按照《北京市2024年药品（含药包材）、医疗器械、化妆品质量抽查检验工作实施方案》，北京市药品监督管理局于2024年组织对全市化妆品生产环节（含注册人、备案人、境内责任人）及互联网开展了监督抽检工作，共完成监督抽检1610批。现将已核查完毕的6批次不合格产品（详见附件）予以公告。相关单位已对不合格化妆品采取必要的控制措施，依据有关法律法规对不合格产品进行查处。特此公告。附件：本期已核查的化妆品监督抽检不合格产品北京市药品监督管理局2025年1月16日相关推荐CIO提供以下相关文库下载、合规服务以及线上培训课程学习。

主体名称象山华源大药房处罚决定书文号象市监处罚﹝2025﹞35号处罚类别罚款处罚决定时间2025-01-16处罚内容由药品监督管理部门或者卫生健康主管部门责令解聘,处五万元以上二十万元以下的罚款;罚款金额（万元）10.000000没收违法所得0.000000暂扣或吊销证照名称及编号-违法行为类型象山华源大药房其它违法行为案处罚依据《中华人民共和国药品管理法》第一百四十条;违法事实主要违法事实:2024年9月13日,本局执法人员依法对位于象山县***的象山**大药房进行检查,检查时当事人正处于营业状态,执法人员在当事人从业人员一览表中发现有王**(身份证号***,联系方式:***)在该店供职,任初级药师、质量管理员、负责药品验收、协助企业负责人做好各项药品质量管理工作。执法人员查看该店阳光药师考勤记录,发现该药师于2024年9月12日17时和22时左右通过手机宁波阳光药师APP考勤打卡,经查该店监控记录,发现该人员于上述时间段内未在店内出勤,查看该店内2024年8月-9月双轨制处方药销售记录、药品进货查验签字记录、温湿度登记记录,均未发现王**有签字记录,该人员未在岗位上履行相关职责。当事人上述行为违反了《中华人民共和国药品管理法》第五十二条第一项、第三项和第五十八条第三款之规定,本局于2024年9月19日予以立案调查。执法人员对药店负责人高**、质量管理员王**进行询问调查,当事人向本局提交相关证明材料,执法人员围绕当事人违法聘用药学技术人员的违法行为收集相关证据材料,确定其违法事实。2024年10月15日案件调查终结。经查,当事人象山**大药房于2023年5月29日成立,主要从事药品零售活动。药房经营者高**与药师王**签订聘用合同,聘用王**为驻店药师,约定支付报酬为2000元/月,聘用时间自2023年6月1日至2024年6月30日。当事人实际经营期间,王**仅在开业初期在药房供职,按200元/天计算薪酬,后续在药房挂靠药师证,实际工资薪酬为900元/月。药房实际仅高**一名执业药师(注册证编号***)完成处方药的售过程中的审方、调配、发药等环节并在“处方药登记销售记录”上签字,2024年9月13日被本局依法查获。另查明:药师王**于2021年10月起入职宁波必正医药科技有限公司,之后一直在该公司任职,2019年10月13日取得药学专业初级资格证书,经朋友介绍与高**取得联系,自签订劳动合同后,在药房开业初期,药师王**安排在店内上岗,后未安排在店内上岗,而在当事人处以挂靠药师证取得相应报酬,并通过手机软件修改定位进行阳光药师异地考勤。行政处罚种类、依据、内容:《中华人民共和国药品管理法》第五十二条第一项、第三项规定“从事药品经营活动应当具备以下条例:(一)有依法经过资格认定的药师或者其他药学技术人员。……(三)有与所经营药品相适应的质量管理机构或者人员”和《药品经营质量管理规范》第二十二条第一项、第二十三条规定“企业应当配备符合以下资格要求的质量管理、验收及养护等岗位人员:(一)从事质量管理工作的,应当具有药学中专或者医学、生物、化学等相关专业大学专科以上学历或者具有药学初级以上专业技术职称”“从事质量管理、验收工作的人员应当在职在岗,不得兼职其他业务工作,”当事人为节省成本,采取挂靠初级药师的形式,药师实际并没有真正履行质量管理员的义务,当事人的上述行为违反了该规定,构成违法聘用药学技术人员的违法行为。依据《中华人民共和国药品管理法》第一百四十条规定“药品上市许可持有人、药品生产企业、药品经营企业或者医疗机构违反本法规定聘用人员的,由药品监督管理部门或者卫生健康主管部门责令解聘,处五万元以上二十万元以下的罚款,”应当责令当事人改正,并处五万元以上二十万元以下的罚款。鉴于当事人有一定的主观故意性,直至被本局执法人员查获,违法行为仍在持续,时间较长,符合《药品监督管理行政处罚裁量适用规则》第九条第八项规定的从重处罚情节;鉴于当事人积极配合市场监督管理部门调查,如实陈述违法事实并主动提供证据材料,且是初次查获,在药店开业初期,药师王**在当事人处供职,负责人高**作为执业药师一直正常在工作,负责药房的质量管理、合理用药指导等,完成处方药的销售过程中的审方、调配、发药等环节,符合《***行政处罚裁量适用规则》第十一条第二项、第四项规定的从轻处罚情节。根据《中华人民共和国行政处罚法》第五条第一款、《***处罚裁量适用规则》第十七条之规定,综合考虑违法行为的事实、性质、情节、社会危害程度、主观过错及公平公正要求等方面,决定予以当事人一般处罚。综上,当事人上述行为违反了《中华人民共和国药品管理法》第五十二条第一项、第三项和《***质量管理规范》第二十二条第一项、第二十三条之规定,依据《中华人民共和国药品管理法》第一百四十条和《中华人民共和国行政处罚法》第二十八条第一款之规定,决定责令当事人立即改正上述违法行为,并处罚如下:责令解聘挂证药师王**,并处罚款100000元。行政处罚履行方式和期限:当事人自收到行政处罚决定书之日起十五日内,按照行政处罚决定书载明的履行方式履行。处罚机关象山县市场监督管理局处罚机关统一社会信用代码113302253090755452数据来源单位省市场监管局数据来源单位统一社会信用代码11330000MB19062420相关推荐CIO提供以下相关文库下载、合规服务以及线上培训课程学习。

序号行政处罚决定书文号违法企业名称或自然人姓名法定代表人姓名违法企业组织机构代码违法行为类型主要违法事实行政处罚的内容行政处罚的依据履行方式和期限作出处罚决定的行政机关和日期1鄂药监武药处罚〔2024〕12号武汉贝参药业股份有限公司董枭914201007282747418未遵守药品生产质量管理规范当事人未遵守药品生产质量管理规范。罚款。当事人违反《药品管理法》第四十三条和第四十五条第一款规定，依据《药品管理法》第一百二十六条规定当事人已于2024年9月5日主动履行完毕。湖北省药品监督管理局2024年09月03日相关推荐CIO提供以下相关文库下载、合规服务以及线上培训课程学习。

行政相对人名称江苏百草药业科技有限公司行政相对人类别法人及非法人组织统一社会信用代码913212027796675107工商注册号组织机构代码税务登记号事业单位证书号社会组织登记证号法定代表人秦林法定代表人证件类型身份证法定代表人证件号码3****************8证件类型证件号码行政处罚决定书文号苏药监泰检处字〔2024〕13号违法行为类型生产销售劣药违法事实当事人生产的炙甘草（批号：24032601）在2024年镇江市市场监督管理局组织的监督抽检中，〔含量测定〕项下甘草苷不符合规定。处罚依据《药品管理法》第一百一十七条第一款、《行政处罚法》第三十二条第一项、参照国家局《药品监督管理行政处罚裁量适用规则》第十条第二项、第十一条第二项、第四项等规定处罚类别罚款;没收违法所得、没收非法财物处罚内容没收违法所得16431元、没收涉案炙甘草（批号：24032601）12kg，罚款30000元。罚款金额（万元）3没收违法所得没收非法财物的金额（万元）1.6431暂扣或吊销证照名称及编号处罚决定日期2025/01/15处罚有效期2025/06/12公示截止期2026/01/15处罚机关江苏省药品监督管理局处罚机关统一社会信用代码11320000014000394R数据来源单位江苏省药品监督管理局数据来源单位统一社会信用代码11320000014000394R备注相关推荐CIO提供以下相关文库下载、合规服务以及线上培训课程学习。

主体名称舟山市万民大药房有限公司金塘沥港分店处罚决定书文号舟金市监处罚﹝2025﹞3号处罚类别警告;罚款处罚决定时间2025-01-15处罚内容责令限期改正;逾期不改正的,处五千元以上五万元以下罚款;造成危害后果的,处五万元以上二十万元以下罚款。;责令限期改正,给予警告;逾期不改正的,处罚款;情节严重的,处罚款,责令停产停业整顿直至吊销药品批准证明文件、许可证,对相关其他责任人员,没收违法行为发生期间自本单位所获收入,并处罚款,十年直至终身禁止从事药品生产经营等活动。;罚款金额（万元）0.500000没收违法所得0.000000暂扣或吊销证照名称及编号-违法行为类型舟山市万民大药房有限公司金塘沥港分店未遵守GSP案处罚依据《药品经营和使用质量监督管理办法》第七十二条第一款“药品零售企业有以下情形之一的,由药品监督管理部门责令限期改正;逾期不改正的,处五千元以上五万元以下罚款;造成危害后果的,处五万元以上二十万元以下罚款:(一)未按规定凭处方销售处方药的;”;《中华人民共和国药品管理法》第一百二十六条　除本法另有规定的情形外,药品上市许可持有人、药品生产企业、药品经营企业、药物非临床安全性评价研究机构、药物临床试验机构等未遵守药品生产质量管理规范、药品经营质量管理规范、药物非临床研究质量管理规范、药物临床试验质量管理规范等的,责令限期改正,给予警告;逾期不改正的,处十万元以上五十万元以下的罚款;情节严重的,处五十万元以上二百万元以下的罚款,责令停产停业整顿直至吊销药品批准证明文件、药品生产许可证、药品经营许可证等,药物非临床安全性评价研究机构、药物临床试验机构等五年内不得开展药物非临床安全性评价研究、药物临床试验,对法定代表人、主要负责人、直接负责的主管人员和其他责任人员,没收违法行为发生期间自本单位所获收入,并处所获收入百分之十以上百分之五十以下的罚款,十年直至终身禁止从事药品生产经...违法事实主要违法事实:2024年10月22日,被处罚人舟山市万民大药房有限公司金塘沥港分店执业药师不在岗,未能对当日处方药销售予以审核。行政处罚种类、依据、内容:当事人未经依法经过资格认定的药师或者其他药学技术人员审核销售处方药的行为违反了《药品经营和使用质量监督管理办法》第四十二条第五款之规定,依据《药品经营和使用质量监督管理办法》第七十二条之规定,本局决定对当事人作如下处理:罚款人民币5000元整。行政处罚履行方式和期限:当事人自收到行政处罚决定书之日起十五日内,按照行政处罚决定书载明的履行方式履行。处罚机关舟山市市场监督管理局金塘分局处罚机关统一社会信用代码113309000909950478数据来源单位省市场监管局数据来源单位统一社会信用代码11330000MB19062420相关推荐CIO提供以下相关文库下载、合规服务以及线上培训课程学习。

Delivery Method:VIA Electronic MailProduct:Medical DevicesRecipient:Steven Peter FitzGeraldFounder and Managing DirectorRandox Laboratories Limited30 Randalstown RoadAntrimBT41 4FLUnited Kingdompeter.fitzgerald@randox.comIssuing Office:Center for Devices and Radiological HealthUnited StatesWARNING LETTERDecember 6, 2024Dear Mr. Steven Peter FitzGerald:During an inspection of your firm located in Antrim, United Kingdom on August 5, 2024 through August 8, 2024, an investigator from the United States Food and Drug Administration (FDA) determined that your firm manufactures the RX series test systems, including the RX daytona, the RX daytona + (plus), and the RX imola test systems. 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 function of the body.This inspection revealed that these 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, their 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.We received responses from Linda A Magee, Chief Operating Officer dated August 29. 2024, and Oisin Quinn, Quality Improvement Manager dated November 8, 2024 concerning our investigator’s observations noted on the Form FDA 483 (FDA 483), List of Inspectional Observations, which was issued to your firm. We address these responses below, in relation to each of the noted violations. These violations include, but are not limited to, the following:1. Failure to adequately establish and maintain procedures for validating device design, including appropriate risk analysis, as required by 21 CFR 820.30(g). For example, your firm has initiated five Class II Recalls, beginning in 2018 (Event IDs 81746, 86236, 91097, 92650, 93775), related to assay reagents from the previously used assays carrying over to the subsequent assay test, which caused erroneous results of the subsequent assay conducted on your RX series analyzers, including RX daytona and RX imola. Your firm’s procedure, Risk Management, RQA-1707, Revision O, drafted on June 6, 2023, section 5.1.3.4 Post Market surveillance, states “The Risk Management Report must be updated with any new hazards or hazardous situations identified and or any additional control measures that are required”. Additionally, section 5.2.4 Risk Control requires that control measures should be implemented using “(b)(4),” in that order of priority. However, your firm has not conducted adequate risk analysis nor identified adequate control measures to address the risks of reagents from the precedent assays carrying over to the subsequent assay conducted on the RX series analyzers to ensure the devices (i.e., manufactured assays tested on RX series analyzers) meet their intended use.We reviewed your firm’s responses and conclude that they are not adequate. Your firm has identified that the root cause is related to ambiguity in your risk analysis procedures, lack of clear responsibility for the activities, and that maintenance of the risk management files and not been effective. Your firm states that you have reviewed and updated the risk management files for the recalled products, however, copies of those files were not provided for review because they are currently under review by specified teams at your firm. An estimated date of completion was not provided.Your firm also provided Risk Management Report for RX Series Analyzers – Automated RX modena, RX daytona+, RX daytona, RX imola, RX monaco, dated September 30, 2024 and Risk Analysis for RX Series Analyzers – Automated, revision number 4, approved on September 30, 2024. A carryover and contamination category was added to analyzer risk analysis. The risk evaluation before(b)(4).” However, no information was provided to support(b)(4)as required by RQA-1707.Your firm provided a revised job description for the Device Documentation Specialist (JD1402), who is within the(b)(4)of RQA-1707, revision Q, drafted September 20, 2024. The procedure has been revised to require the Quality Assurance department to review(b)(4). Post Market Surveillance, RQA-1664, revision M, drafted September 20, 2024 was revised to, among other things, define that the Quality Assurance Department is responsible(b)(4). Control of Non-Conforming Product or Process, RGP-2032, revision U, drafted November 7, 2024 was revised to include responsibility for Quality Assurance Department for(b)(4). However, RQA-1707, RQA-1664, and RGP-2032 do not reference the Device Documentation Specialist. Therefore, it is unclear how the revised job description will prevent similar failures in the future. Your firm stated retraining on RQA-1707, RQA-1664, and RGP-2032 was completed and provided examples for how a completion of training event was documented. However, information on the verification or validation of the retraining (a corrective action) to ensure that the action is effective was not provided. Your firm plans to(b)(4). However, evidence that appropriate control measures will be applied has not been provided. Your firm should provide an update on this review and any remediation efforts needed. You firm also stated that RGP-1002 has been updated but FDA was unable to open this file to review and therefore the Agency unable is unable to determine whether this action is effective.2. Failure to establish and maintain adequate procedures for implementing corrective and preventive action, as required by 21 CFR 820.100(a). For example, CAPA NCP INC612, was initiated on October 16, 2023, due to a customer complaint related to issues when running Copper assay on a RX daytona + analyzer. Your firm confirmed the testing of total protein carried over to the subsequent copper assay, causing falsely elevated Copper results. The root cause description states, “Carryover from both cuvettes and pipettes,” but fails to identify the underlying cause of why the reagent from the previously used assay carried over to the subsequent assay. The CAPA was closed on May 20, 2024, with the correction, “Technical bulletin RXTB-0121 to be updated with as a result of the testing recommending that Copper and Total protein on the same machine.” Since December 2018, your firm has initiated five US market Class II Recalls (Event IDs 81746, 86236, 91097, 92650, 93775) due to erroneous results caused by reagent carryover and, in each your firm has issued an updated Technical Bulletin for carryover avoidance (RXTB-0083, issued February 16, 2018 and RXTB-0098, issued November 20, 2018; RXTB-0121, issued July 31, 2020; RXTB-0136, issued September 22, 2022; RXTB-0148, issued June 6, 2023; RXTB-0148, issued November 22, 2023). The bulletin currently includes a list of over 50 combinations of assays to avoid running in sequence. CAPA #NCP INC612 fails to identify the action(s) needed to correct and prevent recurrence of carryover of assays run on the RX series analyzers. Additionally, activities to ensure the effectiveness of the corrective actions were not identified. Your firm states “Confirm no further complaints since bulletin” but fails to verify or validate the corrective and preventive action to ensure that such action is effective.We reviewed your firm’s responses and conclude that they are not adequate. Your firm has identified the root cause is related to inadequate procedure and absence of dedicated training resources on root cause analysis for the staff to perform root cause analysis adequately and effectively. Your firm determined the actual root cause for the carryover event from CAPA #NCP INC612 is because of inadequate cleaning of the pipette/cuvette after programmed cleaning on the automated analyzer so the remaining residue of the reagents from Total Protein assay, which contains copper, impacted the subsequent Copper assay. Your firm has not identified corrective and prevention actions for CAPA #NCP INC612 and has not provided information on how you will verify or validate the corrective and preventive action is effective.Your firm has updated the CAPA procedure “Control of Non-Conforming Product or Process, RGP-2032, revision U, drafted November 7, 2024” to include reference to root cause analysis training material and created training slides “QAT 2.17.pptx” for performing root-cause analysis. Your firm stated training on RGP-2032 and QAT 2.17 was completed and provided an example for how the completion of training event documented. However, information on the verification or validation of the retraining (a corrective action) to ensure that the action is effective was not provided.Your firm proposed(b)(4). Your firm should provide an update on this review and any remediation efforts needed.Your firm initiated a CAPA (qNCP 1394) dated August 29, 2024 to determine(b)(4). Your firm has yet identified the root cause for causing the inadequate cleaning which your firm stated in an email dated November 8, 2024, is the common root cause of all the initiated recalls related to carryover on the RX series instruments. Your firm has yet to define actions to prevent recurrence.Your firm plans to review CAPAs and root cause(b)(4). Your firm should provide an update on this review and any remediation efforts needed.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.Additionally, based on information provided to the investigator during and following the inspection, it appears that your establishment registrations and device listings are incorrect and should be further clarified. During teleconferences following the inspection with the investigator on September 5 and 11, 2024, you promised to evaluate(b)(4). However, as of the date of this letter your registration and listing data remains unchanged.Please notify this office in writing within fifteen business days from the date you receive this letter of the specific steps your firm has taken to address the noted violations, including an explanation of how your firm plans to prevent these violations, or similar violations, from occurring again. Include documentation of the corrections and/or corrective action (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. Please provide a translation of documentation not in English to facilitate our review. We will notify you regarding the adequacy of your firm’s response(s) and the need to re-inspect your firm’s facility to verify that the appropriate corrections and/or corrective actions have been made. If you believe that your products are not in violation of the FD&C Act, include your reasoning and any supporting information for our consideration as part of your response.Your firm’s response should be sent via email to CDRHWarningLetterResponses@fda.hhs.gov.Refer to CMS case #696569 when replying. If you have any questions about the contents of this letter, please contact: I-Lin Wu at i-lin.wu@fda.hhs.gov.Finally, you should know that this letter is not intended to be an all-inclusive list of the violations at your firm’s facility. It is your firm’s responsibility to ensure compliance with applicable laws and regulations administered by FDA. The specific violations 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 any violations and take prompt actions to address any violations and bring the products into compliance.Sincerely yours,/S/Courtney H. Lias, Ph.D.DirectorOHT7: Office of In Vitro Diagnostic DevicesOffice of Product Evaluation and QualityCenter for Devices and Radiological HealthCC:Cheryl OHaganUS Agent

