翻译： JULIA 来源： Julia法规翻译
Warning Letter 320-18-56 May 31, 2018
Dr. George Ko
Chairman, Taiwan Biotech Company, Ltd.
22, Chieh-Shou Road, Taoyuan District, Taoyuan City,Taiwan R.O.C.
Dear Dr. Ko:
The U.S. Food and Drug Administration (FDA) inspected your drug manufacturing facility, Taiwan Biotech Company, Ltd at 22, Chieh-Shou Road, Taoyuan District, Taoyuan City, from September 1 to 11, 2017.
美国FDA于2017年9月1-11检查了你们位于台湾桃园市桃园区介寿路22号的信东生技股份有限公司生产场所。
This warning letter summarizes significant violations of current good manufacturing practice (CGMP) regulations for finished pharmaceuticals. See 21 CFR, parts 210 and 211.
本警告信总结了制剂生产严重违反CGMP要求。参见21CFR第210和211部分。
Because your methods, facilities, or controls for manufacturing, processing, packing, or holding do not conform to CGMP, your drug products 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).
由于你们的药品生产、加工、包装或保存的方法、场所或控制不符合CGMP要求，你们的药品根据FDCA的501(a)(2)(B)以及21 U.S.C. 351(a)(2)(B)被认为是掺假药品。
We reviewed your November 2, 2017, response in detail and acknowledge receipt of your subsequent correspondence.
我们已详细审核了你公司2017年11月2日的回复。
During our inspection, our investigator observed specific violations 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. Your firm failed to establish an adequate system for monitoring environmental conditions in aseptic processing areas (21 CFR 211.42(c)(10)(iv)).你公司未能建立充分的系统以监测无菌加工区域的环境条件（21 CFR 211.42(c)(10)(iv)）。
During the inspection, our investigator found the following issues related to your sterile over-the-counter (b)(4): (b)(4) and (b)(4).
在检查期间，我们调查人员发现以下与你们的无菌OTCXX：XX与XX的问题。
Environmental and Personnel Monitoring Alert Investigations环境与人员监测警报调查
Our investigator identified several environmental monitoring plates from the ISO 5 (Class A) and the surrounding ISO 8 (Class C) clean areas which exceeded action limits and for which investigations were not initiated.
我们的调查人员发现几个ISO5（A级区）与周围ISO8（C级区）级洁净区的环境监测碟，超出了行动限，但未启动调查。
On September 6, 2017, our investigator found containers storing environmental and personnel monitoring microbiological samples, dated August 30 and 31, 2017. Numerous samples lacked basic documentation, including missing colony-forming unit (CFU) counts and the identity of the person who collected the sample. At the request of our investigator, your firm enumerated CFU for these plates. While several plates exhibited counts outside of actionlimits, your firm had not initiated investigations. As an example, a sampletaken for (b)(4) lot (b)(4) yielded an extremely high count of140 CFUs in your ISO 5 area. The action limit for this critical area is < (b)(4)CFU.
2017年9月6日，我们的调查人员发现容器存贮环境和人员监测微生物样品，标示日期为2017年8月30和31日。大量样品缺乏基本文件记录，包括缺失这些碟的菌落单位计数（CFU）以及取样人信息。在我们调查人员要求之下，你公司对这些碟进行了CFU计数。有几个碟计数结果超出了行动限，你们公司未启动调查。举例来说，从ISO5级区XX批次XX所取样品的计数结果高达140CFU。该关键区域的行动限<XXCFU。
Due to our investigator’s findings, you initiated investigations during the inspection regarding the undocumented microbial growth. On September 7, 2017, you provided a copy of these initial investigations.
由于我们的调查人员发现了此事，你们在检查期间启动了针对未记录的微生物生长情况的调查。2017年9月7日，你们提交了一份这些初始调查的副本。
Notably, when asked by the investigator to provide all deviations from environmental monitoring limits, your firm had reported noresults outside limits for over a year prior to the inspection date. This reported level of environmental control is dubious, in that during the current FDA inspection, several environmental monitoring samples were found to have significant growth, and these results had not been enumerated and recorded.
显然，当我们调查人员要求提供所有环境监测限度偏差时，你们公司报告说截止检查日期在过去一年没有过超限结果。此环境控制的报告水平太可疑了，在当时FDA检查期间，几个环境监测样品均发现有显著的生长，这些结果均未被计数亦未记录。
Your failure to accurately account for numerous environmental monitoring plates, enumerate the results, and fully investigate the systemic flaws that led to the unreported data raises questions regardingthe integrity of data generated by your firm.
