2024 年 10 月 28 日，FDA发布了对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 日对该公司的Cronus HP PTA OTW 球囊导管产品进行了检查，检查显示其不符合 美国联邦法规 （CFR） 第 820 部分，对于检查员开具的FDA 483表格，该公司质量保障经理分别在2024年8月2日、2024年9月10日和2024年9月30日进行了回复， FDA认为企业还存在问题。主要为：

 

1.工艺的结果无法通过后续检查和测试进行完全验证，该工艺未按照 21 CFR 820.75(a)的要求进行高度验证，也未按照既定程序获得批准。

 

举例：灭菌验证不满足 ISO 11135-1:2007 标准要求。

 

2.FDA检查还发现，依据502(t)(2), 21 U.S.C. § 352(t)(2)，Cronus HP PTA OTW 球囊导管器械属于不当标识，因为该公司未能或拒绝提供21 U.S.C. § 360i中519条款以及 21 CFR 803 部分—医疗器械报告所要求或规定的器械材料或信息。

 

未能按照 21 CFR 803.17 的要求充分制定、维护和实施书面的 MDR 程序。

 

FDA要求企业收到警告信后15个工作日内进行回复，包括解释计划如何防止这些违规行为或类似违规行为再次发生，采取的纠正和/或纠正措施（必须解决系统性问题）的书面证据。

 

警告信主要内容翻译：

 

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).

 

工艺的结果无法通过后续检查和测试进行完全验证，该工艺未按照 21 CFR 820.75(a)的要求进行高度验证，也未按照既定程序获得批准。

 

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，关于为满足 ISO 11135-1:2007 标准而进行的灭菌验证，验证基础设施公用事业部门环氧乙烷（ETO）灭菌工艺、协议、验证代码 C1/2013，10/1/2013，验证基础设施公用事业部门环氧乙烷灭菌工艺协议年度鉴定，C1/2013-R/2023，15/3/2023，验证基础设施公用事业部门环氧乙烷灭菌工艺年度鉴定报告，以及 2013 年 3 月 14 日的环氧乙烷灭菌报告：

 

a. The 2013 validation was performed on (b)(4) without EtO gas.

 

a.2013 年的验证在不含环氧乙烷气体的 (b)(4) 上进行。

 

b. The 2023 validation was performed with (b)(4) without EtO gas.

 

b.2023 年的验证是在不含环氧乙烷气体的 (b)(4) 上进行的。

 

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) 环氧乙烷灭菌的 CC BE 髂骨支架报告指出存在偏差，但未提供对偏差影响的讨论和评估，也未提供使用 CC BE 髂骨支架支持 Cronus HP PTA 球囊导管灭菌验证的理由。

 

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.上述所有报告均未按照 ISO 11135-1:2007 和最新的 ISO 11135:2014（FDA 认可标准的当前版本）的要求提供所选产品的理由。此外，验证未使用环氧乙烷气体或完整的灭菌周期完成。你们的 510(k)s (K151141 和 K190037) 和验证报告称 “验证研究完全按照相关验证协议进行，并符合 ISO 11135-1:2007”。然而，根据 ISO 11135:2007 和最新的 ISO 11135:2014，第 9.4.3.2 节规定，工艺性能鉴定 (PPQ) 应确认工艺，使气态环氧乙烷进入灭菌器室，并确定压力上升和所用环氧乙烷的数量或灭菌器室中环氧乙烷的浓度。此外，根据 ISO 11135-1:2007 和 ISO 11135:2014，在 PPQ 期间应测量灭菌器腔内的温度和湿度，因为温度和湿度读数可能会受到 EtO 气体存在和不存在的影响。最后，ISO 11135:2014 规定：“必须证明有能力在计划的整个周期内将工艺参数维持在规定的限度内”。

 

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 年重新验证报告中没有记录 Cronus HP PTA 导管产品在现有环氧乙烷灭菌循环中的采用情况。如果根据 AAMI TIR28:2016 “环氧乙烷灭菌的产品采用和工艺等效性”，2023 年完成的重新验证研究未采用该产品，则不清楚 2023 年完成的采用是否证明 Cronus HP PTA 导管已充分灭菌。

 

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艺性能合格验证报告，因此目前无法确定贵公司 2024 年 8 月 2 日、2024 年 9 月 10 日和 2024 年 9 月 30 日的答复是否充分。请执行所有纠正措施并提供相关文件，包括但不限于使用环氧乙烷气体进行完整灭菌周期的完整测试报告。

 

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:

 

我们的检查还发现，依据502(t)(2), 21 U.S.C. § 352(t)(2)，Cronus HP PTA OTW 球囊导管器械属于不当标识，因为该公司未能或拒绝提供21 U.S.C. § 360i中519条款以及 21 CFR 803 部分—医疗器械报告所要求或规定的器械材料或信息。重大违规行为包括但不限于以下内容：

 