Delivery Method:VIA Electronic MailProduct:Medical DevicesRecipient:Stephen MacMillanCEO/PresidentHologic, Inc.250 Campus DriveMarlborough,MA01752-3020United StatesSteve.MacMillan@hologic.comIssuing Office:Center for Devices and Radiological HealthUnited StatesWARNING LETTERCMS # 698214December 18, 2024Dear Mr. MacMillan:During an inspection of your firm located in Marlborough, MA on July 30, 2024, through September 24, 2024, an investigator from the United States Food and Drug Administration (FDA) determined that your firm manufactures class II implantable radiographic markers, such as your BioZorb product line. 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.This inspection revealed that these 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, their 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.We received a response from Adam Gorzeman, Senior Director BSH Quality, dated October 15, 2024, concerning our investigator’s observations noted on the Form FDA 483 (FDA 483), List of Inspectional Observations, that was issued to your firm. We are aware that Hologic has made the decision to discontinue the manufacture of the BioZorb product line. We address your response below, in relation to each of the noted violations. These violations include, but are not limited to, the following:1. Failure to establish and maintain procedures to control the design of the device in order to ensure that specified design requirements are met, as required by 21 CFR 820.30(a). You did not implement your Design Control Procedures, including Design Control SOP0018 dated 01/31/2017, Product Development Procedure ENG0100 dated 03/19/2024 and User Needs and Intended Use Statement Procedure ENG-0100-02 dated 04/21/2022. Specifically:a. You failed to establish design inputs to ensure that the design requirements relating to a device are appropriate and address the intended use of the device, including the needs of the user and patient, as required by 21 CFR 820.30(c). The design history file for the BioZorb medical device product family:• Did not identify the intended patient population, nor did it address intended anatomy types, nor the surgical requirements such as the appropriate placement and fixation of the device, nor the appropriate depth of the implant into the soft tissue.• Did not include a requirement related to how in-vivo radiation treatments can impact the performance of the device and the ability of the device to resorb into the patient’s body.• Did not define the length of time for when the spacer material would be completely resorbed.b. You failed to verify your device design to confirm that the design output meets the design input requirements, as required by 21CFR 820.30(f).• Your firm does not have any verification testing to demonstrate that the bioabsorbable spacer material (poly lactic acid) is absorbed by the body. Your Design Description Document DDD-0001 dated August 22, 2017, includes a user requirement that the BioZorb medical device spacer material is resorbable into soft body tissue. Your verification testing report, VER-10394 dated June 27, 2022, only documents the inherent viscosity profile of the spacer during in-vitro degradation and does not provide sufficient data to support the claim that that spacer material is absorbed by the body. Your firm received complaints and filed Medical Device Reports regarding devices requiring explant and a lack of resorption, including Hologic Complaint Report CPT-01345922 which stated that the device failed to dissolve for almost five (5) years.c. You failed to validate your device design to ensure that devices conform to defined user/patient needs and intended uses, as required by 21 CFR 820.30(g).• Your Design Validation studies performed under Marker Simulated Use Test Report TR-004 Rev P dated 08/17-20/2018 and Marker Simulated Use Test Report TR-004 Rev L dated 02/09/2016 did not take the following critical user needs into account: variation in soft tissue types, anatomies of the patient population, the appropriate placement and fixation of the device into the patient, nor the appropriate depth of the implant into the soft tissue.d. You failed to ensure that the device design is correctly translated into production specifications, as required by 21 CFR 820.30(h).• The production of the devices was transferred to Costa Rica in November of 2022 after the quality system was updated to include BioZorb medical devices. Your Design History File does not include documentation that the device design was appropriately translated into production specifications and does not include identification of the product undergoing transfer and design review as required by Design Control SOP0018 dated 03/01/2011 and current Product Development Procedure ENG0100 dated 03/19/2024.We reviewed your firm’s response and concluded that it is not adequate. We are aware that The BioZorb Product Line was put on Stop Ship Notice on September 29, 2024, and Hologic will not continue to manufacture the BioZorb product. We also understand that you will not be performing any specific design studies to address the above deficiencies. FDA continues to have safety concerns for patients in whom this device has been implanted. You have not appropriately evaluated your device design to ensure the following risks are mitigated for patients that already have the Biozorb device implanted, such as and not limited to: the potential of device interference with detection of cancer recurrence or new cancers; whether in-vivo radiation treatments can impact the performance of the device; and the ability of the device to resorb into the patient’s body. Your firm should address the contribution of the device design to adverse events and identify those patients who may be at risk for adverse events and therefore potentially benefit from intervention by device explantation.Additionally, you will be reviewing and revising design control procedures that focus on your remaining BSH products. However, your response does not yet include the documentation that includes your retrospective review of your BSH products and any remediation efforts that may be warranted after this review is completed.2. Failure to establish and maintain procedures for implementing corrective and preventive actions, including requirements for analyzing processes, work operations, concessions, quality audit reports, quality records, service records, complaints, returned product, and other sources of quality data to identify existing and potential causes of nonconforming product, or other quality problems using appropriate statistical methodology, as required by 21 CFR 820.100(a)(1). Specifically, your Corporate Corrective Action Preventive Action (CAPA) Procedure CORP-00007, Rev. 007 is not adequate. For example:• Your review of quality data was not sufficient to detect recurring problems. For example, in September of 2023, your firm received a spike of adverse event complaints regarding breast discomfort/pain, erythema, itching sensation, burning sensation, infection, scar tissue, sleep dysfunction, seroma, necrosis, additional surgery/device explantation, medication/scanning required, deformity/ disfigurement, migration, device palpability, and tissue damage/skin erosion. Your CAPA procedure only defines opening a CAPA if the severity of risk is considered high which the procedure defines as a severity level of 4 (critical) or 5 (catastrophic). Your firm’s management stated there is no justification for this rationale and a CAPA was not opened until May of 2024, to investigate the root cause of the adverse events that may not have risen to a severity level of 4 or 5.• You did not calculate the occurrence rate accurately when evaluating a spike of BioZorb medical device complaints and Medical Device Reports. Your Health Risk Assessment RSK-04622, dated March 8, 2024, does not take the patient population into account as required by Health Risk Assessment (HRA) procedure QUA-2364, dated August 14, 2020. This Assessment utilized units sold from 2016 to 2024 whereas the complaint data utilized in this review was from 2021 to 2024. Your procedure, QUA-3106, Investigation of Post Market Surveillance Spikes and Adverse Trends, step 7.2.3. discusses occurrence estimation and includes, “(b)(4).” Neither the above referenced procedures, or your CAPA procedure, provide sufficient instructions for calculating an accurate occurrence rate when complaint spikes and adverse trends are identified, nor do they clearly define when a CAPA should be opened.We reviewed your firm’s response and concluded that it is not adequate. We understand that you will be reviewing and revising your CAPA procedures moving forward. However, you have not described how you will be able to prevent this lack of oversight of your implementation of CAPA procedures in the future.Our inspection also revealed that your firm’s BioZorb Marker is 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:Failure 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 may have caused or contributed to a death or serious injury, as required by 21 CFR 803.50(a)(1).The information provided in the Complaint Reports CPT-00635201, CPT-00661454, CPT-00624611, CPT-00732163, and CPT-00775690 reasonably suggests that patients developed infections following the implantation of your firm’s BioZorb Marker, needing antibiotic treatment and in some cases, surgical device explantation. We believe these medical or surgical interventions were needed to preclude permanent impairment of a body function or permanent damage to a body structure. Furthermore, there is no information in your firm’s complaint records that definitively rules out that the device may have been a factor in these serious injuries. As such, each of the referenced adverse events represents an MDR reportable serious injury event, as defined in 21 CFR 803.3. Your firm became aware of the events associated with CPT-00635201 on February 4, 2020, CPT-00661454 on April 14, 2020, CPT-00624611 on January 17, 2020, CPT-00732163 on September 16, 2020, and CPT-00775690 on December 7, 2020.However, your firm failed to submit an MDR for each referenced adverse event within the required 30-calendar-day timeframe.The adequacy of your firm’s response dated October 15, 2024, cannot be determined at this time.In the response, your firm states that it has initiated corrective actions to address the underlying root causes and plans to conduct a retrospective review of all BioZorb complaints for reportability. The response also noted your firm(b)(4). However, your firm did not provide documentation or evidence of implementation of its systemic corrective actions as the planned corrective actions are still ongoing.Our inspection also revealed that your firm’s BioZorb Sizer Set accessory 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 806 – Medical Devices; Reports of Corrections and Removals. Significant violations include, but are not limited to, the following:Failure to submit any report required within 10 working days of initiating a correction or removal, as required by 21 CFR 806.10. For example: your firm conducted a correction of your BioZorb Sizer Set accessory device which can lead to probability of a serious adverse health consequence or death occurring as a result of using the device(s) under review is “reasonable”. You sent a customer notification letter to your customers instructing them to 1) immediately steam autoclave F0101 in accordance with the revised IFU sterilization parameters, and 2) when sterilizing the F0101, do not use the 2 layers or one layer of 2-ply wrap to provide a sterile barrier for each sterilization tray. The IFU supplied for these instructions for the sizers within F0101 has not yet been updated to reflect this change. This action meets the definition of a medical device correction or removal initiated to remedy a violation which may present a risk to health, for which you are required to submit a Report of Correction or Removal to FDA. As of 11/26/2024, your firm submitted a Medical Device Report of Correction or Removal to FDA for this action.Your firm’s response(s) to the FDA-483, dated 10/15/2024, is adequate. You submitted a Report of Correction or Removal to FDA as of 11/26/2024. However, your response does not contain evidence of completion of the updated procedures and documents. We recommend updating your procedures to follow the requirements under 21 CFR Part 806 Medical Devices; Reports of Corrections and Removals to ensure compliance; and recommend