CAPA管理以及投诉管理不符合cGMP要求，FDA发出警告信。
WARNING LETTER
Medtronic, Inc.
MARCS-CMS 617539 — DECEMBER 09, 2021
CMS 617539
December 9, 2021
Dear Mr. Martha:
During an inspection of your firm located in Northridge, California, on June 7, 2021 through July 7, 2021, an investigator from the United States Food and Drug Administration (FDA) determined that your firm manufactures the MiniMed 600 series insulin infusion pumps, and software and remote controllers used in conjunction with the Paradigm and MiniMed series insulin infusion pumps. Under section 201(h) of the Federal Food, Drug, and Cosmetic Act (the Act) [21 U.S.C. § 321(h)], these products are devices because they are intended for use in the diagnosis of disease or other conditions, or in the cure, mitigation, treatment, or prevention of disease, or to affect the structure or any function of the body.
2021年6月7日至2021年7月7日对位于加利福尼亚州北岭的贵公司进行的检查期间，美国食品和药物管理局(FDA)的一名调查人员确定，贵公司生产MiniMed 600系列胰岛素输注泵，以及与Paradigm和MiniMed系列胰岛素输注泵一起使用的软件和遥控器。根据《联邦食品、药品和化妆品法》(《法案》)[21 U.S.C.§321(h)]第201(h)条，这些产品是设备，因为它们用于疾病或其他状况的诊断，或用于治疗、缓解、治疗或预防疾病，或用于影响身体结构或任何功能。
This inspection revealed the devices are adulterated within the meaning of section 501(h) of the Act [21 U.S.C. § 351(h)] in that the methods used in, or the facilities or controls used for, the manufacture, packing, storage, or installation are not in conformity with the current good manufacturing practice requirements of the Quality System regulation found at Title 21, Code of Federal Regulations (CFR), Part 820. You may find the Act and FDA’s regulations through links in the FDA’s home page www.fda.gov.External Link Disclaimer We received your responses from Sean Salmon, Executive Vice President and President Diabetes Operating Unit, and Chirag Tilara, Vice President, Quality Management Representative, dated July 28, September 3, October 8, November 5, and December 3, 2021, concerning our investigator’s observations noted on the Form FDA 483, Inspectional Observations, that was issued to your firm on July 7, 2021. We have considered these responses in relation to our observations noted during the inspection, which include, but are not limited to, the following:
此次检查显示，根据《法案》第501(h)条的含义，这些设备存在掺假，因为在制造、包装、储存或安装中使用的方法、设施或控制不符合《联邦法规法典》(CFR)第820部分第21篇《质量体系法规》当前的良好生产规范要求。我们收到了企业于2021年7月28日、9月3日、10月8日、11月5日和12月3日分别从执行副总裁兼Diabetes Operating Unit主任Sean Salmon和副总裁兼质量管理代表Chirag Tilara发来的回复，内容涉及我们在FDA 483表格“检查观察”中记录的调查人员的观察结果。是在2021年7月7日发给贵公司的。我们就检查期间所注意到的意见考虑了这些回应，其中包括但不限于以下几点:
1. You failed to adequately establish procedures for corrective and preventive action, as required by 21 CFR 820.100(a).
1. 企业未能按照21 CFR 820.100(a)的要求充分建立纠正和预防措施程序。
a. Specifically, in June 2016, your firm initiated CAPA (b)(4)#299677 to address anincrease in complaints of damaged retainer rings (clear retainer rings) in the MiniMed 600 Series Insulin Infusion Pumps. Your investigation determined the device failures were caused by the (b)(4) retainer ring, which in turn caused a (b)(4). A damaged retainer ring may result in the over or under-delivery of insulin, which may lead to hypoglycemia or hyperglycemia.Beginning August 2019, your firm began releasing the re-designed pumps (which were manufactured with a black retainer ring) for distribution. You began notifying customers of retainer ring failures in November 2019. FDA determined that there was a reasonable probability that the use of, or exposure to, the pumps manufactured with the clear retainer ring would cause serious adverse health consequences, including severe hypoglycemia which can result in loss of consciousness, seizure; severe hyperglycemia which can result in diabetic ketoacidosis or hyperosmolar hyperglycemic state, metabolic abnormalities; or death and classified the recall (RES84430) as class 1. However, your firm failed to adequately implement procedures for corrective and preventive action (CAPA) in that you failed to adequately analyze all sources of quality data, failed to identify actions needed to correct nonconforming product, and you did not appropriately verify or validate the change to your device to ensure corrective and preventive actions taken were effective and did not adversely affect the finished device. While you implemented your procedure, we disagree with your characterization of the risk threshold which led to a conclusion of a lower risk than was appropriate. For example:
a.具体来说，在2016年6月，贵公司启动了299677 CAPA (b)(4)#，以解决MiniMed 600系列胰岛素输液泵中固位环(透明固位环)损坏投诉增加的问题。企业的调查确定设备故障是由xx固定环引起的，而xx固定环又导致了xx。损坏的固定环可能导致胰岛素的过量或不足，从而可能导致低血糖或高血糖。从2019年8月开始，贵公司开始发布重新设计的泵(使用黑色固定环制造)进行分销。2019年11月，企业开始通知客户固定环故障。FDA确定有合理的可能性使用或接触透明固定环制造的泵将导致严重的不良健康后果，包括严重的低血糖，可导致意识丧失，癫痫发作;严重高血糖，可导致糖尿病酮症酸中毒或高渗透性高血糖状态，代谢异常;或死亡，并将召回(RES84430)归为1类。然而，贵公司未能充分实施纠正和预防措施程序(CAPA)，因为企业未能充分分析所有质量数据来源，未能确定纠正不合格品所需的措施，且企业未能适当确认或验证对设备的变更，以确保所采取的纠正和预防措施是有效的，且不会对成品设备产生不利影响。当企业实施程序时，我们不同意企业对风险阈值的描述，这导致了风险低于适当的结论。例如:
i. Your CAPA System procedure (SOP114-01DOC, Effective Date 5/19/2015, Version L) requires your firm to determine whether distributed product is potentially affected by a nonconformance and to conduct additional risk assessment activities per the Product Risk Management Process (SOP104- 08, Version W). In June 2016, your firm conducted a (b)(4)16-1051, Version A) which, per your Product Risk Management Process, outlines affected product in the field, and is a risk assessment and health hazard evaluation for informing field corrective action (“FCA”) decisions. Based on FDA’s own evaluation of risk, your outcomes of risk assessment do not appear to be appropriate. In conducting your (b)(4) you did not accurately calculate the risk associated with the failed retainer rings in the MiniMed 600 Series Insulin Infusion Pumps because your risk calculation formula underestimated the probability of occurrence of harm, resulting in your firm classifying the risk as “(b)(4)” (zone (b)(4)) (b)(4)” (zone (b)(4)). Consequently, your firm did not initiate a correction or removal to address the defective devices from the field because per your (b)(4), the risk of serious adverse health consequences was “improbable.”
