FDA警告信：珠海联邦制药

Warning Letter 320-18-61                                          June 27, 2018

Ms. Shirley Cai, Chief Executive Officer

Zhuhai United Laboratories Co., Ltd.

No. 2428 Anji Road, SanzaoTown, Jinwan District, Zhuhai, Guangdong 519040 China

Dear Ms. Cai:

The U.S. Food and Drug Administration (FDA) inspected your drug manufacturing facility, Zhuhai United Laboratories Co., Ltd., at No. 2428 Anji Road, Sanzao Town, Jinwan District, Zhuhai, from September 11 to 15, 2017.

美国FDA于2017年9月11-15日检查了你们位于中国广东省珠海市国家高新技术产业开发区三灶镇安基路2428号的珠海联邦制药股份有限公司生产场所。

This warning letter summarizes significant deviations from CGMP for active pharmaceutical ingredients (API).

本警告信总结了原料药（API）生产严重违反CGMP的行为。

Because your methods, facilities, or controls for manufacturing, processing, packing, or holding do not conform to CGMP, your drugs 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).

由于你们的原料药生产、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21U.S.C. 351(a)(2)(B)被认为是掺假药品。

We reviewed your October 6, 2017, response in detail.

 我们已详细审核了你公司2017年10月6日的回复。

During our inspection, our investigators 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 adequately investigate and document out-of-specification results according to a procedure.未依据程序充分调查并记录OOS结果。

Our review of your out-of-specification (OOS) investigations found that you lacked adequate procedures for investigating, and scientific justification to invalidate, OOS results.

我们在对你们的OOS调查审核中你们缺乏足够的OOS结果调查程序，缺乏科学论证即宣布OOS结果无效。

OOS Results for Assay  含量OOS结果

You initiated an investigation of an initial OOS assay result for (b)(4) batch (b)(4), which was found to be significantly below specification ((b)(4)–(b)(4)%). You also initiated an investigation of an initial OOS assay result for (b)(4) batch (b)(4), which also yielded a test result below specification ((b)(4)–(b)(4)%).

你们启动了一份针对XX产品XX批次初始OOS含量结果的调查，该结果显著低于标准规定（XX-XX%）。你们还启动了对XX产品XX批次的初始OOS含量结果调查，该结果亦低于标准规定（XX-XX%）。

In both cases, your brief investigations found no anomalies and only stated that it was possible that the sample glassware was not thoroughly cleaned. Although you did not identify a laboratory error and lacked scientific justification, you invalidated the OOS results. Your firm released both batches based on passing retests.

在2个案例中，你们的简要调查说未发现异常，只是声称可能是样品玻璃仪器未清洁彻底。尽管你们并未发现实验室错误，亦缺乏科学论证，但你们宣布该OOS结果无效。你公司依据复验合格结果放行了这2个批次。

Your acceptance of the passing results based on an assumed laboratory error was insufficient to invalidate the original failing result and conclude the investigation.

你们依据假定的实验室错误接受了合格结果，用以宣布原始不合格结果并对调查做出结论是不充分的。

Re-analysis of the actual solutions, test units, and glassware is an integral part of an investigation to determine whether alaboratory error may have occurred. This assessment, in tandem with hypothesis testing if initial re-examinations do not reveal a root cause, is instrumental in determining whether there was a causative laboratory error. Whenever a laboratory investigation lacks conclusive evidence of laboratory error, it is essential that the investigation extends to a thorough investigation of potential manufacturing causes.

对当初实际检测用溶液、检测单元以及玻璃仪器进行重新分析是调查中不可分割的部分，这些调查可用以确定是否可能曾发生过化验室误差。如果初始重新检查并未发现根本原因，则这些评估，同假定测试一起，可帮助确定是否有可归因的实验室错误。当实验室调查缺乏证据做出实验室错误结论时，将调查延伸至可能的生产原因全面调查是很重要的。

Your response acknowledged that there was “no scientific justification or studies performed to evaluate or prove this hypothetical root cause.”

你们的回复说“没有科学论证或进行研究用以评估或证明此假设性根本原因”。

Since our inspection, your indicated that you have shown that the API may degrade in the presence of residual detergent in glassware.However, your response did not include your study data.