using the guidance provided by the 21 CFR Part 7 Recall Policy to ensure that all required information is provided or documented. In addition, we further recommend that you conduct health risk assessments following the definition of risk to health in 21 CFR 806.2(j), to support the reporting decisions for future medical device corrections or removals.Your firm should take prompt action to address any violations identified in this letter. Failure to adequately address this matter 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.Other federal agencies may take your compliance with the FD&C Act and its implementing 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. Should FDA determine that your devices or facilities do not meet the requirements of the Act, requests for Certificates to Foreign Governments (CFG) may not be granted.Please notify this office in writing within fifteen business days from the date you receive this letter of the specific steps your firm has taken to address the noted violations, as well as an explanation of how your firm plans to prevent these violations, or similar violations, 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 any violations included in this Warning Letter. If you believe that your products are not in violation of the FD&C Act, include your reasoning and any supporting information for our consideration as part of your response.Your firm’s response should be sent by email to CDRHWarningLetterResponses@fda.hhs.gov to the attention of Gina Brackett, Assistant Director, Establishment Assessment Team 1. Refer to CMS case #698214 when replying. If you have any questions about the contents of this letter, please contact: Karen Archdeacon, Compliance Officer, at (781-587-7491) or karen.archdeacon@fda.hhs.gov.Finally, you should know that this letter is not intended to be an all-inclusive list of the violations at your firm’s facility. It is your firm’s responsibility to ensure compliance with applicable laws and regulations administered by FDA. The specific violations 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 any violations and take prompt actions to address any violations and bring the products into compliance.Sincerely yours,/S/RDML Sean M. Boyd, MPH, USPHSDirectorOffice of Regulatory ProgramsOffice of Product Evaluation and QualityCenter for Devices and Radiological HealthCC: Adam Gorzeman, Senior Director BSH Quality,(b)(4)

Delivery Method:VIA Electronic MailProduct:Medical DevicesRecipient:Mr. Jan De WittePresident and CEOIntegra LifeSciences Corporation1100 Campus RoadPrinceton,NJ08540United States(b)(4)@integralife.comIssuing Office:Center for Devices and Radiological HealthUnited StatesWARNING LETTERCMS # 698850December 19, 2024Dear Mr. DeWitte:The United States Food and Drug Administration (FDA) conducted the following inspections of your firm’s medical device facilities:Integra LifeSciences Corporation, located at 11 Cabot Blvd, Mansfield, MA, FEI 3014334038, from March 12, 2024 through June 5, 2024Integra LifeSciences Corporation, located at 105 And 109 Morgan Ln, Plainsboro, NJ, FEI 1121308, from April 9, 2024 through August 22, 2024Integra LifeSciences Corporation, located at 1100 Campus Rd, Princeton, NJ, FEI 3003418325, from March 12, 2034 through August 22, 2024During these inspections, FDA investigators and a microbiologist determined that the above firms manufacture a variety of neurological and neurosurgical devices, including but not limited to, cranial perforators, disposable cottonoid patties and strips as well as collagen based medical devices, that are used for wound care, soft tissue repair and reconstruction surgery. 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.The above inspections revealed that the above 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, their 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.We received responses from Jeffrey Caldwell, Vice President, Quality Operations dated June 27, 2024, August 27, 2024, and October 25, 2024 concerning our investigator’s and microbiologist’s observations noted on the Form FDA 483 (FDA 483), List of Inspectional Observations, that was issued to your firm’s Mansfield, MA location on June 5, 2024.We received responses from Brenda Romero, Director, Quality Operations, CMC dated September 27, 2024 and December 5, 2024 concerning our investigator’s observations noted on the Form FDA 483 (FDA 483), List of Inspectional Observations, that was issued to your firm’s Plainsboro, NJ location on August 22, 2024.We received responses from Jessica Smith, Corporate Vice President, Chief Regulatory Officer, and interim Chief Quality Officer dated September 13, 2024 and from Lacey Gigante, Sr. Director, CAPA & Compliance November 15, 2024 concerning our investigator’s observations noted on the Form FDA 483 (FDA 483), List of Inspectional Observations, that was issued to your firm’s Princeton, NJ location on August 22, 2024.We address these responses below, in relation to each of the noted violations. These violations include, but are not limited to, the following:1. Failure to establish and maintain procedures to control product that does not conform to specified requirements. The procedures shall address the identification, documentation, evaluation, segregation, and disposition of nonconforming product. The evaluation of nonconformance shall include a determination of the need for an investigation and notification of the persons or organizations responsible for the nonconformance. The evaluation and any investigation shall be documented, as required by 21 CFR § 820.90(a).Specifically, during an inspection of your Mansfield, MA location, a review of 4 non-conforming reports from October 2022 through June 2023 (NC-101352, NC-101446, NC-101628, and NC-101642) were opened due to Out of Specification (OOS) endotoxin results on three separate lots of surgical patties and one lot of Duraform. In the above instances, after the laboratory investigation concluded there was no assignable laboratory error or root cause, your firm retested the lots, even though your Pyrogen Testing procedure, MPS-PC340, did not specify that a retest was allowed. Your firm then released the above referenced lots without conducting a complete investigation of the manufacturing processes, as required by your Non-Conformance procedure, GSOP-773 and MPS-PC340.We reviewed your firm’s responses and the adequacy cannot be determined. We acknowledge that your firm initiated a recall of Duraform, lot CT007694 on September 6, 2024 as well as a recall of multiple lots of surgical patties and strips manufactured between 2022 and 2023 on September 20, 2024. However, your firm continues to implement a number of corrective actions at your Mansfield, MA facility that will not be completed until May 2025.2. Failure to establish and maintain procedures for acceptance activities. Acceptance activities include inspections, tests, or other verification activities; as required by 21 CFR § 820.80(a).Specifically, your Plainsboro, NJ location utilizes procedure CMC-MB-049 “Determination of Endotoxin in(b)(4)Product Using the(b)(4)Methods” to determine the bacterial endotoxin concentration in products manufactured at the Integra LifeSciences Collagen Manufacturing Center (CMC), Buildings(b)(4)and(b)(4), including(b)(4). According to section 9.6.3.3 of this procedure, “the Coefficient of Variation (CV%) for each pair of standard series samples must be less than(b)(4)” for the overall test to be considered valid. However, during our inspection we observed that ten of fifty-two tests conducted in 2023 failed due to the CV% exceeding the(b)(4)limit. These ten tests were observed to be repeatedly retested until the CV% fell below(b)(4). For example, endotoxin test (LAL-24-2012) and its two subsequent retests (LAL-24-0012 Retest, LAL-24-0012 Retest 2) all failed to meet CV% criteria. It was then retested on a different day under a new ID (LAL-24-0013) and finally passed on the fourth attempt (LAL-24-0013 Retest 3). Your firm’s microbiology manager attributed the CV% failures to low endotoxin concentration in the controls. Additionally, your CMC-MB-049 procedure does not specify the circumstances under which a retest could be performed or which result should be utilized if a retest was conducted.We reviewed your firm’s responses and the adequacy cannot be determined. We acknowledge that your firm initiated three CAPAs (CAPA-00133, CAPA-00134, and CAPA-00135) to address the observations. As part of these CAPAs, we acknowledge that your firm has performed a statistical assessment of historical reagent qualification data for CV% in which you determined that the appropriate CV% for the(b)(4)EU/mL standard concentration would be(b)(4)% and made updates to affected procedures, including CMC-MB-049. However, verification of the effectiveness of the corrective actions are still ongoing with a target date of June 2025. Please provide the results of your firm’s planned 6-month effectiveness check when it becomes available.3. Failure to establish and maintain procedures for finished device acceptance to ensure that each production run, lot, or batch of finished devices meets acceptance criteria, as required by 21 CFR § 820.80(d).Specifically, your Mansfield, MA location utilizes MPS-PC340, Preparing Products for Pyrogen Testing (Rev: 068, Effective Date: 30Mar2023) to describe the procedures and materials needed to prepare test samples for pyrogenicity and how to investigate results that exceed acceptable criteria. However, review of this procedure determined it lacks the following requirements to ensure devices meet established endotoxins specifications for device sterility prior to release. For example, Adequate instructions for OOS laboratory investigations where the original endotoxins results are determined to be valid because no laboratory error or assignable cause was found. Documentation of how many times the device lot or device extract may be re- analyzed or retested during the investigation after an OOS result is reported. Lack of details regarding sample selection to ensure samples are representative of the entire lot to account for endotoxins not evenly distributed within the lot. No requirement to include documentation of endotoxin test result units (EU/ml or EU/device) on thePost-Sterile Releasesection of your Device History Records.For example, verification of Pyrogen Lab Results receipt for Lot # 7260687 of Product Code(b)(4)lists the Lab Result as “(b)(4).” The Endotoxin Action Limit for this product code is(b)(4)EU/Device. Your Bacterial Endotoxin Test Final Report (Study Number 1621708-S01), dated June 15, 2023 concluded that the pooled test articles for Lot # 7260687 “exceeded the endotoxin limit of not more than(b)(4)EU/device.”We reviewed your firm’s responses and the adequacy cannot be determined. We acknowledge that your firm initiated NC-001411 on June 7, 2024 and CAPA-100183 on June 11, 2024 to address updates needed to the procedural requirements, updates to DHRs so that BET result units are accurately recorded among other actions. However, your firm continues to implement a number of corrective actions that will not be completed until March 2025.4. Failure to establish and maintain procedures for corrective and preventive action, as required by 21 § CFR 820.100(a). For example,During the inspection of the Princeton, NJ corporate headquarters, your Corrective and Preventive Action (CAPA) Process (GSOP-758; Rev 007), specifically, Section 7.1, describes the process of CAPA Escalation. Section 7.1.2.3 of GSOP-758 describes when a decision is made to not initiate a CAPA, including documentation of the justification for not initiating a CAPA on Form GSOP-758A (CAPA Escalation Decision Form). A review of quality data sources over individual Integra sites, including corrective and preventive actions (CAPAs) and quality plans (QPs) taken at numerous Integra firm locations revealed that site specific CAPAs are not evaluated for escalation to corporate wide CAPAs.For example, CAPA 23-008 opened on April 7, 2023 at the(b)(4)manufacturing location in(b)(4)was related to endotoxin testing at that location. Endotoxin testing is performed at other locations, including collagen manufacturing in Plainsboro, NJ and neurological manufacturing in Mansfield, MA. The decision and justification to not escalate endotoxin testing to a corporate wide CAPA was not documented.Additionally, per Section 5.2.1 of the Quality Objectives & Quality Planning document (GSOP-763; Rev. 003) “quality planning is not used to investigate or correct actual or potential problems or concerns arising from the QMS or its data sources.” However, during our inspections, you provided several quality plans that were being utilized for investigating or correcting actual and potential problems with the quality systems. The GSOP-763 procedure used for quality planning does not include pertinent sections required for corrective and preventive actions such as: investigating the cause of nonconformities, identifying the actions needed to correct and prevent recurrence, and verifying or validating the action to ensure it is effective. These sections are found within the CAPA procedure GSOP-758. At the time of our inspections, CAPAs had not been opened to address these issues. Examples of quality plans currently being used to correct problems with the quality system are:• At your Princeton, NJ location o QP-2023-12, Quality Plan for Assessing Endotoxin Program Compliance, initiated on March 25, 2024 to assess endotoxin issues across Integra organizations. This quality plan lists a target completion date for site-specific gap assessments as 12/31/2026 and the target due date for developing an action plan to close and/or mitigate any identified compliance gaps as 6/30/2027.• At your Plainsboro, NJ location o QP-2023-02, Quality Plan for the Closure of Overdue SCARs at the Collagen Manufacturing Center, initiated on December 7, 2023 to document the closure of overdue SCARs at the Collagen Manufacturing Center (CMC). Eleven SCARs were identified as overdue in section 2.2 of this document.