i.企业的CAPA体系程序(SOP114-01DOC，生效日期2015年5月19日，版本L)要求贵公司确定分布式产品是否可能受到不合格的影响，并根据产品风险管理规程(SOP104- 08，版本W)进行额外的风险评估活动。2016年6月，贵公司进行了(b)(4)16-1051，版本a)，根据企业的产品风险管理过程，概述了现场受影响的产品。是一种风险评估和健康危害评估，用于告知现场纠正行动(“FCA”)决定。根据FDA自己的风险评估，企业的风险评估结果似乎不合适。在进行企业xx操作时，企业没有准确计算MiniMed 600系列胰岛素输注泵中失效固定环的相关风险，因为企业的风险计算公式低估了发生伤害的概率，导致贵公司将风险分类为“xx”(区xx)(区xx)。因此，贵公司没有开始纠正或移除现场有缺陷的设备，因为根据企业xx的规定，造成严重不良健康后果的风险是“不可能的”。
ii. In March 2021, your firm revised your Product Risk Management Process (SOP104-08, Version AL), which updated the formula for risk calculation; however, this also did not result in accurate risk calculation. The updated formula uses the “total shipment of affected product” which again underestimates the probability of occurrence because the number of products shipped includes devices not in use by patients (e.g., devices shipped to distributors that have not yet been distributed to customers). Further, the update also changed the parameters on the risk evaluation matrix, increasing the (b)(4) parameters (zones (b)(4)) and (b)(4) parameters (zone (b)(4)), thus requiring a higher occurrence for a harm to be classified as “(b)(4)” (zone (b)(4)). In June 2021 your firm again repeated the (b)(4), but due to the changes made in your risk evaluation formula and matrix, your firm again classified the risk as “(b)(4)” (zone (b)(4) (zone (b)(4)).
ii.22021年3月，贵公司修订了《产品风险管理程序》(SOP104-08，版本AL)，更新了风险计算公式;然而，这也没有获得准确的风险计算。更新后的公式使用了“受影响产品的总发货量”，这再次低估了发生的概率，因为发货的产品数量包括了患者未使用的设备(例如，发货给分销商的设备尚未分发给客户)。此外，更新还改变了风险评估矩阵上的参数，增加了(b)(4)参数(区域(b)(4))和(b)(4)参数(区域(b)(4))，因此需要更高的发生率才能将伤害分类为“(b)(4)”(区域(b)(4))。2021年6月，贵公司再次重复了xx，但由于企业的风险评估公式和矩阵的更改，贵公司再次将风险归类为xx (xx区)。
iii. Your firm did not identify the actions needed to control devices already in distribution. As previously discussed, your firm’s justification in June 2016 for not initiating a recall was based on your firm’s underestimated risk calculation. Per your Product Review Board Decision Form, dated September 2, 2016 and signed by your VP/President IIM Diabetes on October 3, 2016, while your firm initially planned to develop a customer communication regarding the reservoir retainer ring issue, the decision to not initiate a customer communication was based on “(b)(4).” Your firm then (b)(4) and (b)(4), each time using the (b)(4) and each time (b)(4); your firm consequently did not initiate a recall until November 20, 2019. From initiation of CAPA (b)(4)#299677 in June 2016 to November 20, 2019, the date you initiated the recall, you received over 74,000 retainer ring complaints, with over 57,000 of those reported to FDA as MDRs.
iii. 贵公司没有确定需要采取什么行动来控制已经销售的设备。如前所述，贵公司在2016年6月没有启动召回的理由是基于贵公司低估的风险计算。根据2016年9月2日由企业IIM Diabetes副总裁/总裁签署的产品评审委员会决议表，尽管贵公司最初计划就贮液圈固定环问题与客户进行沟通，但不启动客户沟通的决定基于“xx”。那么贵公司(b)(4)和(b)(4)，每次使用(b)(4)和(b)(4);因此，贵公司直到2019年11月20日才启动召回。从2016年6月CAPA (b)(4)#299677启动到2019年11月20日(企业启动召回之日)，企业收到了超过74000起固位环投诉，其中超过57000起作为mdr报告给FDA。
iv. After you initiated the recall of the MiniMed 600 Series Insulin Infusion Pumps on November 20, 2019, your firm further failed to implement changes in your methods and procedures needed to correct and prevent the recurrence of quality problems. Your recall consisted of a customer notification informing customers with affected insulin pumps to examine their devices for retainer ring damage and to contact Medtronic for a replacement pump if damage was noted; if no damage was noted by the customer, your notification instructed customers to continue using the device and to examine the retainer ring if the device was dropped or bumped. Thus, after redesigning the retainer ring to prevent further risk, you failed to adequately remove the pumps containing the older, less robust ring from the market.
iv.在企业于2019年11月20日开始召回MiniMed 600系列胰岛素输液泵后，贵公司进一步未能在纠正和防止质量问题再发生所需的方法和程序上实施更改。企业的召回包括一份客户通知，通知使用受影响胰岛素泵的客户检查其设备的固定环损坏情况，如果发现损坏，请联系美敦力更换泵;如果客户没有注意到损坏，企业的通知指示客户继续使用设备，并在设备掉落或碰撞时检查固定环。因此，在重新设计固位环以防止进一步的风险之后，企业未能充分地从市场上召回包含旧的、不太耐用的环的泵。
v. Your firm failed to verify and/or validate the corrective and preventive actions to ensure the action taken was effective to prevent recurrence of the nonconformance and did not adversely affect the finished device. Your firm began releasing the re-designed pump with the black retainer ring beginning August 2019 and closed CAPA (b)(4)#299677 as effective on October 2, 2020. Per your CAPA effectiveness plan, your firm compared the complaint rate of the newly released pumps (b)(4) to the complaint rate of the previous pump design with the clear retainer ring (b)(4)…” You concluded the effectiveness criteria were met because the complaint rate for the re-designed pumps was (b)(4) while the complaint rate for the previous design was (b)(4). However, you received 322 complaints during the (b)(4) effectiveness check period ((b)(4) to (b)(4)), and as of May 25, 2021, you had received a total of (b)(4) complaints of defective black retainer rings. You did not re-evaluate the effectiveness of your corrective and preventive actions to determine whether CAPA (b)(4)#299677 should be re-evaluated.