鉴于我们的检查，你们说你们已发现API在玻璃仪器中有残留清洁剂情况下可能会降解。但是你们的回复中并未包括你们的研究数据。

OOS Results for Residual Solvent残留溶剂OOS结果

You initiated investigation P201611001 for an initial OOS result of (b)(4) parts per million (ppm) in your (b)(4) residual solvent test (specification: not more than (b)(4) ppm) for (b)(4) API batch (b)(4). The investigation did not reveal laboratory testing anomalies. You tested another sample preparation three times and obtained results very close to the specification upper limit ((b)(4), and (b)(4)ppm). You invalidated the initial failing result, stating that your statistical analysis showed a significant difference between the original value and there test results. Your investigation lacked further assessment of the root cause of the failing result.

你们启动了XX原料药批号XX的XX残留溶剂初始OOS结果XXppm调查P201611001（标准规定：不得过XXppm）。调查并未发现实验室检测异常。你们检查了另一份样品溶液3次，得到了非常接受标准上限的结果（XX和XXppm）。你们宣布了初始不合格结果无效，声称你们的统计分析显示原始结果与复验结果之间存在显著差异。你们的调查缺少了对不合格结果根本原因的进一步评估。

You released the batch to use as an intermediate in your in-house production of (b)(4) batches of (b)(4)API (batches (b)(4)).

 你们将该批次放行用作你们XX原料药XX批次的内部生产（批号XX）用中间体。

It is not appropriate to use an “outlier test” to invalidateyour API test results. Such statistical treatments do not identify the cause of an extreme observation and are only of informational use. In this case, your investigation included multiple retests that were near the upper limit of (b)(4)ppm, similar to the original OOS result.

使用“离群检验”来宣布你们的API检验结果无效是不恰当的。此统计学处理方法并不能识别出极端观察值的原因，只能作为参考使用。在此案例中，你们的调查包括了多个接近上限XXppm的结果，这些结果与原始的OOS结果类似。

Furthermore, your OOS investigation procedure, Q0100012.001, was inadequate because it did not adequately address the need to retest the original sample and specify when a new sample should be tested.

另外，你们的OOS调查程序Q0100012.001是不充分的，因为其中并未充分说明需要对原始样品进行复验，未说明应在何时检查新样品。

We acknowledge receipt of your revised OOS investigation procedure. However, your response is inadequate because it does not meet CGMP. Your response stated that you can use an outlier test in determining whether to “waive the requirement for conducting appropriate laboratory investigation todetermine definitive or potential root cause(s) for the atypical result(s).” It is inappropriate for your procedure to permit waiver of this requirement. Your OOS procedure should specify that outlier tests cannot be used for anything other than auxiliary, informational purposes.

我们在此知会我们已收到你们修订后的OOS调查程序。但是，你们的回复是不充分的，因为该程序并不符合CGMP要求。你们的回复声称你们可使用“离群检验”来确定是否“免除为确定异常结果的明确或潜在根本原因而进行的适当的化验室调查”。你们的程序允许免除此要求是不恰当的。你们的OOS程序应指明离群检验只能作为辅助参考之用。

Your response also indicated that your firm was retrospectively assessing effects of previously- reported OOS results on your products. However, your response did not provide related records to document your review or summarize findings. It is unclear whether the retrospective review included an evaluation of your use of the statistical outlier test to invalidate OOS results.

你们的回复还说你们公司回顾性评估了之前所报告的OOS结果对你们产品的影响。但是，你们的回复并未提交相关记录来记录你们对发现问题的审核和汇总。我们并不清楚该回顾性审核是否包括了对你们使用统计性离群检验宣布OOS结果无效的评估。

In response to this letter:

在回复此函时：

• Provide a retrospective review of all invalidated OOS results obtained for products on the U.S. market. Assess whether the scientific justification and evidence was conclusive. For investigations that established the laboratory root cause conclusively, determine the adequacy of the corrective action and preventive action (CAPA) plan and ensure the other     laboratory methods vulnerable to the same root cause have been identified for remediation. For any OOS results that had an inconclusive or no root cause identified in the laboratory, include a thorough review of production, such as batch manufacturing records, adequacy of manufacturing steps, process capability, deviation history, and batch failure history. Provide a CAPA plan that identifies the potential manufacturing root causes for each such investigation. Include process improvements where appropriate.

