Warning Letter 320-19-37
AMENDED 修订
(This letter replaces Warning Letter No. 320-19-37 dated August 14, 2019)
（本函取代日期为2019-08-14的警告信320-19-37）
August 19, 2019
Dear Mr. Lim:
The U.S. Food and Drug Administration (FDA) inspected your drug manufacturing facility, Haw Par Healthcare Limited at 2 Chia Ping Road, #09-03, Haw Par TIGER BALM Building, Singapore, from February 25 to March 1, 2019.
美国FDA于2019年2月25日至3月1日检查了你们位于新加坡的Haw Par Healthcare Limited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的行为。参见21CFR第210与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).
由于你们的制剂生产、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。
In addition, your firm manufactures “TIGER BALM LINIMENT.” The product is misbranded under section 502(f)(2) of the FD&CAct, 21 U.S.C. 352(f)(2). Introduction or delivery for introduction of such products into interstate commerce is prohibited under section 301(a) of the FD&C Act, 21 U.S.C.331(a).
此外你公司生产的“TIGER BALM LINIMENT”根据FDCA第502(f)(2)条款21 U.S.C. 352(f)(2)为错标药品。将此类产品引入州际贸易及在州间运输违反了FDCA第301(a)条款21 U.S.C. 331(a)。
We reviewed your March 22, 2019, response in detailand acknowledge receipt of your subsequent correspondence.
我们已详细审核了你公司2019年3月22日的回复，并此告知已收到后续通信。
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：
CGMP Violations CGMP违规
1. Your firm failed to thoroughly investigate any unexplained discrepancy or failure of a batch or any of its components to meet any of its specifications, whether or not the batch has already been distributed (21 CFR 211.192). 你公司未能彻底调查所有无解释的差异以及已销售和未销售批次及其成分不符合其质量标准的情况（21 CFR 211.192）。
You invalidated out-of-specification (OOS) test results for assay for (b)(4), active pharmaceutical ingredient (API) (batches (b)(4) and (b)(4)) without scientific justification. Batch (b)(4) of this API was subsequently used to manufacture multiple batches of your (b)(4) Patch over-the-counter (OTC) drug product. Several batches of OTC drug product made from these OOS API lots also had OOS results for (b)(4) assay. In addition, your API supplier informed you of the potential for (b)(4) extract to separate and have changes in viscosity. The supplier recommended performing additional processing steps before use in manufacturing.
你们宣布API（批次XX和XX）含量OOS结果无效，但没有科学理由。该API的批次XX后来被用于多批你们OTC贴剂药品的生产。有几批使用该OOSAPI批次生产的OTC药品含量亦为OOS。另外，你们的API供应商通知你们可能萃取物分离，并且粘度有变化。供应商建议在生产使用之前使用之前做更多处理。
During your initial investigation you determined adequate raw material mixing had not occurred. Even though all sub lots of drug product were made using API from a deficient mixing process, you only rejected portions of the drug product batches that were found to be OOS. You also invalidated an assay OOS result for (b)(4), a (b)(4) activeingredient, in (b)(4) Patch without adequately investigating the root cause and released the drug product for distribution. Moreover, for the samedrug product, you did not adequately investigate a customer complaint reported for a lack of drug effect. You failed to test the returned sample to confirm the amount of active ingredient in the product.
在你们初次调查中，你们认为是未对原料进行足够混合。虽然该批次的所有子批均使用不充分混合工艺制得，但你们只是拒收了这些药品批次中发现是OOS的那一部分。你们还宣布XX贴剂中活性成分含量OOS结果无效，却没有对根本原因进行足够调查，并且将该药品放行销售。另外，对同一药品，你们未充分调查一份报告效果缺失的客户投诉。你们未检查退回的样品，以确认药品中活性成分数量。
In your response, you acknowledge inadequate mixing of (b)(4) API led to the OOS drug product results. You also provided sampling data on one batch of (b)(4) from two containers as evidence that your mixing process can achieve homogeneity.
在你们的回复中，你们承认XX API混合不够导致了药品OOS结果。你们还提供了对一批XX的两个容器中取样数据作为证据证明你们的混合工艺可达到均一。
Your response is inadequate because your mixing study did not evaluate multiple batches from your suppliers to determine if your process can consistently achieve homogeneity with varying levels of raw material quality. You have not provided an adequate investigation of the additional mixing parameters required for your API to achieve homogeneity. Your approach to demonstrate that your manufacturing process is validated should be scientifically based.
