正文
Via UPS Warning Letter 320-18-10
November 20, 2017
Mr. JongWoo Kim
Chief Executive Officer
Dae Young Foods Company, Ltd.
7F. KTIS Sungin Bldg. 390
Jong-ro, Jongno-gu, Seoul 110-825 Korea
Dear Mr. Kim:
The U.S. Food and Drug Administration (FDA) inspectedyour drug manufacturing facility, Dae Young Foods at 32 Gumgul-4-gil Boeun-eup,Boeun-gun, Chungchongbuk-do, from March 13 to 17, 2017.
美国FDA于2017年3月13日至17日检查了你们位于韩国忠清北道的Dae Young Foods生产场所。
This warning letter summarizes significant violationsof current good manufacturing practice (CGMP) regulations for finishedpharmaceuticals. 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。
Because your methods, facilities, or controls formanufacturing, processing, packing, or holding do not conform to CGMP, yourdrug products are adulterated within the meaning of section 501(a)(2)(B) of theFederal 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, the FDA reviewed your product label forSmoker’s Appetite Relief and determined that your product is a misbranded drugunder section 502(a) of the FD&C Act, 21 U.S.C. 352(a).
此外，FDA还审核了你们的吸烟者食欲缓解产品标签，认为你们的产品依据FDCA第502（a）和21 U.S.C. 352(a)为冒牌药品。
We reviewed your April 9, 2017, response in detail andacknowledge receipt of your subsequent correspondence.
我们收到并详细审核了你们公司于4月9日及之后的回复。你
During our inspection, our investigator observedspecific 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 visuallyexamine each container of components for appropriate labeling as to contentsupon receipt and before acceptance (21 CFR 211.82(a)).
你们公司没有在接收和放行之前对每个成分容器目视检查其标签是否恰当(21 CFR 211.82(a))。
Your firm accepted at least one shipment of a drugcomponent without ensuring it was properly labeled. For example, the label ondrums of an in-process (b)(4) #(b)(4) containing multiple activeingredients indicated “(b)(4)” only and failed to identify any of theactive ingredients in the component or list their concentrations. Furthermore,the batch number on the drums did not match the batch number in the documentsyou provided to support the use of this component.
你们公司接受了一种药品成分的至少一次运送批，而没有确保其有适当的标签。例如，一个中间体XX中包含有多个活性成分，桶上的标签只显示了XX，而没有标识出其中的任何活性成分，也未列出其对应浓度。另外，桶上的批号与你们所提供的用以支持使用此成分的文件中所列的批号不符。
This in-process (b)(4) was manufactured fromingredients that pose potentially toxic effects, such as (b)(4),which contains (b)(4). You manufactured a homeopathic drug product, (b)(4),using a portion of the component that you accepted without examining forappropriate labeling.
此中间体是采用具有潜在毒性效果的成分所生产的，例如 XX，其中含有YY。你们生产一种顺势疗法药品ZZ，使用了此成分的一总分，而你们在接受该成分时并没有检查其标签是否适当。
You cannot accept drug components unless thecontainers are appropriately labeled as to contents. In response to thisletter provide your detailed plan for ensuring that incoming drug componentsyou receive from your suppliers are appropriately labeled as to contents, forexample, accurately labeled with the identity and strength of all ingredients.
如果容器标签未依据其内容物进行适当标示，你们是不能接受该药品成分的。在回复此函时，请提交你们的详细计划，确保你们从你们供应商处接受的进厂药品成分按其内容物进行了适当标示，例如，准确标明其成分和所有成分的含量。
2. Your firm failed to conduct at leastone test to verify the identity of each component of a drug product. Your firmalso failed to test each component for conformity with all appropriate writtenspecifications for purity, strength, and quality (21 CFR 211.84(d)(1) &(2)).
你们公司未能实施至少一项检测来核查药品的每种成分的鉴别。你们公司也没有对每种成分进行检查，确认其符合所有适当的书面纯度、含量和质量标准(21 CFR 211.84(d)(1) & (2))。
Your firm failed to test incoming drug components, thein-process (b)(4) received from (b)(4), for identity or anyquality criteria prior to use in your drug manufacturing process. By notadequately analyzing these in-process (b)(4) for identity, purity,strength, and quality, you failed to ensure the suitability of incoming rawmaterials for processing.
