FDA警告信：香港南山藥廠
Warning Letter 320-18-36
February 23, 2018
Ms. Cheuk Yin Cheung, Owner
Nan San (HK) PharmaceuticalFactory Limited
Hoi Bun Industrial Building, 6Wing Yip Street, Unit C1, 10/F, Kwun Tong Kowloon, 5678, Hong Kong
Dear Ms. Cheung:
The U.S. Food and DrugAdministration (FDA) inspected your drug manufacturing facility, Nan San (HK)Pharmaceutical Factory Limited at Hoi Bun Industrial Building, 6 Wing YipStreet, Unit C1, 10/F, Kwun Tong Kowloon, Hong Kong, from September 25 to 29,2017.
美國FDA於2017年9月18-22日檢查了你們位於香港觀塘區觀塘榮業街6號海濱工業大廈10樓C1室的香港南山藥廠生產場所。
This warning letter summarizessignificant violations of current good manufacturing practice (CGMP)regulations for finished pharmaceuticals. See 21 CFR, parts 210 and 211.
本警告信總結了製劑生產嚴重違反CGMP的行為。參見21CFR第210和211部分。
Because your methods,facilities, or controls for manufacturing, processing, packing, or holding donot conform to CGMP, your drug products are adulterated within the meaning ofsection 501(a)(2)(B) of the Federal Food, Drug, and Cosmetic Act (FD&CAct), 21 U.S.C. 351(a)(2)(B).
由於你們的製劑生產、加工、包裝或保存的方法、場所或控制不符合CGMP要求，你們的製劑根據FDCA的501(a)(2)(B)以及21 U.S.C. 351(a)(2)(B)被認為是摻假藥品。
In addition, your firm alsomanufactures misbranded drug products. Specifically, as formulated and labeled,Musflex and Easy-Flex are misbranded under sections 502(e)(1)(A)(ii), (iii) and(f)(2) of the FD&C Act, 21 U.S.C. 352(e)(1)(A)(ii), (iii) and (f)(2).
此外，你公司還生產了冒牌藥品。具體來說，根據其配方和標籤，活絡油和舒筋露依FDCA第502(e)(1)(A)(ii),(iii)和(f)(2)條以及21 U.S.C. 352(e)(1)(A)(ii), (iii)和(f)(2)是為冒牌藥品。
CGMP ViolationsCGMP違規
During our inspection, ourinvestigator observed specific violations including, but not limited to, thefollowing.
檢查期間，我們的調查人員發現的具體問題包括但不僅限於以下：
1. Your firmfailed to perform, for each batch of drug product, appropriate laboratorydetermination of satisfactory conformance to final specifications for the drugproduct, including the identity and strength of each active ingredient, priorto release, and for each batch of drug product required to be free ofobjectionable microorganisms, appropriate laboratory testing, as necessary (21CFR 211.165(a) and (b)).你們公司未對每批藥品進行適當的化驗室測試，確保其在放行之前符合藥品的最終標準，包括每種活性成分的鑒別和劑量，未對每批需要無致病菌的藥品在需要時進行適當的化驗室測試(21 CFR 211.165(a)和(b))。
Your firm failed to test allbatches of over-the-counter (OTC) topical liquid analgesics for conformance totheir specifications before releasing each batch. For example, you did notperform microbial limit tests for each batch of your Easy-Flex analgesic lotionreleased between 2013 and 2016. Instead, you performed microbial limit testingon one batch in 2013, and reported the same results to releasesubsequently-manufactured batches to the United States.
你公司未檢測所有批次OTC局部液體止痛劑確保其各批次在放行之前符合質量標準。例如，你們未對你們在2013-2016年間放行的舒筋露止痛膏進行微生物限度檢查。相反，你們只是對2013年一個批次進行了微生物限度檢查，然後報告了相同的結果來放行後續生產銷售至美國的批次。
You also used a contractlaboratory to conduct finished product testing. Although your finisheddrug products contain(b)(4)active ingredients, your contractlaboratory only tested for the strength and identity of one of thoseingredients in the finished product testing on which you relied to release yourdrug products.
