Warning Letter 320-20-38

 

June 11, 2020

 

Dear Mr. Emond:

 

The U.S. Food and Drug Administration (FDA) inspected your drug manufacturing facility, 8046255 Canada Inc., doing business as (dba) Viatrexx, FEI 3010033797, at 1360 Rue Louis-Marchand, Beloeil, fromSeptember 16 to 24, 2019.

 

美国FDA于2019年9月16日至24日检查了你们位于加拿大的8046255 Canada Inc（dba Viatrexx）生产场所。

 

This warning letter summarizes significant violations of current good manufacturing practice (CGMP) regulations for finished pharmaceuticals. See Title 21 Code of Federal Regulations (CFR), parts 210 and 211 (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与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，你们的药品根据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, FDA reviewed your labeling obtained from the inspection. Based on our review, your injectable homeopathic products“Articula,” “Mesenchyme,” “Connectissue,” “MuSkel-Neural,” “Ouch,” “Ithurts,”“Adipose,” “Systemic Detox,” “Hair,” “Neuro 3,” “Infla,” “Collagen,” “Prolo,”“Lymph 1,” “GI,” “Neuro,” “Arthros,” “Male+,” “Immunexx,” “Relief+,”“Intra-Cell,” “Facial,” and “ANS/CNS” (“injectable homeopathic products”) are unapproved new drugs under section 505 of the Federal Food, Drug, and CosmeticAct (FD&C Act), 21 U.S.C. 355. Introducing or delivering these products for introduction into interstate commerce violates section 301 of the FD&C Act,21 U.S.C. 331.

 

此外，FDA还审核了检查中获取的标签内容。根据我们的审核，你们的注射用顺势疗法药品“Articula,” “Mesenchyme,” “Connectissue,” “MuSkel-Neural,”“Ouch,” “Ithurts,” “Adipose,” “Systemic Detox,” “Hair,” “Neuro 3,” “Infla,”“Collagen,” “Prolo,” “Lymph 1,” “GI,” “Neuro,” “Arthros,” “Male+,” “Immunexx,”“Relief+,” “Intra-Cell,” “Facial,” 和 “ANS/CNS”（“顺势疗法注射剂”）根据FDCA第505条款21U.S.C. 355均为未批准的新药。引入或输送此类药品至州际贸易是被FDCA第301(a)款21 U.S.C. 331(a) 和 (d)禁止的。

 

These products are especially concerning from apublic health perspective because injectable drug products can pose risks of serious harm to users; these risks are less likely to occur with topical or ingested products, i.e., those applied to the skin or taken by mouth. Injectable products are delivered directly into the body, sometimes directly into the bloodstream, and therefore, bypass some of the body’s key defenses against toxins and microorganisms that can lead to serious and life-threatening conditions. Your injectable products are further concerning because they are labeled to contain potentially toxic or otherwise harmful ingredients, such as “Nux Vomica” (contains strychnine), “Rectum,” and “Belladonna,” thereby presenting additional risk of serious harm to patients when delivered directly into the body. Your firm’s significant violations of current good manufacturing practice regulations, as described below, enhances the risk of harm to patients even further.

 

这些药品在公众健康角度尤其令人担忧，因为注射剂可能会对使用者带来严重伤害风险，这些风险不太可能发生在消化道用药或局部用药，因为这些药品仅用于皮肤或经口摄入。注射剂是直接注入身体，有时直接进入血液，因此，绕开了人体的一些关键毒物和微生物防御系统，这样可能导致危及生命的严重情形。你们的注射剂有着更多担忧，因为其标示为含有潜在毒性或有害成分，例如“Nux Vomica”（含有马钱子碱），“Rectum”和“Belladonna”，因此当直接输入体内时对患者具有额外的严重伤害风险。如下所述，你公司严重违反了CGMP法规，更是大大增加了对患者的危害风险。

 

We reviewed your October 16, 2019, response to our Form FDA 483 in detail and acknowledge receipt of your subsequent correspondence.

