20170802 FDA警告信：加拿大Homeolab-蒲公英
翻译：JULIA来源：Julia法规翻译
ViaUPS
Warning Letter320-17-45
August 2, 2017
Michele Boisvert
Chief Executive Officer
Homeolab USA Inc.
(Part of the parent company, Homeocan Inc.)
3025 De L’Assomption Blvd.
Montreal, QC, Canada, H1N 2H2
Dear Ms. Boisvert:
The U.S. Food and Drug Administration (FDA) inspectedyour drug manufacturing facility, Homeolab USA Inc. (part of the parentcompany, Homeocan Inc.) at 3025 De L’Assomption Blvd.洪荒记 , Montreal, Québec, fromJanuary 9 to 13, 2017.
美国FDA于2017年2月13-17日检查了你们位于加拿大魁北克的HOMEOLAB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。参见21CFR第210和211部分。
Because your methods, facilities, or controls formanufacturing, processing, packing, or holding do not conform to CGMP, yourdrugs are adulterated within the meaning of section 501(a)(2)(B) of the FederalFood, 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。
We reviewed your January 26, 2017, response in detailand acknowledge your subsequent correspondence.
我们详细审核了你们公司2017年1月26日及之后的回复。
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：
1. Your firm failed to establish andfollow adequate control procedures to monitor the output and to validate theperformance of those manufacturing processes that may be responsible forcausing variability in the characteristics of in-process material and the drugproduct (21 CFR 211.110(a)).
你公司未能建立和遵守充分的控制程序，监测输出，验证这些可能会导致中间物料和药品特性波动的生产工艺的性能（21 CFR 211.110(a)）。
Your firm released multiple lots of homeopathicin-process powder blends prior to attempting to validate your manufacturingprocess. You manufacture(b)(4)homeopathic in-process powder blendmixtures which you send to Raritan Pharmaceuticals Inc. (Raritan), a contractmanufacturing organization, to produce finished homeopathic drug products forthe United States (U.S.) market. Some of your powder blend mixtures aremanufactured from ingredients that pose potentially toxic effects. For example,your Infants’ Teething Tablet(b)(4)contains belladonna. Raritan usesthis powder blend mixture to produce finished drug products for infants andchildren, a population vulnerable to the toxic effects of belladonna. Youshipped(b)(4)lot(b)(4)of Infants’ Teething Tablet(b)(4)tothe U.S. market before evaluating whether your manufacturing process wasreliable and reproducible.
你公司放行了多批顺势疗法中间物料粉末混合体，然后才试图验证你们的生产工艺。你们生产的XX顺势疗法中间物料粉末混合物发送至RARITAN公司，该公司为委托生产机构，用以生产用于美国市场的顺势疗法药品成品。有一些粉末混合物是采用可能有毒性影响的成分生产的白头神探3 。例如，你们的婴儿牙片XX含有颠茄。RARITAN使用这些粉末混合物生产婴儿和儿童药品成品，该受众易受到颠茄的毒性影响春光美歌词 。在评估你们的生产工艺是否可靠和可重复之前，你们将婴儿牙片XX的XX批发往美国市场。
Your operators use a(b)(4), an inherentlyvariable process, to(b)(4)produce in-process powder blends, includingthose made from toxic ingredients. You did not test the in-process powderblends for adequacy of mixing to assure uniformity and homogeneity prior torelease and shipment to your contract manufacturer, Raritan.
你们的操作人员使用了XX，这是一种内在易波动的工艺，来生产中间物料粉末混合物，包括采用毒性成分生产的工艺。你们没有测试中间物料粉末混合物是否充分混合，以在放行和发送给你们的委托生产商RARITAN之前确保其均一性。
FDA collected samples of your in-process drugs ((b)(4)lot(b)(4)) during our September-October 2016 inspection of Raritan.FDA analyses indicated that your in-process drugs were not homogeneous incomposition.
FDA在2016年9-10月对RARITAN的检查中采集了你们的在制药品XX批号XX的样品。FDA分析结果显示你们的在制药品组分不均一。
Raritan used your powder blends to contractmanufacture adulterated finished drug products that you marketed for use ininfants and children in the United States. FDA analysis of finished drugproducts made from your in-process blends also demonstrated non-homogeneouscomposition. We acknowledge that the teething tablets made from yournon-uniform powder blends were recalled.