你们未能准确计算大量环境监测碟、计数结果，亦未全面调查系统性瑕疵，导致未报告的数据引发你公司所生成数据的完整性问题。
Insufficient surface monitoring 表面微生物监测不充分
On September 6, 2017, our investigator determined that your microbiology technician had not collected required surface samples since September 1, 2017. Further, our inspection revealed that your firm lacked environmental sampling during your (b)(4) and (b)(4). Your management acknowledged that deficient environmental monitoring on these production (b)(4) had been occurring for approximately 1–2 years.
2017年9月6日，我们调查人员发现你们的化验室技术员自2017年9月1日起即未采集所需的表面样品。另外，我们的检查揭示你公司在你们的XX和XX期间缺少环境取样。你们的管理人员知晓这些生产XX环境监测缺陷已持续发生约1-2年。
In your response, you stated that you created a standard operating procedure (SOP) to track your environmental monitoring samples, and committed to hiring more personnel to supervise activities. However, your response was inadequate. You did not provide the SOP or indicate plans to fully remediate your environmental monitoring program. You also did not indicate whether all unaccounted samples identified by our investigator were enumerated,and if investigations and risk assessments were initiated in response to anyresults outside established limits. In addition, you did not indicate whether acomprehensive review of all laboratory practices and controls was conducted toensure reliable laboratory operations, including but not limited toaccurate reporting of all laboratory data.
在你们的回复中，你们声称你们制订了SOP来追踪你们的环境监测样品，并承诺会聘用更多人员来监管活动。但是，你们的回复是不充分的。你们并未提供SOP亦未写明全面弥补你们环境监测程序的计划。你们亦未说明我们调查人员发现的所有未计数的样品是否均已计数，并且针对所有超出既定限度的结果均启动了调查和风险评估。此外，你们并未说明是否对所有化验室做法和控制进行了全面审核以确保可靠的化验室操作，包括但不仅限于准确报告所有化验室数据。
In response to this letter, provide the following.
在回复此函时，请提交以下：
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Further details on additional microbiological plates that were not initially enumerated and the results that your firm ultimately obtained for these plates. Also, summarize all lots made without sufficient environmental monitoring on the (b)(4) and (b)(4). Provide risk assessments for any potentially affected products marketed to the United States.
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更多初始未计数的其它微生物碟的细节，以及你公司最后从这些碟上获得的结果。还有，要汇总所有在XX和XX无充分环境监测情况下生产的批次。请提交所有在美国销售并可能受影响的产品的风险评估。
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Your investigations of multiple deviations from action limits for ISO 5 and other clean areas.
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对ISO5级和其它洁净区超出行动限的多个偏差的调查。
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A thorough, independent assessment with corrective actions and preventive actions (CAPA) for your environmental monitoring and personnel monitoring programs. For instance, your remediation should include adequate sampling procedures, media suitability, sample accountability (e.g., identification, storage, logging, analysis dates/times), appropriate locations and frequencies, proper responses to alert and action limits, routine identification of microbes isolated from clean room and personnel samples, and various other elements of an effective program.
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为环境监测和人员监测程序所制订的CAPA的全面独立评估。例如，你们的弥补措施应包括足够的取样程序、培养基适用性、样品可靠性（例如，标记、存贮、登记、分析日期/时间）、恰当位置和频次、对警报和行动限的适当响应、从洁净区和人员样品中分离出来的微生物的日常鉴别，以及一个有效程序的其它不同要素。
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A comprehensive, independent review of your laboratory practices, methods, equipment, and analyst competencies. Based on this review, provide a detailed CAPA plan to fully remediate your laboratory system. Your plan should also include the process you will use to evaluate the effectiveness of the implemented CAPA.
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对你们化验室做法、方法、设备和化验室资质的全面独立审核。基于此审核，提交一份详细的CAPA计划全面弥补你们的化验室系统。你们的计划亦应包括你们将用以评估所实施CAPA有效性的流程。
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A comprehensive identification of all contamination hazards in your aseptic processes, equipment, and facilities. Provide an independent risk assessment that covers, among other things, all human interactions with the ISO 5 area, equipment placement and ergonomics, air quality in the ISO 5 area and surrounding room, facility layout, personnel flow, and material flow.