• At your Mansfield, MA location o QP-20-001, Quality Plan for CerebroFlo EVD Catheter design history file remediation initiated on April 9, 2020, to address 30 observations found during a third-party review of the CerebroFlo EVD catheter design project.We reviewed your firm’s responses and the adequacy cannot be determined. We acknowledge that your firm initiated several CAPAs at multiple sites, including a corporate-wide CAPA-00143 on September 6, 2024 to address the extension of CAPAs and Quality Plans across multiple Integra locations including planned implementation of a CAPA escalation decision tree and form by December 15, 2024; planned review of all CAPAs initiated at Integra corporate and all manufacturing sites since November 2, 2022; and planned updates to GSOP-758 to require an evaluation of each CAPA to determine whether it may be applicable to multiple manufacturing sites. However, your firm continues to implement corrective actions that will not be completed until November 2025 when verification of effectiveness is targeted to be completed.5. Failure to review and evaluate process changes and deviations and perform revalidation when changes or process deviations occur, as required by 21 CFR § 820.75(c).For example, at your Mansfield, MA location, your firm failed to assess the impact of annual sterilization requalification parameter failures for Ethylene Oxide (EO) cycle #(b)(4)used to demonstrate a continued sterility assurance level of(b)(4)EO sterilization is performed by(b)(4). EO cycle #(b)(4)is used sterilization of several devices manufactured at Mansfield, MA including neurological surgical patties. For example,• On December 2, 2020, a deviation occurred with eight temperature sensors recording temperatures below the minimum(b)(4)degrees Fahrenheit for the product temperature during the EO exposure dwell phase, failing to meet the predetermined validation acceptance criteria of(b)(4). o Your firm failed to investigate the cause of the temperature failure and the potential effect on the EO cycle for routine sterilization.• The 2022 requalification of the EO cycle(b)(4)for Vessel #1 and Vessel # 2, ((b)(4)-0007898) approved by your firm on November 23, 2022, exceeded your firm’s predetermined acceptance criteria for product load relative humidity (RH) of(b)(4)when RH readings ranged from(b)(4)during the preconditioning product phase, exceeding the allowable upper RH limit of(b)(4). o Your firm reported this RH protocol deviation as part of the 2022 requalification. However, your firm concluded: “…the re-qualification using dunnage devices has no effect on finished goods and no immediate actions are needed. There is no impact to sterility assurance of EO devices due to this event.” This conclusion was reached without an adequate investigation into the failed re-validation and determination of the root causes of the failure.• The 2023 requalification of the EO cycle(b)(4)for Vessel # 1 and Vessel #2 ((b)(4)-0009433) approved by your firm on March 15, 2024, failed to meet your firm’s predetermined acceptance criteria that all internal and external biological indicators (BI) were required to be negative for growth as one external process challenge devices (PCD) resulted in positive growth. Further, the RH specification of(b)(4)was not met as RH readings ranged from(b)(4)during the preconditioning product phase, exceeding the allowable upper RH limit of(b)(4). o As a result of the 2023 requalification failures, Vessel #2 was disqualified for EO cycle(b)(4). However, your firm continues to use Vessel #1 which also failed to meet the same EO requalification predetermined acceptance criteria (RH) that caused your firm to disqualify Vessel #2 and similar conclusions used during the 2022 deviation report were again restated in 2023 to justify continued use of Vessel #1.We reviewed your firm’s responses and the adequacy cannot be determined. We acknowledge that your firm initiated NC-001007 on June 7, 2024 which was later escalated to CAPA-00179 on June 11, 2024 to address, in part, annual parameter failures associated with EO cycle(b)(4)including revisions made to yourAnnual EO Revalidation(b)(4)work instruction (WI-10007) and planned performance of requalification for EO cycle(b)(4)for the current year utilizing the updated WI. However, this requalification has not occurred as it has a target date of December 31, 2024.Additionally, at your Princeton, NJ location, your firm initiated a Supplier Change Request (SCAR #NC-101873) to change the pouch sealing machine to(b)(4), which supplies pouches (product number(b)(4)) to your firm’s Le Locle, Switzerland facility for packaging of sterile medical devices after detection that the pouch was opened on the(b)(4)sealing side. Investigation into the seal strength caused your supplier to perform a revalidation of(b)(4)to challenge the ability to produce product that meets specifications.In the performance qualification protocol performed by your supplier ((b)(4)-24010), a minimum acceptable seal value lower specification limit (LSL) of(b)(4)lb/in was utilized. In your Retrospective Validation Report for Bactiseal Pouch Supplier Sealer Performance (Document ENG-199915-MEMO) the seal strength lower spec. is listed as(b)(4)lbf/in. However, the validation qualification report for Package Performance and Package Stability Study for Bactiseal EVD (applicable to your Le Locle, Switzerland and Mansfield, MA locations) concluded that the(b)(4)minimum specification will meet the(b)(4)lb/in post sterilization requirement specified in the BSN 868-5 standard. This validation qualification report was performed in 2021 prior to the change to your supplier’s(b)(4)and does not account for your supplier’s use of a(b)(4)lb/in LSL.We reviewed your firm’s responses and the adequacy cannot be determined. We acknowledge that your firm initiated CAPA-00146 on September 6, 2024 to address the lack of consistent assessment of validations when changes occur, as well as state a commitment to: update your product and process change decisions tree; create a global procedure for assessment of supplier changes; obsolete your supplier change process at Mansfield and Le Locle; and perform a retrospective review of Integra supplier change procedures. However, your firm continues to implement a number of corrective actions that will not be completed until January 20256. Failure to establish and maintain procedures to prevent contamination of equipment or product by substances that could reasonably be expected to have an adverse effect on product quality, as required by 21 CFR 820.70(e).For example, the Controlled Environment and Cleanroom Operating and Monitoring Procedure (Rev: 065, Effective Date: 20 April 2021) utilized at your Mansfield, MA location was not followed. Multiple (18) viable and non-viable particulate environmental excursion results, occurring from January 2023 to April 2024, for your(b)(4)cleanroom were observed near a(b)(4), equipment identification #(b)(4)) located in room(b)(4). As a result, your firm updated the(b)(4)cleaning procedure to “include routine cleaning of the locations which had visible particulate accumulation on the surface” and determined the risk to product quality as “Low – no product impact” without adequate investigation or a risk-based assessment to evaluate product impact. Several devices, including surgical patties, are manufactured using the identified(b)(4)machine, where the(b)(4)cleanroom failed your firm’s pre-established alert and action limits.We reviewed your firm’s responses and the adequacy cannot be determined. We acknowledge that your firm initiated CAPA-100180 on June 11, 2024 to address updates needed to address this observation. We also acknowledge that your firm has updated your non-routine cleaning frequency for the(b)(4)machine, plans to complete a Health Hazard Evaluation, and develop a contamination control plan. However, your firm continues to implement these corrective actions that have a target date in January 2025.For your Plainsboro, NJ location, during review of Particulate Air Sampling records (CNS-G-630A), it was observed that your firm set the(b)(4)cleanroom action limit at(b)(4)um sized particles per cubic meter. This action limit selected is the maximum allowance specified in the(b)(4)standard. Your firm’s action limit being set at the maximum allowable level does not provide an opportunity to take action before exceeding the specification.We reviewed your firm’s responses and the adequacy cannot be determined. We acknowledge that your firm initiated CAPA-00151 on September 5, 2024 to address updates needed to resolve the observation. We also acknowledge that your firm plans to establish alert/action limits for(b)(4)cleanrooms that allow proactive actions to prevent exceeding particulate specifications along with planned changes to associated procedures. However, these corrective actions have not been implemented as a number of corrective actions have target completion dates in February 2025.7. Failure to validate with a high degree of assurance, a process whose results cannot be fully verified by subsequent inspection and test, as required by 21 CFR § 820.75(a).Specifically, your firm failed to follow your corporate-wide procedure for Process Validation (GSOP-738; Rev 007), in that section 5.2.5 states a protocol may be generated for each qualification, and section 5.2.6.6 states a qualification report is required for each qualification activity.For example, at your Plainsboro, NJ location, your firm’s validation of procedure CMC-AH-10, (determination of bacterial endotoxins in Integra products,(b)(4)and(b)(4)using the(b)(4)), lacks a validation protocol and validation report. The validation for the inhibition and enhancement testing for Limulus Amebocyte Lysate (LAL) was performed in 2004 under a previous process validation procedure (MD-029; obsoleted 5/5/2022). The only record for validation of this LAL test were results from Inhibition/Enhancement Testing –(b)(4)performed on four lots of INTEGRA Dermal Regeneration Template (IRDT)-TS(b)(4). Approximately(b)(4)lots of IDRT have been produced since 12/1/2004.We reviewed your firm’s responses and the adequacy cannot be determined. We acknowledge that your firm initiated CAPA-00136 on September 10, 2024 to address the lack of protocol and report for the validation of inhibition/enhancement Testing of LAL, as well as a commitment to(b)(4)validations for all Collagen Manufacturing Center (CMC) products, revisions to your CMC-AH-10 test method, and revisions to your change control procedures. However, your firm continues to implement a number of corrective actions that will not be completed until January 2025.Your firm should take prompt action to address any violations identified in this letter. Failure to adequately address this matter 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.Other federal agencies may take your compliance with the FD&C Act and its implementing 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. Should FDA determine that your devices or facilities do not meet the requirements of the Act, requests for Certificates to Foreign Governments (CFG) may not be granted.Please notify this office in writing within fifteen business days from the date you receive this letter of the specific steps your firm has taken to address the noted violations, as well as an explanation of how your firm plans to prevent these violations, or similar violations, 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 any violations included in this Warning Letter. If you believe that your products are not in violation of the FD&C Act, include your reasoning and any supporting information for our consideration as part of your response.Your firm’s response should be sent via email to Assistant Director Gina Brackett at CDRHWarningLetterResponses@fda.hhs.gov. Please include in the subject lineCMS Case 698850when replying. If you have any questions about the contents of this letter, please contact: Sean Moynihan, Consumer Safety Officer at sean.moynihan@fda.hhs.gov.Finally, you should know that this letter is not intended to be an all-inclusive list of the violations at your firm’s facility. It is your firm’s responsibility to ensure compliance with applicable laws and regulations administered by FDA. The specific violations 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 any violations and take prompt actions to address any violations and bring the products into compliance.Sincerely,/S/RDML Sean M. Boyd, MPH, USPHSDirector Office of Regulatory ProgramsOffice of Product Evaluation and QualityCenter for Devices and Radiological Health

