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嘉峪檢測網(wǎng) 2024-12-28 10:22
2024 年 10 月 28 日，F(xiàn)DA發(fā)布了對Rontis Hellas S.A. 的警告信，起因是FDA在 2024 年 7 月 22 日至 2024 年 7 月 25 日對該公司的Cronus HP PTA OTW 球囊導管產品進行了檢查，檢查顯示其不符合 美國聯(lián)邦法規(guī) （CFR） 第 820 部分，對于檢查員開具的FDA 483表格，該公司質量保障經理分別在2024年8月2日、2024年9月10日和2024年9月30日進行了回復， FDA認為企業(yè)還存在問題。主要為：
1.工藝的結果無法通過后續(xù)檢查和測試進行完全驗證，該工藝未按照 21 CFR 820.75(a)的要求進行高度驗證，也未按照既定程序獲得批準。
舉例：滅菌驗證不滿足 ISO 11135-1:2007 標準要求。
2.FDA檢查還發(fā)現(xiàn)，依據(jù)502(t)(2), 21 U.S.C. § 352(t)(2)，Cronus HP PTA OTW 球囊導管器械屬于不當標識，因為該公司未能或拒絕提供21 U.S.C. § 360i中519條款以及 21 CFR 803 部分—醫(yī)療器械報告所要求或規(guī)定的器械材料或信息。
未能按照 21 CFR 803.17 的要求充分制定、維護和實施書面的 MDR 程序。
FDA要求企業(yè)收到警告信后15個工作日內進行回復，包括解釋計劃如何防止這些違規(guī)行為或類似違規(guī)行為再次發(fā)生，采取的糾正和/或糾正措施（必須解決系統(tǒng)性問題）的書面證據(jù)。
警告信主要內容翻譯：
1. A process where results cannot be fully verified by subsequent inspection and test, the process has not been validated with a high degree of assurance and approved according to established procedures as required by 21 CFR 820.75(a).
工藝的結果無法通過后續(xù)檢查和測試進行完全驗證，該工藝未按照 21 CFR 820.75(a)的要求進行高度驗證，也未按照既定程序獲得批準。
For example, in regard to sterilization validation conducted to meet ISO 11135-1:2007, Validation Infrastructure Utilities Ethylene Oxide (EtO) Sterilization Process, Protocol, Validation Code C1/2013, 10/1/2013, Validation Infrastructure Utilities EtO Sterilization Process Annual Qualification of EtO Sterilization Process Protocol, C1/2013-R/2023, 15/3/2023, Validation of Infrastructure Utilities Annual Qualification of EtO Sterilization Process Report, and EtO Sterilization Report on 14/3/2013:
例如，關于為滿足 ISO 11135-1:2007 標準而進行的滅菌驗證，驗證基礎設施公用事業(yè)部門環(huán)氧乙烷（ETO）滅菌工藝、協(xié)議、驗證代碼 C1/2013，10/1/2013，驗證基礎設施公用事業(yè)部門環(huán)氧乙烷滅菌工藝協(xié)議年度鑒定，C1/2013-R/2023，15/3/2023，驗證基礎設施公用事業(yè)部門環(huán)氧乙烷滅菌工藝年度鑒定報告，以及 2013 年 3 月 14 日的環(huán)氧乙烷滅菌報告：
a. The 2013 validation was performed on (b)(4) without EtO gas.
a.2013 年的驗證在不含環(huán)氧乙烷氣體的 (b)(4) 上進行。
b. The 2023 validation was performed with (b)(4) without EtO gas.
b.2023 年的驗證是在不含環(huán)氧乙烷氣體的 (b)(4) 上進行的。
c.The 2013 report of CC BE Iliac Stent sterilized with EtO on 14/3/2013 with (b)(4) noted a deviation yet a discussion and evaluation of the impact of the deviation and a justification for the use of the CC BE iliac stent for supporting the sterilization validation for the Cronus HP PTA Balloon Catheter was not provided.