RARITAN使用了你们的粉末混合物合同生产掺假药品，你们则销售至美国供婴儿和儿童使用。FDA分析了使用你们的在制混合物生产的成品，结果也证明其组分不均匀。我们了解使用你们不均匀的粉末混合物生产的牙片已召回。
We also note that during the inspection of yourfacility, you provided a validation report initiated two weeks after wecontacted you to schedule the inspection. However, your process validation doesnot adequately address potential sources of variation or critical parametersthat should be monitored and controlled in order to produce drugs of uniformcharacter and quality. For example:
我们还在对你们场所的检查中注意到你们提供的验证报告是在我们联系你们告知检查日程后的2周才开始的。但是，你们的工艺验证并没有充分说明波动的可能来源点裙臣，也没有说明为了生产出具备均匀属性和质量的药品所需监测和收集的关键参数。例如：
You have not validated the uniformity of active ingredients in yourin-process drugs. You use(b)(4)solution as a surrogate for theactive ingredients, rather than validating the actual processes. There isno scientific justification for use of(b)(4). It has not beendemonstrated to have the same physicochemical properties and mixingcharacteristics as the actual drug ingredients mixed in your process.
你们没有验证你们在制药品中的活性成分的均一性。你们使用了XX溶液替代你们活性成分。而没有验证实际的工艺。对于使用XX并没有科学的论证无耻盗贼。也没有证明其具备与你们工艺中混合的实际药物成分相同的理化特性。
Your manufacturing instructions are not well specified.
你们的生产指令不够具体
The validation protocol and analysis lack well defined acceptancecriteria and sufficiently detailed parameters (e.g. particle size,endpoints of(b)(4)) to ensure that your manufacturing process isreliable and reproducible.
验证方案和分析缺少界定好的可接受标准和足够详细的参数（例如，粒径，XX终点）以确保你们的和平工艺可靠以及可重复
Your protocol explicitly refers to “the person being validated.” Ifthe results are not compliant, the person can then be “subjected to newvalidations.”Your process validation appears to be used as trialruns to evaluate people and lacks sufficient focus on ensuring that theprocess itself湘夫人教案 , as designed, is adequate to enable reproducibility.
你们的方案明确指出“对人员进行验证”。如果结果不符合要求，则该人可以“进行新的验证”。你们的工艺验证貌似用作试验批次来评估人员，而对于确保工艺本身设计足以确保其可重复性缺乏足够的关注。
Your firm lacks adequate written procedures thatestablish an ongoing program for monitoring process control and detectingvariation to ensure maintenance of a stable manufacturing operation. Reliablemanufacturing operations are essential to ensure consistent drug quality throughouteach batch. When significant variability is observed in one or more stages ofpharmaceutical production, it is essential that executive management supportand implement effective actions to address the source(s) of the variation andprovide for a continued state of control.
你公司缺乏足够的书面程序用以建立持续的工艺控制监测计划，发现差异，以确保维持稳定的生产操作。可靠的生产操作对于确保每批药品具有持续的药品质量至关重要。如果在一个或多个药品生产阶段发现重大波动，则具备高层管理支持和实施有效的措施来解决波动来源，提供持续受控状态是非常重要的。
In response to this letter, we request that youprovide:
在回复此函时，我们要求你们提供：
A data-driven and scientifically sound program that identifies andcontrols all sources of variability, such that your in-process powderblend mixtures will consistently meet appropriate quality attributes. Thisincludes, but is not limited to, evaluating suitability of equipment forits intended use, assuring quality of input materials认错吉他谱 , and determining thecapability of each manufacturing process step and control.
基于数据的科学合理计划，在其中识别和控制所有波动的来源，使得你们制程中的粉末混合物持续符合适当的质量属性。这包括但不仅限于评估设备是否适合其既定用途，确保输入物料的质量，确定每个生产工艺步骤和控制的能力。
A risk assessment for distributed drug products manufactured within-process powder blend mixtures produced by an un-validated process. Yourrisk assessment should address any such products intended for vulnerablepopulations, distributed within the United States, and still withinexpiry.
使用中间物料粉末混合物采用未经验证的工艺生产的已销售药品的风险评估。你们的风险评估应说明所有准备用于易受影响人群的在美国国内销售且仍在有效期的产品的问题。
Refer to the FDA 2011 guidance for industry,ProcessValidation: General Principles and Practicesathttps://www.fda.gov/downloads/drugs/guidances/ucm070336.pdf.