v.贵公司未能确认和/或验证纠正和预防措施，以确保所采取的措施有效地防止不符合项的再次发生，且没有对成品产生不利影响。贵公司从2019年8月开始放行重新设计的带黑色固定环的泵，并于2020年10月2日关闭CAPA (b)(4)#299677。根据企业的CAPA有效性计划，贵公司比较了新发布泵的投诉率(xx)和之前设计的带有透明固定环的泵(xx)的投诉率……“企业得出的结论是，由于重新设计的泵的投诉率为xx，而之前设计的泵的投诉率为xx，所以达到了有效性标准。然而，在xx有效性检查期间(xx至xx)，企业收到了322起投诉，截至2021年5月25日，企业总共收到了xx起关于黑色固定环缺陷的投诉。企业没有重新评估纠正和预防措施的有效性，以确定是否需要重新评估CAPA 299677。
b. Specifically, your firm initiated CAPA (b)(4)#401464 on June 29, 2018, to address a cybersecurity vulnerability with the remote controllers used with your Medtronic MiniMed 508 Insulin Infusion Pump and your MiniMed Paradigm Insulin Infusion Pumps. The identified cybersecurity vulnerability revealed unauthorized individuals could (b)(4).” The root cause investigation in CAPA (b)(4)#401464 indicated the “(b)(4).” In evaluating the risk of patient harm, your firm determined the lack of (b)(4) that could lead to delivery of (b)(4) could result in catastrophic harm to patients. Per your CAPA (b)(4)#401464, to address the root cause of the lack of cyber security requirements in the design, all current and future Medtronic Diabetes software products would be evaluated for encryption security requirements. Your firm also discontinued the manufacture and distribution of the Paradigm Pump products and scrapped remaining inventory of the remote controllers; however, these corrective actions did not address the devices in the field. While your firm initiated a recall of 15,787 remote controllers shipped to customers in the previous four years, you have distributed over (b)(4) remote controllers since its release in 1999, and you did not notify all customers of this safety issue.
b.具体来说，贵公司于2018年6月29日启动了CAPA (b)(4)#401464，以解决美敦力MiniMed 508胰岛素注射泵和MiniMed Paradigm胰岛素注射泵使用的遥控器存在的网络安全漏洞。已识别的网络安全漏洞显示未经授权的个人可以(b)(4)。”在CAPA (xx)#401464中的根本原因调查指出了(xx)。在评估患者伤害风险时，贵公司确定缺乏xx可能导致xx的交付可能对患者造成灾难性的伤害。根据企业的CAPA (b)(4)#401464，为了解决设计中缺乏网络安全要求的根本原因，所有当前和未来的美敦力糖尿病软件产品都将根据加密安全要求进行评估。贵公司还停止了Paradigm Pump产品的生产和销售，并报废了剩余的远程控制器库存;然而，这些纠正措施并没有针对现场的设备。虽然贵公司在过去四年里召回了分发给客户的15787个遥控器，但自1999年发布以来，企业已经分发了xx遥控器，而且没有通知所有客户这个安全问题。
We have reviewed your responses and conclude that they are not adequate because you have not yet provided evidence of implementation for all corrections and corrective actions. We acknowledge your firm has committed to replacing MiniMed 600 Series Insulin Infusion Pumps with the clear retainer ring for all US customers, regardless of warranty status, and will retrieve all Medtronic MiniMed remote controllers from active users, and opened CAPA 539888 in order to track completion of your proposed corrective actions.
我们已经审阅了企业的回复，并得出结论认为它们是不充分的，因为企业尚未提供实施所有纠正和纠正措施的证据。我们了解到贵公司已承诺为所有美国客户更换带透明固定环的MiniMed 600系列胰岛素输液泵，无论保修状态如何，并将从活动用户处回收所有美敦力MiniMed遥控器，并打开CAPA 539888，以跟踪企业提出的纠正措施的完成情况。
You stated you have updated relevant procedures, including but not limited to the risk management procedures, including Product Risk Management Process (SOP104- 08DOC), Risk Management Post Production Procedure (DOP104-068DOC), your recall procedure, Diabetes FCA Program Governance (10578148DOC), to address observation 1 on the FDA 483. You also state you will no longer use a device’s warranty status as a factor in determining the scope of recalls associated with the risk patient harm. Additionally, you state you have updated the Medtronic Internal Message Guide to characterize the field action as a recall to US customers, and opened CAPA 539942 to investigate reports of black retainer ring damage “in light of complaints that have been received.”
企业声明更新了相关程序，包括但不限于风险管理程序，包括产品风险管理程序(SOP104- 08DOC)、风险管理生产后程序(DOP104-068DOC)、企业的召回程序、糖尿病FCA项目治理(10578148DOC)，以解决FDA 483中的观察。企业还声明，将不再使用设备的保修状态作为决定与患者伤害风险相关的召回范围的因素。此外，企业声称已经更新了美敦力内部信息指南，将现场行动定性为对美国客户的召回，并“根据已收到的投诉”开启了CAPA 539942，以调查黑色固定环损坏的报告。
We acknowledge that you provided a copy of Engineering Report; NGP 6015265-020 Retainer Ring Damage Investigation, Version B in which you conclude that no manufacturing or design non-conformance was identified. However, you also stated that you have opened CAPA (b)(4)#539942 to further investigate damaged retainer rings and that activity is still ongoing.
我们知道企业提供了一份工程报告的副本;NGP 6015265-020固定环损坏调查，版本B，在该调查中企业得出结论，没有发现制造或设计上的不合格。然而，有也声明已经打开了CAPA (b) 539942 #，以进一步调查损坏的固定环，该活动仍在进行中。
You have also provided DOP104-068DOC, Risk Management Post Production Procedure, Revision U. This procedure is not adequate. You have (b)(4) for the (b)(4) “Medtronic MiniMed believes the (b)(4) is common practice in the industry”, however you have not provided adequate justification to demonstrate that it is appropriate for your risk calculation. For example, on pg. 200 of “Appendix B_1 of 2” provided in your response dated July 28, 2021 you provided the number of MiniMed 600 Series pumps with clear retainer rings shipped to the field as of February 28, 2021. There is a large difference between the number of products shipped ((b)(4)) and number of products actually in use in the field ((b)(4)% of product shipped). It is unclear to us if the difference was due to the number of devices currently with distributors. If that is not the case, using the number of products shipped (including devices that are not in use by patients) could under- estimate the probability of occurrence of hazardous situations, even after subtracting products currently with distributors.
企业还提供了DOP104-068DOC，风险管理后期生产程序，修订版u。对于xx“美敦力MiniMed认为xx是该行业的普遍做法”，企业有xx，但没有提供充分的理由证明其适合于企业的风险计算。例如，在企业2021年7月28日的回复中提供的“附录B_1 of 2”第200页中，企业提供了截至2021年2月28日运送到现场的MiniMed 600系列透明固定环泵的数量。发货的产品数量(xx)和实际在该领域使用的产品数量(xx)占发货产品的%)之间有很大的差异。我们还不清楚这一差异是否与目前分销商的设备数量有关。如果情况并非如此，使用已发货的产品数量(包括患者未使用的设备)可能会低估发生危险情况的概率，即使在减去目前与分销商合作的产品之后也是如此。
In addition, you started (b)(4) in (b)(4) but did not (b)(4) (SOP104-08DOC, Revision AP), stating that the one-year delay was “(b)(4)”, however you should not have delayed implementing the (b)(4) method. You further attempted to justify your interpretation of the (b)(4) in your July 2021 response as follows: “(b)(4), etc.) (b)(4)”. However, you have not explained how your (b)(4) i.e., that for (b)(4)” as the (b)(4), especially when the (b)(4).
