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嘉峪檢測網(wǎng) 2021-10-11 12:21
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.
美國FDA于2019年9月16日至24日檢查了你們位于加拿大的8046255 Canada Inc（dba Viatrexx）生產場所。
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).
本警告信總結了制劑生產嚴重違反CGMP的行為。參見21CFR第210與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).
由于你們的制劑生產、加工、包裝或保存的方法、場所或控制不符合CGMP要求，你們的藥品根據(jù)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, 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，F(xiàn)DA還審核了檢查中獲取的標簽內容。根據(jù)我們的審核，你們的注射用順勢療法藥品“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”（“順勢療法注射劑”）根據(jù)FDCA第505條款21U.S.C. 355均為未批準的新藥。引入或輸送此類藥品至州際貿易是被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.
這些藥品在公眾健康角度尤其令人擔憂，因為注射劑可能會對使用者帶來嚴重傷害風險，這些風險不太可能發(fā)生在消化道用藥或局部用藥，因為這些藥品僅用于皮膚或經(jīng)口攝入。注射劑是直接注入身體，有時直接進入血液，因此，繞開了人體的一些關鍵毒物和微生物防御系統(tǒng)，這樣可能導致危及生命的嚴重情形。你們的注射劑有著更多擔憂，因為其標示為含有潛在毒性或有害成分，例如“Nux Vomica”（含有馬錢子堿），“Rectum”和“Belladonna”，因此當直接輸入體內時對患者具有額外的嚴重傷害風險。如下所述，你公司嚴重違反了CGMP法規(guī)，更是大大增加了對患者的危害風險。
We reviewed your October 16, 2019, response to our Form FDA 483 in detail and acknowledge receipt of your subsequent correspondence.
我們已詳細審核了你公司2019年10月16日對我們FDA483表的回復，并此告知已收到后續(xù)通信。
During our inspection, our investigator observed specific violations including, but not limited to, the following.
檢查期間，我們的調查人員發(fā)現(xiàn)的具體問題包括但不僅限于以下：
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)). 你公司未遵守適當?shù)臅娉绦颍O計用于防止既定無菌的藥品微生物污染，并包括所有無菌和滅菌工藝的驗證（21 CFR 211.113(b)）。
You manufactured and distributed sterile injectable homeopathic drug products without adequately validating your aseptic manufacturing processes.
你們生產和銷售無菌注射用順勢療法藥品，但并沒有充分驗證你們的無菌生產工藝。
Process Simulations (Media Fills) 工藝模擬（培養(yǎng)基灌裝）
You failed to establish appropriate procedures and perform media fills to evaluate your manual aseptic filling and stoppering operations.
你們并未建立起適當?shù)某绦虿?zhí)行培養(yǎng)基灌裝，以評估你們的人工無菌灌裝和加塞操作。
Filter Suitability 過濾器適用性
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.
你們并未確認你們注射藥品中除菌過濾時使用的是恰當?shù)倪^濾器。你們使用了XX過濾器用于除菌過濾，而不是使用適合于無菌藥品生產的除菌過濾器。你們在使用之后亦未檢測過濾器完整性。
Poor Aseptic Techniques 無菌技巧不良
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.
你們未能確保使用適當?shù)臒o菌技巧用于生產無菌注射藥品。我們的檢查員觀察了你們人工灌裝和加塞操作員工的行為，他們擋住了XX氣流的路徑。
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，你公司召回了你們生產的所有無菌注射產品。但是你們提出的糾正措施允許繼續(xù)使用不適當?shù)倪^濾器對你們的藥品滅菌。你們的回復亦未解決培養(yǎng)基培養(yǎng)執(zhí)行頻次問題。
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.