参见FDA于2011年发布的行业指南“工艺验证：通则和规范”。
2. Your firm failed to test samplesof each component for identity and conformity with all appropriate writtenspecifications for purity, strength, and quality (21 CFR 211.84(d)(1) and (2)).
你公司未能检测每种成分的样品的鉴别，确定其符合所有适当的书面质量标准中的纯度、剂量和质量（21 CFR 211.84(d)(1) and (2)）。
Our inspection findings indicate that you do not performappropriate identity testing for the components that you use in your drugmanufacturing process (e.g., belladonna(b)(4)). You also do not test orappropriately validate test results for the purity, strength, and quality ofthese components. By not adequately analyzing your components for identity,purity, strength, and quality, you failed to ensure the suitability of incomingraw materials for processing.
我们的检查缺陷显示你们没有对你们用于药品生产工艺的组分执行适当的鉴别检测（例如，颠茄XX）。你们也没有检测或适当这些组分验证检验结果中的纯度、剂量和质量。在没有充分分析你们的成分中的鉴别、纯度、剂量和质量前提下，你们无法确保进厂用于加工的物料的适用性。
In your response, you said that you “perform testingaccording to the requirements of the Homeopathic Pharmacopeia, which are usedto identify the(b)(4)….” The Homeopathic Pharmacopeia of the UnitedStates (HPUS) requires multiple analytical identity tests. Your response failedto adequately describe whether each lot of components will be fully andappropriately tested for identity prior to use in manufacturing, and whetherother attributes will also be tested.
在你们的回复中，你们说你们“依据顺势疗法药典的要求进行了测试，该药典是用于识别XX……”。美国顺势疗法药典（HPUS）要求进行多个分析鉴别测试。你们的回复未能充分描述你们是否会在用于生产之前对每批组分的鉴别进行全部适当的检测，以及是否也会检测其它属性。
Furthermore, in your response dated June 7, 2017, yousaid that you accept “incoming material receipts on the basis of the supplier’sCertificate of Analysis.” Also, the SOP you provided, “Supplier certificationProcedure,” indicates that the quality unit must assure that the supplier’sanalytical results comply with the HPUS, internal specifications, or the“HAB/GAP.” Your response and SOP do not clearly indicate that validation ofsuppliers’ certificates of analysis will occur at appropriate intervals toensure that results (e.g., assay for alkaloids) continue to be reliable.Provide adequate scientific justification for how you will assure thatcomponents that pose potentially toxic effects meet appropriate specificationsbefore use in operations. Include remediation of your supplier qualificationprocedure (e.g., clearly predefined specifications, periodic revalidation).
另外，在你们2017年6月7日的回复中，你们说你们接受“进厂物料是基于供应商的COA”。还有，你们所提供的SOP“供应商认证程序”说质量部门必须确保供应商的分析结果符合HPUS，内部质量标准，或者是“HAB/GAP”。你们的回复和SOP并没有清楚指明会以适当的周期执行供应商COA的验证，以确保其结果（例如，生物碱的含量）持续可靠。请提供充分的科学论证，证明你们要如何确保具有潜在毒性影响的组分符合适当的质量标准，然后才用于生产操作。请在回复中包括你们供应商确认程序的弥补方法（例如，清晰界定质量标准、定期重新验证）。
Also僵尸流 , we request that you provide a risk assessmentfor any drug product lots manufactured using components which were notadequately tested and controlled. Your risk assessment should address allproducts within expiry and distributed within the United States, and placeparticular emphasis on those intended for infants and children.我们也要求你们提供一份针对使用未进行充分检测和控制的组分生产的药品批次进行的风险分析。你们的风险分析应包括所有在美国国内销售并且仍在效期内的药品，并且要重点关注用于婴儿和儿童的药品。
Contract Agreements委托协议
Your quality agreement with your contractmanufacturing organization, Raritan,(b)(4). Note that when amanufacturer employs a contract facility for part of drug manufacturing(including processing, packing, holding, or testing), the manufacturer’squality unit is responsible for approving or rejecting drug productsmanufactured by the contract facility,(b)(4). See 21 CFR 200.10(b) and211.22(a). Furthermore, it is important to note that quality agreements cannotbe used to delegate statutory or regulatory responsibilities to comply withCGMP. Refer also to the FDA 2016 guidance for industry,ContractManufacturing Arrangements for Drugs: Quality Agreements, athttps://www.fda.gov/downloads/drugs/guidances/ucm353925.pdf.
