Dear Mr. Sun Jia Quan:
The U.S. Food and Drug Administration (FDA) inspected your drug manufacturing facility, Jiangsu NHWA Pharmaceutical Co., Ltd. (Jiawang site), FEI 3005619485, at No. 6 Tianyong Road, Industrial Park, Xuzhou, Jiangsu, from April 1 to 5, 2019.
2019年4月1日至5日，美国FDA对位于江苏徐州工业园区天永路6号的贾汪工厂（FEI 3005619485）进行了检查。
This warning letter summarizes significant deviations from current good manufacturing practice (CGMP) for active pharmaceutical ingredients (API).
本警告信总结了严重违反API cGMP的情况。
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。
Additionally, your drug products, (b)(4) are adulterated under section 501(b) of the FD&C Act, 21 U.S.C. 351(b), for failure to conform to compendial standards for strength, quality, or purity.
此外，药品(b)(4)在FD&C Act, 21 U.S.C. 351(b)的第501(b)条中被认为是掺假，原因是其规格、质量或纯度不符合药典标准。
We reviewed your April 26, 2019, response to our Form FDA 483 in detail and acknowledge receipt of your subsequent correspondence.
我们审核了你们2019年4月26日的答复信，并以此确认收到您随后的来信。
During our inspection, our investigator observed specific deviations including, but not limited to, the following.
在检查期间，我们的检查员观察到具体的违规情况，包括但不限于以下情况。
1.    Failure to ensure that all sampling plans and test procedures are scientifically sound and appropriate to ensure that your API conform to established standards of quality and purity.
      未能确保所有取样计划和检测程序是合理科学和适当的，以确保你的原料药符合既定的质量和纯度标准。
You manufacture multiple API listed in the United States Pharmacopeia (USP) that were imported into the United States and supplied to compounding pharmacies. For (b)(4) API, the laboratory stability protocols used to support expiration dating of these API are based on methods and specifications in the 2015 Chinese Pharmacopeia. You were not able to demonstrate that the tests used are equivalent to or better than the current USP 42 compendial methods. FDA compared your test methods, based on the Chinese Pharmacopeia, to the current standard in the USP. We found multiple differences in specifications and test methods. We also found that required tests for quality attributes in the USP were not part of the Chinese Pharmacopeia or your stability protocols. Beyond a deviation from CGMP, this also causes your drugs to be adulterated within the meaning of 501(b) of the FD&C Act, 21 U.S.C. 351(b), in that their strength, quality, or purity falls below the standards set forth in an official compendium recognized in the FD&C Act.
你们生产多种美国药典(USP)中列出的原料药，这些原料药被进口到美国并供应给制剂厂商。对于(b)(4)原料药，用于支持这些原料药有效期的实验室稳定性方案是基于2015版中国药典的方法和规范制定的。无法证明所使用的测试等同于或优于当前的USP 42 Compendial方法。FDA将基于《中国药典》的检测方法与USP现行标准进行了比较。我们发现在标准和测试方法上存在多种差异。我们还发现USP中所要求的质量属性测试并不在中国药典或您的稳定性方案中。除了cGMP的偏差外，这还会导致您的药物FD&C Act, 21 U.S.C. 351(b)的第501(b)条中被认为是掺假，因为它们的规格、质量或纯度低于FD&C Act认可的官方标准。
Additionally, forced degradation studies were not validated for your USP-grade? (b)(4).
In your response, you stated that you would cease distribution until you have updated your methods, conducted a comparison of your test methods versus the current USP compendial methods, and tested reserve samples against the current USP standards. You stated that you would take appropriate action if you found quality issues with U.S. distributed product within expiry.
此外，对于USP级-(b)(4)产品，强制降解研究没有得到验证。在回复中，您声明将停止销售，直到您更新方法，将测试方法与当前USP方法进行了比较，并根据当前USP标准测试了留样。您声称，如果发现美国分销的产品在有效期内存在质量问题，将采取适当的行动。
In response to this letter, provide:
作为答复，请提供：
Your commitment to using current USP compendial methods until any alternative methods have been demonstrated to be equivalent or better than the USP methods.
承诺使用当前的USP方法，直到任何替代方法被证明等同或优于USP方法。
A comprehensive study that determines whether your test methods for your API are equivalent to, or better than, the USP method, if you are not using current USP compendial methods. Include all findings and deviations encountered in assessing whether your alternative method is equivalent or superior to the USP compendial method. For FDA’s current thinking regarding analytical test method validation, see Analytical Procedures and Methods Validation for Drugs and Biologics at https://www.fda.gov/media/87801/download.
如果没有使用当前的USP方法，应开展一项全面的研究，以确定API测试方法是否等同于或优于USP方法，包括在评估替代方法是否等同或优于USP方法时遇到的所有发现和偏差。有关FDA关于分析测试方法验证的想法，请参见https://www.fda.gov/media/87801/download《药品和生物制品的分析程序和方法验证》。
Updated test results using a validated test method (e.g., USP method) of all reserve samples for all drugs released to the U.S. market within expiry to ensure that your drug products conform to appropriate standards of identity, strength, quality, and purity.
使用有效的测试方法(如USP方法)，对在有效期内投放美国市场的所有药品的所有留样进行测试，并更新测试结果，以确保药品符合适当的鉴别、规格、质量和纯度标准。
Your action plan to address any product quality or patient safety risks for your drug products in U.S. distribution, including potential customer notifications, recalls, or market withdrawals.
行动计划，以解决在美国分销的任何有产品质量或患者安全风险的药品，包括潜在的客户通知，召回，或市场撤回。
Your procedure for documenting and investigating any deviations from laboratory control procedures.
记录和调查任何偏离实验室控制程序的程序。
2.    Failure to adequately investigate and document out-of-specification results according to a procedure and implement appropriate corrective actions.
       未能根据程序充分调查和记录OOS结果，并采取适当的纠正措施。
Our investigator discovered that (b)(4) batches of (b)(4) API failed finished release testing due to the discovery of foreign particles during color/clarity solution testing. The investigations, OOS-201607109 and OOS-201608130, failed to identify the root cause and source of the foreign materials.
我们的调查员发现(b)(4)批(b)(4)原料药放行测试失败，原因是在溶液颜色/澄清度测试中发现了颗粒异物。调查显示，OOS-201607109和OOS-201608130未能查明异物的根本原因和来源。
Additionally, in October 2016, (b)(4) of (b)(4) API (b)(4) were returned to your firm due to the presence of (b)(4) of foreign particles ((b)(4) and (b)(4)).
此外，2016年10月，由于在产品中发现异物颗粒(b)(4)和 (b)(4)，(b)(4)产退回到你们公司。
In your response, you stated that you would reexamine your procedures for evaluating laboratory investigations, customer complaints, and deviations. You also committed to review all out-of-specification (OOS) results. Your response was inadequate in that you did not review the analytical test results you used to release drugs to the U.S. supply chain, using non-USP methods, to determine if any passing test results were, in fact, out of specification when compared to the USP standards.
在答复中，你们声称将重新检查评估实验室调查、客户投诉和偏差的程序。还承诺审查所有OOS的结果。您的回答是不充分的，因为没有审查用于向美国供应链销售药物使用非USP方法的分析测试结果，以确定与USP标准相比，任何通过的测试结果实际上是否超出了标准。
In response to this letter, provide:
作为答复，请提供：
A comparison of the test methods used to release API to the U.S. market versus the USP compendial standards. For any tests with differing specifications, investigate whether you released OOS material.
用于向美国市场API的测试方法与USP标准的比较。对于任何不同标准的测试，调查是否放行了OOS物料。
A retrospective, independent review of all invalidated OOS (in-process and finished testing) results for products currently on the U.S. market within expiry. Assess whether the scientific justification and evidence for each invalidated OOS result was conclusive. For investigations that establish laboratory root cause, ensure that other laboratory methods vulnerable to the same root cause are identified for remediation.
对目前在美国市场上销售的产品的所有无效的OOS(中间产品和成品测试)结果进行回顾性、独立的审查。评估每一个无效OOS结果的科学依据和证据是否具有结论性。对于确定为实验室根本原因的调查，确保易受同一根本原因影响的其他实验室方法已进行识别和纠正。
A thorough review of production (e.g., batch manufacturing records, adequacy of manufacturing steps, raw materials, process capability, deviation history, batch failure history) for any OOS results with inconclusive or no root cause identified.
对不确定或没有根本原因的OOS结果进行彻底的审核(如:批生产记录、生产步骤的充足性、原材料、工艺能力、偏差历史、不合格历史)。
A corrective actions and preventive actions (CAPA) plan that identifies manufacturing root causes and specifies meaningful improvements.
纠正和预防措施(CAPA)计划，确定生产的根本原因并制定有意义的改进。
A review and remediation of your system for investigating OOS results. Provide a CAPA plan to improve OOS handling. Your CAPA plan should ensure that your revised OOS investigations procedure includes:
审核和纠正OOS结果的系统调查。提供CAPA计划以改进OOS处理。CAPA计划应确保修订的OOS调查程序包括:
Enhanced quality unit oversight of laboratory investigations
加强质量部门对实验室调查的监察
Identification of adverse laboratory control trends
识别不良实验室控制趋势
Resolution of causes of laboratory variation
解决实验室变异的原因
Investigations of potential manufacturing causes when a laboratory cause cannot be conclusively identified
当无法确定实验室原因时，对潜在生产原因的调查
Drug Distribution Ceased Until Corrective Actions Implemented
在采取纠正行动之前，停止药品销售
 