• 请提交对所有销往美国的产品中得到的宣布无效的OOS结果的回顾性审核。评估科学论证和证据是否支持相关结论。对于可支持实验室根本原因结论的调查，请确定CAPA计划的充分性，确保识别出其它容易受到相同根本原因影响的化验室方法并对其进行补救。对于所有无结论的或未在化验室识别出根本原因的OOS结果，提交一份全面的生产审核，例如批生产记录、生产步骤充分性、工艺能力、偏差历史以及批不合格历史。提交一份CAPA计划，识别出每个此类调查中可能的生产根本原因，适当时还应包括工艺改进。

• Evaluate all instances in which a statistical outlier test was used to invalidate OOS results. Determine the potential effect on drug quality.

• 评估所有使用了统计学离群检验宣布OOS结果无效的事件，确定是否对药品质量有潜在影响。

• Assess your overall system for investigating OOS results. Provide a CAPA plan to improve the quality of OOS investigations. Your CAPA should ensure that your revised OOS investigations procedure includes improved quality unit oversight of laboratory investigations, identification of adverse laboratory control trends, and investigation of potential manufacturing     causes when a laboratory cause cannot be conclusively identified.

• 评估你们OOS结果调查整体系统。提交一份OOS调查质量改进的CAPA计划。你们的CAPA应确保你们修订了OOS调查程序，包括改进质量部门对化验室调查的监管、识别出不良化验室控制趋势，以及当不能识别出可给出结论的化验室原因时对潜在生产原因的调查。

• Comprehensive independent assessment of your overall system for investigations of deviations, discrepancies, complaints, OOS results, and failures. Your CAPA should include, but not be limited to, improvements in investigation competencies, root cause analysis, written procedures, and quality unit oversight. Also include your process for evaluating CAPA effectiveness.

• 对你们偏差、不符合、投诉、OOS结果和不合格调查的整体系统的全面独立评估。你们的CAPA应包括但不仅限于对调查能力、根本原因分析、书面程序以及质量部门监管的改进。还应包括你们评估CAPA有效性的流程。

For more information about handling failing,out-of-specification, out-of-trend, or other unexpected results and documentationof your investigations, see FDA’s guidance document, InvestigatingOut-of-Specification (OOS) Test Results for Pharmaceutical Production, athttps://www.fda.gov/downloads/drugs/guidances/ucm070287.pdf.

更多OOS处理信息参见FDA官网。

2.      Failure of your quality unit to ensure that critical deviations are investigated and resolved.质量部门未能确保调查并解决关键偏差。

You did not adequately investigate findings from your February 2015 retrospective review of analytical chromatography data irregularities (e.g., data deletion, sample trial injections, and missing audit trails). You did not sufficiently expand the scope of your limited review to a larger data set when you found significant data integrity lapses. Your investigation was also insufficient because your corrective actions failed to prevent recurrence of major data integrity deviations. For example, our investigators found that your firm deleted the initial chromatographic injection of (b)(4) API, batch (b)(4), during batch release testing performed several months after the retrospective investigation.

你们未充分调查在2015年2月对分析色谱数据管理不良（例如，数据删除、样品试针以及审计追踪缺失）回顾性审核所发现的问题。当你们发现有严重的数据完整性失误时，你们并未充分扩展你们有限审核的范围至更多的数据序列。你们的调查不充分还因为你们的纠正措施未能防止严重数据完整性偏差的重复发生。例如，我们的调查人员发现你们公司删除了在回顾性调查之后几个月所执行的XX原料药批号XX批放行检测中的初始色谱进样。

Your response stated that you performed a further retrospective review (protocol SD-Q0100011.000) of analytical chromatographic data and found further residual solvents results with inappropriate integration, system suitability testing data showing non-consecutive injectionsof the reference solution, and repeat injections. Your response was inadequate because you did not include sufficient details to demonstrate that you confirmedthe validity of initial test results. Such detail would include retest sample testing dates and results, comparison of retest data to original data, and your“comprehensive review records” for the batches included in the assessment. Your response also lacked an assessment of the root cause of data integrity breaches and corrective actions for any products that failed to meet specifications.