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一份你们无菌工艺、设备和设施的所有污染全面识别。提交一份独立的风险评估，覆盖所有人员与ISO5区域的互动、设备位置和人体工程学、ISO5区域和周围房间的空气质量、设施平台、人流和物流。
2. Your firm failed to follow an adequate written testing program designed to assess the stability characteristics of drug products (21 CFR 211.166(a)).你公司未能遵守设计用以评估药品稳定性属性的足够的书面检测程序（21 CFR 211.166(a)）。
Your firm failed to conduct on-going stability testing of (b)(4) and (b)(4) at various time intervals, as specified in your stability program. For example, in September 2016, you failed to perform testing at the12-month stability time interval for (b)(4) batch (b)(4).Further, you performed the scheduled 6-month stability testing of (b)(4) batch (b)(4) four months late (in March 2017). You lacked an investigation to address the missed and delayed stability testing.
你公司未能按你们的稳定性程序所要求实施XX和XX不同时间点的持续稳定性测试。例如，2016年9月，你们未做XX批次XX的12个月时间点的检测。另外，你们XX产品XX批次的6个月稳定性时间点迟了4个月才做（2017年3月）。你们缺乏调查解决稳定性检测缺失和延迟的问题。
In your response, you indicated that you revised the SOPQOP-046, Receiving/Using/ Destroying, and you committed to ensure allfuture stability testing is conducted in a timely manner. However, you failedto provide the revised SOP and a retrospective analysis to determine the root cause of all missing and delayed testing.
在你们的回复中，你们说你们修订了SOPQOP-046“接收/使用/销毁”，你们承诺将确保未来所有稳定性测试将及时执行。但是，你们并未提交修订后的SOP和一份回顾性分析以确定所有缺失和延迟测试的根本原因。
In response to this letter, provide the following.
在回复此函时，请提交以下：
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A retrospective review into all missing or delayed stability testing that is intended to support the shelf-life of each of your U.S. products.
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一份对所有缺失和延迟的用以支持你们美国产品货架期的稳定性测试的回顾性审核
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An impact assessment for the missed or delayed stability testing, and an updated summary of all stability data (i.e., data obtained for each testing) supporting each of your U.S. products.
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一份稳定性测试缺失和延迟影响评估，以及支持你们所有美国产品的所有稳定性数据的更新后的汇总（即所有检测中获得的数据）
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A comprehensive assessment and CAPA to ensure the adequacy of your stability program. Your CAPA should include, but should not be limited to, correcting the root causes of the missed and delayed stations, ensuring adequate number of qualified quality control personnel, improved procedures, and comprehensive personnel training.
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一份全面的评估和CAPA以确保你们稳定性程序的充分性。你们的CAPA应包括但不仅限于纠正缺失和延迟点的根本原因、确保足够数量的具备资质的质量控制人员、改进程序以及全面的人员培训
3. Your firm failed to maintain written records so that data therein could be used for evaluating, atleast annually, the quality standards of each drug product to determine the need for changes in drug product specifications or manufacturing or control procedures (21 CFR 211.180(e)).你公司未能维护书面记录使得其中数据能用于（至少每年的）评估每种药品的质量标准以确定是否需要修改药品质量标准或生产或控制程序（21 CFR 211.180(e)）。
Your annual product reviews (APR) only included batches shipped to the United States and the associated deviation investigations. TheAPR did not include batches shipped to countries other than the United States,but manufactured under the same conditions.
你们的年度产品回顾（APR）只包括了发运至美国的批次，以及相关的偏差调查。该APR并未包括发运至美国以外其它国家的批次，但这些批次都是在相同条件下生产的。
For example, your 2016 APR of (b)(4) mL included only (b)(4) batches and two deviation investigations. However, in 2016, you manufactured (b)(4) batches of this product for all markets at your facility and conducted 16 investigations of which 15 were related to product yield failures. Because all the batches were manufactured using the same manufacturing operation, each of these batches should be included in your APR to allow meaningful trends to be detected.
例如，你们的2016年XXmL产品的APR只有XX批次和2个偏差调查。但是在2016年，你们在你们场所内生产了XX批次此产品供应所有市场，并有16次调查，其中15个调查与产品收率不合格有关。由于所有批次的生产均使用了相同的生产操作，每个此类批次均应包括在你们的APR中以使得可以发现有意义的趋势。
Your firm did not provide a sufficient response to thisviolation. For example, there was no indication that you are remediating your APR program or retrospectively reviewing trends by incorporating batches not shipped to the United States into annual reviews.