你们的回复是不充分的，因为你们的混合研究并未评估来自你们供应商的多个批次，以确定你们的工艺是否可持续达到不同水平原料质量的均一度。你们并未提交对你们API达到均一所需的额外混合参数的充分调查。你们证明生产工艺经过验证的方法应基于科学。
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/media/71001/download.
失败、OOS、OOT或其它非预期结果更多信息和调查文件，参见FDA指南文件。
In response to this letter, provide:
在回复此函时请提交
· A retrospective review of all invalidated OOS (in-process and release testing for raw materials and finished drug products) results obtained for products on the U.S. marketand within expiry/retest date. Assess whether the scientific justification and evidence was conclusive. For investigations that conclusively establish laboratory root cause, determine adequacy of the corrective and preventive action (CAPA), and ensure that other laboratory methods vulnerable to the same root cause are identified for remediation. For any OOS with inconclusive or no root cause identified in the laboratory, include a thorough review of production (e.g., batch manufacturing records, adequacy of the manufacturing steps, raw materials, process capability, deviation history, batch failure history).
· 对销售至美国且在效期内药品检测所得所有宣布无效的OOS结果的一份回顾（原料和制剂的中控和放行检测）。评估科学论证和证据是否可得出结论。对于可得出化验室根本原因的调查，确定CAPA的充分性，确保已识别出受相同根本原因影响的其它实验室方法并进行补救。对于所有不能得出结论或未识别出实验室根本原因的所有OOS，包括一份彻底的生产审核（例如，批生产记录、生产步骤充分性、原料、工艺能力、偏差历史、批失败历史）。
· A CAPA plan that identifies the potential manufacturing root causes for each such investigation and includes process improvements where appropriate. Your CAPA plan should also include, but not be limited to, improvements in investigation competencies, root cause analysis, written procedures, quality unit oversight, and a process for evaluating CAPA effectiveness.
· 一份识别所有此类调查中潜在生产根本原因的CAPA计划，包括工艺改进（适当时）。你们的CAPA计划亦应包括但不仅限于改进调查能力、根本原因分析、书面程序、质量部门监管和评估CAPA有效性的流程
· An independent assessment and CAPA of your overall investigation systems, including investigating deviations, atypical events, OOS results, complaints, and failures. The CAPA should include, but not be limited to, enhanced investigation competencies, improved procedures, and substantial improvementsin quality unit oversight of investigations.
· 一份对你们全面调查系统的独立评估和CAPA，包括偏差、异常事件、OOS结果、投诉和失败调查。CAPA应包括但不仅限于提高调查能力、改进程序和质量部门监管调查的重大改进
2. Your firm failed to establish laboratory controls that include scientifically sound and appropriate specifications, standards, sampling plans, and test procedures designed to assure that components, drug product containers, closures, in-process materials, labeling, and drug products conform to appropriate standards of identity, strength, quality, and purity (21 CFR 211.160(b)). 你公司未能建议实验室控制，包括科学合理和恰当的规范、标准、取样计划和检测方法，设计用于确保组份、药品容器密闭器、中间体、标签和药品符合适当的鉴别、剂量、质量和纯度标准（21 CFR 211.160(b)）。
Your firm completed forced degradation studies for your OTC drug products but did not use the data to scientifically establish stability acceptance criteria. For example, degradation chromatographic peaks of less than (b)(4)% of the API were determined to be insignificant. In addition, there is no assurance that the analytical test methods that you used were capable of quantifying all drug product impurities resulting from the forced degradation studies you performed.
你公司未完成了OTC药品的强降解研究，但并未使用这些数据来科学地建立稳定性可接受标准。例如，API中小于XX%的降解色谱峰被认为是无足轻重的。另外，不能确保所用的分析方法可以定量检测你们所执行的强降解研究中得到的所有药品杂质。
For example, the main peak area of your API (b)(4)for (b)(4) Patch decreased by approximately 12% after the oxidative degradation study, yet your chromatographic report did not include a record of impurities resulting from the API degradation. You did not establish associated specifications or monitor your drug products for potential impurities or degradation products you identified during your degradation studies.
例如，你们XX贴剂中API的主峰在氧化降解后下到了约12%，但你们的色谱报告并未记录API降解中所得到的杂质。你们并未建立相关的质量标准或监测你们药品中的潜在杂质或降解研究中识别的降解产物。
In your response, you stated that you will “re-study your forced degradation approach,” complete a protocol that includes acceptance criteria, and establish test procedures with specifications for monitoring impurities.