無菌工藝的驗證需要建立具有高度保證的文件化證據(jù)，保證具體的工藝可持續(xù)生產出符合其既定標準和質量屬性的產品。培養(yǎng)基灌裝和各種系統(tǒng)控制，包括但不僅限于日常遵守嚴格的無菌工藝標準、穩(wěn)定的設施、穩(wěn)健的環(huán)境控制，和令人滿意的產品無菌性檢測，聯(lián)合起來確保注射藥品是無菌的。如果注射藥品不是無菌的，則它們會對患者有著不可接受的風險，包括感染風險。
In response to this letter, provide the following:
在回復本函時請?zhí)峤灰韵聝热荩?/span>
• 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:
• 對你們無菌工藝、設備和設施所有污染危害的全面風險評估，包括一份包括但不僅限于以下內容的獨立評估：
All human interactions within the ISO 5 area
ISO5區(qū)域內所有人間互動
Equipment placement and ergonomics
設備安裝位置和人體工程學
Air quality in the ISO 5 area and surrounding room
ISO5區(qū)域和周邊房間的空氣質量
Facility layout
設施平面布局圖
Personnel flows and material flows (throughout all rooms used to conduct and support sterile operations)
人流和物流（執(zhí)行和支持無菌操作的所有房間之間）
• 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.
• 一份詳細的補救計劃及時間表，解決獨立污染危害風險評估期間發(fā)現(xiàn)的問題。闡明準備對無菌工藝操作設施和控制所做的具體實際的改進
• 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.
• 你們確保生產期間的無菌操作和潔凈間行為恰當?shù)挠媱?。包括確保對所有生產批次進行日常和有效監(jiān)管的措施。亦請說明質量部門在無菌加工及其支持性操作期間的監(jiān)管（例如審計）頻次
• 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:
• 你們確保所有滅菌方法有著穩(wěn)健滅菌工藝的計劃。提交你們的所有滅菌操作確認和驗證計劃。另外，關于除菌過濾，請?zhí)峤灰环軨APA計劃以確保：
Selection of a suitable (b)(4) filter for drug sterilization
選擇了適當?shù)腦X過濾器用于藥品除菌
Appropriate filtration efficacy validation study protocols for each product and that incorporates the worst-case filtration conditions
對每個產品進行恰當?shù)倪^濾器效率驗證研究的方案，要包括最差過濾情形
Proper responsibilities for proper conduct, full documentation, review, and approval of these studies
恰當執(zhí)行、全面記錄、審核和批次這些研究的人員職責
Products will not be distributed before complete and adequate studies are performed
在完成充分的研究之前不會將銷售產品
2. Your firm failed to ensure that manufacturing personnel wear clothing appropriate to protect drug product from contamination (21 CFR 211.28(a)). 你公司未能確保生產人員穿著適合于保護藥品不受污染的服裝（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.
你們沒有順勢療法注射劑生產的適當著裝程序。除了手套外，你們使用了非無菌服裝，還重復使用這些服裝材料進行無菌操作。我們的檢查員亦觀察到有面部皮膚暴露，操作員在緊鄰無菌操作ISO5氣流罩的地方將無菌手套戴到裸手上。
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.
你們回復聲稱你們會在生產中使用無菌服裝。但是你們回復中的服裝圖片不足以用于無菌注射藥品生產，因為例如，操作員面部皮膚有暴露。
In response to this letter, provide the following:
在回復本函時請?zhí)峤灰韵聝热荩?/span>
• 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).
• 一份你們裝備使用的服裝材料的清單（例如，已滅菌無脫落物的服裝，遮住皮膚和毛發(fā)，如面罩、兜帽、胡須套、保護性手套和手套）
• 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.
• 一份更衣確認程序，首次和定期證明個人可以無菌方式穿戴完整的無菌服裝的能力
• 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.
• 質量部門在服裝供應商選擇和持續(xù)確認決策方面的作用。確保是質量部門做出最終決策，包括生產用供應商選擇、原料和供應商放行（例如，潔凈服），以及其它供應商可靠性的持續(xù)決策
• Details regarding how you will establish adequate gowning, training, gowning qualification, and supervision on an ongoing basis.
• 關于你們準備如何建立足夠的更衣、培訓、更衣確認和持續(xù)監(jiān)管的詳細信息
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)). 你公司未能建立一個用于監(jiān)測無菌加工區(qū)域的環(huán)境條件的體系，以及一個清潔和消毒產生無菌條件的房間與設備的體系（21 CFR 211.42(c)(10)(iv) 和(v)）。
Cleaning and Disinfecting 清潔和消毒
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.
你們的清潔和消毒程序不充分。例如，你們缺少程序確保XX劑的使用頻次。你們亦未能持續(xù)記錄清潔和消毒操作。
Environmental Conditions 環(huán)境條件
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.