Delivery Method:VIA Electronic MailProduct:Medical DevicesRecipient:Robert P. BryanChief Executive Officer (CEO)Xoran Technologies, LLC5210 S State RdAnn Arbor,MI48108United StatesIssuing Office:Center for Devices and Radiological HealthUnited StatesWARNING LETTERCMS # 694229December 9, 2024Dear Mr. Bryan:During an inspection of your firm located in Ann Arbor, MI on June 25, 2024 through July 11, 2024, an investigator from the United States Food and Drug Administration (FDA) determined that your firm manufactures computed tomography (CT) systems and supporting software to include (but not limited to) the MiniCAT 2020, MiniCAT IQ, xCAT IQ, and xCAT XL devices and XoranConnect image processing software. 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.This inspection revealed that these 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, their 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.We received responses from Mr. Zeke Church, Director of Quality & Regulatory, dated July 29, 2024, August 30, 2024, and September 30, 2024 concerning our investigator’s observations noted on the Form FDA 483 (FDA 483), List of Inspectional Observations, that was issued to your firm. We address these responses below, in relation to each of the noted violations. These violations include, but are not limited to, the following:1. Failure to establish and maintain procedures to ensure that all purchased or otherwise received product and services conform to specified requirements, as required by 21 CFR 820.50.Specifically, you failed to implement section 9.0 of your “Supplier Approval and Removal” procedure (WI 14.5; Rev. 9; 7/21/15) which requires your suppliers to complete the “Supplier Self-Assessment” Form F 14.5.1 to verify they can meet requirements of the Quality Management System (e.g., process validation under production and process controls, corrective action processes, control of nonconforming product, etc.) and the “Supplier Criteria and Setup Request” Form (F 14.5.9) to ensure your firm’s requirements can be met. For example, you did not ensure that your two (2) suppliers of printed circuit boards (PCBs) – Supplier A approved on or around June 3, 2022 and Supplier B approved on or around April 4, 2016 – conducted process validations for the(b)(4)soldering processes used in your MiniCAT 2020 and MiniCAT IQ devices.The(b)(4)soldering processes cannot be fully verified by subsequent inspection and test in that your functional, electrical continuity testing, and visual inspections cannot detect voids in the solder joints. Of the two suppliers, Supplier B has been manufacturing 10 of your unvalidated PCBs ((b)(4)) used in the devices for the last 8 years. Over the last 2 years, there were at least 4 confirmed complaints of PCB failures which required earlier-than-expected replacement of these boards within 2 years of installation. Recent distribution records covering the last 4 years revealed that 121 MiniCAT 2020 devices and 83 MiniCAT IQ devices were assembled with unvalidated PCBs from at least one or both of these suppliers. Moreover, there are currently 156 MiniCAT 2020 devices and 175 MiniCAT IQ devices installed in the field with unvalidated PCBs from one or both of your suppliers.We reviewed your firm’s responses and conclude that they are not adequate. Although you opened CAPA 294 (not provided) to determine why your supplier files are incomplete; are no longer using Supplier B effective August 28, 2024; plan to obtain the required completed forms; will require component qualification on all PCBs received; and plan to establish a written agreement from Supplier A, your responses do not address reviewing all supplier files for completeness, including whether any additional process validations are required. Furthermore, you did not provide any details on whether you assessed the risk of using PCBs in existing inventory from unvalidated(b)(4)soldering processes as well as in the field.2. Failure to adequately establish and maintain procedures for validating the device design to include an adequate software validation, as required by 21 CFR 820.30(g).Specifically, your firm’s XoranCAT software used to control MiniCAT diagnostic CT x-ray systems has not been adequately validated. For example, your “Testing” procedure (SOP 40; Rev. 5; Effective: 7/31/15) defines four levels of testing, including component testing, integration testing, system testing, and acceptance testing. The XoranCAT software release v5.17.3, dated February 19, 2024, introduced features (e.g., supporting the detector panels) and fixed anomalies (e.g., 64-bit Region of Interest (ROI) tool, which “[did] not work properly”). However, the test cases and results indicate that the software was validated at the software system level, utilizing only functional testing (i.e., black-box) techniques. The validation documentation does not include component testing and integration testing. Since January 2020, your firm has logged approximately 460 complaints which include “Software Issue > XoranCAT” in the complaint categorization code. These complaints allege problems such as freezing/crashing software, image reconstruction issues, and corrupted files.We reviewed your firm’s responses dated July 29, 2024, August 30, 2024, and September 30, 2024, and conclude that they are not adequate. Your firm’s responses state(b)(4). However, your responses do not yet include the documentation for our evaluation. Furthermore, your responses do not include a retrospective review of previously completed software changes to evaluate whether they have been validated adequately, in accordance with the SOP. It is unclear whether regression analysis was conducted to determine the need to re-execute unit, integration, and software-system level testing and if level of code coverage was commensurate with risk. Your response should include procedures for regression analysis and testing as well as procedures to ensure adequate code coverage during software testing, in accordance with the guidance document,General Principles of Software Validation.3. Failure to adequately establish and maintain procedures for receiving, reviewing, and evaluating complaints by a formally designated unit to ensure that all complaints are processed in a uniform and timely manner, as required by 21 CFR 820.198(a).Specifically, you failed to implement section 9.0 of your “Complaint Management” procedure (SOP 6; Rev. 31-33; Effective: 2/21/19; 5/30/23; 12/15/23) to categorize customer calls as complaints instead of inquiries when they meet the definition of complaints as defined by 21 CFR 820.3(b). A cursory review of inquiries logged between January 1, 2022 and June 25, 2024 revealed that at least three (3) customer calls were incorrectly logged as inquiries instead of complaints. For example, you logged the following customer calls as inquiries and not complaints although they allege deficiencies related to the identity, quality, durability, reliability, safety, effectiveness, or performance:Case ID # 00047929 (3/28/24):“Customer called due to gantry not returning to home position. I was able to zero the gantry in CTDT. This is the 2nd time this year this issue has occurred. Customer is due for PM and requests an onsite visit […]”Case ID # 00045482 (2/14/23):“Receiving shutter errors when attempting patient scans. ACQ must be rebooted to remove error and complete scans. Error has occured [sic] multiple times.”Case ID # 00045056 (12/14/22):Customer is unable to select protocol and reccived [sic] ‘unable to initialize panel’ message. Restarted ACQ, performed gain calibration message did not return and able to select protocol and continue with scan”We reviewed your firm’s responses and conclude that they are not adequate. Although you opened CAPA 296 (not provided) to determine why your complaint procedures were inadequate; plan to create a process to ensure inquiries are evaluated prior to closure to ensure complaints are not misidentified as inquiries; and conduct retraining, there were no corrective actions identified to retrospectively review inquiries, for a reasonable time frame, to determine if any meet the definition of complaints, and there were no corrections to process the inquiries in the observation as complaints.4. Failure to establish and maintain procedures for validating the device design to include an adequate risk analysis, as required by 21 CFR 820.30(g).Specifically:(a) You failed to implement section 9.3 of your “Risk Management” procedure (SOP 39; Rev. 3 and 10; Effective: 5/23/11 and 12/15/23) which requires use of a hazard analysis to identify foreseeable hazards in both normal and fault conditions and estimate the risk for each hazard by determining the probability of occurrence of harm and severity of the possible consequences of that harm as a part of your risk analysis. For example, you have not calculated risks under normal use of your MiniCAT devices since your hazard analysis titled “Device Hazards and Harms Matrix” (01-2.5; Rev. 1; 6/9/11) only documents the severity of harms associated with hazards and not the probability of occurrence.(b) Your “FMEA Work Instruction” (WI 39.2; Rev. 8; Effective: 12/15/23) states that “***a post-mitigation RP [Risk Priority] of ‘B’ should always prompt consideration of further control measures***”; however, it does not define how to document this assessment. Your “MiniCAT DFMEA” includes approximately 29 line items with a post-mitigation Risk Priority of “B” with a blank under the “Recommended Action” field for which your firm was unable to provide evidence that additional control measures were considered.(c) You failed to implement section 9.8 of your current revision of your “Risk Management” procedure (SOP 39; Rev. 10; Effective: 12/15/23) which requires evaluation of the overall residual risk acceptability. For example, your firm has not re-evaluated and documented the overall residual risk acceptability of your MiniCAT devices despite the “MiniCAT DFMEA” (01-2.3) being revised(b)(4)since approval of the “MiniCATTM Risk Management Report” (Rev. 2.0) on August 5, 2011 which determined that “***the benefits of the MiniCATTM CT scanner outweigh the inherent and residual risks***.”(d) You failed to implement section 9.10 of your “Risk Management” procedure (SOP 39; Rev. 10; Effective; 12/15/23) and “Production and Post-Production Information” section of your “MiniCATTM Risk Management Report” (Rev. 2.0; Approved 8/5/11) which require you to monitor customer complaints and other quality data sources to identify new risks and failure modes and update the risk management file. In particular, you do not assess the need to update your risk management file for your complaints unless they are investigated under a Failure Investigation Analysis (FIA) such that complaints without FIAs are excluded from this assessment. For example, a risk assessment was not conducted for Complaint # 47856 to determine whether the FMEA needed to be updated because it lacked an FIA.The adequacy of your firm’s responses cannot be determined at this time. You opened CAPA 297 (not provided) to determine why risk analysis is not adequate and stated you plan to add probability of occurrence to your harms analysis; update the FMEAs with a column for risk priority justification; update your management review work instruction (WI 1.1) to require review of the risk management report at a minimum yearly to determine if an update is needed; and review and revise the current risk management report. Please provide updates on the progress of these corrective actions and corrections, including CAPA 297, and any supporting evidence. Also, please respond with how you plan to address the finding that your risk management file is not updated with complaints without FIAs.Our inspection also revealed that the MiniCAT 2020, MiniCAT IQ, xCAT IQ, and xCAT XL devices are adulterated under section 501(f)(1)(B) of the Act, 21 U.S.C. § 351(f)(1)(B), because your firm does not have an approved application for premarket approval (PMA) in effect pursuant to section 515(a) of the Act, 21 U.S.C. § 360e(a), or an approved application for an investigational device exemption under section 520(g) of the Act, 21 U.S.C. § 360j(g). The devices are also misbranded under section 502(o) of the Act, 21 U.S.C. § 352(o), because your firm did not notify the agency of its intent to introduce the devices into commercial distribution, as required by section 510(k) of the Act, 21 U.S.C. § 360(k). For a device requiring premarket approval, the notification required by section 510(k) is deemed satisfied when a PMA is pending before the agency [21 CFR 807.81(b)]. The kind of information that your firm needs to submit in order to obtain approval or clearance for the device is described on the Internet at http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/HowtoMarketYourDevice/default.htm. The FDA will evaluate the information that your firm submits and decide whether the product may be legally marketed.Specifically, the MiniCAT 2020, MiniCAT IQ, xCAT IQ, and xCAT XL devices do not have 510(k) clearance. While a previous version of the MiniCAT device does have a 510(k) clearance (K113421) and while a previous version of the xCAT device does have a 510(k) clearance (K061834), the following design modifications – as documented in your firm’s US Regulatory Assessment of Product or Process Design Changes for 510(k) Cleared Medical Device – require the imaging performance and/or software to be evaluated in order to ascertain their impact to safety and effectiveness. These changes may be accepted in a Special 510(k) submission.The following changes could significantly affect the safety or effectiveness of these devices:MiniCAT2020: New model of Varex x-ray receptor panel: Varex 2121DXV. Technology and principle of operation of the 2121DXV are the same as current MiniCAT panels Varex 2520DX and 2520XI. The panel is just smaller in overall dimensions and cost. Changes to the position of the receptor panel in the gantry (offset) to maintain a field of view (FOV) size similar to MiniCAT/IQ while scanning with the smaller size panel (21x21cm vs. 25x20cm) Removal of Beam Limiter board and corresponding revision to PLC firmware; use of fixed collimation Software changes to add support for the new receptor panel and reconstruction algorithmMiniCAT IQ: Software changes causing increased number of post-processing viewing filter levelsxCAT IQ: New model of x-ray source Change in hardware components requiring new firmware and software controls New type of receptor panel mode that requires a new acquisition method New patient head holder that introduces biocompatibility concerns Revised XoranCAT software with a new construction protocol to accommodate soft tissue reconstruction, new soft tissue protocol and new receptor panel acquisition modesxCAT XL: Dimensional changes in system geometry that may affect imaging, including a reduction of the FoV Possible change in scattered radiation due to removal of gantry shields Change in filters that may affect scattered or leakage radiation Software uses new imaging protocols, the safety of which is unclear without more informationYour firm should take prompt action to address any violations identified in this letter. Failure to adequately address this matter 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.Other federal agencies may take your compliance with the FD&C Act and its implementing 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. Should FDA determine that your devices or facilities do not meet the requirements of the Act, requests for Certificates to Foreign Governments (CFG) may not be granted.Please notify this office in writing within fifteen business days from the date you receive this letter of the specific steps your firm has taken to address the noted violations, as well as an explanation of how your firm plans to prevent these violations, or similar violations, 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 any violations included in this Warning Letter. If you believe that your products are not in violation of the FD&C Act, include your reasoning and any supporting information for our consideration as part of your response.Your firm’s response should be sent by email to CDRHWarningLetterResponses@fda.hhs.gov. Refer to CMS case # 694229 when replying. If you have any questions about the contents of this letter, please contact: Sargum C. Morgan, Compliance Offer at (313) 393-8253 or sargum.morgan@fda.hhs.gov.Finally, you should know that this letter is not intended to be an all-inclusive list of the violations at your firm’s facility. It is your firm’s responsibility to ensure compliance with applicable laws and regulations administered by FDA. The specific violations 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 any violations and take prompt actions to address any violations and bring the products into compliance.Sincerely yours,/S/RDML Sean M. Boyd, MPH, USPHSDirectorOffice of Regulatory ProgramsOffice of Product Evaluation and QualityCenter for Devices and Radiological Health

