外资大型制药公司技术、研发、质量总监，验证管理资深专家，多家制药公司顾问，药学硕士。国家工艺核对未雨绸缪之际，成功解决了多家在产产品处方、工艺问题。处方工艺的二次开发，免费咨询，全程保密。邮箱：1193686015@qq.com。
受检公司：Zhejiang Huahai Pharmaceutical Co., Ltd. 浙江华海药业
受检地址：Xunqiao, Linhai, Zhejiang 317024, China 中国浙江临海汛桥
受检身份：制剂和原料药生产商
FEI号：3003999190
检查员：Justin A, Boyd, Investigator / Peter E.Baker, Investigator
检查日期：2016-011-14 至 2016-11-18
签发日期：2016-11-18
发布日期：2018-08-09
This document lists observations made by the FDA representative(s) during the inspection of your facility. They are inspectional observations. And do not represent a final agency determination regarding your compliance if you have an objection regarding an observation, or have implemented, or plan to implement corrective action in response to an observation, you may discuss the objection or action with the FDA representative(s) during the inspection or submit this information to FDA to address above. If you have any questions, please contact FDA at the phone number and address above.
本文件列出了FDA代表在对你工厂检查期间所发现的问题。这些只是检查发现，并不代表FDA对你公司合规性的最终结论。如你们对某一缺陷有异议，或已实施或计划实施纠正措施来纠正某个缺陷，你们在检查期间与FDA代表讨论你们的异议与措施，或通过上述地址向FDA提交资料。如有问题，请通过上述地址电话与FDA取得联系。
DURING AN INSPECTION OF YOUR FIRM WEOBSERVED: 检查你公司期间我们发现
OBSERVATION 1 缺陷1
Written procedures designed to prevent contamination of drug products purporting to be sterile are not followed. 未遵守设计用以防止理应无菌的药品交叉污染的书面程序。
1. During set-up and interventions using the RABS (b)(4) operators were observed to use the (b)(4) directly above sterile surfaces and components. For example, (b)(4) the stopper bowl and stoppers, and open vials at the (b)(4). 在使用RABS XX装配和干预期间，发现操作人员在无菌表面和成分正上方使用XX。例如，XX加塞盘和塞子，以及在XX打开西林瓶。
2. Intervention during filling operations have not been defined in procedures and were not documented in the (b)(4) submission batch records. 程序中未定义在灌装操作期间的干预，亦未记录在XX申报批记录中。
3. There is no preventive change frequency forthe clean room RABS (b)(4). 未规定洁净间RABS XX的预防性更换频次。
4. No defect set of vials is maintained for training and qualification of the visual inspection process. 未制作目检操作培训和确认用缺陷西林瓶系列。
OBSERVATION 2 缺陷2
Failure to establish laboratory controls that include scientifically sound and appropriate specifications, standard sampling plans, and test procedures designed to assure that drug products conform to appropriate standards of identity, strength, quality and purity.. 未建立化验室控制使其包括科学合理适当的质量标准、标准取样计划和检测方法用以确保药品符合适当的鉴别、剂量、质量和纯度标准。
1. Assessments to establish environmental monitoring sampling points were not comprehensive. For example, they did not evaluate expanded sampling points or thoroughly evaluate common activities occurring in the clean room. Further, the environmental monitoring procedures did not define sampling locations with description diagrams to ensurere producible sampling. 设置环境监测取样点的评估不全面。例如，其中未评估增加取样点或彻底评估在洁净间通常所发生的活动。另外，环境监测程序并未采用描述性图形来定义取样位置以确保取样具有重复性。
2. Environmental monitoring media for air, surface, and personnel monitoring does not contain any neutralizer for the disinfectants used in the clean room. 环境监测中空气、表面和人员监测用培养基并不含有任何洁净间所用消毒剂的中和剂。