c.2013 年 3 月 14 日使用 (b)(4) 環(huán)氧乙烷滅菌的 CC BE 髂骨支架報告指出存在偏差，但未提供對偏差影響的討論和評估，也未提供使用 CC BE 髂骨支架支持 Cronus HP PTA 球囊導管滅菌驗證的理由。
d.All of the above identified reports do not provide a justification for the product selected as required by ISO 11135-1:2007 and the more recent ISO 11135:2014, which is the current version of the FDA recognized standard. Further, the validation was not completed with EtO gas or with full sterilization cycles. Your 510(k)s (K151141 and K190037) and validation reports state that “the validation study has been performed in full compliance with the relevant validation protocol and in conformity with ISO 11135-1:2007”. However, Per ISO 11135:2007 and the more recent ISO 11135:2014, Section 9.4.3.2, the process performance qualification (PPQ) shall confirm the process such that gaseous EtO has been admitted to the sterilizer chamber, and the pressure rise and quantity of EtO used or the concentration of EtO in the sterilizer chamber have been established. Additionally, per ISO 11135-1:2007 and ISO 11135:2014, temperature and humidity in the chamber should be measured during the PPQ, as it is possible that temperature and humidity readings may be impacted by the presence and absence of EtO gas. Lastly, ISO 11135:2014 states, “Demonstration of the ability to maintain process parameters within defined limits during the proposed full cycle is necessary.”
d.上述所有報告均未按照 ISO 11135-1:2007 和最新的 ISO 11135:2014（FDA 認可標準的當前版本）的要求提供所選產品的理由。此外，驗證未使用環(huán)氧乙烷氣體或完整的滅菌周期完成。你們的 510(k)s (K151141 和 K190037) 和驗證報告稱 “驗證研究完全按照相關驗證協(xié)議進行，并符合 ISO 11135-1:2007”。然而，根據(jù) ISO 11135:2007 和最新的 ISO 11135:2014，第 9.4.3.2 節(jié)規(guī)定，工藝性能鑒定 (PPQ) 應確認工藝，使氣態(tài)環(huán)氧乙烷進入滅菌器室，并確定壓力上升和所用環(huán)氧乙烷的數(shù)量或滅菌器室中環(huán)氧乙烷的濃度。此外，根據(jù) ISO 11135-1:2007 和 ISO 11135:2014，在 PPQ 期間應測量滅菌器腔內的溫度和濕度，因為溫度和濕度讀數(shù)可能會受到 EtO 氣體存在和不存在的影響。最后，ISO 11135:2014 規(guī)定：“必須證明有能力在計劃的整個周期內將工藝參數(shù)維持在規(guī)定的限度內”。
e.The product adoption of the Cronus HP PTA catheter into the existing EtO sterilization cycle was not documented in the 2023 revalidation report. If the product has not been adopted into the completed 2023 revalidation studies per AAMI TIR28:2016, “Product adoption and process equivalence for ethylene oxide sterilization”, then it is unclear if the completed adoption in 2023 demonstrates that the Cronus HP PTA catheter is adequately sterilized.
e.2023 年重新驗證報告中沒有記錄 Cronus HP PTA 導管產品在現(xiàn)有環(huán)氧乙烷滅菌循環(huán)中的采用情況。如果根據(jù) AAMI TIR28:2016 “環(huán)氧乙烷滅菌的產品采用和工藝等效性”，2023 年完成的重新驗證研究未采用該產品，則不清楚 2023 年完成的采用是否證明 Cronus HP PTA 導管已充分滅菌。
The adequacy of your responses dated August 2, 2024, September 10, 2024, and September 30, 2024 cannot be determined at this time as the establishment and completion of the process performance qualification validation report has not been completed. Please perform all corrective actions and provide the associated documentation including, but not limited to, full test reports of a full sterilization cycle with EtO gas.