Delivery Method:VIA Electronic MailProduct:Medical DevicesRecipient:Jeanne M. PhillipsOwner and CEOPhillips Precision, Inc.7 Paul Kohner PlElmwood Park,NJ07407United StatesIssuing Office:Center for Devices and Radiological HealthUnited StatesWARNING LETTERCMS # 697119December 9, 2024Dear Ms. Jeanne M. Phillips:During an inspection of your firm located in Elmwood Park, NJ on April 22, 2024 through July 17, 2024, investigators from the United States Food and Drug Administration (FDA) determined that your firm contract manufactures orthopedic implants and instruments. 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.This inspection revealed that these 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, their 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.We received a response from Ms. Shalyn Creighton, Quality Assurance and Regulatory Compliance Manager, dated August 8, 2024 concerning our investigator’s observations noted on the Form FDA 483 (FDA 483), List of Inspectional Observations, that was issued to your firm. We address this response below, in relation to each of the noted violations. These violations include, but are not limited to, the following:1. Failure to ensure that when the results of a process cannot be fully verified by subsequent inspection and test, the process shall be validated with a high degree of assurance and approved according to established procedures, as required by 21 CFR 820.75(a).Specifically, you either failed to adequately implement or define and document requirements for your “Master Validation Plan Process and Software Validation” procedure (SOP-34; Rev. M and O; Effective: 6/13/14 and 5/9/19) which governed process validations for the(b)(4)Cleaning Machine “(b)(4)” (model #(b)(4), serial #(b)(4)) and(b)(4)processes. For example:A. Cleaning validations conducted for the “(b)(4)” used to(b)(4)clean orthopedic implants and instruments, for which your firm functions as the final cleaner for(b)(4)out of(b)(4)top customers, do not provide adequate assurance that the process consistently produces product that meets specifications. For example:1. You failed to adequately implement sections 5.3.7 and 5.3.9.3 of your process validation procedure (SOP-34; Rev. M) which required you to challenge your cleaning process under the worst-case product and process conditions during the operational qualification (OQ) of your “(b)(4)” conducted under “Final(b)(4)Cleaning Operational Qualification (OQ) Protocol” (OQ_920-001; Rev. B; Approved 2/5/15), which includes the report. For example:i. Although your performance qualification (PQ) protocol required cytotoxicity, endotoxin, and particulate testing for the “(b)(4)” to demonstrate that cleanliness requirements were consistently met, you failed to conduct such testing during OQ which is defined in your procedure as “***documented verification that equipment performs in accordance with manufacturer’s specifications and process operating at [sic] the extremes of the equipment or process operating capabilities***.”ii. You failed to adequately challenge the cleaning process under worst-case process parameters and product based on types and/or geometries, surface finishes, and processes conducted during OQ. For example, you did not challenge(b)(4)as all loads were run at(b)(4); system(b)(4)quality above(b)(4)microsiemens/ cm; clean time below(b)(4)minutes; and load weight above(b)(4)pounds. You also failed to define the worst-case setting for degassing time in the OQ protocol which your firm’s management stated is under(b)(4)minutes as well as document the degassing time during OQ.In addition, you executed work orders during OQ without the(b)(4)manufacturing process, which your firm’s management identified during the inspection as a process that challenges your firm’s surface finishes and equipment process capabilities in(b)(4)out of(b)(4)work (WO #: 99343, 99284, 99336, and 98026-1) which were provided as worst case products.Furthermore, our investigator observed adhesive tape on the proximal femur left plasma implant (PF-2000L-02M; WO 102275) in the finishing department on 4/26/24. However, your OQ did not include challenges associated with the removal of adhesives and your “Final(b)(4)Cleaning ((b)(4))” (WI-920-001; Rev. K; Effective: 12/10/21) does not establish cleaning specifications associated with this process.iii. You failed to define or document the load configuration for work orders 65926 ((b)(4)devices), 64205 ((b)(4)devices), 63988 ((b)(4)devices), 65917 ((b)(4)devices), 65921 ((b)(4)75 devices), and 65791 ((b)(4)devices) in the OQ protocol and report in that your firm could not determine if devices were put in a single cleaning load or broken up into multiple(b)(4). In addition, you failed to challenge different loading configurations that your firm’s management stated are used during routine production such as the use of(b)(4)which is allowed in section 5.2.4.2.6 of your “Final(b)(4)Cleaning ((b)(4))” (WI-920-001; Rev. K; Effective: 12/10/21) and(b)(4). On 4/26/24, our investigator observed the tibia stylus assembly instrument (Part #(b)(4); WO 101881) enclosed in a(b)(4)and the(b)(4)instrument (Part #(b)(4); WO 98151) placed on top of a(b)(4), neither of which were evaluated during OQ.2. You failed to adequately implement section 5.3.9.4 of process validation procedure (SOP-34; Rev. M) which required “***documented evidence that a process system performs as intended and that it demonstrates the capability to consistently meet appropriate specifications***” for the performance qualification (PQ) of your “(b)(4)” conducted under “Final(b)(4)Cleaning Process Qualification (PQ) Protocol” (PQ_920-001; Rev. B; Approved 3/30/15), which includes the report. For example:i. As specified in section 5.2.2 of your “Final(b)(4)Cleaning ((b)(4))” procedure (WI-920-001; Rev. K; Effective: 12/10/21), you are to ensure that the system(b)(4)quality of the rinse tank is below (≤(b)(4)microsiemens/cm) during normal operation of your(b)(4)cleaner. However, you failed to conduct PQ under normal operating conditions for system(b)(4)quality in that only(b)(4)out of(b)(4)runs were run at ≤(b)(4)microsiemens/cm while the remaining cycles were run at(b)(4)and(b)(4)microsiemens/cm. In addition, you failed to define the optimal setting for degassing time in the PQ protocol as well as document the degassing time during execution of your PQ.ii. You failed to utilize(b)(4)and(b)(4)which were sufficiently representative of manufactured devices. For example, WO # 99284 (Part #(b)(4)) includes surface finishes such as vibratory, deburring, and finishing and equipment processes such as(b)(4), assembly, machine, and(b)(4); however, these processes were not represented in the(b)(4)and(b)(4)utilized during your PQ and your firm did not document justification for the equivalency of those(b)(4)and(b)(4)through objective evidence.3. You failed to adequately implement section 5.1 of your process validation procedure (SOP-34; Rev. M) which requires a completed process failure modes and effects analysis (PFMEA) as a part of an approved validation plan and for which the definition under section 5.3.14 indicates that a PFMEA is used to “***assess quality risk levels to each step in a manufacturing process***” with a reference to your “Risk Management” procedure (SOP-35; Rev. K; Effective: 3/9/15) which outlines the criteria for severity scores on a scale of(b)(4)through(b)(4). For example, per section 10.4 of the “Final(b)(4)Cleaning Validation Plan” (VP_920_001; Rev. D; Effective: 3/31/15) for the “(b)(4)”, you utilized a PFMEA to assess quality risk levels that “***reflect[ed] the worst case process (for both clean and rinse) via processing***at maximum loading conditions (i.e. weight) for variable(b)(4)states @(b)(4),(b)(4), and(b)(4)***.” However, you assigned a severity of(b)(4)((b)(4)) out of(b)(4)for all but one of the failure modes for devices cleaned with your “Zenith” without determining if your firm was the final clean and if a severity score of 4 was appropriate. Your firm did not learn that it was the final clean for(b)(4)out of(b)(4)of your top customers until this information was requested during the inspection on 5/2/24. As of the close of the inspection, your firm had not evaluated the 8 other customers you have manufactured for since 2020 to determine if your firm is the final clean for them as well. For the 4 top customers for which your firm was the final cleaner, your firm manufactured and shipped(b)(4)implants and(b)(4)instruments for Customer(b)(4);(b)(4)implants and(b)(4)instruments for Customer(b)(4);(b)(4)implants and(b)(4)instruments for Customer(b)(4); and(b)(4)instruments for Customer(b)(4).B. You failed to adequately implement 5.3.8 of your process validation procedure (SOP-34; Rev. O) which requires “***documented evidence providing high degree of assurance that a process***will consistently perform as intended” in that:1. You have not conducted a process validation for additional post-production final cleaning processes listed in the “Final(b)(4)Cleaning ((b)(4))” procedure (WI-920-001; Rev. K; Effective: 12/10/21), which allows for the use of(b)(4)and(b)(4), to provide adequate assurance that the process will consistently produce product that meet specifications. For example, on 4/22/24 and 4/26/24, our investigator observed your operators using(b)(4)and(b)(4)to wipe devices which had already been cleaned on the “(b)(4)”.2. The “Validation Plan for(b)(4)” (VP_920-012; Rev. C; Effective: 6/18/19) only included devices composed of(b)(4)and(b)(4)stainless steel and did not include devices composed of titanium (which your firm’s management stated are also treated with(b)(4)during manufacturing) or documented justification for why validation of such devices was not necessary.C. You failed to adequately implement section 5.3.9.4 of your process validation procedure (SOP-34; Rev. M and O) which required “***documented evidence that a process system***demonstrates the capability to consistently meet appropriate specification***” and “***how/when samples will be taken, labeled, transported, and tested***” for the performance qualification (PQ) of your “(b)(4)”. For example:1. Your “Final(b)(4)Cleaning Process Qualification (PQ) Protocol” (PQ_920-001; Rev. B; Approved 3/30/15), which includes the report, for the “(b)(4)” did not utilize a sampling plan based on a valid statistical rationale for cytotoxicity, endotoxin, and particulate testing. Although your “PPI Sampling Plan” procedure (DOC-03; Rev. E; Effective: 12/10/14) requires you to use an AQL of(b)(4)unless otherwise specified, the number of(b)(4)tested per lot for cytotoxicity and endotoxin was(b)(4)and(b)(4), respectively and the number of(b)(4)units tested for cytotoxicity, endotoxin, and particulate was(b)(4), and(b)(4), respectively. An AQL of(b)(4)for a sample size of(b)(4)and(b)(4)units per lot would have required testing on(b)(4)samples per lot for each test.2. Your “Validation Plan for(b)(4)” (VP_920-012; Rev. C; Effective: 6/18/19) did not utilize a sampling plan based on a valid statistical rationale. Although your “PPI Sampling Plan” procedure (DOC-03; Rev. E; Effective: 12/10/14) requires you to use an AQL of(b)(4)unless otherwise specified, cytotoxicity testing was only conducted on(b)(4)out of(b)(4)per lot and endotoxicity and particulate testing was conducted on(b)(4)per lot. An AQL of(b)(4)would have required a sufficient number of samples to be able to test a minimum of(b)(4)samples each for endotoxins, cytotoxicity, and particulates for a lot size between(b)(4)and(b)(4).We reviewed your firm’s response and conclude that it is not adequate.With regards to the OQ for the “(b)(4)”, you plan to update the(b)(4)cleaning procedure and perform a revalidation which will challenge: the minimum and maximum critical process parameters with worst-case product and process(b)(4); removal of any adhesives; load configurations; comingling; multiple(b)(4); and(b)(4). However, there was no confirmatory statement that you plan to conduct cytotoxicity, endotoxin, and particulate testing during OQ or rationale for why this would not be necessary and explanation provided for use of worst-case product and process(b)(4)instead of actual products during OQ.With regards to PQ for the “(b)(4)”, you dispute that(b)(4)purity of the rinse tank was not conducted at nominal; however, the(b)(4)and(b)(4)cycle was not done under normal operating conditions. You plan to update the(b)(4)cleaning procedure and perform a revalidation to include notation of the degassing time and use of worst-case product(b)(4). However, there was no corrective action identified to run system(b)(4)purity under normal operating conditions (≤(b)(4)microsiemens/cm) and define the optimal degassing time.With regards to the PFMEA for the “(b)(4)”, you intend to review and update the existing PFMEA as needed; contact(b)(4)of