3. During open door interventions, environmental monitoring is not performed. For example, non-viable particle counts, active air monitoring, or settle plates is discontinued during open door interventions. 在开门干预期间未执行环境监测。例如，尘埃粒子计数、主动取样监测，或沉降菌在开门干预期间被中止了。
4. Monitoring of the unfiltered bulk compounded batch does not include evaluation for endotoxin and the samples are collectedat least (b)(4) prior to the start of (b)(4). 对过滤前配制药液的监测没有内毒素项目，在XX开始之前至少取样XX。
5. There is a lack of scientific rationale for the establishment of the parameters for the RABS (b)(4) integrity test of(b)(4) pressure hold time between (b)(4) Pa and greater than (b)(4) Pa drop in pressure. 对RABS XX 完整性测试中XX帕和大于XX帕压降保压时长参数设定缺乏科学合理性。
6. Limits on reject type are not established inthe visual inspection procedures. 目检程序中未设定拒收类型的限度。
OBSERVATION 3 缺陷3
Processing areas are deficient regarding the system for cleaning and disinfecting the equipment. 工艺区域的设备清洁和消毒系统有缺陷。
1. The (b)(4) ducts of the (b)(4) are not periodically inspected and cleaned. On 18 November 2016, the (b)(4) duct for (b)(4) GJC008 was observed to have unidentified white dust on the innersurfaces of the (b)(4) duct. XX的XX风管未定期检查和清洁。2016年11月18日，发现XX GJC008的XX风管中内表面有不明白色粉尘。
2. (b)(4) of the filling room is done (b)(4) to control spores with a (b)(4) solution. The validation of the (b)(4) process didnot include placement of biological indicators in hard to reach areas, such asin RABS (b)(4) areas that may be clocked by equipment, high areas or low areas.灌装间的XX已完成用以使用XX溶液控制孢子。XX工艺的验证未包括在难接近区域放置生物指示剂，例如在可能被设备阻碍的RABS的XX区域、较高区域或较低区域。
3. Disinfectant efficacy studies did not evaluate the effectiveness on (b)(4) used for the RABS (b)(4) or (b)(4) used as (b)(4) parts for the filling line. During execution of the studies the challenged surfaces were physically wiped preventing evaluation of the effectiveness of the disinfectant that is sprayed. 消毒剂有效性研究并未评估用于RABS的XX的有效性，和灌装线中用作XX部分的XX的有效性。在研究执行期间，挑战表面进行了物理擦拭因此无法对所喷消毒剂进行有效性评估。
4. Transfer of the filling machine (b)(4) parts from their storage in unclassified areas to the Grade A areas was not evaluated in the validation “Efficiency Qualification of Material Transferring by Non-Sterilization Method into Grade B”. 验证“非灭菌方法转移物料至B级区的有效性确认”中未评估灌装机XX部件从其非洁净区存贮处转移至B级区的操作。
OBSERVATION 4 缺陷4
Data is not recorded contemporaneously. 数据记录不同步。
1. The “checked by” entries for batch (b)(4) of(b)(4) Tablets were not documented at the time of batch production. XX片剂XX批次批记录中复核项未在批生产时记录。
2. The QC analyst responsible for environmental monitoring does not document sampling at the time it occurs. It was reported the analyst remembers the times and documents all at once after finishing. 负责环境监测的QC化验员未在取样时即行记录。报告说化验员凭记忆记下时间然后在完成之后全部写下来。
FDA警告信：日本Yuki Gosei Kogyo
Warning Letter 320-18-63 July 17, 2018
Mr. Masaru Matsui
President and CEO, Yuki Gosei Kogyo Co., Ltd.
10-4, Nihonbashi-Ningyocho 3-Chome, Chuo-Ku, Tokyo 103-0013, Japan
Dear Mr. Matsui:
The U.S. Food and Drug Administration (FDA) inspected yourdrug manufacturing facility, Yuki Gosei Kogyo Co., Ltd. at Ochiai 788, Joban Nishigo-machi, Jobannishigo-Machi Iwaki, Fukushima, from November 13 to 17, 2017.