你们公司在药品生产前，未对所用进厂药品成分，从XX接受的中间体，检测其鉴别或任何的质量标准。由于未能对这些中间体的鉴别、纯度、含量和质量进行充分的分析检测，你们无法确保用于工艺生产的进厂原料的适用性。
Your firm also has not established the reliability ofyour in-process (b)(4) supplier’s certificates of analysis. Your use ofsupplier questionnaires, without appropriate validation of your supplier’s testresults, is inadequate to ensure the certificates of analysis you receive canbe used in lieu of testing your drug components for quality attributes.
你们公司亦未建立你们中间体XX供应商的COA的可靠性。你们使用了供应商问卷，而没有对你们供应商的检测结果进行适当的验证，这样无法确保你们所收到的COA可以用于替代你们对药品成分的质量属性的检测。
In your response, you stated that you will begintesting your incoming in-process (b)(4) for the presence of (b)(4),but not the active ingredients in this (b)(4). The active ingredientsyou purport to use are potentially toxic and could pose a significant safetyhazard if present in levels higher than the labeled content.
在你们的回复中，你们声称你们要开始检测你们的进厂中间体中XX是否存在，而不检测其中的活性成分。你们所使用的该活性成分具有潜在毒性，如果其含量水平高于其标示含量，可能具有重大的安全危害性。
In response to this letter, provide your scientificjustification for how you will assure that all of your components, includingthose containing ingredients that pose potentially toxic effects, will meetappropriate specifications before use in manufacturing. Also describe how youwill correct your supplier qualification procedure with steps such as clearlypredefined specifications and periodic revalidation of supplier test results.
在回复此函时，请提交你们要如何确保你们用于生产的所有成分，包括这些含有存在潜在毒性效果的成分，符合适当的质量标准的科学论证。还请在其中描述你们要如何纠正你们的供应商确认程序，其中包括有例如清楚界定既定质量标准和定期重新验证供应商检测结果的步骤。
Also provide a risk assessment for any drug productlots manufactured using components that were not adequately tested andqualified. Your risk assessment should address all products within expiry anddistributed within the United States.
还请提交一份使用这些未经充分检测和确认的成分所生产的所有药品批次的风险评估。你们的风险评估应包括销往美国的仍在有效期内的所有药品。
3. Your firm failed to establish anadequate quality control unit and procedures applicable to the quality controlunit with the responsibility and authority to approve or reject all components,drug product containers, closures, in-process materials, packaging materials,labeling, and drug products (21 CFR 211.22(a) and (d)).
你们公司未建立足够的质量部门和程序，使得质量部门具备职责和权力来批准或拒收所有成分、药品容器、密闭器、中间物料、包装物料、标签和药品(21 CFR 211.22(a) and (d))。
Your firm lacks an adequate quality control unit.
你们公司缺乏足够的质量部门。
You failed to establish written procedures fornumerous functions. For example, there were no procedures addressing thequality control unit, complaints, deviations, investigations, and various otherbasic drug manufacturing operations.
你们有许多的职能均未建立书面程序。例如，没有关于质量部门、投诉、偏差处理、调查和其它不同基本药品生产操作的程序。
Further, your quality unit lacked documentation todemonstrate acceptability of batch manufacturing and quality. For instance, youlacked records relating to:
另外，你们的质量部门缺乏文件记录来证明批生产和质量的可接受性。例如，你们缺少以下相关记录：
change control; 变更控制
annual product reviews; 年度产品回顾
batch record review to assure that any errors were discovered and fully investigated; and 批记录审核，以确保发现和全面调查所有错误，以及
approval or rejection of your drug products. 你们药品的批准和拒收
During our inspection one of your employees confirmedthat that your quality unit does not review the complete batch records for yourfinished drug products prior to release. In response to this letter, provideyour corrective actions to ensure that:
在我们检查期间，你们的一位员工确认你们的质量部门在放行药品之前并没有审核你们制剂产品的完整批记录。在回复此函时，请提交你们的纠正措施以确保：
you establish an adequate quality control unit with the appropriate authority and sufficient resources to carry out its responsibilities and consistently ensure drug quality;
你们建立充分的质量部门，具备适当的权力和足够的资源来履行其职责，持续确保药品质量；
you establish adequate procedures in accord with CGMP covering all aspects of your facility and operations that may compromise the identity, strength, quality, and purity of your drug products; and
你们依据CGMP建立足够的程序，覆盖你们设施和运行中可能影响你们药品鉴别、含量、质量和纯度的各个方面，以及
you create and maintain full documentation to demonstrate acceptability of all operations.