你們在2019年5月初次確認時進行了環(huán)境監(jiān)測。但是你們在2019年9月連續(xù)生產，沒有進行常規(guī)環(huán)境監(jiān)測。你們亦缺少環(huán)境監(jiān)測書面程序。
An environmental monitoring program provides meaningful information about the quality of the aseptic processing environment, as well as additional clean areas.
環(huán)境監(jiān)測計劃應提供無菌加工環(huán)境以及其它潔凈區(qū)域質量的有意義的信息。
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.
你們的回復是不充分的，因為其中并未提供你們環(huán)境監(jiān)測程序的足夠的詳細信息或程序。你們亦未提交任何證據(jù)證明你們的生產環(huán)境持續(xù)處于受控狀態(tài)。
In response to this letter, provide the following:
在回復本函時請?zhí)峤灰韵聝热荩?/span>
• 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計劃，基于你們清潔和消毒程序的回顧性評估，其中包括對你們清潔/消毒工藝和做法的適當補救措施，以及完成時間表。提交一份你們工藝中設備清潔和消毒生命周期管理方面薄弱點的詳細綜述，包括改進清潔有效性，改進所有產品和設備的清潔和消毒執(zhí)行方面的持續(xù)確認，以及所有其它所需補救措施。
• 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.
• 一份對你們設施的全面環(huán)境監(jiān)測計劃，包括但不僅限于監(jiān)測頻次、監(jiān)測點、監(jiān)測類型和方法。計劃應包括嚴格監(jiān)測日常結果和趨勢的條款。
• A comprehensive personnel monitoring program for operators involved in aseptic processing operations.
• 一份對參與無菌工藝操作的操作員的全面人員監(jiān)測計劃。
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)).你公司未能建立實驗室控制，在其中包括科學合理和恰當?shù)馁|量標準、取樣計劃和檢測方法，以確保組份、藥品容器、密閉器、中控物料、標簽和成品符合恰當?shù)蔫b別、劑量、質量和純度標準（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.
你們并未驗證你們的無菌檢測方法，亦未使用適當?shù)呐囵B(yǎng)基對你們的無菌順勢療法注射藥品進行無菌性檢測。另外，你們并未對你們的無菌順勢療法注射藥品進行內毒素和顆粒物檢測。
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.
你們的回復包括有第三方對多個產品的分析報告，但并未解決你們無菌檢測方法驗證的問題。對每個批次進行無菌檢測是確保藥品是無菌并適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:
在你們的回復中請?zhí)峤唬?/span>
• 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.
• 一份對你們實驗室規(guī)范、程序、方法、設備、文件記錄和化驗員能力的全面獨立評估。根據(jù)此審核，提交一份補救和評估你們實驗室系統(tǒng)有效性的詳細計劃
• An update of all testing methods used by your firm and your method validation status.
• 你們所用所有檢測方法的更新情況，以及方法驗證的狀態(tài)
Additional Guidance on Aseptic Processing 其它無菌加工指南
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.
參見上述鏈接FDA的指南文件“采用無菌加工生產的無菌藥品CGMP”，幫助你們在采用無菌工藝生產無菌藥品時符合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.
除了要解決上述CGMP違規(guī)問題外，所有你公司銷售的藥品必須符合所有適用的FDCA要求，包括在以下未批準新藥指揮部分中所列要求。
Unapproved New Drugs 未批準新藥（略）
Conclusion 結論
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.
此函中所引用的違規(guī)并不是全部。你們有責任對這些偏差進行調查，確定原因，防止其再次發(fā)生，防止你們設施內其它偏差的發(fā)生。你們有義務確保你公司符合所有的聯(lián)邦法律和FDA法規(guī)要求。你們應即刻采取措施糾正本函中所引用的違規(guī)情況。
FDA placed your firm on Import Alert 66-40 on October 9, 2019.
FDA已于2019年10月9日將你公司置于進口禁令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.
在貴公司未能完成所有偏差糾正并且由我們確認你們符合CGMP之前，F(xiàn)DA可能會擱置所有將你公司列為藥品生產商的新申報和增補申報的批準。
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).
未能糾正這些偏差可能還會導致FDA依據(jù)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 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，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后，你們做了哪些工作來糾正你們的偏差，防止其再次發(fā)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。
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
來源：Internet
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