你们的回复声称你们进行了更深入的分析色谱数据回顾性审核（方案SD-Q0100011.000），发现更多积分不当的残留溶剂结果、系统适用性测试数据显示对照液进样不连续以及重复进样。你们的回复是不充分的，因为你们并未包括足够的详细信息来证明你们确定了初始检测结果的有效性。此类详细信息应包括有复验样品检测日期和结果、复验数据与原始数据的比较以及你们对评估中所包括批次的“全面审核记录”。你们的回复亦缺少了对数据完整性问题根本原因的评估，以及对所有不符合标准产品的纠正措施。

In response to this letter, provide:

在回复此函时请提交：

• a copy of the deviation investigation, GOV-2017001, initiated in response to our inspectional findings;

• 回复我们检查缺陷所启动的偏差调查的副本GOV-2017001

• completed reports for all review stages in your retrospective review (protocol SD-Q0100011.000) including related annex documents; and

• 在你们回顾性审核（方案SD-Q0100011.000）的所有审核阶段已完成的报告，包括相关附录文件，以及

• the additional information requested in the Data Integrity Remediation section of this letter.

• 本函中数据完整性补救部分所要求的其它资料

Additional Concerns Related to Aseptic Processing  无菌工艺有关的其它问题

Our investigators found additional examples of incomplete data relating to the sterile manufacturing operations evaluated as part of our pre-approval inspection. For instance, your firm failed to maintain electronicdata documenting decontamination cycles for the grade A area of workshop (b)(4) where you aseptically manufacture sterile powders. Your firm overwrote the electronic data and kept only a cursory written record.

我们调查人员发现了作为我们PAI检查一部分的与无菌生产操作有关的其它数据不完整例子，例如，你公司未维护记录你们以无菌工艺生产无菌粉的XX车间A级区除污染循环的电子数据。你公司覆盖了电子数据，只保存了一份潦草写就的记录。

You also did not assure reliability of electronic data for monitoring non-viable particles in your manufacturing areas. Our investigators observed that you disabled the electronic audit trail function for your non-viable particle monitoring system for grade A and B areas of workshops (b)(4)and (b)(4) on at least two days in August 2017 when sterile API was manufactured. Also, data files containing particle counts had been modifiedwith no indication of who made the changes or what was modified.

你们亦未确保你们生产区域的尘粒监测电子数据的可靠性。我们调查人员发现你们在2017年8月至少有2天关闭了你们XX车间和XX车间的A级和B级区尘粒监测系统的电子审计追踪功能，当时有无菌API正在生产。还有，含有尘粒计数的数据文件已被修改，未显示是谁修改，修改了什么。

In your response, you provided a review of these findings.Your firm committed to assess the effects on your products of any additional insufficient non-viable particulate monitoring records since the last FDA inspection in March 2015. Your response was inadequate because you did not provide sufficient data to support your conclusions, or commit to a more comprehensive CAPA to assess data systems integrity.

在你们的回复中，你们提交了一份对这些问题的审核。你们公司承诺会评估自上次2015年3月FDA检查以来所有其它尘粒监测记录不充分对你们产品的影响。你们的回复是不充分的，因为你们并未提交充分的数据来支持你们的结论，或承诺制订更为全面的CAPA来评估数据系统完整性。

Our inspection also revealed poor aseptic processing operation behaviors. In response to this letter, provide:

我们的检查还发现无菌工艺操作行为不良。在回复此函时，请提交：

• Your plan to assure appropriate aseptic practices and cleanroom behavior during production. Include specific steps to ensure routine supervisory oversight for all production batches. Also describe the frequency of quality assurance oversight during aseptic processing and other operations.

• 你们确保在生产期间执行适当的无菌操作和洁净间行为的计划。包括确保对所有生产批次进行常规督导监管的具体步骤。还要描述在无菌生产和其它操作执行过程中QA的监管频次。

• Comprehensive identification of all contamination hazards with respect to your aseptic     processes, equipment, and facilities. Provide a risk assessment that covers 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. Also include a detailed CAPA plan, with timelines, to address the findings of the contamination hazards risk assessment. 

• 全面识别所有与你们无菌工艺、设备和设施有关的污染危害。提交一份风险评估，在其中覆盖所有人与ISO 5区域的互动、设备放置与人体工程学、ISO 5区域内空气质量与周围房间、设施平面布局图、人流和物流。还要包括详细的CAPA计划以及时间表，解决污染危害风险评估问题。

Also, see FDA’s guidance document, Sterile Drug ProductsProduced by Aseptic Processing—Current Good Manufacturing Practice, to helpyou meet the CGMP requirements when manufacturing sterile drugs using asepticprocessing, at https://www.fda.gov/downloads/Drugs/Guidances/ucm070342.pdf.