此外，企业在xx中启动xx，但没有启动xx (SOP104-08DOC，修订版AP)，声明一年的延迟是“xx”，但企业不应该延迟实施xx方法。企业在2021年7月的回复中进一步试图证明企业对xx的解释如下:“xx，等等”。但是，企业没有解释xx(4)，即xx(4)“如何作为xx(4)，特别是当xx(4)。
Following change in the (b)(4) situations, you have also re-evaluated your risk zone classification matrix in March 2021 (Change Order QCH00047208, SOP104-08 DOC, Revision AL), stating that “t(b)(4)”, which resulted in changes in classification of risk zones. (b)(4): specifically, “(b)(4) from (b)(4). In Attachment 1.6 of your response provided on July 28, 2021 you stated that your assessment of suitability of the risk acceptability criteria was conducted based on mortality rates associated with type 1 diabetes, however death is not the only serious consequence for population for which insulin pump therapy is indicated. Other adverse events such as severe hypoglycemia (SH) and diabetic ketoacidosis (DKA) can also present serious harms to users and should be considered in your hazard analysis. Similarly, your justification for the reassignment of risk zones for (b)(4) events relies heavily on the above calculation of mortality rates only. Furthermore, you argued that, with the removal of the factor of (b)(4) from your (b)(4) of (b)(4).” However, the risk calculation for (b)(4) and severity of the risk zones are separate issues and should be assessed separately; addressing the risk calculation does not justify changing the risk zone classification to maintain the overall risk levels. You have not provided adequate information to support that your revised risk zones are clinically acceptable because they appear to be based only on mortality rates, and not all the adverse events that can occur in the intended use population.
在xx情况发生变化后，企业也在2021年3月重新评估了风险区域分类矩阵(更改令QCH00047208, SOP104-08 DOC，修订版AL)，声明“t(b)(4)”，这导致了风险区域分类的变化。(b)(4):具体来说，“(b)(4)从(b)(4)。在你们2021年7月28日提供的回复附件1.6中，企业指出，企业对风险可接受性标准适用性的评估是基于与1型糖尿病相关的死亡率进行的，然而，死亡并不是需要接受胰岛素泵治疗的人群的唯一严重后果。其他不良事件，如严重低血糖(SH)和糖尿病酮症酸中毒(DKA)也会对使用者造成严重伤害，应该在危害分析中加以考虑。同样，企业为xx事件重新分配危险区的理由在很大程度上仅依赖上述死亡率的计算。此外，企业认为，从企业的xx xx中除去xx xx的因子后。”但是，xx的风险计算和风险区域的严重性是单独的问题，应单独评估;处理风险计算并不证明更改风险区域分类以保持总体风险水平是合理的。企业没有提供足够的信息来支持企业修订的危险区在临床上是可接受的，因为它们似乎只基于死亡率，而不是预期使用人群中可能发生的所有不良事件。
In your response, you should explain how your mortality-based risk calculation is appropriate to address all health risks especially as it led to a down-classification of the risk severity, and update your risk zone classifications if necessary. Finally, in your November 5, 2021 update you stated that you evaluated the Issue Impact Assessments (IIAs) initiated in the last (b)(4) and identified 20 IIAs that require remediation to reflect the (b)(4) per DOP104-068DOC, (b)(4) that is planned to be complete by (b)(4). However, as it is unclear if your revised procedure is adequate and because this corrective action is not yet complete, we cannot evaluate the adequacy at this time.
回复中，企业应解释基于死亡率的风险计算如何适用于处理所有健康风险，特别是因为它导致了风险严重性的降级，并在必要时更新企业的风险区域分类。最后，在企业2021年11月5日的更新中，企业表示，评估了上次xx启动的问题影响评估(IIAs)，并确定了20个需要进行整改的IIAs，以反映DOP104-068DOC的xx，并计划由xx完成。然而，由于尚不清楚企业修订后的程序是否充分，且纠正措施尚未完成，我们目前无法评估其充分性。
In summary, your corrective actions are still in process, and you have not yet conducted effectiveness checks to ensure the updated procedures and required employee training will prevent reoccurrence of the identified deficiencies. In your November 5, 2021 update you stated that you completed a retrospective review of CAPA effectiveness criteria and of CAPA effectiveness monitoring thresholds but 38 CAPAs were identified as requiring remediation and/or clarification and 14 CAPAs were identified as requiring a new complaint monitoring plan. You should remediate those CAPAs using an adequate risk analysis and provide a summary of your review and remediation efforts.
总之，企业的纠正措施仍在进行中，企业还没有进行有效性检查，以确保更新的程序和所需的员工培训将防止已确定缺陷的再次发生。在企业2021年11月5日的更新中，企业表示，完成了对CAPA有效性标准和CAPA有效性监测阈值的回顾性审查，但有38个CAPA被确定为需要整改和/或澄清，14个CAPA被确定为需要新的投诉监测计划。企业应该使用充分的风险分析来纠正这些CAPA，并提供企业的审查和纠正工作的总结。
2. You failed to review, evaluate, and investigate complaints involving the possible failure of a device to meet any of its specifications, as required by 21 CFR 820.198(c).
2. 企业未能按照21 CFR 820.198(c)的要求，审查、评估和调查涉及设备可能无法满足其任何规格的投诉。
a. Your firm failed to investigate over 800 complaints of defective black retainer rings. In June 2016, your firm initiated CAPA (b)(4)#299677 to address an increase in complaints of damaged retainer rings in the MiniMed 600 Series Insulin Infusion Pumps; as part of the CAPA investigation, your firm determined the retainer ring required re-design, and you changed the retainer ring from a clear (b)(4) ring to a black (b)(4) ring. You began releasing the re-designed pump with black retainer ring in August 2019, and you closed CAPA (b)(4)#299677 as effective October 2020. From December 2019 to May 2021, you received 887 complaints of defective black retainer rings; in 772 of the 887 complaints your firm referenced CAPA (b)(4)#299677 as the “Formal Investigation
a.贵公司未能调查超过800起关于黑色固定环有缺陷的投诉。2016年6月，贵公司启动了299677 CAPA (b)，以解决MiniMed 600系列胰岛素输液泵内固定环损坏投诉增加的问题;作为CAPA调查的一部分，贵公司确定固定环需要重新设计，并将固定环由透明的xx环改为黑色xx环。企业于2019年8月开始分发重新设计的带黑色固定环的泵，并于2020年10月关闭了CAPA (b)(4)#299677。从2019年12月到2021年5月，企业收到了887起关于黑色扣环缺陷的投诉;在887起投诉中，贵公司在772起投诉中将CAPA (b)(4)#299677作为“正式调查”
Reference Number” even though this CAPA was an investigation of the previous clear retainer ring design. For example:
参考编号”，尽管此CAPA是对之前的固定环设计的调查。例如:
i. On January 21, 2020, you received a complaint (CASE-2020-00056605) from a customer reporting a crack on their insulin pump reservoir compartment, and damage to the retainer ring. Your product analysis on the returned device confirmed the device had a “partially broken retainer, cracked reservoir tube lip, missing reservoir tube lip O-ring, and broken reservoir tube lip.” On April 24, 2020, you determined no formal investigation was necessary due to existing/previous formal investigation and referenced CAPA (b)(4)#299677. You closed this complaint on April 24, 2020.