在你们的回复中，你们声称你们会“重新研究你们的强降解方法”，完成方案，在其中包括可接受标准，并建立检验方法和标准监测杂质。
Your response is inadequate because you have not provided an interim plan of action to ensure that the products released to the market are of appropriate purity.
你们的回复是不充分的，因为你们并未提交一份临时措施计划，以确保放行到市场的药品具备适当的纯度。
In response to this letter, provide:
在回复此函时请提交
· The drug product specifications established for monitoring impurities. Your acceptance criteria and study design should be scientifically justified.
· 为监测杂质所建立的药品标准。你们的可接受标准和研究设计应经过科学论证。
· The drug product degradation protocol and report, which should include but not be limited to the impurities that will be monitored throughout the product life cycle.
· 药品降解方案和报告，其中应包括但不仅限于在产品生命周期中要监测的杂质
· Your studies demonstrating that your analytical test methods, established to monitor impurities in each finished drug product manufactured for the U.S. market are stability indicating. Also include the validation protocol and report completed for these test methods.
· 你们证明你们所建立用于监测为美国市场所生产的制剂中杂质的分析方法为稳定性指示性的研究。还要包括这些检验方法的验证方案和已完成的报告。
· An independent assessment of all test methods and data review procedures used by your firm to ensure they have appropriate instructions, method suitability criteria, and validation to determine whether they are fit for intended purposes.
· 一份对所有检验方法和你公司用于数据审核程序的独立评估，以确保你们有适当的指导、方法适用性标准和验证，以确定其是否适合其既定目的。
3. Your firm failed to ensure that laboratory records included complete data derived from all tests necessary to ensure compliance with established specifications and standards (21 CFR 211.194(a)). 你公司未能确保实验室记录中包括了为确保符合既定标准而执行的所有必要测试中生成的完整数据（21 CFR 211.194(a)）。
The computer systems you use to control the operations of your analytical instrumentation do not have audit trail capabilities, including Gas Chromatography (GC) instruments used for drug product stability analyses and Fourier Transform Infrared Spectroscopy (FTIR) and Ultraviolet (UV) spectroscopy instruments used for raw material release testing.
你们用于控制你们分析仪器操作的计算机系统没有审计追踪能力，包括用于药品稳定性分析的GC和用于原料放行检测的FTIR及UV。
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. See FDA’s guidance document Data Integrity and Compliance With Drug CGMP for guidance on establishing and following CGMP compliant data integrity practices at https://www.fda.gov/media/119267/download.
你们的质量体系不能充分确保支持你们所生产药品安全性、有效性和质量的数据的准确性和完整性。参见FDA指南文件。
In your response, you stated that you moved GC testing to other instruments with audit trail functionality, and you will update your FTIR and UV instrumentation with audit trails in 2020. In the interim you will initiate a program to protect raw data from deletion.
在你们的回复中，你们声称你们会将GC检测转至其它具备审计追踪功能的仪器，并且你们会在2020年将你们的FTIR和UV仪器更新为具备审计追踪功能。作为临时措施你们会启动一个计划保护原始数据不被删除。
Your response is inadequate because you did not provide sufficient details of how you plan to ensure the integrity of the electronic data you generate until implementation of your updated instrumentation controls.
你们的回复是不充分的，因为你们并未提供足够详细信息说明你们计划在更新仪器控制之前如何确保你们所生成的电子数据的完整性。
In response to this letter, provide:
在回复此函时请提交
· A comprehensive independent review of your entire data system and investigation into the inadequacies in data, records, and reporting. Describe all parts of your facility’s operations in which CGMP information is not recorded and maintained.
· 一份对你们整个数据系统和数据、记录及报告不充分情况的全面独立审核。说明你们工厂操作中所有CGMP未记录或未保存的情况。
· Your detailed CAPA plan to remediate data recording and record retention practices throughout your operation. Your CAPA plan should include, but not be limited to, appropriate controls to maintain and prevent the deletion and alteration of raw data files.
· 你们用于补救所有操作中数据记录和记录保存做法的详细CAPA计划。你们的CAPA计划应包括但不仅限于维护和防止删除和修改原始数据文件的适当控制
· Provide a risk assessment summarizing the effect of incomplete data on assessing laboratory results and product quality.