亦请参见FDA指南文件“无菌工艺生产的无菌药品—CGMP”。

Data Integrity Remediation 数据完整性补救措施

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:

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：

A.    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。

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 ofdata 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. The detailed CAPA plan should describe how you intend to ensurethe reliability and completeness of all data generated by your firm, including all laboratory data, manufacturing records, and all data submitted to FDA. Part of this CAPA plan should be focused on remediating vulnerabilities in the design and controls (configurations, administrative rights, oversight, etc.)of your computer systems.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CAPA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，包括所有化验室数据、生产记录和所有提交给FDA的数据。此CAPA计划的一部分应重点写明你们计算机系统设计和控制（参数设置、管理权限、监管等）中易受影响部分的补救。

CGMP Consultant Recommended CGMP顾问建议

Based upon the nature of the deviations we identified atyour firm, we strongly recommend engaging a consultant qualified to evaluate your operations to assist your firm in meeting CGMP requirements. We also recommend that the qualified third party perform a comprehensive systems auditof your entire operation for CGMP compliance (including data integrity), and evaluate the completion and effectiveness of your corrective actions and preventive actions.

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21 CFR211.34所述资质的顾问来协助你们公司符合CGMP要求。我们还建议具备资质的第三方对你们全面操作进行综合审计（包括数据完整性），并你们CAPA的完整性和有效性。

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

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 depend on 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 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 Zhuhai United Laboratories Co.,Ltd., at No. 2428 Anji Road, Sanzao Town, Jinwan District, Zhuhai, into the United 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, in that the methods and controls used in their manufacture do not appear to conform 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 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.govor mail your reply to:

Ms. Carrie Ann Plucinski

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 3006531950.

Sincerely,

/S/

Francis Godwin

Acting Director

Office of Manufacturing Quality

Office of Compliance

Center for Drug Evaluation and Research

Via UPS                                                                                 Warning Letter 320-18-61

Return Receipt Requested

June 27, 2018

Ms. Shirley Cai

Chief Executive Officer

Zhuhai United Laboratories Co., Ltd.

No. 2428 Anji Road

Sanzao Town, Jinwan District

Zhuhai, Guangdong 519040

China

Dear Ms. Cai:

The U.S. Food and Drug Administration (FDA) inspected your drug manufacturing facility, Zhuhai United Laboratories Co., Ltd., at No. 2428 Anji Road, Sanzao Town, Jinwan District, Zhuhai, from September 11 to 15, 2017.

This warning letter summarizes significant deviations from CGMP for active pharmaceutical ingredients (API).

Because your methods, facilities, or controls for manufacturing, processing, packing, or holding do not conform to CGMP, your drugs 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).

We reviewed your October 6, 2017, response in detail.

During our inspection, our investigators observed specific deviations including, but not limited to, the following.

1.   Failure to adequately investigate and document out-of-specification results according to a procedure.

Our review of your out-of-specification (OOS) investigations found that you lacked adequate procedures for investigating, and scientific justification to invalidate, OOS results.

OOS Results for Assay

You initiated an investigation of an initial OOS assay result for (b)(4) batch (b)(4), which was found to be significantly below specification ((b)(4)–(b)(4)%). You also initiated an investigation of an initial OOS assay result for (b)(4) batch (b)(4), which also yielded a test result below specification ((b)(4)–(b)(4)%).

In both cases, your brief investigations found no anomalies and only stated that it was possible that the sample glassware was not thoroughly cleaned. Although you did not identify a laboratory error and lacked scientific justification, you invalidated the OOS results. Your firm released both batches based on passing retests.

Your acceptance of the passing results based on an assumed laboratory error was insufficient to invalidate the original failing result and conclude the investigation.

Re-analysis of the actual solutions, test units, and glassware is an integral part of an investigation to determine whether a laboratory error may have occurred. This assessment, in tandem with hypothesis testing if initial re-examinations do not reveal a root cause, is instrumental in determining whether there was a causative laboratory error. Whenever a laboratory investigation lacks conclusive evidence of laboratory error, it is essential that the investigation extends to a thorough investigation of potential manufacturing causes.

Your response acknowledged that there was “no scientific justification or studies performed to evaluate or prove this hypothetical root cause.”

Since our inspection, your indicated that you have shown that the API may degrade in the presence of residual detergent in glassware. However, your response did not include your study data.