i. 2020年1月21日，企业收到了客户的投诉(CASE-2020-00056605)，客户报告他们的胰岛素泵储液舱出现裂缝，固定环损坏。企业对归还装置的产品分析证实该装置有“部分断裂的固定环，储层管唇裂，储层管唇o形环缺失，储层管唇破裂。”2020年4月24日，由于已有/以前的正式调查，企业确定不需要进行正式调查，并参考了CAPA (b)(4)#299677。企业于2020年4月24日关闭。
ii. On February 20, 2020, you received a complaint (CASE-2020-00139368) from a customer reporting they experience hyperglycemia, with blood glucose levels of 450 mg/dL. The customer stated that the lip ring was missing. Your product analysis on the returned device confirmed the device was missing the reservoir retainer ring and the reservoir tube lip O-ring, and the reservoir would not stay locked in place due to the missing retainer. On May 8, 2020, you determined no formal investigation was necessary due to existing/previous formal investigation and referenced CAPA (b)(4)#299677. You closed this complaint on May 8, 2020.
ii.2020年2月20日，企业收到一名客户的投诉(CASE-2020-00139368)，称他们出现高血糖，血糖水平为450 mg/dL。顾客说固定环不见了。企业对退回设备的产品分析证实，该设备缺少储层护圈和储层管唇o形圈，由于缺少护圈，储层无法保持锁定。2020年5月8日，由于已有/以前的正式调查，企业确定不需要进行正式调查，并参考了CAPA (b)(4)#299677。企业于2020年5月8日关闭。
iii. On April 7, 2020, you received a complaint (CASE-2020-00260639) from a customer experiencing a high blood glucose level of 434 mg/dL. The customer reported that the retainer ring was loose, and the reservoir did not lock into place when inserted into the pump. Your product analysis on the returned device confirmed a broken retainer and missing reservoir tube O- ring, and the reservoir did not lock into place. On June 5, 2020, you determined no formal investigation was necessary due to existing/previous formal investigation and referenced CAPA (b)(4)#299677. You closed this complaint on June 6, 2020.
iii. 2020年4月7日，企业收到了一名客户的投诉(CASE-2020-00260639)，该客户的血糖水平为434 mg/dL。客户报告说，固定环松动，当插入泵时，储液器没有锁定到位。企业对退回设备的产品分析证实了护圈破损，储液管O形环缺失，储液管没有锁定到位。2020年6月5日，由于已有/以前的正式调查，企业确定不需要进行正式调查，并参考了CAPA (b)(4)#299677。企业于2020年6月6日关闭。
b. Your firm failed to adequately investigate a complaint in which the customer reported (b)(4) of insulin that were not programmed by the customer. You received a complaint on December 25, 2019 (CASE-2019-00921665) where the customer alleged that their low blood glucose was the result of over-delivery of insulin by their Paradigm Insulin Infusion Pump (Model MMT-715WWS), which per the (b)(4), reflected (b)(4) that were not programmed by the customer. The device was returned to your firm for analysis and the complaint was escalated to your cybersecurity Incident Response Management Team. Your investigation included a review of the downloaded CareLink data, in which the (b)(4) reported by the customer were not reflected. However, your firm’s investigation did not include reviewing the actual pump history to verify the presence of the additional (b)(4). This complaint was closed June 26, 2021 as “the cause of the event cannot be determined, as product analysis found no failure or anomaly in the device.”
b.贵公司未能充分调查客户报告的胰岛素未被客户编程的投诉。企业在2019年12月25日收到了一份投诉(CASE-2019-00921665)，客户声称他们的低血糖是由模范胰岛素输液泵(型号MMT-715WWS)过量输送胰岛素造成的，根据xx, xx反映了客户没有编程的xx。该设备已被送回贵公司进行分析，投诉已升级到企业的网络安全事件响应管理团队。企业的调查包括对下载的CareLink数据的审查，其中客户报告的xx没有反映出来。然而，贵公司的调查没有包括审查实际泵历史以验证附加xx的存在。该投诉于2021年6月26日结束，因为“无法确定事件的原因，因为产品分析在设备中没有发现故障或异常。”
c. Your firm failed to adequately investigate complaints of Enlite3 MMT-7020A glucose sensor failures. You received two complaints of sensor failures, both of which were closed as “analysis is not required as this complaint is not reportable, and the sensor lot number is unknown.” However, there is no evidence in either complaint record that technical support attempted to determine the lot numbers when communicating with the complainants, even though your Guides, Troubleshooting, Glucose Sensor procedure (DOP114-691DOC, Revisions AL and AM) requires all service notifications to include a lot or batch number for the product. Furthermore, while your Failure Analysis-Glucose Sensor Products procedure (DOP830DOC, Version V) indicates expired sensors are not required to be analyzed, it is not clear how your firm determined the sensors were expired when neither complaint record lists an expiration date, and you failed to determine the lot or batch number of the returned sensors. Last, your Failure Analysis-Glucose Sensor Products procedure does not include MDR reportability as a requirement for sensor analysis.
c.贵公司未能充分调查关于Enlite3 MMT-7020A葡萄糖传感器故障的投诉。企业收到了两起传感器故障投诉，这两起投诉都被关闭了，因为“不需要分析，因为该投诉不可报告，而且传感器批号未知。”然而，尽管企业的指南、故障排除、葡萄糖传感器程序(DOP114-691DOC，修订版AL和AM)要求所有服务通知包括产品的批号或批号，但在任何投诉记录中都没有证据表明技术支持在与投诉人沟通时试图确定批号。此外，虽然企业的故障分析-葡萄糖传感器产品程序(DOP830DOC, Version V)表明不需要分析过期的传感器，但不清楚贵公司是如何确定传感器过期的，因为投诉记录都没有列出过期日期，而且企业未能确定送回的传感器的批号。最后，企业的故障分析-葡萄糖传感器产品程序没有将MDR报告性作为传感器分析的要求。
d. Your firm failed to adequately investigate reported issues with your CareLink software that your firm manufactures; this software uses information transmitted from insulin infusion pumps and glucose meters to create reports intended to assist users with diabetes management. Of the 25 complaints reviewed during our inspection, your firm documented “software error unknown” in 20 of the complaints; however, there is no evidence in your complaint records that technical support attempted to determine the version of software used by the device in order to conduct an investigation. During the inspection, your VP of Quality Assurance explained to our investigator that all versions of the software are maintained and could be analyzed to investigate the reported software errors.
d.贵公司未能充分调查贵公司生产的CareLink软件报告的问题;该软件使用从胰岛素输注泵和血糖仪传输的信息来创建报告，旨在帮助用户进行糖尿病管理。在我们检查期间审查的25个投诉中，贵公司记录了20个投诉中“未知软件错误”;然而，在企业的投诉记录中没有证据表明技术支持人员试图确定设备使用的软件版本以进行调查。在检查期间，企业的质量保证副总裁向我们的调查人员解释说，软件的所有版本都得到了维护，可以通过分析来调查报告的软件错误。
We have reviewed your responses and acknowledge you have opened CAPA 539889 to track completion of your proposed corrective actions, including updating complaint investigation and post market trending, as well as implementation of an enhanced training program for complaint handling, technical support, and failure analysis personnel. You have also committed to performing a retrospective review of complaint files for the issues identified on the FDA 483, Inspectional Observations.