We acknowledge your commitment to cease distribution of drugs manufactured at the Jiawang site to the U.S. market until you have completed your CAPA plan and confirmed its effectiveness.
我们认同贵公司承诺在完成CAPA计划并确认其有效性之前，将停止在贾汪工厂生产药品在美国市场的销售。
 
In response to this letter, please confirm that you will not resume manufacturing drugs for the U.S. market until the FDA has verified the adequacy of your CAPA. When you have completed your corrective actions, notify this office in writing.
作为答复，请确认在FDA确认CAPA充分之前，不会恢复美国市场产品的生产。当完成了纠正措施时，请书面通知本办公室。 
Conclusion
结论
 
The deviations cited in this letter are not intended to be an all-inclusive list of deviations that exist at your facility. You are responsible for investigating and determining the causes of these deviations and for preventing their recurrence or the occurrence of 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，防止你们工厂内其它偏差的发生。
 
Until you correct all deviations completely and we confirm your compliance with CGMP, FDA may withhold approval of any new drug 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。
 
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 cannot complete corrective actions within 15 working days, state your reasons for delay and your schedule for completion.
在收到此函后，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:
 
Rokhsana Jazi
Compliance Officer
U.S. Food and Drug Administration
White Oak Building 51, Room 4235
10903 New Hampshire Avenue
Silver Spring, MD 20993
USA
 
Please identify your response with FEI 3005619485.
Sincerely,
/S/
Francis Godwin
Director
Office of Manufacturing Quality
Office of Compliance
Center for Drug Evaluation and Research