你们与委托生产商RARITAN之间的质量协议注意当生产商使用合同场所进行部分药品生产活动时（包括加工、包装、存贮或检测），生产商的质量部门将负责批准或拒绝由委托生产场所生产的药品。参见21 CFR 200.10(b)和211.22(a)。另外，要注意质量协议并不能用于委派法定和法规GMP合规义务。也请参见FDA于2016年签发的指南“药品合同生产安排：质量协议”。
Limiting Photography限制拍照
During the inspection, our investigator attempted totake pictures of excess material clinging to the sides of the(b)(4)used in the(b)(4)of drugs intended for U.S. distribution. Yourconsultant impeded the inspection by preventing our investigator fromphotographing this piece of equipment.
在检查期间，我们的调查人员尝试对用于美国市场的XX药品所用XX设备的侧面粘附物料进行拍照。你们的顾问阻止我们调查人员对该设备拍照，从而妨碍检查。
When an owner, operator, or agent delays, denies,limits, or refuses an inspection, the drugs may be deemed adulterated undersection 501(j) of the FD&C Act.See FDA’s guidance document,Circumstancesthat Constitute Delaying, Denying, Limiting, or Refusing a Drug Inspection,athttps://www.fda.gov/downloads/regulatoryinformation/guidances/ucm360484.pdf.
如果机构业主、操作人员或代理延误、否决、限制或拒绝检查，则该机构生产的药品依据FDCA第501（j）部分被认定为掺假药品。参见FDA指南。
CGMP Consultant RecommendedCGMP顾问建议
Based upon the nature of the violations we identifiedat your firm, we strongly recommend engaging a consultant qualified in 211.34to assist your firm in meeting CGMP requirements. 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.
根据我们在你们工厂发现的违规情况，我们强烈建议你们聘请一位有能力评估你们操作的顾问，协助你们符合CGMP要求。你们聘用顾问并不能免除你们公司符合CGMP的义务。你们公司的执行管理人员仍保有全面解决所有缺陷，确保持续符合CGMP要求的职责。
Relationship between Homeolab USA, Inc. and ParentCompany Homeocan, Inc.
In your response you state, “Homeolab is NOT amanufacturer. Homeolab is a private label distributor, which has nomanufacturing capabilities.” In your response you also state, “Homeocan is byagreement a contract manufacturer for Homeolab.”
Homeolab USA Inc. and Homeocan Inc. share the sameaddress,谢宗芬 facility, and personnel, including the chief executive officer and thehead of quality. Your head of quality signs email correspondence with “HomeocanInc./Homeolab USA” as your firm’s identity. Homeolab (part of the parent company,Homeocan Inc.) is a registered manufacturer with the FDA. According to yourDutiesand Responsibilitiesdocument, Homeolab is responsible for “GMP Compliancewith regulatory bodies” and “Approval of Batch for Distribution.” In terms ofdrug manufacturing, Homeolab USA Inc. and Homeocan Inc. have no significantseparation, so we are treating Homeolab/Homeocan as a single entity.
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.
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，防止其再次发生，防止其它偏差的发生。
FDA placed your firm on Import Alert 66-40 on May 3,2017.
FDA已于2017年5月4日将你们公司放在进口禁令66-40清单中。
Until you correct all violations completely and weconfirm your compliance with CGMP, FDA may withhold approval of any newapplications 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 inFDA continuing to refuse admission of articles manufactured atHomeolab/Homeocan, 3025 De L’Assomption Blvd., Montreal, Québec夏娜真命吧 , into theUnited States under section 801(a)(3) of the FD&C Act, 21 U.S.C. 381(a)(3).Under this authority, articles may be subject to refusal of admission, in thatthe methods and controls used in their manufacture do not appear to conform toCGMP 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 officein writing within 15 working days. Specify what you have done since ourinspection to correct your violations and 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 toCDER-OC-OMQ-Communications@fda.hhs.govor mail your reply to:
请将你们的电子回复发送至上述邮箱或者以下邮箱。
Matthew Schnupp
Consumer Safety 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 1000399435.
Sincerely,
/S/
Thomas J. Cosgrove, J.D.