你們還使用了合同化驗室來進行成品檢測。儘管你們的成品含有XX活性成分，你們的合同化驗室在成品檢測中卻只是檢測了這些成分中一種成分的含量和鑒別，你們據此放行了你們的藥品。
2. Your firmfailed to establish written procedures for production and process controldesigned to assure that the drug products you manufacture have the identity,strength, quality, and purity they purport or are represented to possess (21CFR 211.100(a)).你公司未能建立書面的生產和工藝控制程序，這些程序應設計用以確保你們所生產的藥品具備其理應具備的鑒別、含量、質量和純度(21 CFR211.100(a))。
You have not validated theprocesses used to manufacture your OTC drug products. You did not performprocess qualification studies, and you also lacked an ongoing program formonitoring process control to ensure stable manufacturing operations andconsistent drug quality. See FDA』s guidance document,Process Validation:General Principles and Practices, for approaches that FDA considersappropriate elements of process validation, athttps://www.fda.gov/downloads/drugs/guidances/ucm070336.pdf.
你們未驗證你們生產你們的OTC藥品所用工藝。你們未進行工藝確認研究，你們還缺乏持續的工藝控制監測程序以確保穩定的生產操作和一致的藥品質量。參見FDA指南。
3. Your firmfailed to conduct at least one test to verify the identity of each component ofa drug product (21 CFR 211.84(d)(1)).你們公司未進行至少一項檢查來核對藥品中每個組份的鑒別(21 CFR211.84(d)(1))。
Your firm failed to testincoming active pharmaceutical ingredients and other components for identity,purity, strength, and quality prior to use in your drug manufacturing process.
你公司未在進廠原料葯和其它組份用於你們的藥品生產工藝之前檢測其鑒別、純度、含量和質量。
4. Your firmfailed to establish and follow an adequate written testing program designed toassess the stability characteristics of drug products and to use results ofsuch stability testing to determine appropriate storage conditions andexpiration dates (21 CFR 211.166(a)).你公司未能建立並遵守足夠的書面程序，這些程序應設計用以評估藥品的穩定性屬性，此穩定性測試結果應被用以確定適當的存貯條件和有效期(21 CFR211.166(a))。
Your firm labeled your drugproducts with a(b)(4)-year expiration date without adequately assessingthe stability characteristics of these drug products. Your firm does not haveadequate stability data to support the assigned expiration date.
你公司標示你們的藥品有效期為X年，但並未充分評估這些藥品的穩定性屬性。你公司並無足夠的穩定性數據來支持所給定的有效期。
We acknowledge your responseto the Form FDA 483 regarding the CGMP observations that you submitted to theFDA on November 14, 2017. Your response to the CGMP observations, including theviolations discussed above, was inadequate because it did not providesufficient evidence of corrective actions to bring your operations intocompliance with CGMP.
我們現告知你們已收到你們2017年11月14日提交給FDA的關於CGMP缺陷的FDA483表的回復。你們對CGMP缺陷的回復，包括上述所討論的違規問題，是不充分的，因為其中並未提交足夠的證據證明你們的糾正措施可以確保你們的操作符合CGMP要求。
CGMP Consultant RecommendedCGMP顧問建議
Based upon the nature of theCGMP violations we identified at your firm, we strongly recommend engaging aconsultant, qualified as set forth in 21 CFR 211.34, to assist your firm inmeeting CGMP requirements.
依據我們在你們公司發現的違規情況，我們強烈建議你們使用一位符合21CFR211.34要求的顧問來協助你們公司符合CGMP要求。
Your use of a consultant doesnot relieve your firm"s obligation to comply with CGMP. Your firm"s executivemanagement remains responsible for fully resolving all deficiencies andensuring ongoing CGMP compliance.