the(b)(4)customers you still do business with to determine whether your firm is the final clean and request their risk assessment; and do the same for any new customers in the future. However, there was no corrective action identified to proceduralized these actions. Furthermore, it is not clear whether you plan to update the respective severity scores for the process failure modes of the “(b)(4)”, for customer devices for which you are determined to be the final clean, in order to establish adequate quality risk levels.With regards to(b)(4), you plan to “amend” the(b)(4)validation to include devices composed of titanium. However, it is unclear what the difference is between an amendment and a revalidation.With regards to process validation for additional post-production cleaning processes, you state that the use of(b)(4), and (medical grade)(b)(4)to wipe post-production and post-final-cleaning is done in accordance with customer requirements. However, no supporting evidence was provided and rationale for why post-production final cleaning processes would be needed if the final cleaning process is meant to assure that cleaning requirements can consistently be met.With regards to sampling, you plan to update the process validation procedure and ensure that the revalidation of the “(b)(4)” and amendment of the(b)(4)validation will utilize a statistically valid sampling plan based on documented rationale.You have not provided any timelines for completion of any of your corrective actions. Please provide an update on the progress of your identified corrective actions, including any supporting evidence of completion for review, timelines for completion, and plan for how you will address the inadequacies pointed out in your response.2. Failure to establish and maintain process control procedures that describe any process controls necessary to ensure conformance to specifications when deviations from device specifications could occur as a result of the manufacturing process, as required by 21 CFR 820.70(a).Specifically, you failed to implement your “Final(b)(4)Cleaning ((b)(4))” (WI-920-001; Rev. K; Effective: 12/10/21). For example:A. You failed to implement section 5.2.4.2.5 which states “(b)(4).” For example, on 4/26/24, our investigator observed comingling of the large(b)(4)instrument (Part #(b)(4); WO 101395) and(b)(4)instrument (Part #(b)(4); WO 99014) in the same(b)(4)load.B. You failed to implement section 5.2.4.2.1 which states “Do not stack product.” For example, on 4/26/24, our investigator observed two instances where devices were stacked upon each other within a cleaning load:(b)(4)release instrument (Part #(b)(4); WO 98145) and(b)(4)instrument (Part #(b)(4); WO 98151), which appeared be stacked in 3 layers. In addition, the “(b)(4)" manual specifically states that “(b)(4).”We reviewed your firm’s response and conclude that it is not adequate. You plan to perform a revalidation on the “(b)(4)” to include challenges such as comingling and load configurations during OQ and review and update the PFMEA and(b)(4)cleaning procedure, as applicable. However, you have not provided any timelines for completion of any of your corrective actions and there was no corrective action identified to address that your employees were not following procedures. Furthermore, it is not clear how a revalidation on the “(b)(4)” that challenges comingling will address the original purpose which was to(b)(4), as noted in your(b)(4)cleaning procedure. Please provide an update on the progress of your identified corrective actions, including any supporting evidence of completion for review, timelines for completion, and plan for how you will address the inadequacies pointed out in your response.3. Failure to adequately establish and maintain procedures for monitoring and control of process parameters for validated processes to ensure that the specified requirements continue to be met, as required by 21 CFR 820.75(b).Specifically:A. You have not defined and documented procedures to monitor and control the following parameters for the validated(b)(4)Cleaning Machine “(b)(4)” (model #(b)(4), serial #(b)(4)) used to clean orthopedic implants and surgical instruments, for which your firm functions as the final cleaner for(b)(4)out of(b)(4)top customers:1.Weight of the Load(b)(4):There is no procedure to ensure that the load(b)(4)weight is below(b)(4)pounds, which was determined to be the limit during validation.2.Batch-to-Batch Temperature of the Cleaning Solution (i.e., Detergent) in the Clean and Rinse Tanks:There is no procedure to ensure that temperatures of the cleaning solution in the clean and rinse tanks between runs do not exceed the temperature limit of(b)(4)℉, which was determined to be the limit during validation.3.Concentration of the Cleaning Solution (i.e., Detergent):There is no procedure to ensure that the concentration of cleaning solution is monitored and controlled on a(b)(4)basis (with the use of a titration kit or other suitable means) to ensure adequate cleaning, which was specified during validation to be established per manufacturer’s instructions.4.Time for Degassing of Cleaning Solution (i.e., Detergent):There is no procedure to ensure that your “(b)(4)”, which operates at(b)(4)kHz, is degassed for(b)(4)to(b)(4)minutes before use for effective cavitation, which was specified during validation to be established per manufacturer’s instructions.B. You failed to implement sections 5.2.1.2 and 5.2.2.4 of your “Final(b)(4)Cleaning ((b)(4))” procedure (WI-920-001; Rev. K; Effective: 12/10/21) which requires verification of the temperature of the cleaning solution (i.e., detergent) in the clean and rinse tanks to ensure it is in the validated range of(b)(4)℉ to(b)(4)℉ and documentation of the temperature on the “(b)(4)Cleaning System Daily Temperature Log” (Form-03_01; Rev. F; Effective: 5/25/19) during startup of your “(b)(4)”. Overall, review of the temperature log from January 2, 2023 and March 26, 2024 revealed that approximately(b)(4)% ((b)(4)out of(b)(4)) of the loads run on your “(b)(4)” were performed at out of specification temperatures. For example, your employees operated your(b)(4)cleaner at temperatures lower than the minimum specified limit of(b)(4)℉ on 2/28/23; 4/6/23; 4/25/23; 5/19/23; 5/20/23; 5/22/23; 5/24/23; and 7/1/23, implicating at least(b)(4)orthopedic devices ((b)(4)implants and(b)(4)surgical instruments).C. You have not established a procedure for the monitoring and control of temperature and time for(b)(4). Section 6.2 of your “(b)(4)” procedure (WI-920-005; Rev. F; Effective: 9/6/17) states that the “***(b)(4)is pre-heated***between(b)(4)and(b)(4)F for a minimum of(b)(4)prior to application.”We reviewed your firm’s response and conclude that it is not adequate.With regards to the inadequate monitoring and control of the above parameters, you plan to reevaluate monitoring and controls after revalidation of the “(b)(4)”; update the frequency as needed; and revise the(b)(4)cleaning procedure to establish the applicable batch-to-batch temperature for the tanks.With regards to out of specification temperature recordings, you explain the temperatures would have increased as the morning went on such that only the first one or two runs of each day would have been affected; your employee may have misunderstood the process and either was not fully aware of the minimum temperature and/or what to do in the event the temperature was below the limit; and that because the minimum temperature proposed in the user manual is(b)(4)℉ and that the(b)(4)cleaning action only begins to deteriorate when temperatures go above certain limits (typically(b)(4)℉), the risk of impact to the parts cleaned on the specified days is low. However, there were temperatures noted above the validated temperature range of(b)(4)℉ on 8/18/23; 10/10/23; 1/15/24; 2/1/24; and 4/1/24. Additional temperatures below(b)(4)℉ were also noted on 8/7/23; 8/12/23; 8/24/23; and 11/3/23.You also plan to update the(b)(4)cleaning procedure to include an explanation of what to do in the event the temperature is below the minimum temperature; train applicable employees as well as to the nonconforming product procedure to identify nonconformances regarding parts themselves; and update the PFMEA to include the risks associated with parts processed outside of the specified temperature limits. However, there were no corrective actions identified to (1) address that your employees were not following procedures to ensure that the startup temperatures were within specified limits and (2) update the(b)(4)cleaning procedure to specify how long employees should wait before measuring the temperature for verification before use of the(b)(4)cleaner.With regards to the inadequate monitoring and control of parameters for(b)(4), you plan to review the(b)(4)validation and establish the applicable monitoring and control and amend the(b)(4)procedure to these said controls.You have not provided any timelines for completion of any of your corrective actions. Please provide an update on the progress of your identified corrective actions, including any supporting evidence of completion for review, timelines for completion, and plan for how you will address the inadequacies pointed out in your response.4. Failure to adequately establish and maintain procedures for implementing corrective and preventive action, as required by 21 CFR 820.100(a). Specifically:A. You either failed to define and document requirements in your Corrective/ Preventive Action Process” procedure (SOP-29, Rev. F, Effective: 10/19/18) or adequately implement sections 5.3, 5.4, and 5.5 which require a “***comprehensive and thorough***” root cause analysis, identification “***of all the actions to prevent recurrence***,” and verification “***that the issue has in fact gone away or been reduced***,” respectively, as required by 21 CFR 820.100(a)(2), 820.100(a)(3), and 820.100(a)(4). For example:1. Your corrective and preventative action (CAPA) procedure is inadequate in that it does not define or document the requirement to verify or validate corrective actions prior to implementation to ensure they are effective. For CAPA 1175 opened on 11/30/23 for(b)(4)blades received with metal debris, leftover burrs, and residue corresponding to(b)(4)devices (Part #(b)(4)), the corrective actions included (1) increasing clean time to(b)(4)minutes for your in-process(b)(4)cleaning machines; (2) verifying use of the custom(b)(4)fixture; and (3) utilizing additional inspectional tools with both magnification and lighting. However, you did not perform verification or validation activities prior to implementation of the corrective actions to ensure they would be able to remove residue.2. For CAPA 1175, you failed to adequately implement section 5.3 of your CAPA procedure because your investigation did not include an assessment on whether the residue, caused by improper placement of the devices in the in-process(b)(4)machines, may have affected other devices with similar geometries which also use the in-process(b)(4)machines to remove residue and metal shards.3. For CAPA 1166 opened on 7/11/22 to address “staining and contaminants on the(b)(4)” on at least(b)(4)devices (Part #(b)(4)) you contract manufactured under 30 work orders between 1/7/19 to 8/22/22, you failed to implement sections 5.3, 5.4, and 5.5 of your CAPA procedure: (1) investigate the specific causes behind the different types of stains (light stain, glue/transfer, oxidation, dark stain, and material transfer); (2) provide objective evidence that return material authorizations (RMAs) for(b)(4)lines were monitored from 3/10/23 to 3/17/23 per the verification plan; and (3) prevent recurrence of this issue in that from 3/17/23 to 4/1/24, you received 7 additional customer complaints/external NCMs (3893; 3902; 3946; 3947; 3980; 3982; and 3984) for stains on at least 7 of the same part numbers ((b)(4)) processed under 7 different work orders that were shipped after implementation of the corrective action on 3/10/23.B. Your “Control of Nonconforming Product” procedure (SOP-33; Rev. P; Eff. 6/28/22), which includes criteria for when corrective and preventive actions (CAPAs) should be initiated, is inadequate in that it does not define and document requirements for analyzing quality data (e.g., complaints, nonconformances, processes, returns, CAPAs, etc.) to identify existing and potential causes of nonconforming product, or other quality problems, using appropriate statistical methodology where necessary to detect recurring quality problems, as required by 21 CFR 820.100(a)(1). For example:1. Section 6.0 outlines the threshold for when a CAPA should be initiated for a nonconformance report. Threshold categories include Critical to Quality (Score:(b)(4)); Rejection % (Score:(b)(4)); Occurrence (Score(b)(4)); and Detectability ((b)(4)). A combined score of(b)(4)or above requires initiation of a CAPA. However, your “Detectability” rating does not associate lower ability to detect a nonconformity with a higher risk as a score of(b)(4)is defined as “Almost Certain” while a score of(b)(4)is defined as “Low to Almost Impossible.” Under this scoring system, recurring quality problems may not be detected because a CAPA would not be initiated for cases where detection was low to almost impossible.2. Section 5.8.3 states “***the QC Operations Manager***shall review nonconformance data***and determine if trends [for scrapped items, reworked product, nonconforming materials (NCMs)] or significant issue are identifiable and corrective action is warranted***” and that NCM/CAPA meetings will be held periodically to discuss the status of open NCM/CAPAs, trends, and NCM history. However, the procedure does not define and document how you are to analyze internal and external nonconformances as well as other quality data sources (e.g.,(b)(4)data) to identify existing and potential causes of nonconforming product, or other quality problems using appropriate statistical methodology.3. Your nonconformance procedure does not define and document requirements to analyze nonconformances generated from a process that may encompass various part numbers in that your firm’s