Director
Office of Manufacturing Quality
Office of Compliance
Center for Drug Evaluation and Research
翻译：JULIA来源：Julia法规翻译
ViaUPS
Warning Letter320-17-45
August 2, 2017
Michele Boisvert
Chief Executive Officer
Homeolab USA Inc.
(Part of the parent company, Homeocan Inc.)
3025 De L’Assomption Blvd.
Montreal, QC, Canada, H1N 2H2
Dear Ms. Boisvert:
The U.S. Food and Drug Administration (FDA) inspectedyour drug manufacturing facility, Homeolab USA Inc. (part of the parentcompany, Homeocan Inc.) at 3025 De L’Assomption Blvd.洪荒记 , Montreal, Québec, fromJanuary 9 to 13, 2017.
美国FDA于2017年2月13-17日检查了你们位于加拿大魁北克的HOMEOLAB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。参见21CFR第210和211部分。
Because your methods, facilities, or controls formanufacturing, processing, packing, or holding do not conform to CGMP, yourdrugs are adulterated within the meaning of section 501(a)(2)(B) of the FederalFood, 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。
We reviewed your January 26, 2017, response in detailand acknowledge your subsequent correspondence.
我们详细审核了你们公司2017年1月26日及之后的回复。
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：
1. Your firm failed to establish andfollow adequate control procedures to monitor the output and to validate theperformance of those manufacturing processes that may be responsible forcausing variability in the characteristics of in-process material and the drugproduct (21 CFR 211.110(a)).
你公司未能建立和遵守充分的控制程序，监测输出，验证这些可能会导致中间物料和药品特性波动的生产工艺的性能（21 CFR 211.110(a)）。
Your firm released multiple lots of homeopathicin-process powder blends prior to attempting to validate your manufacturingprocess. You manufacture(b)(4)homeopathic in-process powder blendmixtures which you send to Raritan Pharmaceuticals Inc. (Raritan), a contractmanufacturing organization, to produce finished homeopathic drug products forthe United States (U.S.) market. Some of your powder blend mixtures aremanufactured from ingredients that pose potentially toxic effects. For example,your Infants’ Teething Tablet(b)(4)contains belladonna. Raritan usesthis powder blend mixture to produce finished drug products for infants andchildren, a population vulnerable to the toxic effects of belladonna. Youshipped(b)(4)lot(b)(4)of Infants’ Teething Tablet(b)(4)tothe U.S. market before evaluating whether your manufacturing process wasreliable and reproducible.
你公司放行了多批顺势疗法中间物料粉末混合体，然后才试图验证你们的生产工艺。你们生产的XX顺势疗法中间物料粉末混合物发送至RARITAN公司，该公司为委托生产机构，用以生产用于美国市场的顺势疗法药品成品。有一些粉末混合物是采用可能有毒性影响的成分生产的白头神探3 。例如，你们的婴儿牙片XX含有颠茄。RARITAN使用这些粉末混合物生产婴儿和儿童药品成品，该受众易受到颠茄的毒性影响春光美歌词 。在评估你们的生产工艺是否可靠和可重复之前，你们将婴儿牙片XX的XX批发往美国市场。
Your operators use a(b)(4), an inherentlyvariable process, to(b)(4)produce in-process powder blends, includingthose made from toxic ingredients. You did not test the in-process powderblends for adequacy of mixing to assure uniformity and homogeneity prior torelease and shipment to your contract manufacturer, Raritan.
你们的操作人员使用了XX，这是一种内在易波动的工艺，来生产中间物料粉末混合物，包括采用毒性成分生产的工艺。你们没有测试中间物料粉末混合物是否充分混合，以在放行和发送给你们的委托生产商RARITAN之前确保其均一性。
FDA collected samples of your in-process drugs ((b)(4)lot(b)(4)) during our September-October 2016 inspection of Raritan.FDA analyses indicated that your in-process drugs were not homogeneous incomposition.
FDA在2016年9-10月对RARITAN的检查中采集了你们的在制药品XX批号XX的样品。FDA分析结果显示你们的在制药品组分不均一。
Raritan used your powder blends to contractmanufacture adulterated finished drug products that you marketed for use ininfants and children in the United States. FDA analysis of finished drugproducts made from your in-process blends also demonstrated non-homogeneouscomposition. We acknowledge that the teething tablets made from yournon-uniform powder blends were recalled.
