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.
美国FDA于2017年9月18-22日检查了你们位于 香港观塘区观塘荣业街6号海滨工业大厦10楼C1室的香港南山药厂生产场所。
This warning letter summarizessignificant violations of current good manufacturing practice (C
GMP)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，你们的制剂根据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 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，你公司还生产了冒牌药品。具体来说，根据其配方和标签，活络油和舒筋露依FDCA第502(e)(1)(A)(ii),(iii) 和 (f)(2) 条以及 21 U.S.C. 352(e)(1)(A)(ii), (iii)和 (f)(2)是为冒牌药品。
CGMP Violations CGMP违规
During our inspection, ourinvestigator observed specific violations including, but not limited to, thefollowing.
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. 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)). 你们公司未对每批药品进行适当的化验室测试，确保其在放行之前符合药品的最终标准，包括每种活性成分的鉴别和剂量，未对每批需要无致病菌的药品在需要时进行适当的化验室测试(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.
你公司未检测所有批次OTC局部液体止痛剂确保其各批次在放行之前符合质量标准。例如，你们未对你们在2013-2016年间放行的舒筋露止痛膏进行微生物限度检查。相反，你们只是对2013年一个批次进行了微生物限度检查，然后报告了相同的结果来放行后续生产销售至美国的批次。
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.
你们还使用了合同化验室来进行成品检测。尽管你们的成品含有XX活性成分，你们的合同化验室在成品检测中却只是检测了这些成分中一种成分的含量和鉴别，你们据此放行了你们的药品。
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)). 你公司未能建立书面的生产和工艺控制程序，这些程序应设计用以确保你们所生产的药品具备其理应具备的鉴别、含量、质量和纯度(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, at
https://www.fda.gov/downloads/drugs/guidances/ucm070336.pdf.你们未验证你们生产你们的OTC药品所用工艺。你们未进行工艺确认研究，你们还缺乏持续的工艺控制监测程序以确保稳定的生产操作和一致的药品质量。参见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)). 你们公司未进行至少一项检查来核对药品中每个组份的鉴别(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.
你公司未在进厂原料药和其它组份用于你们的药品生产工艺之前检测其鉴别、纯度、含量和质量。
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)). 你公司未能建立并遵守足够的书面程序，这些程序应设计用以评估药品的稳定性属性，此稳定性测试结果应被用以确定适当的存贮条件和有效期(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.
你公司标示你们的药品有效期为X年，但并未充分评估这些药品的稳定性属性。你公司并无足够的稳定性数据来支持所给定的有效期。
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.
我们现告知你们已收到你们2017年11月14日提交给FDA的关于CGMP缺陷的FDA483表的回复。你们对CGMP缺陷的回复，包括上述所讨论的违规问题，是不充分的，因为其中并未提交足够的证据证明你们的纠正措施可以确保你们的操作符合CGMP要求。
CGMP Consultant Recommended CGMP顾问建议
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.
依据我们在你们公司发现的违规情况，我们强烈建议你们使用一位符合21CFR211.34要求的顾问来协助你们公司符合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。
Misbranding Violations: Musflex and Easy-Flex 冒牌违规活络油和舒筋露
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:
在你们的活络油和舒筋露药品标签上所发现的声称样例指明该药品的适用范围包括但不仅限于以下：
“Uses: For the temporaryrelief of minor aches and pains of muscles and joints associated with simplebackache, arthritis, strains, bruises, and sprains.”
用途：暂时缓解轻微肌肉和关节疼痛、跌打肿痛、腰酸背痛、筋络抽缩。
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.
根据上述声明，活络油和舒筋露依FDCA第201(g)(1)(B) 条及21 U.S.C. 321(g)(1)(B)被定义为“药品”，因为其既定用途为诊断、治愈、缓解、治疗或预防疾病，和/或依FDCA第201(g)(1)(C) 条或21 U.S.C. 321(g)(1)(C)定义为药品，因为其用于影响人体结构或功能。具体来说，此药品用途外用止痛剂。
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 the Tentative 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.
活络油和舒筋露此类药品用作外用止痛剂，如暂时缓解轻微疼痛，应依OTC药品审核进行评估。如果该药品符合TFM所有条件和21CFR330.1的所有通用条件，则依TFM人用外用止痛药OTC可归类为公认安全有效的药品，而不是冒牌药品。
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).
由于上述规定尚未定稿，FDA无意对已上市且符合TFM条件和21CFR330.1条件的药品采取法规措施。但如果TFM规定最后定稿时要求重新配方和/或重新标签或FDA需要通过FDCA第505部分“新药”程序进行批准，则此类上市销售必须符合FDCA第502条所有要求，以及21CFR中所有适用规定。
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.
活络油和舒筋露依FDCA第502(e)(1)(A)(ii)和 (iii)及21 U.S.C. 352(e)(1)(A)(ii) 和 (iii)为冒牌药品，因为其标签未明确其活性成分，每种活性成分和非活性成分的比例。在检查期间发现XX、薄荷和XX被用于活络油和舒筋露的生产。
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，你们公司知晓这些XX成分在两药品中均被用作活性成分，但所有的XX成分在产品标签中均未声称为活性成分。具体来说，活络油药品标签未声称XX为其活性成分，舒筋露药品标签未声明XX为其活性成分。检查期间还发现你们公司在活络油和舒筋露生产中使用了XX非活性成分。你们公司未能提供非活性成分的XX组成中所有成分的完整清单，你们知晓在药品标签中并未声明所有非活性成分。
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).
活络油和舒筋露依FDCA第502(f)(2)条及21 U.S.C. 352(f)(2)亦为冒牌药品，因为该药品的标签未载有所需的警示信息，例如，2药品均未提示所需的警示信息“不得用于指示以外情形”，参见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.
将冒牌药品引入或运送进入州际贸易依FDCA第301(a)部分及21 U.S.C. 331(a)是被禁止的。因此，活络油和舒筋露的上市违反了FDCA的此条款。
Conclusion结论
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，防止这些偏差的再次发生，防止其它偏差的发生。
FDA placed your firm on ImportAlert 66-40 on January 8, 2018.
FDA已于2018年1月8将你公司列入66-40项下进口禁令中。
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 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 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。
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
Please identify your responsewith FEI: 3003723042.
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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发表于 2018-3-7 10:34:44
置顶卡
变色卡
楼主
发表于 2018-3-7 13:34:41
。或者原谅我的孤陋寡闻