我们已经审查了企业的回复，并确认有已开启CAPA 539889以跟踪企业所提议的纠正措施的完成情况，包括更新投诉调查和市场趋势，以及实施针对投诉处理、技术支持和故障分析人员的强化培训计划。企业还承诺对FDA 483“检查观察”中确定的问题的投诉文件进行回顾性审查。
In your initial response, you acknowledge CAPA (b)(4)#299677 should not have been used to justify not investigating complaints of the re-designed insulin infusion pumps, and you recognize complaints of damaged black retainer rings should have been escalated to a new formal investigation; you have opened CAPA 539942 to conduct this formal investigation. However, your response does not address why your firm deemed the original CAPA (b)(4)#299677 as adequate justification for not investigating over 800 complaints in the re-designed pump, nor does it address changes made to prevent recurrence of similar events.
在企业最初的回复中，企业承认不应使用CAPA (b) #299677作为不调查重新设计胰岛素输液泵投诉的理由，有认识到关于黑色固定环损坏的投诉应升级为新的正式调查;企业已经开启了CAPA 539942进行正式调查。然而，企业的回复并没有说明为什么贵公司认为最初的CAPA (b)(4)#299677是不调查重新设计泵中超过800起投诉的充分理由，也没有说明为防止类似事件再次发生而做出的改变。
Your response indicates you conducted further analysis of complaint CASE-2019-00921665, in which the customer received (b)(4) not programmed into the device; in your supplementary investigation, your firm reviewed the downloaded pump history file and found (b)(4) of similar size to those recorded in the complaint. Your supplementary investigation concluded the extra (b)(4) were not received over (b)(4), which “rules out the possibility of a cyber security incident.” We acknowledge your firm has updated your Failure Analysis, Paradigm (DOP114-858DOC) and Failure Analysis, NGP (DOP114- 888DOC) procedures, and will update failure analyses as warranted; however, your response does not address your firm’s initial limited investigation, nor does it address changes made to prevent recurrence of similar events.
企业的回复表明企业对投诉CASE-2019-00921665进行了进一步分析，在该投诉中，客户收到了未编程到设备中的xx;在企业的补充调查中，贵公司审查了下载的泵历史文件，发现xx与投诉中记录的大小相似。企业的补充调查得出结论，额外的xx没有收到xx，这“排除了网络安全事件的可能性”。我们了解到贵公司已经更新了企业的故障分析，范例(DOP114- 858doc)和故障分析，NGP (DOP114- 888DOC)程序，并将根据需要更新故障分析;然而，企业的回复没有说明贵公司最初的有限调查，也没有说明为防止类似事件再次发生而做出的改变。
Your response also describes further investigations of the two complaints of Enlite3 MMT- 7020A glucose sensor failures. Per your response, your firm was able to narrow down and/or determine lot numbers of the sensors via patient history and reassessment of complaint files. In your reassessment you conducted a Lot History Review (LHR) and determined for both complaints “there were no process deviations or out of specification test results observed that would have contributed to a sensor performance issues.” We acknowledge you opened CAPA 541992 to investigate methods to reliably investigate and analyze sensors; however, as this corrective action is not yet complete, we cannot evaluate the adequacy at this time.
企业的回复还描述了对Enlite3 MMT- 7020A葡萄糖传感器故障两起投诉的进一步调查。根据企业的回复，贵公司能够通过患者病史和对投诉文件的重新评估缩小和/或确定传感器的批号。在企业的重新评估中，企业进行了大量历史回顾(LHR)，并确定对于这两个投诉，“没有观察到导致传感器性能问题的工艺偏差或超出规格的测试结果。”我们知道企业开放了CAPA 541992来研究可靠地调查和分析传感器的方法;然而，由于这一纠正措施尚未完成，我们目前无法评估其充分性。
We also acknowledge your firm committed to implementing a new failure analysis process specific to software complaints, and opened CAPA 541994 to investigate and identify actions needed, and complaints with “software error unknown” will be investigated as part of that CAPA. However, as part of your corrective actions are not yet complete, including your, retrospective complaint review and systemic complaint investigation processes and training, we cannot evaluate the adequacy of your response at this time.
我们也认识到贵公司致力于实施针对软件投诉的新的故障分析流程，并开放了CAPA 541994，以调查和确定所需的行动，“软件错误未知”的投诉将作为该CAPA的一部分进行调查。然而，由于企业纠正措施的一部分尚未完成，包括企业的回顾性投诉审查和系统投诉调查流程和培训，我们目前无法评估企业回应的充分性。
Our inspection also revealed that your insulin infusion pump 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 deficiencies include, but are not limited to, the following:
我们的检查还发现，企业的胰岛素输注泵设备根据《法案》第502(t)(2)条、21 U.S.C.§352(t)(2)条的规定被定义为错标，因为贵公司未能或拒绝提供《法案》第519条、21 U.S.C.§360i和21 CFR Part 803 -医疗设备报告要求提供的有关该设备的材料或信息。重大缺陷包括但不限于以下方面:
3. Your firm failed to submit a report to FDA no later than 30 calendar days of receiving or otherwise becoming aware of information that reasonably suggests that a marketed device may have caused or contributed to a death or serious injury, as required by 21 CFR 803.50(a)(1).
3.贵公司未能在收到或以其他方式获悉合理表明已上市器械可能导致或增加死亡风险或严重伤害的信息后30个日历天内向FDA提交报告，符合21 CFR 803.50(a)(1)的要求。
For example, the information included for complaint #CASE-2020-00236012 describes an event in which your firm’s MiniMed Insulin Pump malfunctioned; after using the device the patient exhibited low glucose reading of 36 mg/dL and was treated with food. We believe that the treatment received by the patient was necessitated to preclude permanent impairment of a body function or permanent damage to a body structure. There is no information included in the firm’s complaint file that rules out the device may not have caused or contributed to the referenced serious injury. As such, the referenced complaint meets the definition of a reportable serious injury, as defined in 21 CFR 803.3. The firm became aware of the event on March 27, 2020. However, your firm did not submit an MDR to the FDA.
例如，投诉#CASE-2020-00236012所包含的信息描述了贵公司的MiniMed胰岛素泵发生故障的事件;使用该设备后，患者表现为36 mg/dL的低血糖，并进行了食物治疗。我们认为，患者接受的治疗是必要的，以防止身体功能的永久性损伤或身体结构的永久性损伤。在该公司的投诉文件中，没有任何信息可以排除该设备可能没有导致或增加上述严重伤害的可能性。因此，所引用的投诉符合21 CFR 803.3中所定义的可报告严重伤害的定义。该公司于2020年3月27日意识到这一事件。然而，贵公司没有向FDA提交MDR。
The adequacy of your firm’s response dated July 28, 2021 cannot be determined at this time. The response noted that your firm is implementing systemic corrective actions, including updates to its reportability criteria, a retrospective review of the complaints and staff training. However, your firm did not provide documentation or evidence that all the corrections and corrective actions, including submission of the referenced serious injury MDR, have been implemented and completed as they are still in progress.