RARITAN使用了你们的粉末混合物合同生产掺假药品，你们则销售至美国供婴儿和儿童使用。FDA分析了使用你们的在制混合物生产的成品，结果也证明其组分不均匀。我们了解使用你们不均匀的粉末混合物生产的牙片已召回。
We also note that during the inspection of yourfacility, you provided a validation report initiated two weeks after wecontacted you to schedule the inspection. However, your process validation doesnot adequately address potential sources of variation or critical parametersthat should be monitored and controlled in order to produce drugs of uniformcharacter and quality. For example:
我们还在对你们场所的检查中注意到你们提供的验证报告是在我们联系你们告知检查日程后的2周才开始的。但是，你们的工艺验证并没有充分说明波动的可能来源点裙臣，也没有说明为了生产出具备均匀属性和质量的药品所需监测和收集的关键参数。例如：
You have not validated the uniformity of active ingredients in yourin-process drugs. You use(b)(4)solution as a surrogate for theactive ingredients, rather than validating the actual processes. There isno scientific justification for use of(b)(4). It has not beendemonstrated to have the same physicochemical properties and mixingcharacteristics as the actual drug ingredients mixed in your process.
你们没有验证你们在制药品中的活性成分的均一性。你们使用了XX溶液替代你们活性成分。而没有验证实际的工艺。对于使用XX并没有科学的论证无耻盗贼。也没有证明其具备与你们工艺中混合的实际药物成分相同的理化特性。
Your manufacturing instructions are not well specified.
你们的生产指令不够具体
The validation protocol and analysis lack well defined acceptancecriteria and sufficiently detailed parameters (e.g. particle size,endpoints of(b)(4)) to ensure that your manufacturing process isreliable and reproducible.
验证方案和分析缺少界定好的可接受标准和足够详细的参数（例如，粒径，XX终点）以确保你们的和平工艺可靠以及可重复
Your protocol explicitly refers to “the person being validated.” Ifthe results are not compliant, the person can then be “subjected to newvalidations.”Your process validation appears to be used as trialruns to evaluate people and lacks sufficient focus on ensuring that theprocess itself湘夫人教案 , as designed, is adequate to enable reproducibility.
你们的方案明确指出“对人员进行验证”。如果结果不符合要求，则该人可以“进行新的验证”。你们的工艺验证貌似用作试验批次来评估人员，而对于确保工艺本身设计足以确保其可重复性缺乏足够的关注。
Your firm lacks adequate written procedures thatestablish an ongoing program for monitoring process control and detectingvariation to ensure maintenance of a stable manufacturing operation. Reliablemanufacturing operations are essential to ensure consistent drug quality throughouteach batch. When significant variability is observed in one or more stages ofpharmaceutical production, it is essential that executive management supportand implement effective actions to address the source(s) of the variation andprovide for a continued state of control.
你公司缺乏足够的书面程序用以建立持续的工艺控制监测计划，发现差异，以确保维持稳定的生产操作。可靠的生产操作对于确保每批药品具有持续的药品质量至关重要。如果在一个或多个药品生产阶段发现重大波动，则具备高层管理支持和实施有效的措施来解决波动来源，提供持续受控状态是非常重要的。
In response to this letter, we request that youprovide:
在回复此函时，我们要求你们提供：
A data-driven and scientifically sound program that identifies andcontrols all sources of variability, such that your in-process powderblend mixtures will consistently meet appropriate quality attributes. Thisincludes, but is not limited to, evaluating suitability of equipment forits intended use, assuring quality of input materials认错吉他谱 , and determining thecapability of each manufacturing process step and control.
基于数据的科学合理计划，在其中识别和控制所有波动的来源，使得你们制程中的粉末混合物持续符合适当的质量属性。这包括但不仅限于评估设备是否适合其既定用途，确保输入物料的质量，确定每个生产工艺步骤和控制的能力。
A risk assessment for distributed drug products manufactured within-process powder blend mixtures produced by an un-validated process. Yourrisk assessment should address any such products intended for vulnerablepopulations, distributed within the United States, and still withinexpiry.
使用中间物料粉末混合物采用未经验证的工艺生产的已销售药品的风险评估。你们的风险评估应说明所有准备用于易受影响人群的在美国国内销售且仍在有效期的产品的问题。
Refer to the FDA 2011 guidance for industry,ProcessValidation: General Principles and Practicesathttps://www.fda.gov/downloads/drugs/guidances/ucm070336.pdf.