· 提交一份风险评估，总结不完整数据对实验室结果和产品质量评估的影响
4. Your firm failed to use equipment in the manufacture, processing, packing, or holding of drug products that is of appropriate design, adequate size, and suitably located to facilitate operations for its intended use and for its cleaning and maintenance (21 CFR 211.63). 你公司在药品生产、加工、包装或保存中未使用经过根据其既定用途和清洁维护而适当设计、具备足够尺寸，以及适当定位便于操作的设备（21 CFR 211.63）。
Your (b)(4) system used to generate (b)(4)for the manufacture of your drug product has “dead legs.” This inadequate system design could foster the development of biofilms and lead to contamination of (b)(4) used in drug manufacturing. In addition, your practice of flushing the system at the manufacturing sampling points before sample collection for (b)(4) analysis is not consistent with how you use these (b)(4) points of use in production. This inconsistent sampling practice could potentially lead to inaccurate microbial results for (b)(4) analysis.
你们用于药品生产生成XX的XX系统有“死管”。其设计不充分可能会导致生物膜滋长，导致生产用XX的污染。另外，你们在生产取样点采集用于XX分析的样品之前淋洗系统的做法与你们在生产中实际使用这些XX点的做法是不一致的。取样操作不一致可能导致XX分析的微生物结果不准确。
In your response, you stated that you have re-designed your (b)(4) circulation line.
在你们的回复中，你们声称你们重新设计了你们的XX循环管线。
Your response is inadequate because you have not provided your data and evaluation of all (b)(4) sampling points, with consistent sampling procedures, used for manufacturing to ensure that your microbial results comply with specifications.
你们的回复是不充分的，因为你们并未提交依据取样程序所得的生产用所有XX取样点的数据和评估，确保你们的微生物结果符合质量标准。
In response to this letter, provide:
在回复此函时请提交
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Your (b)(4) system validation protocol and report and a summary of improvements made to your (b)(4) system design.
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你们XX系统验证方案和报告，以及对你们XX系统设计所做改进的摘要
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Your current procedures for routine monitoring of the redesigned (b)(4) system as well as system controls and maintenance. This should include, but not be limited to, test methods, appropriate microbial limits (total count, objectionable organisms), and (b)(4) analysis frequency and locations of sampling points.
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你们目前用于日常监测重新设计后XX系统和系统控制及维护的程序。其中应包括但不仅限于检测方法、适当的微生物限度（总计数、致病菌）和XX分析频次及取样点位置。
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Justification that the frequency of sanitization and (b)(4) analysis of your (b)(4) system is adequate for ensuring that no biofilm exists in your (b)(4) system.
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你们XX系统消毒和XX分析频次足以确保在你们XX系统中不会生成生物膜的论证
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Data demonstrating appropriate microbial total count to ensure this system produces (b)(4) suitable for the intended uses of each of your drug products.
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证明微生物总计数适当的数据，确保该系统能生成适合于你们每个药品既定用途的XX
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A detailed risk assessment addressing the potential effects of (b)(4) system failures on the quality of all drug product lots currently in U.S. distribution and within expiry. Specify actions that you will take in response to the risk assessment, such as customer notifications and product recalls.
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一份详细的风险评估，说明XX系统失败可能对所有目前销往美国且在效期内药品批次产生的影响。说明你们为应对风险评估将要采取的措施，例如通知客户和产品召回
CGMP Consultant Recommended CGMP顾问建议
Based upon the nature of the violations we identified at your firm, we strongly recommend engaging a consultant, qualifiedas set forth in 21 CFR 211.34, to assist your firm in meeting CGMP requirements.
根据我们在你公司发现的违规情况，我们强烈建议你们使用一位有21CFR 211.34所述资质的顾问来协助你们公司符合CGMP要求。
Your use of a consultant does not relieve your firm’s obligation to comply with CGMP. Your firm’s executive management remains responsible for resolving all deficiencies and systemic flaws to ensure ongoing CGMP compliance.
你们使用顾问并不能解除你们公司符合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。
Misbranding Charge 错标指控（略）
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。
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 admission of articles manufactured at Haw Par HealthcareLimited at 2 Chia Ping Road, #09-03, Haw Par TIGER BALM Bldg., Singapore, 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 in writing within 15 working days. Specify what you have done since our inspection to 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.
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:
Christina Alemu-Cruickshank
Compliance Officer
U.S. Food and Drug Administration
White Oak Building 51, Room 4212
10903 New Hampshire Avenue
Silver Spring, MD 20993
USA
Please identify your response with FEI No.3001432470.
Sincerely,
/S/
Francis Godwin
Director
Office of Manufacturing Quality
Office of Compliance
Center for Drug Evaluation and Research