贵公司在2021年7月28日的回复是否充分，目前还无法确定。答复中指出，贵公司正在实施系统性纠正措施，包括更新报告性标准、对投诉进行回顾性审查和对员工进行培训。然而，贵公司没有提供文件或证据证明所有的纠正和纠正措施，包括提交参考的严重伤害MDR，已经实施和完成，因为它们仍在进行中。
The adequacy of your firm’s response dated September 3, 2021 also cannot be determined at this time. Your response provided an update to its planned or newly added corrective actions, including identification and submission of reportable events associated with retainer ring damage complaints, and implementation of late regulatory review process. However, your firm did not provide documentation or evidence that all the corrections and corrective actions, including submission of the referenced serious injury MDR and planned re-evaluation of its reportability criteria, have been implemented and completed as they are still in progress.
贵公司在2021年9月3日的回复是否充分，目前也无法确定。企业的回复提供了计划或新增加的纠正措施的更新，包括确定和提交与固位圈损坏投诉相关的应报告事件，以及实施后期监管审查流程。然而，贵公司没有提供文件或证据证明所有的纠正和纠正行动，包括提交参考的严重伤害MDR和计划的报告性标准重新评估，已得到实施和完成，因为它们仍在进行中。
The adequacy of your firm’s responses dated October 8, November 5, and December 2, 2021 also cannot be determined at this time. Your responses provided an update to the planned corrective actions. You provided your new MDR Training Program. However, you also report that training of personnel will not be completed until (b)(4). You also provided D00603958 MDR Decision Alignment with Risk Management Remediation Plan for Diabetes. It is unclear if this plan incorporates an adequate risk analysis (see review under item #1) and you state that your planned actions will not be completed until (b)(4). You did not provide documentation or evidence that all the corrections and corrective actions, including submission of the referenced serious injury MDR and planned re-evaluation of its reportability criteria, have been implemented and completed as they are still in progress.
贵公司在2021年10月8日、11月5日和12月2日的回复是否充分，目前也无法确定。企业的回复提供了整改计划的更新。企业提供了新的MDR培训计划。然而，企业也报告说，人员培训要到xx才能完成。企业还提供了D00603958 MDR决策与糖尿病风险管理整改计划的一致性。不清楚该计划是否包含了充分的风险分析(见第1项下的审查)，企业声明企业计划的行动将在xx之前完成。企业没有提供文件或证据证明所有的纠正和纠正行动，包括提交参考的严重伤害MDR和计划中的报告性标准重新评估，已得到实施和完成，因为这些纠正和纠正行动仍在进行中。
4. Your firm failed to submit a report to FDA no later than 30 calendar days after the day that the firm received or otherwise became aware of information, from any source, that reasonably suggests that a device that the firm markets has malfunctioned and this device or a similar device that it markets would be likely to cause or contribute to a death or serious injury, if the malfunction were to recur, as required by 21 CFR 803.50(a)(2).
4. 贵公司未能在收到或以其他方式获悉来自任何来源的信息之日起30个日历日内向FDA提交报告，该信息合理地表明，贵公司所销售的设备已发生故障，且如果故障再次发生，该设备或其所销售的类似设备可能会导致或增加死亡风险或严重伤害，按照21 CFR 803.50(a)(2)的要求。
For example, the information included for Complaints #CASE-2018-00270399 and #CASE-2018-00437534 reasonably suggests that your firm’s insulin pump malfunctioned (e.g. broken or missing retainer ring) while in use. The same malfunction is the subject of the recall Z-0956-2020 for the same device. Per the 1995 Preamble, a malfunction is reportable if the manufacturer takes, or would be required to take, an action under section 518 or 519(g) of the FD&C as a result of the malfunction of the device or other similar devices {60 FR 63578, 63585 (Dec. 11, 1995)}. Please note that the preamble reference is section 519(f), but the appropriate designation for the section is now section 519(g) due to amendments to the FD&C Act. There is no information included for the complaint files that justifies that the malfunction would not be likely to cause or contribute to a death or serious injury, if it were to recur. As such, your firm should have submitted within the required timeframes, an MDR for each MDR reportable event subject of the referenced complaints. The corresponding MDRs 2032227-2021-157630 and 2032227-2021-157620 were received by FDA beyond the required 30 calendar days timeframe.
例如，投诉#CASE-2018-00270399和#CASE-2018-00437534所包含的信息合理地表明，贵公司的胰岛素泵在使用过程中出现了故障(例如，固定环损坏或丢失)。同样的故障也是召回Z-0956-2020的原因。根据1995年序言，如果由于设备或其他类似设备的故障，制造商根据FD&C第518或519(g)条采取了或将被要求采取措施，则故障是可报告的{60 FR 63578, 63585(1995年12月11日)}。请注意，序言引用的是第519(f)条，但由于FD&C法案的修订，该章节的适当名称现在是第519(g)条。投诉档案中没有任何信息证明，如果故障再次发生，该故障不太可能导致或增加死亡风险或严重伤害。因此，贵公司应该在规定的时间范围内，针对所引用投诉的每个可报告的MDR事件提交一份MDR。FDA收到的相应的药单2032227-2021-157630和2032227-2021-157620超过了规定的30天时间框架。
The adequacy of your firm’s response dated July 28, 2021 cannot be determined at this time. The response noted that your firm is implementing systemic corrective actions, including updates to its reportability criteria, a retrospective review of the complaints and staff training. However, your firm did not provide documentation or evidence that all the corrections and corrective actions, including the planned assessment of its reportability criteria, have been implemented and completed as they are still in progress.
贵公司在2021年7月28日的回复是否充分，目前还无法确定。答复中指出，贵公司正在实施系统性纠正措施，包括更新报告性标准、对投诉进行回顾性审查和对员工进行培训。然而，贵公司没有提供文件或证据证明所有的纠正和纠正措施，包括计划中的报告性标准评估，已经实施和完成，因为它们仍在进行中。
The adequacy of your firm’s response dated September 3, 2021 also cannot be determined at this time. Your response provided an update to its planned or newly added corrective actions, including identification and submission of reportable events associated with retainer ring damage complaints, and implementation of late regulatory review process. However, your firm did not provide documentation or evidence that all the corrections and corrective actions, including the planned re-evaluation of its reportability criteria, have been implemented and completed as they are still in progress.