参见FDA于2011年发布的行业指南“工艺验证：通则和规范”。
2. Your firm failed to test samplesof each component for identity and conformity with all appropriate writtenspecifications for purity, strength, and quality (21 CFR 211.84(d)(1) and (2)).
你公司未能检测每种成分的样品的鉴别，确定其符合所有适当的书面质量标准中的纯度、剂量和质量（21 CFR 211.84(d)(1) and (2)）。
Our inspection findings indicate that you do not performappropriate identity testing for the components that you use in your drugmanufacturing process (e.g., belladonna(b)(4)). You also do not test orappropriately validate test results for the purity, strength, and quality ofthese components. By not adequately analyzing your components for identity,purity, strength, and quality, you failed to ensure the suitability of incomingraw materials for processing.
我们的检查缺陷显示你们没有对你们用于药品生产工艺的组分执行适当的鉴别检测（例如，颠茄XX）。你们也没有检测或适当这些组分验证检验结果中的纯度、剂量和质量。在没有充分分析你们的成分中的鉴别、纯度、剂量和质量前提下，你们无法确保进厂用于加工的物料的适用性。
In your response, you said that you “perform testingaccording to the requirements of the Homeopathic Pharmacopeia, which are usedto identify the(b)(4)….” The Homeopathic Pharmacopeia of the UnitedStates (HPUS) requires multiple analytical identity tests. Your response failedto adequately describe whether each lot of components will be fully andappropriately tested for identity prior to use in manufacturing, and whetherother attributes will also be tested.
在你们的回复中，你们说你们“依据顺势疗法药典的要求进行了测试，该药典是用于识别XX……”。美国顺势疗法药典（HPUS）要求进行多个分析鉴别测试。你们的回复未能充分描述你们是否会在用于生产之前对每批组分的鉴别进行全部适当的检测，以及是否也会检测其它属性。
Furthermore, in your response dated June 7, 2017, yousaid that you accept “incoming material receipts on the basis of the supplier’sCertificate of Analysis.” Also, the SOP you provided, “Supplier certificationProcedure,” indicates that the quality unit must assure that the supplier’sanalytical results comply with the HPUS, internal specifications, or the“HAB/GAP.” Your response and SOP do not clearly indicate that validation ofsuppliers’ certificates of analysis will occur at appropriate intervals toensure that results (e.g., assay for alkaloids) continue to be reliable.Provide adequate scientific justification for how you will assure thatcomponents that pose potentially toxic effects meet appropriate specificationsbefore use in operations. Include remediation of your supplier qualificationprocedure (e.g., clearly predefined specifications, periodic revalidation).
另外，在你们2017年6月7日的回复中，你们说你们接受“进厂物料是基于供应商的COA”。还有，你们所提供的SOP“供应商认证程序”说质量部门必须确保供应商的分析结果符合HPUS，内部质量标准，或者是“HAB/GAP”。你们的回复和SOP并没有清楚指明会以适当的周期执行供应商COA的验证，以确保其结果（例如，生物碱的含量）持续可靠。请提供充分的科学论证，证明你们要如何确保具有潜在毒性影响的组分符合适当的质量标准，然后才用于生产操作。请在回复中包括你们供应商确认程序的弥补方法（例如，清晰界定质量标准、定期重新验证）。
Also僵尸流 , we request that you provide a risk assessmentfor any drug product lots manufactured using components which were notadequately tested and controlled. Your risk assessment should address allproducts within expiry and distributed within the United States, and placeparticular emphasis on those intended for infants and children.我们也要求你们提供一份针对使用未进行充分检测和控制的组分生产的药品批次进行的风险分析。你们的风险分析应包括所有在美国国内销售并且仍在效期内的药品，并且要重点关注用于婴儿和儿童的药品。
Contract Agreements委托协议
Your quality agreement with your contractmanufacturing organization, Raritan,(b)(4). Note that when amanufacturer employs a contract facility for part of drug manufacturing(including processing, packing, holding, or testing), the manufacturer’squality unit is responsible for approving or rejecting drug productsmanufactured by the contract facility,(b)(4). See 21 CFR 200.10(b) and211.22(a). Furthermore, it is important to note that quality agreements cannotbe used to delegate statutory or regulatory responsibilities to comply withCGMP. Refer also to the FDA 2016 guidance for industry,ContractManufacturing Arrangements for Drugs: Quality Agreements, athttps://www.fda.gov/downloads/drugs/guidances/ucm353925.pdf.