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、维护和实施书面的 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，在检查期间，贵公司提交了名为 "RC_SOP-10-003： 医疗器械报告"（第 7 版，日期为 2023 年 7 月 3 日）作为其书面的 MDR 程序。但是，该程序不符合 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. 该程序未按照 21 CFR 803.17(a)(1)的要求建立内部系统，以便及时有效地识别、沟通和评估可能受 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. 该程序省略了 21 CFR 第 803.3 部分中 “意识到”、“造成或促成”、“故障 ”和 “严重伤害 ”等术语的定义。程序中不包括这些术语的定义可能会导致贵公司在评估可能符合《美国联邦法规》第 21 篇第 803.50(a)条规定的报告标准的投诉时，做出错误的报告决定。

 

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. 该程序将其他监管机构或主管当局的要求与《美国联邦法规汇编》第 21 卷第 803 部分的要求结合在一起，会导致对符合《美国联邦法规汇编》第 21 卷第 803 部分规定的可报告性要求的不良事件的报告不完整、不充分，甚至不报告。

 

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. 该程序没有按照 21 CFR 803.17(a)(2)的要求建立内部系统，以提供标准化的审查程序来确定某 事件何时符合本部分规定的报告标准。例如，尽管该程序包括了贵公司如何评估事件信息以做出报告决定的说明，但未包括及时做出决定的说明。

 

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. 该程序没有按照 21 CFR 803.17(a)(3)的要求，建立可及时传送完整医疗器械报告的内 部系统。具体地说，贵公司的程序不包括：

 

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. 如何获取和填写 FDA 3500A 表格的说明。

 

b. 贵公司必须提交补充报告或后续报告的情况，以及提交此类报告的要求。

 

c. 按照 21 CFR 803.12(a)，以电子格式向 FDA 提交初步报告、补充报告或后续报告的程序，以便 FDA 处理、审查和存档；以及： 

 

d. 贵公司将如何确保为每个事件提交贵公司合理知道的所有信息。具体地说，需要填写 3500A 表的哪些部分，以包括贵公司掌握的所有信息和贵公司内部合理跟进后获得的任何信息。

 

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. 该程序未说明贵公司将如何按照 21 CFR 803.17(b)的要求处理文件和记录保存要求，包括按照 21 CFR 803.18(b)(1)(i)的要求，记录用于确定与器械相关的死亡、严重伤害或故障是否应报告的审议和决策过程。

 

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:

 

我们审查了贵公司分别于 2024 年 8 月 2 日、202 年 9 月 10 日和 2024 年 9 月 30 日作出的答复，认为这些答复不够充分。在 2024 年 9 月 30 日的回复中，贵公司提供了修订后的程序 "RC_SOP-10-003： 医疗器械报告"，第 8 版，日期为 2024 年 9 月 30 日。贵公司修订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.修订版未按照 21 CFR 803.17(a)(1)的要求建立内部程序，以便及时有效地识别、沟通和评估可能符合 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. 该程序省略了 21 CFR 第 803.3 部分中 “造成或促成 ”和 “故障 ”这两个术语的定义。程序中未包含这些术语的定义可能导致贵公司在评估可能符合 21 CFR 803.50(a)报告标准的投诉时作出错误的报告决定。

 

b. 严重伤害 “一词被错误地称为 ”严重不良事件"，这可能使贵公司无法正确地将投诉确定为应报告事件。

 

c. 修订稿将其他监管机构或主管当局的要求与《美国联邦法规汇编》第 21 卷第 803 部分的要求相结合，这将导致对符合《美国联邦法规汇编》第 21 卷第 803 部分可报告性要求的不良事件的报告不完整、不充分，甚至不报告。例如，包括但不一定限于 “严重事故 ”和 “严重不良事件 ”等用于美国本土警戒报告的术语，被纳入美国 MDR 报告要求的程序中。

 

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. 修订后的程序没有按照 21 CFR 803.17(a)(3)的要求建立可及时传送完整医疗器械报告的内部系统。具体地说，你们的程序不包括

 

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. 如何获取和填写 FDA 3500A 表格的说明。

 

b. 按照 21 CFR 803.12(a)，以电子格式向 FDA 提交初始报告、补充报告或后续报告的程序，以便 FDA 能处理、审查和存档。

 

c. 贵公司将如何确保为每个事件提交贵公司合理知悉的所有信息。具体地说，需要填写 3500A 表的哪些部分，以包括贵公司掌握的所有信息，以及贵公司内部合理跟进后获得的任何信息。

 

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，经 FDA 核实，截至 2024 年 10 月 17 日，贵公司仍没有一个用于以电子方式提交 MDR 报告的 ESG 生产账户。有关 ESG 和创建账户的信息，请访问以下网站： 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.

 

请注意，贵公司于 2024 年 10 月 15 日对 FDA 483 表格 （FDA 483） 的回复未被审查，因为在 FDA 483 发布后的审查周期中收到该回复的时间太晚。因此，2024 年 10 月 15 日的回复将与为回应本警告信中引用的违规行为而提供的任何其他书面材料一起进行评估。

 

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.

 

其他联邦机构在考虑授予联邦合同时，可能会考虑您对 FD&C 法案及其实施法规的遵守情况。此外，如果 FDA 确定您存在与 III 类器械的上市前批准申请合理相关的质量体系法规违规行为，则在违规行为得到解决之前，此类器械不会获得批准。