贵公司在2021年9月3日的回复是否充分，目前也无法确定。企业的回复提供了计划或新增加的纠正措施的更新，包括确定和提交与固位圈损坏投诉相关的应报告事件，以及实施后期监管审查流程。然而，贵公司没有提供文件或证据证明所有的纠正和纠正措施，包括计划中的报告性标准重新评估，已经得到实施和完成，因为这些措施仍在进行中。
The adequacy of your firm’s responses dated October 8, November 5, and December 2, 2021 also cannot be determined at this time. Your response provided an update to the planned corrective actions. You provided your new MDR Training Program. However, you also report that training of personnel will not be completed until (b)(4). You also provided D00603958 MDR Decision Alignment with Risk Management Remediation Plan for Diabetes. It is unclear if this plan incorporates an adequate risk analysis (see review under item #1) and you state that your planned actions will not be completed until (b)(4). You did not provide documentation or evidence that all the corrections and corrective actions, including submission of the referenced serious injury MDR and planned re-evaluation of its reportability criteria, have been implemented and completed as they are still in progress.
贵公司在2021年10月8日、11月5日和12月2日的回复是否充分，目前也无法确定。企业的回复提供了整改计划的更新。企业提供了新的MDR培训计划。然而，企业也报告说，人员培训要到xx才能完成。企业还提供了D00603958 MDR决策与糖尿病风险管理补救计划的一致性。不清楚该计划是否包含了充分的风险分析(见第1项下的审查)， 企业声明企业计划的行动将在xx之前完成。企业没有提供文件或证据证明所有的纠正和纠正行动，包括提交参考的严重伤害MDR和计划中的报告性标准重新评估，已得到实施和完成，因为这些纠正和纠正行动仍在进行中。
This letter notifies you of our findings and provides you an opportunity to address the above deficiencies. Your firm should investigate and determine the causes of any deficiencies, and take prompt actions to correct the deficiencies and bring the products into compliance. Failure to promptly correct these deficiencies may result in regulatory action being initiated by the FDA without further notice. These actions include, but are not limited to, seizure, injunction, and civil money penalties. Additionally, premarket approval applications for Class III devices to which the Quality System regulation deficiencies are reasonably related will not be approved until the deficiencies have been corrected. Also, should FDA determine that your devices do not meet requirements of the Act, requests for Certificates to Foreign Governments (CFG) may not be granted. More information on processes for persons denied a CFG can be found at: https://www.fda.gov/regulatory-information/search-fda-guidance-documents/process-request-review-fdas-decision-not-issue-certain-export-certificates-devices. If you believe that your products are not in violation of the FD&C Act and FDA regulations, please provide us with your reasoning and any supporting information for our consideration within fifteen business days.
这封信通知企业我们的发现，并为有提供了一个解决上述缺陷的机会。贵公司应调查并确定任何缺陷的原因，并立即采取行动纠正缺陷，使产品符合规定。未能及时纠正这些缺陷可能导致FDA在没有进一步通知的情况下启动监管行动。这些行为包括但不限于扣押、禁令和民事罚款。此外，在缺陷得到纠正之前，与质量体系法规缺陷有合理关联的III类器械的上市前批准申请将不予批准。此外，如果FDA确定企业的设备不符合法案的要求，则可能不会批准向外国政府提交证书(CFG)的请求。关于被拒绝获得CFG的人的更多信息，请访问:https://www.fda.gov/regulatory-information/search-fda-guidance-documents/process-request-review-fdas-decision-not-issue-certain-export-certificates-devices。如果企业认为企业的产品没有违反FD&C法案和FDA法规，请在15个工作日内提供企业的理由和任何支持信息供我们考虑。
You should schedule a teleconference with FDA to further discuss your response to this Warning Letter, particularly in response to your revised risk assessment (please see item 1 above) in more detail. Please notify FDA in writing within fifteen business days from the date you receive this letter of the specific steps your firm has taken to correct the noted Quality System and MDR reporting deficiencies, as well as an explanation of how your firm plans to prevent these deficiencies, or similar deficiencies, from occurring again. Include documentation of the corrections and/or corrective actions (which must address systemic problems) that your firm has taken. If your firm’s planned corrections and/or corrective actions will occur over time, please include a timetable for implementation of those activities. If corrections and/or corrective actions cannot be completed within fifteen business days, state the reason for the delay and the time within which these activities will be completed. Your firm’s response should be comprehensive and address all deficiencies included in this Warning Letter.
企业应该安排与FDA的电话会议，进一步讨论企业对本警告信的回应，特别是对企业修订后的风险评估的回应(请参阅上面的第1项)。请在收到本函之日起15个工作日内书面通知FDA贵公司为纠正所述质量体系和MDR报告缺陷所采取的具体措施，以及解释贵公司计划如何防止这些缺陷或类似缺陷再次发生。包括贵公司已经采取的纠正和/或纠正措施(必须针对系统性问题)的文件。如果贵公司计划的纠正和/或纠正措施将随着时间的推移而发生，请提供实施这些活动的时间表。如果纠正和/或纠正措施不能在15个工作日内完成，说明延迟的原因和完成这些活动的时间。贵公司的回复应是全面的，并解决本警告信中包含的所有缺陷。
Your response should be sent to: US Food and Drug Administration, Division 3/West, Office of Medical Device and Radiological Health Operations at oradevices3firmresponse@fda.hhs.gov. Please identify your response with CMS Case #617539. If you have questions about the contents of this letter, please contact Compliance Officer Jamie M. Bumpas at 214-253-5336 or via email at Jamie.bumpas@fda.hhs.gov.
企业的回复应发送到:美国食品和药物管理局， Division 3/West, Office of Medical Device and Radiological Health Operations ，邮箱地址：oradevices3firmresponse@fda.hhs.gov。请用CMS案例#617539识别企业的回复。如对本函内容有任何疑问，请致电214-253-5336或通过电子邮件Jamie.bumpas@fda.hhs.gov与合规官 Jamie M. Bumpas联系。
Finally, you should know that this letter is not intended to be an all-inclusive list of the deficiencies at your firm’s facility. It is your firm’s responsibility to ensure compliance with applicable laws and regulations administered by FDA. The specific deficiencies noted in this letter and in the Inspectional Observations, FDA 483, issued at the close of the inspection may be symptomatic of serious problems in your firm’s manufacturing and quality management systems. Your firm should investigate and determine the causes of the deficiencies, and take prompt actions to correct the deficiencies and bring the products into compliance.
最后，企业应该知道，这封信并不是要列出贵公司设施的所有缺陷。确保遵守FDA管理的适用法律法规是贵公司的责任。本函和检查结束时发布的FDA 483检查意见中指出的具体缺陷可能是贵公司生产和质量管理体系存在的严重缺陷。贵公司应调查并确定缺陷的原因，并立即采取行动纠正缺陷，使产品符合要求。
Sincerely,
/S/
Shari J. Shambaugh
Program Division Director
Office of Medical Device & Radiological Health
West/Division 3
/S/
Timothy T. Stenzel, M.D., Ph.D.
Director
OHT 7: Office of In Vitro Diagnostics and
Radiological Health
Office of Product Evaluation and Quality
Center for Devices and Radiological Health
Cc:
Sean Salmon, Executive Vice President & President
Diabetes Operating Unit
Medtronic, Inc.
Sean.salmon@medtronic.com
Chirag Tilara, Vice President, Quality
Medtronic, Inc.
Chirag.m.tilara@medtronic.com