由于尚未建立和完成工藝性能合格驗證報告，因此目前無法確定貴公司 2024 年 8 月 2 日、2024 年 9 月 10 日和 2024 年 9 月 30 日的答復是否充分。請執(zhí)行所有糾正措施并提供相關文件，包括但不限于使用環(huán)氧乙烷氣體進行完整滅菌周期的完整測試報告。
Our inspection also revealed that your firm’s Cronus HP PTA OTW Balloon Catheter devices are misbranded under section 502(t)(2) of the Act, 21 U.S.C. § 352(t)(2), in that your firm failed or refused to furnish material or information respecting the device that is required by or under section 519 of the Act, 21 U.S.C. § 360i, and 21 CFR Part 803 - Medical Device Reporting. Significant violations include, but are not limited to, the following:
我們的檢查還發(fā)現(xiàn)，依據(jù)502(t)(2), 21 U.S.C. § 352(t)(2)，Cronus HP PTA OTW 球囊導管器械屬于不當標識，因為該公司未能或拒絕提供21 U.S.C. § 360i中519條款以及 21 CFR 803 部分—醫(yī)療器械報告所要求或規(guī)定的器械材料或信息。重大違規(guī)行為包括但不限于以下內容：
Failure to adequately develop, maintain, and implement written MDR procedures as required by 21 CFR 803.17.
未能按照 21 CFR 803.17 的要求充分制定、維護和實施書面的 MDR 程序。
For example, during the inspection, your firm presented the document titled “RC_SOP-10-003: Medical Device Reporting”, Edition 7, dated 3/7/2023 as its written MDR procedure. However, this procedure does not meet the requirements of 12 CFR 803.17. For example:
例如，在檢查期間，貴公司提交了名為 "RC_SOP-10-003： 醫(yī)療器械報告"（第 7 版，日期為 2023 年 7 月 3 日）作為其書面的 MDR 程序。但是，該程序不符合 12 CFR 803.17 的要求。例如:
1.The procedure does not establish internal systems that provide for timely and effective identification, communication, and evaluation of events that may be subject to MDR requirements, as required by 21 CFR 803.17(a)(1).
1. 該程序未按照 21 CFR 803.17(a)(1)的要求建立內部系統(tǒng)，以便及時有效地識別、溝通和評估可能受 MDR 要求管理的事件。
a. The procedure omits definitions of the terms ‘become aware’, ‘caused or contributed’, ‘malfunction’, and ‘serious injury’, from 21 CFR Part 803.3. The exclusion of the definitions for these term from the procedure may lead your firm to make an incorrect reportability decision when evaluating a complaint that may meet the criteria for reporting under 21 CFR 803.50(a).
a. 該程序省略了 21 CFR 第 803.3 部分中 “意識到”、“造成或促成”、“故障 ”和 “嚴重傷害 ”等術語的定義。程序中不包括這些術語的定義可能會導致貴公司在評估可能符合《美國聯(lián)邦法規(guī)》第 21 篇第 803.50(a)條規(guī)定的報告標準的投訴時，做出錯誤的報告決定。
b. The procedure, as written, combines language from the requirements of other regulatory or competent authorities with the requirements in 21 CFR Part 803 in a manner that will result in incomplete, inadequate, or even non-reporting of adverse events that meet the reportability requirements under 21 CFR Part 803.
b. 該程序將其他監(jiān)管機構或主管當局的要求與《美國聯(lián)邦法規(guī)匯編》第 21 卷第 803 部分的要求結合在一起，會導致對符合《美國聯(lián)邦法規(guī)匯編》第 21 卷第 803 部分規(guī)定的可報告性要求的不良事件的報告不完整、不充分，甚至不報告。
2. The procedure does not establish internal systems that provide for a standardized review process to determine when an event meets the criteria for reporting under this part, as required by 21 CFR 803.17(a)(2). For example, although the procedure includes instructions for how your firm will evaluate information about an event to make a reportability decision, it fails to include instructions for making determinations in a timely manner.
2. 該程序沒有按照 21 CFR 803.17(a)(2)的要求建立內部系統(tǒng)，以提供標準化的審查程序來確定某 事件何時符合本部分規(guī)定的報告標準。例如，盡管該程序包括了貴公司如何評估事件信息以做出報告決定的說明，但未包括及時做出決定的說明。
3. The procedure does not establish internal systems that provide for timely transmission of complete medical device reports, as required by 21 CFR 803.17(a)(3). Specifically, your procedure does not include:
3. 該程序沒有按照 21 CFR 803.17(a)(3)的要求，建立可及時傳送完整醫(yī)療器械報告的內 部系統(tǒng)。具體地說，貴公司的程序不包括：
a. Instructions for how to obtain and complete the FDA 3500A form.