 

我们已详细审核了你公司2019年10月16日对我们FDA483表的回复，并此告知已收到后续通信。

 

During our inspection, our investigator observed specific 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 and follow appropriate written procedures that are designed to prevent microbiological contamination of drug products purporting to be sterile, and that include validation of all aseptic and sterilization processes (21 CFR 211.113(b)). 你公司未遵守适当的书面程序，设计用于防止既定无菌的药品微生物污染，并包括所有无菌和灭菌工艺的验证（21 CFR 211.113(b)）。

 

You manufactured and distributed sterile injectable homeopathic drug products without adequately validating your aseptic manufacturing processes.

 

你们生产和销售无菌注射用顺势疗法药品，但并没有充分验证你们的无菌生产工艺。

 

Process Simulations (Media Fills) 工艺模拟（培养基灌装）

 

You failed to establish appropriate procedures and perform media fills to evaluate your manual aseptic filling and stoppering operations.

 

你们并未建立起适当的程序并执行培养基灌装，以评估你们的人工无菌灌装和加塞操作。

 

Filter Suitability 过滤器适用性

 

You failed to qualify the use of an appropriate filter for sterile filtration of your injectable drug products. Rather than using a sterilizing filter suitable for sterile drug manufacturing you used a (b)(4) filter for the sterile filtration. You also failed to test the filter integrity after use.

 

你们并未确认你们注射药品中除菌过滤时使用的是恰当的过滤器。你们使用了XX过滤器用于除菌过滤，而不是使用适合于无菌药品生产的除菌过滤器。你们在使用之后亦未检测过滤器完整性。

 

Poor Aseptic Techniques  无菌技巧不良

 

You failed to ensure use of appropriate aseptic technique for manufacturing sterile injectable drug products. Our investigator observed personnel behaviors in the manual filling and stoppering operations that blocked the path of (b)(4) airflow.

 

你们未能确保使用适当的无菌技巧用于生产无菌注射药品。我们的检查员观察了你们人工灌装和加塞操作员工的行为，他们挡住了XX气流的路径。

 

On October 14, 2019, your firm recalled all sterile injectable drug products you manufactured. However, your proposed corrective actions permitted continued use of an unsuitable filter to sterilize your drug product. Your response also failed to address the frequency for conducting media fills.

 

在2019年10月14日，你公司召回了你们生产的所有无菌注射产品。但是你们提出的纠正措施允许继续使用不适当的过滤器对你们的药品灭菌。你们的回复亦未解决培养基培养执行频次问题。

 

Validation of aseptic processing requires establishing documented evidence with a high degree of assurance that a particular process consistently produces a product meeting its predetermined specifications and quality attributes. Media fills, and various systemic controls including, but not limited to, daily adherence to strict aseptic processing standards, suitable facilities, robust environmental control, and satisfactory product sterility testing, combine to ensure that an injectable drug is sterile. If injectable drugs are not sterile, they pose unacceptable risks to patients, including infection.

 

无菌工艺的验证需要建立具有高度保证的文件化证据，保证具体的工艺可持续生产出符合其既定标准和质量属性的产品。培养基灌装和各种系统控制，包括但不仅限于日常遵守严格的无菌工艺标准、稳定的设施、稳健的环境控制，和令人满意的产品无菌性检测，联合起来确保注射药品是无菌的。如果注射药品不是无菌的，则它们会对患者有着不可接受的风险，包括感染风险。

 

In response to this letter, provide the following:

 

在回复本函时请提交以下内容：

 

•      Comprehensive risk assessment of all contamination hazards with respect to your aseptic processes, equipment, and facilities, including an independent assessment that includes, but is not limited to:

 

•      对你们无菌工艺、设备和设施所有污染危害的全面风险评估，包括一份包括但不仅限于以下内容的独立评估：

 

All human interactions within the ISO 5 area

 

ISO5区域内所有人间互动

 

Equipment placement and ergonomics

 

设备安装位置和人体工程学

 

Air quality in the ISO 5 area and surrounding room

 

ISO5区域和周边房间的空气质量

 

Facility layout

 

设施平面布局图

 

Personnel flows and material flows (throughout all rooms used to conduct and support sterile operations)

 

人流和物流（执行和支持无菌操作的所有房间之间）

 

•      A detailed remediation plan with timelines to address the findings of the independent contamination hazards risk assessment. Describe specific tangible improvements to be made to aseptic processing operation design and control.