OOS Results for Residual Solvent

You initiated investigation P201611001 for an initial OOS result of (b)(4) parts per million (ppm) in your (b)(4)residual solvent test (specification: not more than (b)(4) ppm) for (b)(4) API batch (b)(4). The investigation did not reveal laboratory testing anomalies. You tested another sample preparation three times and obtained results very close to the specification upper limit ((b)(4), and (b)(4) ppm). You invalidated the initial failing result, stating that your statistical analysis showed a significant difference between the original value and the retest results. Your investigation lacked further assessment of the root cause of the failing result.

You released the batch to use as an intermediate in your in-house production of (b)(4) batches of (b)(4) API (batches (b)(4)).

It is not appropriate to use an “outlier test” to invalidate your API test results. Such statistical treatments do not identify the cause of an extreme observation and are only of informational use. In this case, your investigation included multiple retests that were near the upper limit of (b)(4) ppm, similar to the original OOS result.

Furthermore, your OOS investigation procedure, Q0100012.001, was inadequate because it did not adequately address the need to retest the original sample and specify when a new sample should be tested.

We acknowledge receipt of your revised OOS investigation procedure. However, your response is inadequate because it does not meet CGMP. Your response stated that you can use an outlier test in determining whether to “waive the requirement for conducting appropriate laboratory investigation to determine definitive or potential root cause(s) for the atypical result(s).” It is inappropriate for your procedure to permit waiver of this requirement. Your OOS procedure should specify that outlier tests cannot be used for anything other than auxiliary, informational purposes.

Your response also indicated that your firm was retrospectively assessing effects of previously-reported OOS results on your products. However, your response did not provide related records to document your review or summarize findings. It is unclear whether the retrospective review included an evaluation of your use of the statistical outlier test to invalidate OOS results.

In response to this letter:

• Provide a retrospective review of all invalidated OOS results obtained for products on the U.S. market. Assess whether the scientific justification and evidence was conclusive. For investigations that established the laboratory root cause conclusively, determine the adequacy of the corrective action and preventive action (CAPA) plan and ensure the other laboratory methods vulnerable to the same root cause have been identified for remediation. For any OOS results that had an inconclusive or no root cause identified in the laboratory, include a thorough review of production, such as batch manufacturing records, adequacy of manufacturing steps, process capability, deviation history, and batch failure history. Provide a CAPA plan that identifies the potential manufacturing root causes for each such investigation. Include process improvements where appropriate.

• Evaluate all instances in which a statistical outlier test was used to invalidate OOS results. Determine the potential effect on drug quality.

• Assess your overall system for investigating OOS results. Provide a CAPA plan to improve the quality of OOS investigations. Your CAPA should ensure that your revised OOS investigations procedure includes improved quality unit oversight of laboratory investigations, identification of adverse laboratory control trends, and investigation of potential manufacturing causes when a laboratory cause cannot be conclusively identified.

• Comprehensive independent assessment of your overall system for investigations of deviations, discrepancies, complaints, OOS results, and failures. Your CAPA should include, but not be limited to, improvements in investigation competencies, root cause analysis, written procedures, and quality unit oversight. Also include your process for evaluating CAPA effectiveness.

For more information about handling failing, out-of-specification, out-of-trend, or other unexpected results and documentation of your investigations, see FDA’s guidance document, Investigating Out-of-Specification (OOS) Test Results for Pharmaceutical Production, at https://www.fda.gov/downloads/drugs/guidances/ucm070287.pdf.

2.      Failure of your quality unit to ensure that critical deviations are investigated and resolved.

You did not adequately investigate findings from your February 2015 retrospective review of analytical chromatography data irregularities (e.g., data deletion, sample trial injections, and missing audit trails). You did not sufficiently expand the scope of your limited review to a larger data set when you found significant data integrity lapses. Your investigation was also insufficient because your corrective actions failed to prevent recurrence of major data integrity deviations. For example, our investigators found that your firm deleted the initial chromatographic injection of (b)(4) API, batch (b)(4), during batch release testing performed several months after the retrospective investigation.