你们创建和维护全面的文件记录来证明你们所有操作的可接受性。
Misbranded drug charge 冒牌药品指控
Your firm’s product, Smoker’s Appetite Relief is adrug under section 201(g)(1) of the FD&C Act, 21 U.S.C. 321(g)(1), becauseit is intended to diagnose, cure, mitigate, treat, or prevent disease, and/orintended to affect the structure or any function of the body. Examples ofclaims that establish the intended uses for Smoker’s Appetite Relief include,but may not be limited to, the following:
你们公司的药品，吸烟者食欲缓解产品依据FDCA第201(g)和21 U.S.C. 321(g)(1)定义是一种药品，因为其因为其用于诊断、治疗或预防疾病，和/或用于影响人体结构或功能。表明吸烟者食欲缓解产品既定用途的声明内容包括但不仅限于以下：
o Excessive Appetite 过量食欲
o Food Cravings 食物渴望
o Overeating 饮食过量
o Irritability 易怒
o Nicotine cleansing 尼古丁净化
o Excessive appetite, overeating 过量食欲，饮食过量
o Food cravings食物渴望
o Liver support 肝支持
o Digestion / metabolism support 消化/代谢支持
o Melancholy 忧郁
o Mental withdrawal 心理戒断
o Physical withdrawal 物理戒断
o Irritability 易怒
Under section 502(a) of the FD&C Act, 21 U.S.C.352(a), a drug is misbranded if its labeling is false or misleading in anyparticular. Section 201(n) of the FD&C Act, 21 U.S.C. 321(n), providesthat, “in determining whether [an article’s] labeling or advertising ismisleading there shall be taken into account . . . not only representationsmade or suggested . . . but also the extent to which the labeling oradvertising fails to reveal facts material in the light of suchrepresentations.” According to your batch record for Smoker’s Appetite Relief,there are numerous ingredients that were included in the product but were notdeclared on the finished product label, such as (b)(4), and (b)(4).In addition, there are ingredients listed on the finished product label that donot appear in the batch record, such as Carduus marianus, Hypericum, Kreosotum,and Lobelia. The failure to declare ingredients on the label and the inclusionof ingredients on the label that were not included in the product is false ormisleading, and therefore such product is misbranded under section 502(a) ofthe FD&C Act.
依据FDCA第502（a）部分和21 U.S.C. 352(a)规定，一种药品如果其标签错误或者在任何方面有误导，则该药品即为冒牌药品。FDCA第201（n）和21 U.S.C. 321(n)规定“在确定一个产品的标签或广告是否具有误导性时，应考虑……不仅……所呈现或建议的……还有标签或广告在此类呈现中未能揭示的实际材料的程度。”依据你们的吸烟者食欲缓解产品的批记录，产品中含有大量的成分，但在成品标签上并未写明。例如XX和YY。此外，列在成品标签上的成分则并未出现在批记录中，如水飞蓟、金丝桃、木焦油以及半边莲。未能在标签上写明成分，以及标签所指成分实际在产品中并不包括是造假或误导，因此此类产品依据FDCA第502（a）部分被认为是冒牌药品。
We recognize that Smoker’s Appetite Relief is labeled asa homeopathic drug with active ingredients measured in homeopathic strengths.Under section 201(g)(1) of the FD&C Act, 21 U.S.C. 321(g)(1), the term“drug” includes articles recognized in the official Homeopathic Pharmacopeia ofthe United States (HPUS), or any supplement to it. Homeopathic drugs aresubject to the same regulatory requirements as other drugs; nothing in theFD&C Act exempts homeopathic drugs from any of the requirements related toadulteration, labeling, misbranding, or approval. We acknowledge that manyhomeopathic drugs are manufactured and distributed without FDA approval underenforcement policies set out in the FDA’s Compliance Policy Guideentitled, Conditions Under Which Homeopathic Drugs May be Marketed (CPG400.400) (the CPG). As its title suggests, the CPG identifies specificconditions under which homeopathic drugs may ordinarily be marketed; thus, inorder to fall under the enforcement policies set forth in the CPG, ahomeopathic product must meet the conditions set forth in the CPG.