你們使用顧問並不解除你們公司符合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 Violations: Musflex and Easy-Flex冒牌違規活絡油和舒筋露
Examples of claims observed onyour product labels for Musflex and Easy-Flex that establish the intended usesof the products include, but may not be limited to, the following:
在你們的活絡油和舒筋露藥品標籤上所發現的聲稱樣例指明該藥品的適用範圍包括但不僅限於以下：
「Uses: For the temporaryrelief of minor aches and pains of muscles and joints associated with simplebackache, arthritis, strains, bruises, and sprains.」
用途：暫時緩解輕微肌肉和關節疼痛、跌打腫痛、腰酸背痛、筋絡抽縮。
Based on the above claims,Musflex and Easy-Flex are 「drugs」 as defined by section 201(g)(1)(B) of theFD&C Act, 21 U.S.C. 321(g)(1)(B), because they are intended for thediagnosis, cure, mitigation, treatment, or prevention of disease, and/or under section201(g)(1)(C) of the FD&C Act, 21 U.S.C. 321(g)(1)(C) because they areintended to affect the structure or any function of the body. Specifically,this product is intended as an external analgesic.
根據上述聲明，活絡油和舒筋露依FDCA第201(g)(1)(B)條及21 U.S.C. 321(g)(1)(B)被定義為「藥品」，因為其既定用途為診斷、治癒、緩解、治療或預防疾病，和/或依FDCA第201(g)(1)(C)條或21 U.S.C. 321(g)(1)(C)定義為藥品，因為其用於影響人體結構或功能。具體來說，此藥品用途外用止痛劑。
Drug products such as Musflexand Easy-Flex that are intended as external analgesics, such as the temporaryrelief of minor aches and pains, are being evaluated as part of the OTC DrugReview. They have been proposed to be classified as generally recognized assafe and effective and not misbranded under theTentative Final Monograph(TFM) for External Analgesic Drug Products for Over-the-Counter (OTC) HumanUse(48 FR 5852, February 8, 1983) if they meet each condition in the TFMand each general condition in 21 CFR 330.1.
活絡油和舒筋露此類藥品用作外用止痛劑，如暫時緩解輕微疼痛，應依OTC藥品審核進行評估。如果該藥品符合TFM所有條件和21CFR330.1的所有通用條件，則依TFM人用外用止痛藥OTC可歸類為公認安全有效的藥品，而不是冒牌藥品。
Pending a final rule, FDA doesnot intend to pursue regulatory action against products marketed in conformancewith the conditions proposed in the TFM and each general condition in 21 CFR330.1. Such marketing, however, is subject to the risk that a final rule mayrequire reformulation and/or relabeling or FDA approval through the 「new drug」procedures of the FD&C Act (section 505). The labeling for such drugs, likeall OTC drugs, must comply with all the requirements of section 502 of theFD&C Act and all pertinent regulations found in Title 21 of the Code ofFederal Regulations (21 CFR).
由於上述規定尚未定稿，FDA無意對已上市且符合TFM條件和21CFR330.1條件的藥品採取法規措施。但如果TFM規定最後定稿時要求重新配方和/或重新標籤或FDA需要通過FDCA第505部分「新葯」程序進行批准，則此類上市銷售必須符合FDCA第502條所有要求，以及21CFR中所有適用規定。
Musflex and Easy-Flex aremisbranded under section 502(e)(1)(A)(ii) and (iii) of the FD&C Act, 21U.S.C. 352(e)(1)(A)(ii) and (iii), because their labels fail to declare activeingredients, the proportion of each active ingredient, and inactiveingredients. It was observed during the inspection that(b)(4), menthol,and(b)(4)are used in the manufacturing of Musflex and Easy-Flex.
活絡油和舒筋露依FDCA第502(e)(1)(A)(ii)和(iii)及21 U.S.C. 352(e)(1)(A)(ii)和(iii)為冒牌藥品，因為其標籤未明確其活性成分，每種活性成分和非活性成分的比例。在檢查期間發現XX、薄荷和XX被用於活絡油和舒筋露的生產。
Furthermore, your firmacknowledged that these(b)(4)ingredients are used as activeingredients in both products, but all(b)(4)ingredients are notdeclared as active ingredients on the product labels. Specifically, the Musflexproduct label fails to declare(b)(4)as an active ingredient and theEasy-Flex product label fails to declare(b)(4)as active ingredients.It was also observed during the inspection that your firm used a(b)(4)of inactive ingredients in the manufacturing of Musflex and Easy-Flex. Yourfirm was unable to provide a complete list of all the ingredients that made upthe(b)(4)of inactive ingredients, and you acknowledged that not allinactive ingredients are declared on the product labels.