Your response stated that you performed a further retrospective review (protocol SD-Q0100011.000) of analytical chromatographic data and found further residual solvents results with inappropriate integration, system suitability testing data showing non-consecutive injections of the reference solution, and repeat injections. Your response was inadequate because you did not include sufficient details to demonstrate that you confirmed the validity of initial test results. Such detail would include retest sample testing dates and results, comparison of retest data to original data, and your “comprehensive review records” for the batches included in the assessment. Your response also lacked an assessment of the root cause of data integrity breaches and corrective actions for any products that failed to meet specifications.

In response to this letter, provide:

• a copy of the deviation investigation, GOV-2017001, initiated in response to our inspectional findings;

• completed reports for all review stages in your retrospective review (protocol SD-Q0100011.000) including related annex documents; and

• the additional information requested in the Data Integrity Remediation section of this letter.

Additional Concerns Related to Aseptic Processing

Our investigators found additional examples of incomplete data relating to the sterile manufacturing operations evaluated as part of our pre-approval inspection. For instance, your firm failed to maintain electronic data documenting decontamination cycles for the grade A area of workshop (b)(4) where you aseptically manufacture sterile powders. Your firm overwrote the electronic data and kept only a cursory written record.

You also did not assure reliability of electronic data for monitoring non-viable particles in your manufacturing areas. Our investigators observed that you disabled the electronic audit trail function for your non-viable particle monitoring system for grade A and B areas of workshops (b)(4) and (b)(4) on at least two days in August 2017 when sterile API was manufactured. Also, data files containing particle counts had been modified with no indication of who made the changes or what was modified.

In your response, you provided a review of these findings. Your firm committed to assess the effects on your products of any additional insufficient non-viable particulate monitoring records since the last FDA inspection in March 2015. Your response was inadequate because you did not provide sufficient data to support your conclusions, or commit to a more comprehensive CAPA to assess data systems integrity.

Our inspection also revealed poor aseptic processing operation behaviors. In response to this letter, provide:

• Your plan to assure appropriate aseptic practices and cleanroom behavior during production. Include specific steps to ensure routine supervisory oversight for all production batches. Also describe the frequency of quality assurance oversight during aseptic processing and other operations.

• Comprehensive identification of all contamination hazards with respect to your aseptic processes, equipment, and facilities. Provide a risk assessment that covers 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. Also include a detailed CAPA plan, with timelines, to address the findings of the contamination hazards risk assessment. 

Also, see FDA’s guidance document, Sterile Drug Products Produced by Aseptic Processing—Current Good Manufacturing Practice, to help you meet the CGMP requirements when manufacturing sterile drugs using aseptic processing, at https://www.fda.gov/downloads/Drugs/Guidances/ucm070342.pdf.

Data Integrity Remediation

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:

A.    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.

B.    A current risk assessment of the potential effects of the observed failures on the quality of your drugs. Your assessment should include analysesof the risks to patients caused by the release of drugs affected by a lapse of data integrity, and risks posed by ongoing operations.

C.    A management strategy for your firm that includes the details of your global corrective action and preventive action plan. The detailed CAPA plan should describe how you intend to ensure the reliability and completeness of all data generated by your firm, including all laboratory data, manufacturing records, and all data submitted to FDA. Part of this CAPA plan should be focused on remediating vulnerabilities in the design and controls (con-figurations, administrative rights, oversight, etc.) of your computer systems.

CGMP Consultant Recommended

Based upon the nature of the deviations we identified at your firm, we strongly recommend engaging a consultant qualified to evaluate your operations to assist your firm in meeting CGMP requirements. We also recommend that the qualified third party perform a comprehensive systems audit of your entire operation for CGMP compliance (including data integrity), and evaluate the completion and effectiveness of your corrective actions and preventive actions.

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.

Conclusion

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.

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 depend on your products.

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.

Failure to correct these deviations may also result in FDA refusing admission of articles manufactured at Zhuhai United Laboratories Co., Ltd., at No. 2428 Anji Road, Sanzao Town, Jinwan District, Zhuhai, into the United 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, in that the methods and controls used in their manufacture do not appear to conform to CGMP within the meaning of section 501(a)(2)(B) of the FD&C Act, 21 U.S.C. 351(a)(2)(B).

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.

Send your electronic reply to CDER-OC-OMQ-Communications@fda.hhs.gov or mail your reply to:

Ms. Carrie Ann Plucinski

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 3006531950.

Sincerely,

/S/

Francis Godwin

Acting Director

Office of Manufacturing Quality

Office of Compliance

Center for Drug Evaluation and Research