 

•      一份详细的补救计划及时间表，解决独立污染危害风险评估期间发现的问题。阐明准备对无菌工艺操作设施和控制所做的具体实际的改进

 

•      Your plan to ensure appropriate aseptic practices and cleanroom behavior during production. Include steps to ensure routine and effective supervisory oversight for all production batches. Also describe the frequency of quality unit oversight (e.g., audit) during aseptic processing andits support operations.

 

•      你们确保生产期间的无菌操作和洁净间行为恰当的计划。包括确保对所有生产批次进行日常和有效监管的措施。亦请说明质量部门在无菌加工及其支持性操作期间的监管（例如审计）频次

 

•      Your plan to ensure robust sterilization processes for all sterilization methods. Provide your program for qualification and validation of all sterilization operations. Also, regarding sterilizing filtration, provide a corrective action and preventive action (CAPA) plan that ensures:

 

•      你们确保所有灭菌方法有着稳健灭菌工艺的计划。提交你们的所有灭菌操作确认和验证计划。另外，关于除菌过滤，请提交一份CAPA计划以确保：

 

Selection of a suitable (b)(4) filter for drug sterilization

 

选择了适当的XX过滤器用于药品除菌

 

Appropriate filtration efficacy validation study protocols for each product and that incorporates the worst-case filtration conditions

 

对每个产品进行恰当的过滤器效率验证研究的方案，要包括最差过滤情形

 

Proper responsibilities for proper conduct, full documentation, review, and approval of these studies

 

恰当执行、全面记录、审核和批次这些研究的人员职责

 

Products will not be distributed before complete and adequate studies are performed

 

在完成充分的研究之前不会将销售产品

 

2. Your firm failed to ensure that manufacturing personnel wear clothing appropriate to protect drug product from contamination (21 CFR 211.28(a)). 你公司未能确保生产人员穿着适合于保护药品不受污染的服装（21 CFR 211.28(a)）。

 

You failed to have appropriate gowning for manufacturing sterile injectable homeopathic drug products. With the exception of gloves, you used non-sterile gowning and also re-used these gowning materials to perform aseptic operations. Our investigator also observed exposed facial skin and the operator donning sterile gloves over bare hands when right next to the ISO 5 hood where aseptic processing is performed.

 

你们没有顺势疗法注射剂生产的适当着装程序。除了手套外，你们使用了非无菌服装，还重复使用这些服装材料进行无菌操作。我们的检查员亦观察到有面部皮肤暴露，操作员在紧邻无菌操作ISO5气流罩的地方将无菌手套戴到裸手上。

 

Your response stated that you will use sterile gowning for production. However, the gowning pictured in your response is not adequate for sterile injectable drug manufacturing because, for example, skin is exposed on the operator’s face.

 

你们回复声称你们会在生产中使用无菌服装。但是你们回复中的服装图片不足以用于无菌注射药品生产，因为例如，操作员面部皮肤有暴露。

 

In response to this letter, provide the following:

 

在回复本函时请提交以下内容：

 

•      A list of the gowning materials you intend to use(e.g. sterilized nonshedding gowns and covers for the skin and hair, such as,face-masks, hoods, beard/moustache covers, protective goggles, and gloves).

 

•      一份你们装备使用的服装材料的清单（例如，已灭菌无脱落物的服装，遮住皮肤和毛发，如面罩、兜帽、胡须套、保护性手套和手套）

 

•      A gowning qualification program that establishes, both initially and on a periodic basis, the capability of an individual to adequately don the complete sterile gown in an aseptic manner.

 

•      一份更衣确认程序，首次和定期证明个人可以无菌方式穿戴完整的无菌服装的能力

 

•      The role of the quality unit in gown supplier selection and ongoing qualification decisions. Ensure that the quality unit makes final decisions including supplier selection, release of raw materials and supplies (e.g., garments) used in production, and other ongoing decisions about supplier reliability.