美国FDA于2017年11月13-17 日检查了你们位于日本福岛的YukiGosei Kogyo Co., Ltd.生产场所。
This warning letter summarizes significant deviations from current good manufacturing practice (CGMP) for active pharmaceutical ingredients (API).
本警告信总结了原料药（API）生产严重违反CGMP要求。
Because your methods, facilities, or controls for manufacturing, processing, packing, or holding do not conform to CGMP, your API are adulterated within the meaning of section 501(a)(2)(B) of the Federal Food, Drug, and Cosmetic Act (FD&C Act), 21 U.S.C. 351(a)(2)(B).
由于你们的生产、加工、包装或保存的方法、场所或控制不符合CGMP要求，你们的原料药根据FDCA的501(a)(2)(B)以及21U.S.C. 351(a)(2)(B)被认为是掺假药品。
We reviewed your December 8, 2017, response in detail and acknowledge receipt of your subsequent correspondence.
我们已详细审核了你公司2017年12月8日的回复，并此告知收到后续通信。
During our inspection, our investigator observed specific deviations including, but not limited to, the following.
检查期间，我们的调查人员发现的具体问题包括但不仅限于以下：
1. Failure to maintain complete data derived from all laboratory tests conducted to ensure your API complies with established specifications and standards.未能维护为确保你们API符合既定质量标准所执行的所有化验室检测所生成的完整数据。
Your firm does not ensure that complete data from testing of your API are included in the official batch record and reviewed by your quality unit. For example, you reported passing results for related substances testing of (b)(4) lot #(b)(4) analyzed starting at (b)(4) on July 28, 2015. However, our investigator found unreported analyses including out-of-specification (OOS) results for the same lot acquired earlier on the same date, and on the next day as the reported results. You failed to includethis data to be reviewed by your quality unit prior to the release of the lot.Our investigator documented the same pattern with other products not intended for the U.S. market.
你公司未能确保你们API检测所生成的完整数据被放在正式的批记录中，并由你们质量部门进行审核。例如，你们2015年7月28日在XX检测了XX产品XX批次有关物质，报告了合格结果。但是，我们调查人员发现未曾报告的分析中有相同批次的OOS结果，是在同一天早些时间以及在报告结果的次日。你们未能将此数据放入记录由质量部门在放行该批次之前进行审核。我们的调查人员记录了不销往美国的其它产品也存在有相同情况。
In your response, you explained that this “trial analysis” was performed on the sample solution for conditioning the high-performance liquid chromatography (HPLC) column. However, your explanation did not address why the “trial analysis” was performed using a sample solution instead of a standard solution, or why you ran this extra analysis in addition to the system suitability test, which verifies that a chromatographic system is adequate as set forth in USP <621>.
在你们的回复中，你们解释说这种“试分析”是用样品溶液调整HPLC柱。但是，你们的解释并未说明为何会使用样品溶液执行“试分析”而不是用标准溶液，或者是为何你们在系统适用性测试以外还要运行此额外分析，系统适用性测试是用以核查色谱系统符合USP<621>要求的。
You also acknowledged that a retrospective review conducted after the inspection found additional instances of unreported electronic datain original batch records. Your review only assessed laboratory data and did not assess all parts of your facility’s operation where CGMP information is generated and maintained. In addition, you failed to provide details of your review criteria and methodology.
你们亦告知说在检查之后进行的回顾性审核发现在原始批记录中还有未报告的电子数据的其它案例。你们的审核仅评估了化验室数据，并未说明你们工厂生成和保存CGMP信息的所有操作部分。此外，你们亦未提交你们审核标准和方法学详细信息。
Data Integrity Remediation 数据完整性弥补措施
Your quality system does not adequately ensure the accuracy and integrity of data to support the safety, effectiveness, and quality of the drugs you manufacture. We strongly recommend that you retain a qualified consultant to assist in your remediation.