b. The circumstances under which your firm must submit supplemental or follow-up report and the requirements for such reports.
c. A process for submitting initial and supplement or follow-up reports to FDA in an electronic format that FDA can process, review and archive in accordance with 21 CFR 803.12(a); and
d. How your firm will ensure that all information reasonably known to you is submitted for each event. Specifically, which sections of the Form 3500A will need to be completed to include all information found in your firm’s possession and any information that becomes available as a result of a reasonable follow-up within your firm.
a. 如何獲取和填寫 FDA 3500A 表格的說明。
b. 貴公司必須提交補充報告或后續(xù)報告的情況，以及提交此類報告的要求。
c. 按照 21 CFR 803.12(a)，以電子格式向 FDA 提交初步報告、補充報告或后續(xù)報告的程序，以便 FDA 處理、審查和存檔；以及：
d. 貴公司將如何確保為每個事件提交貴公司合理知道的所有信息。具體地說，需要填寫 3500A 表的哪些部分，以包括貴公司掌握的所有信息和貴公司內部合理跟進后獲得的任何信息。
4. The procedure does not describe how your firm will address documentation and recordkeeping requirements, as required by 21 CFR 803.17(b), including documentation of the deliberations and decision-making processes used to determine if a device-related death, serious injury, or malfunction was or was not reportable, as required under 21 CFR 803.18(b)(1)(i).
4. 該程序未說明貴公司將如何按照 21 CFR 803.17(b)的要求處理文件和記錄保存要求，包括按照 21 CFR 803.18(b)(1)(i)的要求，記錄用于確定與器械相關的死亡、嚴重傷害或故障是否應報告的審議和決策過程。
We reviewed your firm’s responses dated August 2, 2024, September 10, 202, and September 30, 2024, and conclude that they are not adequate. In your September 30, 2024 response, you provided the revised procedure “RC_SOP-10-003: Medical Device Reporting”, Edition No. 8, dated 30/09/2024. Your revised procedure continues to not meet the requirements of 21 CFR 803.17. For example:
我們審查了貴公司分別于 2024 年 8 月 2 日、202 年 9 月 10 日和 2024 年 9 月 30 日作出的答復，認為這些答復不夠充分。在 2024 年 9 月 30 日的回復中，貴公司提供了修訂后的程序 "RC_SOP-10-003： 醫(yī)療器械報告"，第 8 版，日期為 2024 年 9 月 30 日。貴公司修訂后的程序仍然不符合 21 CFR 803.17 的要求。例如：
1.The revision does not establish internal systems that provide for timely and effective identification, communication, and evaluation of events that may be subject to MDR requirements, as required by 21 CFR 803.17(a)(1). For example,
1.修訂版未按照 21 CFR 803.17(a)(1)的要求建立內部程序，以便及時有效地識別、溝通和評估可能符合 MDR 要求的事件。例如，
a. The procedure omits definitions of the terms ‘caused or contributed’ and ‘malfunction’ from 21 CFR Part 803.3. The exclusion of the definitions for these term from the procedure may lead your firm to make an incorrect reportability decision when evaluating a complaint that may meet the criteria for reporting under 21 CFR 803.50(a).
b. The term ‘serious injury’ is incorrectly referred to as ‘serious adverse event’, which might not allow your firm to correctly identify complaints as reportable events.
c. The revision, as written, combines language from the requirements of other regulatory or competent authorities with the requirements in 21 CFR Part 803 in a manner that will result in incomplete, inadequate, or even non‐reporting of adverse events that meet the reportability requirements under 21 CFR Part 803. For example, terms including but not necessarily limited to, ‘serious incident’ and ‘serious adverse event’, which are intended for OUS vigilance reporting, are included in the procedure within the context of the US MDR reporting requirements.