另外，你們公司知曉這些XX成分在兩藥品中均被用作活性成分，但所有的XX成分在產品標籤中均未聲稱為活性成分。具體來說，活絡油藥品標籤未聲稱XX為其活性成分，舒筋露藥品標籤未聲明XX為其活性成分。檢查期間還發現你們公司在活絡油和舒筋露生產中使用了XX非活性成分。你們公司未能提供非活性成分的XX組成中所有成分的完整清單，你們知曉在藥品標籤中並未聲明所有非活性成分。
Musflex and Easy-Flex are alsomisbranded under Section 502(f)(2) the FD&C Act, 21 U.S.C. 352(f)(2)because the products』 labeling fails to bear all of the required warnings. Forexample, both products fail to disclose the required warning, 「Do not useotherwise than as directed.」 See 21 CFR 201.314(g)(1).
活絡油和舒筋露依FDCA第502(f)(2)條及21 U.S.C. 352(f)(2)亦為冒牌藥品，因為該藥品的標籤未載有所需的警示信息，例如，2藥品均未提示所需的警示信息「不得用於指示以外情形」，參見21 CFR 201.314(g)(1)。
The introduction or deliveryfor introduction of a misbranded drug into interstate commerce is prohibitedunder section 301(a) of the FD&C Act, 21 U.S.C. 331(a). Therefore, themarketing of Musflex and Easy-Flex violate this provision of the FD&C Act.
將冒牌藥品引入或運送進入州際貿易依FDCA第301(a)部分及21 U.S.C. 331(a)是被禁止的。因此，活絡油和舒筋露的上市違反了FDCA的此條款。
Conclusion結論
Violations cited in thisletter are not intended as an all-inclusive list. You are responsible forinvestigating these violations, for determining the causes, for preventingtheir recurrence, and for preventing other violations.
在此函中所引用的偏差並不是全部。你們有責任對這些偏差進行調查，確定原因，防止這些偏差的再次發生，防止其它偏差的發生。
FDA placed your firm on ImportAlert 66-40 on January 8, 2018.
FDA已於2018年1月8將你公司列入66-40項下進口禁令中。
Until you correct allviolations completely and we confirm your compliance with CGMP, FDA maywithhold approval of any new applications or supplements listing your firm as adrug 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為藥品生產的新申報和增補申報的批准。
Failure to correct theseviolations may also result in FDA continuing to refuse admission of articlesmanufactured at Nan San (HK) Pharmaceutical Factory Limited, Hoi Bun IndustrialBuilding, 6 Wing Yip Street, Unit C1, 10/F, Kwun Tong Kowloon, Hong Kong intothe 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 ofadmission, in that the methods and controls used in their manufacture do notappear to conform to CGMP within the meaning of section 501(a)(2)(B) of theFD&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產的產品進入美國。
After you receive this letter,respond to this office in writing within 15 working days. Specify what you havedone since our inspection to correct your violations and to prevent theirrecurrence. 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個工作日內回復至本辦公室。在回復中說明自從檢查後，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。
CDR Frank Verni, R.Ph.
Compliance Officer
U.S. Food and DrugAdministration
White Oak Building 51, Room4359
10903 New Hampshire Avenue
Silver Spring, MD 20993
USA
Sincerely,
/S/
Francis Godwin
Acting Director
Office of ManufacturingQuality
Office of Compliance
Center for Drug Evaluation andResearch
cc:
Mr. Chi Pun Cheung
Director
Nan San (HK) PharmaceuticalFactory Limited
Hoi Bun Industrial Building
6 Wing Yip Street, Unit C1, 10/F
Kwun Tong Kowloon, 5678
Hong Kong
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