 

•      质量部门在服装供应商选择和持续确认决策方面的作用。确保是质量部门做出最终决策，包括生产用供应商选择、原料和供应商放行（例如，洁净服），以及其它供应商可靠性的持续决策

 

•      Details regarding how you will establish adequate gowning, training, gowning qualification, and supervision on an ongoing basis.

 

•      关于你们准备如何建立足够的更衣、培训、更衣确认和持续监管的详细信息

 

3. Your firm failed to establish a system for monitoring environmental conditions in aseptic processing areas and an adequate system for cleaning and disinfecting the room and equipment to produce aseptic conditions (21 CFR 211.42(c)(10)(iv) and (v)). 你公司未能建立一个用于监测无菌加工区域的环境条件的体系，以及一个清洁和消毒产生无菌条件的房间与设备的体系（21 CFR 211.42(c)(10)(iv) 和(v)）。

 

Cleaning and Disinfecting 清洁和消毒

 

Your procedures for cleaning and disinfecting are inadequate. For example, you lacked procedures to ensure frequent use of a (b)(4) agent. You also failed to consistently document cleaning and disinfecting.

 

你们的清洁和消毒程序不充分。例如，你们缺少程序确保XX剂的使用频次。你们亦未能持续记录清洁和消毒操作。

 

Environmental Conditions 环境条件

 

You performed environmental monitoring during the initial qualification of your facility in May 2019. However, you continued production through September 2019 with no routine environmental monitoring. You also lacked written procedures for environmental monitoring.

 

你们在2019年5月初次确认时进行了环境监测。但是你们在2019年9月连续生产，没有进行常规环境监测。你们亦缺少环境监测书面程序。

 

An environmental monitoring program provides meaningful information about the quality of the aseptic processing environment, as well as additional clean areas.

 

环境监测计划应提供无菌加工环境以及其它洁净区域质量的有意义的信息。

 

Your response is inadequate because it did not provide sufficient details or procedures for your environmental monitoring program. You also did not provide any evidence that your manufacturing environment is under an ongoing state of control.

 

你们的回复是不充分的，因为其中并未提供你们环境监测程序的足够的详细信息或程序。你们亦未提交任何证据证明你们的生产环境持续处于受控状态。

 

In response to this letter, provide the following:

 

在回复本函时请提交以下内容：

 

•      A CAPA plan, based on a retrospective assessment of your cleaning and disinfection program, that includes appropriate remediations to your cleaning/disinfection processes and practices, and timelines for completion. Provide a detailed summary of vulnerabilities in your process for lifecycle management of equipment cleaning and disinfection. Describe improvements to your cleaning and disinfection program, including enhancements to cleaning effectiveness, improved ongoing verification of proper cleaning and disinfection execution for all products and equipment, and all other needed remediations.

 

•      一份CAPA计划，基于你们清洁和消毒程序的回顾性评估，其中包括对你们清洁/消毒工艺和做法的适当补救措施，以及完成时间表。提交一份你们工艺中设备清洁和消毒生命周期管理方面薄弱点的详细综述，包括改进清洁有效性，改进所有产品和设备的清洁和消毒执行方面的持续确认，以及所有其它所需补救措施。

 

•      A comprehensive environmental monitoring program for your facility, including but not limited to, frequency, location, types,and methods of monitoring. The program should include provisions to vigilantly monitor both daily results and trends.

 

•      一份对你们设施的全面环境监测计划，包括但不仅限于监测频次、监测点、监测类型和方法。计划应包括严格监测日常结果和趋势的条款。

 

•      A comprehensive personnel monitoring program for operators involved in aseptic processing operations.