a. 該程序省略了 21 CFR 第 803.3 部分中 “造成或促成 ”和 “故障 ”這兩個術語的定義。程序中未包含這些術語的定義可能導致貴公司在評估可能符合 21 CFR 803.50(a)報告標準的投訴時作出錯誤的報告決定。
b. 嚴重傷害 “一詞被錯誤地稱為 ”嚴重不良事件"，這可能使貴公司無法正確地將投訴確定為應報告事件。
c. 修訂稿將其他監(jiān)管機構或主管當局的要求與《美國聯(lián)邦法規(guī)匯編》第 21 卷第 803 部分的要求相結合，這將導致對符合《美國聯(lián)邦法規(guī)匯編》第 21 卷第 803 部分可報告性要求的不良事件的報告不完整、不充分，甚至不報告。例如，包括但不一定限于 “嚴重事故 ”和 “嚴重不良事件 ”等用于美國本土警戒報告的術語，被納入美國 MDR 報告要求的程序中。
2. The revision does not establish internal systems that provide for timely transmission of complete medical device reports, as required by 21 CFR 803.17(a)(3). Specifically, your procedure does not include:
2. 修訂后的程序沒有按照 21 CFR 803.17(a)(3)的要求建立可及時傳送完整醫(yī)療器械報告的內部系統(tǒng)。具體地說，你們的程序不包括
a. Instructions for how to obtain and complete the FDA 3500A form.
b. A process for submitting initial and supplement or follow‐up reports to FDA in an electronic format that FDA can process, review and archive in accordance with 21 CFR 803.12(a).
c. How your firm will ensure that all information reasonably known to you is submitted for each event. Specifically, which sections of the Form 3500A will need to be completed to include all information found in your firm’s possession and any information that becomes available as a result of a reasonable follow‐up within your firm.
a. 如何獲取和填寫 FDA 3500A 表格的說明。
b. 按照 21 CFR 803.12(a)，以電子格式向 FDA 提交初始報告、補充報告或后續(xù)報告的程序，以便 FDA 能處理、審查和存檔。
c. 貴公司將如何確保為每個事件提交貴公司合理知悉的所有信息。具體地說，需要填寫 3500A 表的哪些部分，以包括貴公司掌握的所有信息，以及貴公司內部合理跟進后獲得的任何信息。
Additionally, the FDA verified that, as of October 17, 2024, your firm still does not have an active ESG production account for the electronic submission of MDR reports. Information about the ESG and creating an account can be found at: How to Enroll in eMDR Program | FDA (https://www.fda.gov/medical-devices/emdr-electronic-medical-device-reporting/how-enrollemdr-program).
此外，經 FDA 核實，截至 2024 年 10 月 17 日，貴公司仍沒有一個用于以電子方式提交 MDR 報告的 ESG 生產賬戶。有關 ESG 和創(chuàng)建賬戶的信息，請訪問以下網(wǎng)站： How to Enroll in eMDR Program | FDA (https://www.fda.gov/medical-devices/emdr-electronic-medical-device-reporting/how-enrollemdr-program)。
Please note that your firm’s response dated October 15, 2024 to the Form FDA 483 (FDA 483) was not reviewed because it was received too late in the review cycle after issuance of the FDA 483. Therefore, the October 15, 2024 response will be evaluated along with any other written material provided in response to the violations cited in this Warning Letter.
請注意，貴公司于 2024 年 10 月 15 日對 FDA 483 表格 （FDA 483） 的回復未被審查，因為在 FDA 483 發(fā)布后的審查周期中收到該回復的時間太晚。因此，2024 年 10 月 15 日的回復將與為回應本警告信中引用的違規(guī)行為而提供的任何其他書面材料一起進行評估。
Other federal agencies may take your compliance with the FD&C Act and its implementation regulations into account when considering the award of federal contracts. Additionally, should FDA determine that you have Quality System regulation violations that are reasonably related to premarket approval applications for Class III devices, such devices will not be approved until the violations have been addressed.
其他聯(lián)邦機構在考慮授予聯(lián)邦合同時，可能會考慮您對 FD&C 法案及其實施法規(guī)的遵守情況。此外，如果 FDA 確定您存在與 III 類器械的上市前批準申請合理相關的質量體系法規(guī)違規(guī)行為，則在違規(guī)行為得到解決之前，此類器械不會獲得批準。
來源：器械QMS
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