包装和贴签，其中一些样品含有“太多数量（too numerous to count）”的颗粒。FDA此次现场核查可能和这些投诉相关。
然而Celltrion指出，在483表格中提到的140项投诉仅限于欧洲范围内，这些投诉并不涉及在美国上市的Inflectra。同时，欧洲药物管理局已经审查并批准了相关整改措施，以解决西林瓶胶塞的问题，但这与FDA核查到的结果有一定出入。
此次Celltrion收到的483报告共10页，涉及12项调查结果：
Failure to review unexplained discrepancies.
未彻底审查原因不明的偏差，无论批次药品是否开始上市销售
Since the fourth quarter of 2015, the FDA has received 140 complaints related to vial stoppers. Celltrion has not implemented adequate corrective and preventative actions to address the issue, nor has it ensured that the affected vials are removed prior to the release of batches. Furthermore, investigations into foreign matter detected in drug products and drug substances were not conducted in a timely manner. Batches of a drug that contained particles were released for packing and labeling, and some samples contained particles “too numerous to count.” Unexpended trends in environmental monitoring data were not investigated thoroughly, and current practices do not ensure that changes in microbial flora are detected and evaluated.
Procedures to prevent microbiological contamination are not established or followed.
未制定并遵守防止无菌制剂被微生物污染的程序
The report notes such practices as operators reaching over exposed sterile surfaces with hands and arms, as well as a lack of oversight of aseptic production operations during some work processes.
Procedures designed to prevent microbiological contamination do not include adequate validation of the sterilization process.
防止无菌制剂微生物污染的程序未经过足够的无菌程序验证
No effective system to identify which personnel have entered the filling room is in place, there exists no documentation of personnel who participate in reading media fill units, nor are there qualifications or procedures for reading media fill units. No dynamic airflow studies have been performed to determine risk to product sterility.
Aseptic processing areas are deficient in environmental monitoring.
无菌加工区域缺少环境条件的监测
Active volumetric air sampling is not included in the monitoring program for aseptic filling areas, the locations for surface monitoring are not described in procedures, and production personnel perform both environmental and personnel monitoring.
Aseptic processing areas are deficient in terms of cleaning and disinfecting.
无菌加工区域缺少清洁和消毒
The disinfectant used failed acceptable criteria for all surfaces, mold was identified on the walls, disinfectant efficacy studies did not include surfaces such as those used for filling machine format parts, and dust buildup was visible on air-intake vents.
Equipment used in manufacturing is not of an appropriate design.
制剂生产区使用的设备设计不合理
Identification numbers for parts were found taped onto equipment surfaces.
Failure to demonstrate that manufacturing processes can reproducibly manufacture drug substances meeting predetermined quality attributes.
无法证明生产工艺可重复生产原料药以满足预定的质量要求
Process validation for a drug substance did not establish sound sampling plans to evaluate variability among batches. The report notes that this observation was also made in a March 2015 Form 483.
Laboratory records do not include complete data.
实验室记录数据完整性不够
Failing test results are not reported, though such reports are mandated by procedure. After failures, tests are repeated without documentation of failing results or actions taken.
Appropriate controls are not exercised over systems.
未对计算机及相关系统采取合理控制措施
Operation personnel share a common login to some systems, allowing the possibility that data could be deleted. Audit trails are not reviewed.
Procedures for master production and control records are not followed.
未遵守主生产和控制记录的准备程序
No system to track issuance and use of laboratory raw data forms is in place. The report also notes that the quality control department had a document shredder that filled with destroyed documents during the inspection.
此次FDA现场核查的结果很可能会影响Celltrion的类似药产品Inflectra在美的销售。Inflectra自2016年4月5日被FDA批准以来，由辉瑞在美进行相关商业化运作，但目前商业化进程缓慢且未能达到预期效果。Remicade原研2016全年在美销售额达到45亿美金，而2017年第二季度的辉瑞报告显示，Inflectra和Remsima（Remsima是Remicade生物类似物在欧盟上市的名称）的销售额总计为7800万美元，虽然同期比2016年的销售额相比翻了一倍还多，但在美销售额仅为1700万美元，市场渗透率不到2%，情况不容乐观。
有分析师认为，实际使用中出现的西林瓶胶塞问题一定程度上解释了为什么辉瑞没有在市场中大力推广Inflectra。目前，随着市场中的竞争者包括三星旗下生物制药公司Bioepis以及默克公司的迅速发展，今年4月FDA已经批准了Remicade的第二个生物类似物Reneflexis，Remicade生物类似物的竞争越来越激烈。
在Remicade的市场价格方面，最早的时候Inflectra 仅比Remicade的价格低15%。但随后 Renflexis把批发商采购成本（wholesale acquisition cost, WAC）定为每100毫克753.39美元，低于Remicade的 WAC 35%, 低于Inflectra 的WAC25%。所以基于这些内部及外部的压力，Pfizer随后将Inflectra的价格调低至和Renflexis相同的价格，据悉10月1日后Pfizer进一步将Inflectra的售价降低至每100毫克737.91美元。
早前Bioepis已经在mAbs上发文，将Reneflexis、Inflectra和Remicade三个进行了头对头的比较，Reneflexis已经在糖基化和生物学活性方面显示其与原研更为接近，其次483报告的发布以及价格方面的竞争，或许会让Inflectra在美的市场渗透雪上加霜。
▲ Bioepis进行的Reneflexis、Inflectra和Remicade头对头质量比对
虽然此次FDA 483表暴露出celltrion仁川工厂相当多的问题，但好在尽管存在一些FDA不允许非法文件和检测过程，但celltrion公司对FDA没有隐瞒行为；同时质量差的产品未被放行或不会被放行；生产设施和企业文化没有结构性问题，基础设施能够满足要求，企业生产人员基本按规定进行生产作业。
西林瓶胶塞的相关问题基本查明，后期处理应该也相对容易，但数据完整性其它问题仍然十分棘手，这也是目前FDA重点监管的部分，其中一些问题甚至在在2015年3月的现场核查中也发现了，这将严重影响FDA对其的评价。可以预见的是，无论对于创新药研发企业还是仿制药企业，数据完整性未来将是悬在生产环节上的一把利剑，重视了则可以逆转胜利，不充分重视将有可能失去市场的先机。目前还未有相关Celltrion整改结果的报道，希望其在限期前能解决相关问题。
参考文献
1.FDA faults Celltrion plant that makes Pfizer's Remicade copy, Inflectra（http://www.fiercepharma.com/manufacturing/fda-faults-celltrion-plant-where-it-makes-pfizer-s-remicade-copy-inflectra）
2.FDA：UCM574767
3.Glycosylation profile and biological activity of Remicade compared with Flixabi and Remsima.mAbs,2017, VOL. 9, NO. 6, 968–977
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