 

•      一份对参与无菌工艺操作的操作员的全面人员监测计划。

 

4. 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)).你公司未能建立实验室控制，在其中包括科学合理和恰当的质量标准、取样计划和检测方法，以确保组份、药品容器、密闭器、中控物料、标签和成品符合恰当的鉴别、剂量、质量和纯度标准（21 CFR 211.160(b)）。

 

You failed to validate your sterility test method and also failed to use suitable media for sterility testing of your sterile injectable homeopathic drug products. Furthermore, you failed to perform endotoxin and particulate matter testing for your sterile injectable homeopathic drug products.

 

你们并未验证你们的无菌检测方法，亦未使用适当的培养基对你们的无菌顺势疗法注射药品进行无菌性检测。另外，你们并未对你们的无菌顺势疗法注射药品进行内毒素和颗粒物检测。

 

Your response included certificates of analysis for third-party testing of multiple products, but did not address validation of your sterility test method. The sterility testing of each batch is the last ina series of essential CGMP controls that ensure that a drug product is sterile and suitable for release.

 

你们的回复包括有第三方对多个产品的分析报告，但并未解决你们无菌检测方法验证的问题。对每个批次进行无菌检测是确保药品是无菌并适合放行的一系列基本CGMP控制的最后一部分。

 

In response to this letter, provide the following:

 

在你们的回复中请提交：

 

•      A comprehensive, independent assessment of your laboratory practices, procedures, methods, equipment, documentation, andanalyst competencies. Based on this review, provide a detailed plan to remediate and evaluate the effectiveness of your laboratory system.

 

•      一份对你们实验室规范、程序、方法、设备、文件记录和化验员能力的全面独立评估。根据此审核，提交一份补救和评估你们实验室系统有效性的详细计划

 

•      An update of all testing methods used by your firm and your method validation status.

 

•      你们所用所有检测方法的更新情况，以及方法验证的状态

 

Additional Guidance on Aseptic Processing 其它无菌加工指南

 

See FDA’s guidance document Sterile Drug Products Produced by Aseptic Processing—Current Good Manufacturing Practiceto help you meet the CGMP requirements when manufacturing sterile drugs using aseptic processing at https://www.fda.gov/media/71026/download.

 

参见上述链接FDA的指南文件“采用无菌加工生产的无菌药品CGMP”，帮助你们在采用无菌工艺生产无菌药品时符合CGMP要求。

 

In addition to addressing the above CGMP violations, any drug marketed by your firm must conform with all applicable requirements of the FD&C Act, including those outlined in the Unapproved New Drug Charges section below.

 

除了要解决上述CGMP违规问题外，所有你公司销售的药品必须符合所有适用的FDCA要求，包括在以下未批准新药指挥部分中所列要求。

 

Unapproved New Drugs 未批准新药（略）

 

Conclusion 结论

 

The violations cited in this letter are not intended to be an all-inclusive list of violations that exist at your facility and in connection with your marketed products. You are responsible for investigating and determining the causes of these violations and for preventingtheir recurrence or the occurrence of other violations. It is your responsibility to ensure that your firm complies with all requirements of federal law and FDA regulations. You should take prompt action to correct the violations cited in this letter.

 

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，防止其再次发生，防止你们设施内其它偏差的发生。你们有义务确保你公司符合所有的联邦法律和FDA法规要求。你们应即刻采取措施纠正本函中所引用的违规情况。

 

FDA placed your firm on Import Alert 66-40 on October 9, 2019.

 

FDA已于2019年10月9日将你公司置于进口禁令66-40中。

 

Until you correct all violations completely and we confirm your compliance with CGMP, FDA may withhold approval of any new drug applications 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商的新申报和增补申报的批准。

 

Failure to correct these violations may also result in the FDA continuing to refuse admission of articles manufactured at 8046255 Canada Inc., dba Viatrexx, FEI 3010033797, at 1360 Rue Louis-Marchand, Beloeilinto the United States under section 801(a)(3) of the FD&C Act, 21 U.S.C.381(a)(3). Articles under this authority 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 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 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.gov

 

Please identify your response with FEI 3010033797and ATTN: Lynnsey Renn.

 

Sincerely,

/S/

 

Francis Godwin

Director

Office of Manufacturing Quality

Office of Compliance

Center for Drug Evaluation and Research