你们的质量体系不能充分确保数据的准确性和完整性，无法支持你们生产的药品的安全性、有效性和质量。我们强烈建议你们聘请一位有资质的顾问来帮助你们进行弥补。
In response to this letter, provide the following.
在回复此函时请提交以下资料：
A. A comprehensive investigation into the extent of the inaccuracies in data records and reporting. Your investigation should include: 一份对数据记录和报告不准确性程度的全面调查。你们的调查应包括
A detailed investigation protocol and methodology; a summary of all laboratories, manufacturing operations, and systems to be covered by the assessment; and a justification for any part of your operation that you propose to exclude.
详细的调查方案和方法学；对评估所覆盖的所有化验室、生产操作和系统的总结，以及对你们意在排除的操作中所有部分的论证。
Interviews of currentand former employees to identify the nature, scope, and root cause of datain accuracies. We recommend that these interviews be conducted by a qualified third party.
与现有的和已离职的员工进行面谈，找出数据不准确的表现、范围、根本原因。我们建议这些面谈由一个有资质的第三方来实施。
An assessment of the extent of data integrity deficiencies at your facility. Identify omissions,alterations, deletions, record destruction, non-contemporaneous record completion, and other deficiencies. Describe all parts of your facility’s operations in which you discovered data integrity lapses.
你们工厂数据完整性缺陷的程度的评估。识别出省略、修改、删除、记录销毁、不同步记录填写和其它缺陷。描述你们工厂操作中发现数据完整性问题的所有部分。
A comprehensive retrospective evaluation of the nature of the testing, manufacturing and otherdata integrity deficiencies. We recommend that a qualified third party with specific expertise in the area where potential breaches were identified should evaluate all data integrity lapses.
一份对数据完整性缺陷状况的全面回顾性评估。我们建议由一个有资质的第三方里具有该领域专业水平的专家评估所有数据完整性问题。
B. A current risk assessment of the potential effects of the observed failures on the quality of your drugs. Your assessment should include analyses of the risks to patients caused by the release of drugs affected by a lapse of data integrity, and risks posed by ongoing operations.
对你们药品质量中所发现的不合格情况的潜在影响的当前风险评估。你们的评估应包括由于受到数据完整性问题影响的药品放行导致的患者风险的分析，以及持续运营所具有的风险。
C. A management strategy for your firm that includes the details of your global corrective action and preventive action plan. Your strategy should include:
你们公司的管理策略，包括你们全球CAPA计划详细情况。你们的策略应包括：
A detailed corrective action plan that describes how you intend to ensure the reliability and completeness of all the data you generate, including analytical data,manufacturing records, and all data submitted to FDA.
详细的CA计划，描述你们如何确保你们生成的所有数据的可靠性和完整性，包括分析数据、生产记录和所有提交给FDA的数据。
A comprehensive description of the root causes of your data integrity lapses, including evidence that the scope and depth of the current action plan is commensurate with the findings of the investigation and risk assessment. Indicate whether individuals responsible for data integrity lapses remain able to influence CGMP-related or drug application data at your firm.
一份完整的描述你们数据完整性问题的根本原因的描述，包括认定当前行动计划的范围和深度与调查和风险评估发现相称的证据。说明是否对数据完整性问题承担责任的个人仍有能力对你公司对CGMP相关或药物应用数据产生影响。
Interim measures describing the actions you have taken or will take to protect patients and to ensure thequality of your drugs, such as notifying your customers, recalling product, conducting additional testing, adding lots to your stability programs to assure stability, drug application actions, and enhanced complaint monitoring.
临时措施，描述你们已采取的行动，或即将采取用以保护患者确保你们药品质量的努力，例如通知你们的客户、召回产品、实施额外测试、向稳定性试验计划中增加批次以确保稳定性、药品申报行动以及加强投诉监测。
Long-term measures describing any remediation efforts and enhancements to procedures, processes,methods, controls, systems, management oversight, and human resources (e.g.,training, staffing improvements) designed to ensure the integrity of your company’s data.