针对此违规情况，你公司并未提交充分的回复。例如，并未说明你们是否在弥补你们的APR程序，或是通过将未发往美国的批次整合进年度回顾里进行回顾性审核趋势。
In response to this letter, provide an assessment of manufacturing and quality data associated with each drug marketed to the United States. Include remediated procedures and retrospective trending to identify any adverse findings and determine the need for changes to manufacturing, control, or specifications.
在回复此函时，请提交对与每个销往美国的药品有关的生产和质量数据的评估。包括弥补程序和回顾趋势以发现所有不良问题并确定是否需要改变生产、控制或质量标准。
Quality Control Unit质量部门
Significant findings in this letter indicate that your quality unit is not able to fully exercise its authority and/or responsibilities. Your firm must provide the quality unit with appropriate authority and sufficient resources and staff to carry out its responsibilities and consistently ensure drug quality.
本函中的重大缺陷显示你们质量部门无法全面履行其权责。你公司必须为质量部门提供适当的权力和足够的资源以及员工来履行其职责并持续确保药品质量。
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. In response to this letter provide the following.
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。在回复此函时，提供以下资料：
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A comprehensive investigation into the extent of the inaccuracies in data records and reporting, including results of the data review for drugs distributed to the United States. Include a detailed description of the scope and root causes of your data integrity lapses.一份对数据记录和报告不准确性程度的全面调查，包括销售至美国的药品的回顾审核结果。包括一份对你们数据完整性问题的范围与根本原因的详细描述。
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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。
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A management strategy for your firm that includes the details of your global corrective action and preventive action plan. The detailed corrective action plan should describe how you intend to ensure the reliability and completeness of all data generated by your firm, including microbiological and analytical data, manufacturing records, and all data submitted to FDA.你们公司的管理策略，包括你们全球CAPA计划详细情况。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，包括微生物和分析数据、生产记录和所有提交给FDA的数据。
CGMP Consultant Recommended CGMP顾问建议
Based upon the nature of the violations we identified atyour firm, we strongly recommend engaging a consultant qualified as set forthin 21 CFR 211.34 to assist your firm in meeting CGMP requirements. The third-party consultant should comprehensively audit and assist with remediatingyour operations, including but not limited to data integrity, environmental monitoring, investigations of deviations, container-closure defects, aseptic processing, laboratory systems, quality unit authorities and resources, equipment and facilities, and all other elements of your quality system.
依据我们在你们工厂发现的违规情况，我们强烈建议你们使用一位有资质的顾问来协助你们公司符合CGMP要求。第三方对你们操作的审核应全面评估和协助弥补你们的操作，包括但不仅限于：数据完整性、环境监测、偏差调查、容器密闭器缺陷、无菌工艺、化验室系统、质量部门权力与资源、设备与设施以及所有你们质量体系的其它要素。
Your use of a consultant does not relieve your firm’s obligation to comply with CGMP. Your firm’s executive management remains responsible for fully resolving all deficiencies and ensuring ongoing CGMP compliance.
你们使用顾问并不解除你们公司符合CGMP的义务。你们公司的高级管理层仍负有义务全面解决所有缺陷，确保持续CGMP符合性。
Conclusion 结论
Violations cited in this letter are not intended as an all-inclusive list. You are responsible for investigating these violations, for determining the causes, for preventing their recurrence, and for preventing other violations.
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 thatyou contact CDER’s Drug Shortages Staff immediately, at drugshortages@fda.hhs.gov, so that FDA can work with you on the most effectiveway to bring your operations into compliance with the law. Contacting the DrugShortages Staff also allows you to meet any obligations you may have to reportdiscontinuances 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21U.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 violations 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 violations may also result in FDA refusing of articles manufactured at Taiwan Biotech Co., Ltd at 22, Chieh-ShouRoad, Taoyuan District, Taoyuan City into the United States under section801(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, in that the methods andcontrols used in their manufacture do not appear to conform to CGMP within themeaning 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21 U.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 inwriting within 15 working days. Specify what you have done since our inspectionto correct your violations and to prevent their recurrence. If you cannot complete 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 toCDER-OC-OMQ-Communications@fda.hhs.gov or mail your reply to:
LT Loan Chin
Pharmacist
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 3003598505.
Sincerely,
/S/
Francis Godwin
Acting Director
Office of Manufacturing Quality
Office of Compliance
Center for Drug Evaluation and Research
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