Warning Letter 320-19-37
AMENDED 修訂
(This letter replaces Warning Letter No. 320-19-37 dated August 14, 2019)
（本函取代日期爲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.
美國FDA于2019年2月25日至3月1日檢查了你們位于新加坡的Haw Par Healthcare Limited生産場所。
This warning letter summarizes significant violations of current good manufacturing practice (CGMP) regulations for finished pharmaceuticals. See 21 CFR, parts 210 and 211.
本警告信總結了制劑生産嚴重違反CGMP的行爲。參見21CFR第210與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).
由于你們的制劑生産、加工、包裝或保存的方法、場所或控制不符合CGMP要求，你們的藥品根據FDCA的501(a)(2)(B)以及21 U.S.C. 351(a)(2)(B)被認爲是摻假藥品。
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).
此外你公司生産的“TIGER BALM LINIMENT”根據FDCA第502(f)(2)條款21 U.S.C. 352(f)(2)爲錯標藥品。將此類産品引入州際貿易及在州間運輸違反了FDCA第301(a)條款21 U.S.C. 331(a)。
We reviewed your March 22, 2019, response in detailand acknowledge receipt of your subsequent correspondence.
我們已詳細審核了你公司2019年3月22日的回複，並此告知已收到後續通信。
During our inspection, our investigator observed specific violations including, but not limited to, the following.
檢查期間，我們的調查人員發現的具體問題包括但不僅限于以下：
CGMP Violations CGMP違規
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). 你公司未能徹底調查所有無解釋的差異以及已銷售和未銷售批次及其成分不符合其質量標准的情況（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.
你們宣布API（批次XX和XX）含量OOS結果無效，但沒有科學理由。該API的批次XX後來被用于多批你們OTC貼劑藥品的生産。有幾批使用該OOSAPI批次生産的OTC藥品含量亦爲OOS。另外，你們的API供應商通知你們可能萃取物分離，並且粘度有變化。供應商建議在生産使用之前使用之前做更多處理。
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.
在你們初次調查中，你們認爲是未對原料進行足夠混合。雖然該批次的所有子批均使用不充分混合工藝制得，但你們只是拒收了這些藥品批次中發現是OOS的那一部分。你們還宣布XX貼劑中活性成分含量OOS結果無效，卻沒有對根本原因進行足夠調查，並且將該藥品放行銷售。另外，對同一藥品，你們未充分調查一份報告效果缺失的客戶投訴。你們未檢查退回的樣品，以確認藥品中活性成分數量。
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.
在你們的回複中，你們承認XX API混合不夠導致了藥品OOS結果。你們還提供了對一批XX的兩個容器中取樣數據作爲證據證明你們的混合工藝可達到均一。
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.
你們的回複是不充分的，因爲你們的混合研究並未評估來自你們供應商的多個批次，以確定你們的工藝是否可持續達到不同水平原料質量的均一度。你們並未提交對你們API達到均一所需的額外混合參數的充分調查。你們證明生産工藝經過驗證的方法應基于科學。
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.
失敗、OOS、OOT或其它非預期結果更多信息和調查文件，參見FDA指南文件。
In response to this letter, provide:
在回複此函時請提交
· 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).
· 對銷售至美國且在效期內藥品檢測所得所有宣布無效的OOS結果的一份回顧（原料和制劑的中控和放行檢測）。評估科學論證和證據是否可得出結論。對于可得出化驗室根本原因的調查，確定CAPA的充分性，確保已識別出受相同根本原因影響的其它實驗室方法並進行補救。對于所有不能得出結論或未識別出實驗室根本原因的所有OOS，包括一份徹底的生産審核（例如，批生産記錄、生産步驟充分性、原料、工藝能力、偏差曆史、批失敗曆史）。
· 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.
· 一份識別所有此類調查中潛在生産根本原因的CAPA計劃，包括工藝改進（適當時）。你們的CAPA計劃亦應包括但不僅限于改進調查能力、根本原因分析、書面程序、質量部門監管和評估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.
· 一份對你們全面調查系統的獨立評估和CAPA，包括偏差、異常事件、OOS結果、投訴和失敗調查。CAPA應包括但不僅限于提高調查能力、改進程序和質量部門監管調查的重大改進
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)). 你公司未能建議實驗室控制，包括科學合理和恰當的規範、標准、取樣計劃和檢測方法，設計用于確保組份、藥品容器密閉器、中間體、標簽和藥品符合適當的鑒別、劑量、質量和純度標准（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藥品的強降解研究，但並未使用這些數據來科學地建立穩定性可接受標准。例如，API中小于XX%的降解色譜峰被認爲是無足輕重的。另外，不能確保所用的分析方法可以定量檢測你們所執行的強降解研究中得到的所有藥品雜質。
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，你們XX貼劑中API的主峰在氧化降解後下到了約12%，但你們的色譜報告並未記錄API降解中所得到的雜質。你們並未建立相關的質量標准或監測你們藥品中的潛在雜質或降解研究中識別的降解産物。
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.
在你們的回複中，你們聲稱你們會“重新研究你們的強降解方法”，完成方案，在其中包括可接受標准，並建立檢驗方法和標准監測雜質。
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.