长期措施，其中描述所有对用以确保你们公司数据完整性的程序、流程、方法、控制、系统、管理监管和人力资源（例如培训、员工提高）的弥补和提升。
A status report forany of the above activities already underway or completed.
对上述活动已开展或已经完成的状态报告。
Conclusion 结论
Deviations cited in this letter are not intended as an all-inclusive list. You are responsible for investigating these deviations, for determining the causes, for preventing their recurrence, and for preventing other deviations.
此函中所引用的违规并不是全部。你们有责任对这些偏差进行调查，确定原因，防止其再次发生，防止你们设施内其它偏差的发生。
If you are considering an action that is likely to lead to a disruption in the supply of drugs produced at your facility, FDA requests that you contact CDER’s Drug Shortages Staff immediately, at drugshortages@fda.hhs.gov, so that FDA can work with you on the most effective way to bring your operations into compliance with the law. Contacting the Drug Shortages Staff also allows you to meet any obligations you may have to report discontinuances or interruptions in your drug manufacture under 21 U.S.C.356C(b) 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 dependon your products.
如果你们在考虑要采取的措施可能会导致你们工厂所生产的药品供应中断，FDA要求你立即联系CDER药品短缺负责人员，这样FDA可以与你们一起采用最为高效的方式引导你们的操作符合法规要求。联系药品短缺负责人员还能让你满足依据21 U.S.C. 356C(b)你可能必须报告你们药品中止或中断的义务，让FDA尽快考虑是否需要采取何种措施来避免短缺，保护依赖于你们药品的患者健康。
Until you correct all deviations completely and we confirm your compliance with CGMP, FDA may withhold approval of any new applications or supplements listing your firm as a drug manufacturer.
在贵公司未能完成所有偏差纠正并且由我们确认你们符合CGMP之前，FDA可能会搁置所有将你公司列为药品生产的新申报和增补申报的批准。
Failure to correct these deviations may also result in FDA refusing admission of articles manufactured at Yuki Gosei Kogyo Co. Ltd., atOchiai 788, Joban Nishigo-machi, Jobannishigo-Machi Iwaki, Fukushima into theUnited States under section 801(a)(3) of the FD&C Act, 21 U.S.C. 381(a)(3).Under the same authority, articles may be subject to refusal of admission, inthat the methods and controls used in their manufacture do not appear toconform to CGMP within the meaning of section 501(a)(2)(B) of the FD&C Act,21 U.S.C. 351(a)(2)(B).
未能纠正这些偏差可能还会导致FDA依据FDCA第801(a)(3)条和21U.S.C. 381(a)(3)拒绝接受在上述地址生产的产品进入美国。
After you receive this letter, respond to this office in writing within 15 working days. Specify what you have done since our inspection to correct your deviations and to prevent their recurrence. If you cannotcomplete corrective actions within 15 working days, state your reasons for delay and your schedule for completion.
收到此函后，请在15个工作日内回复至本办公室。在回复中说明自从检查后，你们做了哪些工作来纠正你们的偏差，防止其再次发生。如果不能在15个工作日内完成纠正措施，说明延迟的原因以及完成计划。
Send your electronic reply to CDER-OC-OMQ-Communications@fda.hhs.gov or mail your reply to:
Rebecca Parrilla
Compliance Officer
U.S. Food and Drug Administration
White Oak Building 51, Room 4359
10903 New Hampshire Avenue
Silver Spring, MD 20993
USA
Please identify your response with FEI 3002808534.
Sincerely,
/S/
Francis Godwin
Acting Director
Office of Manufacturing Quality
Office of Compliance
Center for Drug Evaluation and Research
cc:
Mr. Nobuyoshi Miyata, General Manager Joban Factory
Yuki Gosei Kogyo Co., Ltd.
788, Ochiai, Joban Nishigo-machi
Iwaki-shi, Fukushima, 972-8316 Japan