我们了解吸烟者食欲缓解产品标签作为顺势疗法药品，其中含有活性成分按顺势疗法剂量加入。依据FDCA第201(g)(1)部分和21 U.S.C. 321(g)(1)，术语“药品”包括在美国官方顺势疗法药典（HPUS）及其增补中所认可的产品。顺势疗法药品与其它药品一样受到相同的法规要求约束，FDCA中的条款在掺假、标签、冒牌或批准方面对于顺势疗法药品并无任何豁免。我们知晓许多顺势疗法药品在没有FDA批准情况下生产和销售，不符合FDA符合性政策指南“顺势疗法药品可以上市销售的条件（CPG 400.400）(CPG)”中设定的强制政策。正如其标题所要求，CPG说明了顺势疗法药品通常可以上市销售的具体条件，因此，为了使产品符合CPG所设定的实施政策范围，顺势疗法药品必须符合CGP中所设定的条件。
The introduction or delivery for introduction intointerstate commerce of a drug that is misbranded or adulterated violatessection 301(a) of the FD&C Act, 21 U.S.C. 331(a).
将冒牌或掺假药品引入或发送进入州际贸易违反了FDCA第301（a）部分和21 U.S.C. 331(a)规定。
Responsibilities as a contractor 作为合同生产商的职责
Drugs must be manufactured in conformance with CGMP.FDA is aware that many drug manufacturers use independent contractors, such asproduction facilities, testing laboratories, packagers, and labelers. FDAregards contractors as extensions of the manufacturer.
药品生产必须符合CGMP要求。FDA了解许多药品生产商会使用独立的合同生产商，如何生产设施、检测实验室、包装商和标签商。FDA认为这些合同生产商是生产商的延伸。
You and your customer, (b)(4), have a qualityagreement regarding the manufacture of (b)(4). You are responsiblefor the quality of drugs you produce as a contract facility, regardless of thequality agreements in place. You are required to ensure that drugs are made inaccordance with section 501(a)(2)(B) of the FD&C Act.
你和你的客户XX签订了关于XX生产的质量协议。作为合同场所，无论是否签有质量协议，你们均对你们生产的药品负有责任。你们需要确保你们按FDCA第501(a)(2)(B)部分生产药品。
Refer to the FDA’s guidance for industry, ContractManufacturing Arrangements for Drugs: Quality Agreements, at https://www.fda.gov/downloads/drugs/guidances/ucm353925.pdf.
请参见FDA行业指南“药品合同生产安排：质量协议”。
CGMP Consultant Recommended CGMP顾问建议
Based upon the nature of the violations we identifiedat your firm, we strongly recommend engaging a consultant qualified under 21CFR 211. 34 to assist your firm in meeting CGMP requirements. Your use of aconsultant does not relieve your firm’s obligation to comply with CGMP. Yourfirm’s executive management remains responsible for fully resolving alldeficiencies and ensuring ongoing CGMP compliance.
依据违规情况，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。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
Violations cited in this letter are not intended as anall-inclusive list. You are responsible for investigating these violations, fordetermining the causes, for preventing their recurrence, and for preventingother 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，防止所有场所中这些偏差的再次发生，防止其它偏差的发生。
Until you correct all violations completely and we confirmyour compliance with CGMP, FDA may withhold approval of any new applications orsupplements 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 inFDA refusing admission of articles manufactured at Dae Young Foods, Ltd. at 32Gumgul-4-gil Boeun-eup, at Boeun-gun, Chungchongbuk-do, into the UnitedStates under section 801(a)(3) of the FD&C Act, 21 U.S.C. 381(a)(3). Underthe same authority, articles may be subject to refusal of admission, in that themethods and controls used in their manufacture do not appear to conform to CGMPwithin 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 officein writing within 15 working days. Specify what you have done since ourinspection to correct your violationsand to prevent their recurrence. If youcannot complete corrective actions within 15 working days, state your reasonsfor 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 [email protected]or mail your reply to:
Marie Mathews
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 3009719616.
Sincerely,
/S/
Francis Godwin
Acting Director
Office of Manufacturing Quality
Office of Compliance
Center for Drug Evaluation and Research