你們的回複是不充分的，因爲你們並未提交一份臨時措施計劃，以確保放行到市場的藥品具備適當的純度。
In response to this letter, provide:
在回複此函時請提交
· The drug product specifications established for monitoring impurities. Your acceptance criteria and study design should be scientifically justified.
· 爲監測雜質所建立的藥品標准。你們的可接受標准和研究設計應經過科學論證。
· 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.
· 藥品降解方案和報告，其中應包括但不僅限于在産品生命周期中要監測的雜質
· 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.
· 你們證明你們所建立用于監測爲美國市場所生産的制劑中雜質的分析方法爲穩定性指示性的研究。還要包括這些檢驗方法的驗證方案和已完成的報告。
· 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.
· 一份對所有檢驗方法和你公司用于數據審核程序的獨立評估，以確保你們有適當的指導、方法適用性標准和驗證，以確定其是否適合其既定目的。
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)). 你公司未能確保實驗室記錄中包括了爲確保符合既定標准而執行的所有必要測試中生成的完整數據（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.
你們用于控制你們分析儀器操作的計算機系統沒有審計追蹤能力，包括用于藥品穩定性分析的GC和用于原料放行檢測的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.
你們的質量體系不能充分確保支持你們所生産藥品安全性、有效性和質量的數據的准確性和完整性。參見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.
在你們的回複中，你們聲稱你們會將GC檢測轉至其它具備審計追蹤功能的儀器，並且你們會在2020年將你們的FTIR和UV儀器更新爲具備審計追蹤功能。作爲臨時措施你們會啓動一個計劃保護原始數據不被刪除。
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.
你們的回複是不充分的，因爲你們並未提供足夠詳細信息說明你們計劃在更新儀器控制之前如何確保你們所生成的電子數據的完整性。
In response to this letter, provide:
在回複此函時請提交
· 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.
· 一份對你們整個數據系統和數據、記錄及報告不充分情況的全面獨立審核。說明你們工廠操作中所有CGMP未記錄或未保存的情況。
· 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.
· 你們用于補救所有操作中數據記錄和記錄保存做法的詳細CAPA計劃。你們的CAPA計劃應包括但不僅限于維護和防止刪除和修改原始數據文件的適當控制
· Provide a risk assessment summarizing the effect of incomplete data on assessing laboratory results and product quality.
· 提交一份風險評估，總結不完整數據對實驗室結果和産品質量評估的影響
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). 你公司在藥品生産、加工、包裝或保存中未使用經過根據其既定用途和清潔維護而適當設計、具備足夠尺寸，以及適當定位便于操作的設備（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.
你們用于藥品生産生成XX的XX系統有“死管”。其設計不充分可能會導致生物膜滋長，導致生産用XX的汙染。另外，你們在生産取樣點采集用于XX分析的樣品之前淋洗系統的做法與你們在生産中實際使用這些XX點的做法是不一致的。取樣操作不一致可能導致XX分析的微生物結果不准確。
In your response, you stated that you have re-designed your (b)(4) circulation line.
在你們的回複中，你們聲稱你們重新設計了你們的XX循環管線。
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.
你們的回複是不充分的，因爲你們並未提交依據取樣程序所得的生産用所有XX取樣點的數據和評估，確保你們的微生物結果符合質量標准。
In response to this letter, provide:
在回複此函時請提交
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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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你們XX系統驗證方案和報告，以及對你們XX系統設計所做改進的摘要
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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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你們目前用于日常監測重新設計後XX系統和系統控制及維護的程序。其中應包括但不僅限于檢測方法、適當的微生物限度（總計數、致病菌）和XX分析頻次及取樣點位置。
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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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你們XX系統消毒和XX分析頻次足以確保在你們XX系統中不會生成生物膜的論證
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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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證明微生物總計數適當的數據，確保該系統能生成適合于你們每個藥品既定用途的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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一份詳細的風險評估，說明XX系統失敗可能對所有目前銷往美國且在效期內藥品批次産生的影響。說明你們爲應對風險評估將要采取的措施，例如通知客戶和産品召回
CGMP Consultant Recommended CGMP顧問建議
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.
根據我們在你公司發現的違規情況，我們強烈建議你們使用一位有21CFR 211.34所述資質的顧問來協助你們公司符合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.
你們使用顧問並不能解除你們公司符合CGMP的義務。你們公司的高級管理層仍負有義務全面解決所有缺陷，確保持續CGMP符合性。
Misbranding Charge 錯標指控（略）
Conclusion 結論
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.
此函中所引用的違規並不是全部。你們有責任對這些偏差進行調查，確定原因，防止其再次發生，防止你們設施內其它偏差的發生。
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.
在貴公司未能完成所有偏差糾正並且由我們確認你們符合CGMP之前，FDA可能會擱置所有將你公司列爲藥品生産的新申報和增補申報的批准。
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)).
未能糾正這些偏差可能還會導致FDA依據FDCA第801(a)(3)條和21 U.S.C. 381(a)(3)拒絕接受在上述地址生産的産品進入美國。
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.
在收到此函後，請在15個工作日內回複至本辦公室。在回複中說明自從檢查後，你們做了哪些工作來糾正你們的偏差，防止其再次發生。如果不能在15個工作日內完成糾正措施，說明延遲的原因以及完成計劃。
Send your electronic reply to [email protected] 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