你们与委托生产商RARITAN之间的质量协议注意当生产商使用合同场所进行部分药品生产活动时（包括加工、包装、存贮或检测），生产商的质量部门将负责批准或拒绝由委托生产场所生产的药品。参见21 CFR 200.10(b)和211.22(a)。另外，要注意质量协议并不能用于委派法定和法规GMP合规义务。也请参见FDA于2016年签发的指南“药品合同生产安排：质量协议”。
Limiting Photography限制拍照
During the inspection, our investigator attempted totake pictures of excess material clinging to the sides of the(b)(4)used in the(b)(4)of drugs intended for U.S. distribution. Yourconsultant impeded the inspection by preventing our investigator fromphotographing this piece of equipment.
在检查期间，我们的调查人员尝试对用于美国市场的XX药品所用XX设备的侧面粘附物料进行拍照。你们的顾问阻止我们调查人员对该设备拍照，从而妨碍检查。
When an owner, operator, or agent delays, denies,limits, or refuses an inspection, the drugs may be deemed adulterated undersection 501(j) of the FD&C Act.See FDA’s guidance document,Circumstancesthat Constitute Delaying, Denying, Limiting, or Refusing a Drug Inspection,athttps://www.fda.gov/downloads/regulatoryinformation/guidances/ucm360484.pdf.
如果机构业主、操作人员或代理延误、否决、限制或拒绝检查，则该机构生产的药品依据FDCA第501（j）部分被认定为掺假药品。参见FDA指南。
CGMP Consultant RecommendedCGMP顾问建议
Based upon the nature of the violations we identifiedat your firm, we strongly recommend engaging a consultant qualified in 211.34to assist your firm in meeting CGMP requirements. 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.
根据我们在你们工厂发现的违规情况，我们强烈建议你们聘请一位有能力评估你们操作的顾问，协助你们符合CGMP要求。你们聘用顾问并不能免除你们公司符合CGMP的义务。你们公司的执行管理人员仍保有全面解决所有缺陷，确保持续符合CGMP要求的职责。
Relationship between Homeolab USA, Inc. and ParentCompany Homeocan, Inc.
In your response you state, “Homeolab is NOT amanufacturer. Homeolab is a private label distributor, which has nomanufacturing capabilities.” In your response you also state, “Homeocan is byagreement a contract manufacturer for Homeolab.”
Homeolab USA Inc. and Homeocan Inc. share the sameaddress,谢宗芬 facility, and personnel, including the chief executive officer and thehead of quality. Your head of quality signs email correspondence with “HomeocanInc./Homeolab USA” as your firm’s identity. Homeolab (part of the parent company,Homeocan Inc.) is a registered manufacturer with the FDA. According to yourDutiesand Responsibilitiesdocument, Homeolab is responsible for “GMP Compliancewith regulatory bodies” and “Approval of Batch for Distribution.” In terms ofdrug manufacturing, Homeolab USA Inc. and Homeocan Inc. have no significantseparation, so we are treating Homeolab/Homeocan as a single entity.
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.
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，防止其再次发生，防止其它偏差的发生。
FDA placed your firm on Import Alert 66-40 on May 3,2017.
FDA已于2017年5月4日将你们公司放在进口禁令66-40清单中。
Until you correct all violations completely and weconfirm your compliance with CGMP, FDA may withhold approval of any newapplications 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 inFDA continuing to refuse admission of articles manufactured atHomeolab/Homeocan, 3025 De L’Assomption Blvd., Montreal, Québec夏娜真命吧 , into theUnited States under section 801(a)(3) of the FD&C Act, 21 U.S.C. 381(a)(3).Under this authority, articles may be subject to refusal of admission, in thatthe methods and controls used in their manufacture do not appear to conform toCGMP 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 officein writing within 15 working days. Specify what you have done since ourinspection to correct your violations and 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 toCDER-OC-OMQ-Communications@fda.hhs.govor mail your reply to:
请将你们的电子回复发送至上述邮箱或者以下邮箱。
Matthew Schnupp
Consumer Safety 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 1000399435.
Sincerely,
/S/
Thomas J. Cosgrove, J.D.
Director
Office of Manufacturing Quality
Office of Compliance
Center for Drug Evaluation and Research