management stated you only trend nonconformance types by part number. During the inspection, analysis of nonconformances associated with stains between 1/1/20 to 4/1/24 by part number failed to detect a notable trend. When the same data set was analyzed across part numbers, there were 48 nonconformances associated with stains across(b)(4)unique part numbers.4. Your nonconformance procedure does not define and document the nonconformance types (e.g., Major, Manufacturing, GMP, Functional, Dimensional, Gauge etc.), used to categorize nonconformances, to ensure nonconforming product will be consistently assigned a NCM (nonconforming material) type to allow for accurate analysis of this data to identify existing and potential causes of nonconforming product, or other quality problems. For example, NCM # 3458 and NCM # 3469 represent nonconformances associated with devices failing no-go gauges. Employee(b)(4)categorized NCM # 3458 as “Dimensional” and the same employee characterized NCM # 3469 as “Guage.” These nonconformances referenced different work orders; however, they each contained identical descriptions, dispositions, and verifications which are specific to the same dimension and no-go gauge.We reviewed your firm’s response and conclude that it is not adequate.With regards to CAPA 1175, you plan to investigate the feasibility of the process improvement determined from this CAPA on other product lines. However, there were no corrective actions identified to update your CAPA procedure to include verification or validation of corrective actions prior to implementation.With regards to CAPA 1166, you explain that staining occurred after product left your firm because you were unable to replicate some of the observed staining; you implemented a 100% visual inspection prior to packaging and shipment and plan to document the visual inspection records for the multiples(b)(4)orders verified from 3/10/23 to 3/17/23 as evidence; and you monitored RMAs requests across products lines for(b)(4)associated with staining, marks, and contamination from 3/10/23 to 3/17/23 as required by your verification plan. However, none of these conclusions, details, or activities were documented or referenced in your CAPA as part of the investigation, corrective action, and/or verification activities. Overall, there were no corrective actions identified to address the failure to include objective evidence of verification; incomplete documentation of the full investigation, identified corrective actions, and verification plan; and observed recurrence of the issue.With regards to data analysis, you state you intend to define a final internal nonconforming material (NCM) tracking and trending process within a procedure. However, there were no corrective actions identified to revise the detectability score to ensure that the lowest detectability level equates to the highest score(b)(4)not lowest score(b)(4)and retrospectively review NCMs, for a reasonable period of time, to update CAPA threshold scores to determine whether any CAPAs should have been initiated.With regards to categorization of nonconformances, you plan to review and update the existing NCM types listed within the system (as needed); define NCM types; and add instructions on how to correct NCM types after initial entry. However, there were no corrective actions identified to retrospectively review NCM types for accuracy, for a reasonable period of time, to determine the pervasiveness of the issue to guide further corrective action(s) based on the results of the review.You have not provided any timelines for completion of any of your corrective actions. Please provide an update on the progress of your identified corrective actions, including any supporting evidence of completion for review, timelines for completion, and plan for how you will address the inadequacies pointed out in your response.5. Failure to adequately establish and maintain procedures to control product that does not conform to specified requirements, including the identification, documentation, evaluation, segregation, and disposition of nonconforming product, as required by 21 CFR 820.90(a).Specifically, your “Control of Nonconforming Product” procedure (SOP-33; Rev. P; Effective: 6/28/22) (nor any other procedure) is inadequate in that there is no requirement to identify, document, and evaluate the following internal nonconformances to determine the need for an investigation. For example:A.Internal Nonconformances, found during manufacturing and inspections (excluding(b)(4)inspections– Per your undocumented process, a supervisor logs parts that are out of specification (OOS) into the(b)(4)software application and informs your Quality Control (QC) Operations Manager, who in turn enters it on the “Internal NO NCM Issues” log and decides whether to open an official NCM report requiring an investigation per the nonconforming product procedure.B.Internal nonconformances, only found during(b)(4)inspections conducted during manufacturing– Per your undocumented process, your QC Operations Manager evaluates the part, approves the disposition of scrap on the inspection guide sheet (IGS), documents it on the “NCM Internal(b)(4)Scrap Log” and then discards the part along with the(b)(4)report containing the OOS measurement. In turn, your operator enters the scrap on the IGS and(b)(4).We reviewed your firm’s response and conclude that it is not adequate. There were no actions identified to define and document how internal nonconformances will be evaluated to determine the need for an investigation. Furthermore, you have not provided any timelines for completion of any of your corrective actions. Please provide an update on the progress of your identified corrective actions, including any supporting evidence of completion for review, timelines for completion, and plan for how you will address the inadequacies pointed out in your response.6. Failure to establish and maintain procedures for acceptance activities, including inspections, tests, or other verification activities, as required by 21 CFR 820.80(a).Specifically, you failed to implement section 6.1.6.1(o) of your “Inspection Process” procedure (SOP-54; Rev. L; Effective: 3/17/23) which states the supervisor (or designate) “***must adhere to the Inspection Frequency as written. If the Inspection Frequency is at an AQL level, the Inspection Frequency is derived from DOC-03 PPI Sampling Plan***.” DOC-3 further references “(b)(4)Acceptance Number Sampling Plan Fifth Edition” which requires(b)(4)sampling. For example:A. During in-process inspection of the small spacer intended for implantation during shoulder surgery (Part #(b)(4)), your personnel only used your(b)(4)to measure the critical diameter feature(b)(4)times (to include(b)(4)). Per your inspection guide sheet (IGS) for this part, the feature was required to be measured(b)(4)times at(b)(4)since the inspection plan was specified to follow the Acceptable Quality Limit of(b)(4)(AQL(b)(4)) defined in “PPI Sampling Plan” (DOC-03; Rev. E; Effective: 12/10/14) for lot sizes of(b)(4)and(b)(4)under the respective Work Orders (WO) 86995 and 99431, respectively. For WO # 86995, you received a complaint/external nonconformance (NCM # 3287/CAPA 1122) which resulted in(b)(4)devices being returned and scrapped due to diameters exceeding the specified limit of(b)(4)+/-(b)(4).B. On 5/17/24, our investigator observed employee(b)(4)operate the(b)(4)for machining of the metal locking date ring (Part #(b)(4)) under WO # 102106. Your operator explained that every(b)(4)piece is inspected using a caliper. However, the in-process router states that this operation requires a 100% inspection.We reviewed your firm’s response and conclude that it is not adequate. You plan to revise the IGS to include column headers and an explanation to record the data for the first setup piece, middle piece, and last piece; review and update the inspection process procedure with the above changes; and provide training on these requirements with an emphasis for operators to follow the specified(b)(4)frequency. However, there were no actions identified to determine to determine the pervasiveness of the issue to guide further corrective action(s) based on the results of the review. Furthermore, you have not provided any timelines for completion of any of your corrective actions. Please provide an update on the progress of your identified corrective actions, including any supporting evidence of completion for review, timelines for completion, and plan for how you will address the inadequacies pointed out in your response.7. Failure to adequately establish and maintain schedules for the adjustment, cleaning, and other maintenance of equipment to ensure that manufacturing specifications are met, as required by 21 CFR 820.70(g)(1).Specifically:A. Your procedure to define and document the schedule for the(b)(4)bowl and filter gauge pressure of the(b)(4)Cleaning Machine “(b)(4)” (model #(b)(4), serial #(b)(4)) is inadequate. The “(b)(4)” manual requires drainage and monitoring of the(b)(4)volume on a(b)(4)basis to prevent liquid from dripping on internal machine components. However, your firm only conducts and documents this maintenance(b)(4)on the(b)(4)Cleaning System Maintenance Log (Form-03). In addition, although the manual states that the filter gauge pressure should be checked(b)(4)and changed if it reaches(b)(4)PSI, there is no requirement to check the filter gauge pressure under the “(b)(4)” section of your maintenance log (or elsewhere).B. You do not define, document, and maintain schedules for the adjustment and maintenance of tooling to ensure manufacturing specifications are met. For example, on 4/26/24, our investigator observed an instance where your(b)(4)machine was operating with a 0% tool life during the manufacturing of Work Order 101053-1. Per your firm’s management, tool changes may be considered when the machinist deems it necessary based on associated feature measurements, visual checks for a nonconformity on the surface finish of the part, or changes in the tool sound while engaged in the cut. In addition, the machinist may make an adjustment in the tool data page to compensate for the tool wear.We reviewed your firm’s response and conclude that it is not adequate. As a part of the revalidation of the “(b)(4)”, you plan to review the “(b)(4)” manual and compare it with the existing preventive maintenance form and update the frequency as needed, and if you determine that a frequency different from what the manual dictates is acceptable, a risk assessment will be performed and documented. You also state that the tooling observation is under review while you consider the best course of action. However, you have not provided any timelines for completion of any of your corrective actions. Please provide an update on the progress of your identified corrective actions, including any supporting evidence of completion for review, timelines for completion, and plan for how you will address the inadequacies pointed out in your response.8. Failure to adequately establish procedures for identifying training needs and ensure that all personnel are trained to adequately perform their assigned responsibilities, as required by 21 CFR 820.25(b).Specifically, operators who conduct machining of raw materials, assembly, and finishing have not been trained on your “Control of Nonconforming Product” procedure (SOP-33; Rev. P; Effective: 6/28/22). For example, review of 11 training records revealed(b)(4)operators who have not been trained in this procedure. These individuals perform in-process inspections and have the ability to reject and accept devices.We reviewed your firm’s response and conclude that it is not adequate. You plan to update your nonconforming product procedure to include a section for all operators, finishers, and inspectors to state what should be done in the event nonconforming product is found during manufacturing and train all applicable employees to this updated procedure. However, you have not provided any timelines for completion of any of your corrective actions. Please provide an update on the progress of your identified corrective actions, including any supporting evidence of completion for review and timelines for completion.Your firm should take prompt action to address any violations identified in this letter. Failure to adequately address this matter 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.Other federal agencies may take your compliance with the FD&C Act and its implementing 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. Should FDA determine that your devices or facilities do not meet the requirements of the Act, requests for Certificates to Foreign Governments (CFG) may not be granted.Please notify this office in writing within fifteen business days from the date you receive this letter of the specific steps your firm has taken to address the noted violations, as well as an explanation of how your firm plans to prevent these violations, or similar violations, 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 any violations included in this Warning Letter. If you believe that your products are not in violation of the FD&C Act, include your reasoning and any supporting information for our consideration as part of your response.Your firm’s response should be sent by email to CDRHWarningLetterResponses@fda.hhs.gov. Refer to CMS Case # 697119 when replying. If you have any questions about the contents of this letter, please contact: Sargum C. Morgan, Compliance Offer at (313) 393-8253 or sargum.morgan@fda.hhs.gov.Finally, you should know that this letter is not intended to be an all-inclusive list of the violations at your firm’s facility. It is your firm’s responsibility to ensure compliance with applicable laws and regulations administered by FDA. The specific violations 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 any violations and take prompt actions to address any violations and bring the products into compliance.Sincerely yours,/S/RDML Sean M. Boyd, MPH, USPHSDirectorOffice of Regulatory ProgramsOffice of Product Evaluation and QualityCenter for Devices and Radiological Health