按照《中华人民共和国药品管理法》《中华人民共和国行政许可法》和《药品经营和使用质量监督管理办法》等相关规定，根据河南医圣堂药业有限公司南阳分公司申请，现注销河南医圣堂药业有限公司南阳分公司的《药品经营许可证》（证书编号：豫AA377000732）。　　特此公告。　　附件：河南医圣堂药业有限公司南阳分公司《药品经营许可证》有关信息表　　2026年3月11日附 件河南医圣堂药业有限公司南阳分公司《药品经营许可证》（批发）有关信息表企业名称企业法人（负责人）主要负责人质量负责人经营方式经营范围经营地址仓库地址证书编号河南医圣堂药业有限公司南阳分公司张新杨杰姚学文批发中药饮片***河南省南阳市卧龙区卧龙岗街道车站南路3366号院内医圣堂健康产品研发基地办公楼4楼河南省南阳市卧龙区车站南路3366号8#厂房《药品经营许可证》（证号：豫AA377000732）

根据《药品管理法》、《药品生产监督管理办法》有关规定，经现场检查并综合评定，现将福建海峡金芝堂药业有限公司《药品生产质量管理规范》符合性检查结果公告。企业名称检查地址检查范围检查时间类型检查结果福建海峡金芝堂药业有限公司福建省平潭县金井镇顺意路16号平潭海峡医药健康产业园2#厂房一至三层中药饮片（净制、切制、炒制、酒炙、醋炙、蜜炙、煅炙、蒸炙、煮炙、盐炙）2026年1月7～9日依申请符合福建省药品监督管理局2026年3月10日

各第二类、第三类医疗器械经营企业：　　依据《医疗器械监督管理条例》和《医疗器械经营质量管理规范》（2024年7月实施）相关要求，现组织我市医疗器械经营企业2025年度自查报告填写工作：　　一、填报主体　　依据《医疗器械经营质量管理规范》（2024年7月实施）第十二条，从事第二类、第三类医疗器械经营的企业应当提交上一年度的自查报告。自查报告内容应当真实、准确、完整和可追溯。　　二、填报时间　　2026年3月11日14：00-2026年4月30日23：59　　三、填报地址　　https://zwfw.yjj.beijing.gov.cn　　四、填报要求　　依据《医疗器械经营质量管理规范》（2024年7月实施）第十二条，年报报告内容应当真实、准确、完整和可追溯。　　五、填报操作指南　　图文版用户手册见附件。　　六、其他要求　　二三类医疗器械经营企业年报系统近期用户访问量较大，如遇到登陆或操作问题，您可以：　　1.发送电子邮件至jszc2025@163.com。详细描述“办理何类事项时遇到什么问题”，注明联系方式并上传问题截图，工作人员将在1个工作日内给予答复（建议优先发送邮件，技术热线繁忙）。　　2.拨打技术支持热线：400 900 1866。服务时间：9:00-18:00（工作日）　　有关填报内容的疑问可咨询各区监管部门：附件：二三类医疗器械经营企业企业年度自查报告_用户手册　　北京市药品监督管理局　　2026年3月10日

　　按照《医疗器械监督管理条例》有关规定，根据企业申请，国家药品监督管理局注销以下4家企业共9个产品的医疗器械注册证：　　一、蒲兰纳医疗器械有限公司Planer Limited的1个产品：胚胎培养箱Incubators，注册证编号：国械注进20222180361。　　二、创生医疗器械（中国）有限公司的4个产品：脊柱通用后路内固定器，注册证编号：国械注准20173134720；脊柱通用前路内固定器，国械注准20183131572；脊柱通用后路内固定器，注册证编号：国械注准20153130118；椎间融合器，注册证编号：国械注准20173131463。　　三、江苏双羊医疗器械有限公司的3个产品：钛质接骨板（加压和保护性接骨板），注册证编号：国械注准20163130368；钛质接骨板（解剖型接骨板），注册证编号：国械注准20163130451；钛质接骨板（DHS、DCS），注册证编号：国械注准20163130369。　　四、广东宝莱特医用科技股份有限公司的1个产品：血液透析器，注册证编号：国械注准20223100152。　　特此公告。　　　　　　国家药监局2026年3月9日

Delivery Method:VIA Electronic MailProduct:Medical DevicesRecipient:Aurelio SahagunPresident and Chief Executive OfficerExactech, Inc. dba Advita Ortho2320 Nw 66th CtGainesville,FL32653-1630United Statesaurelio.sahagun@advita.comIssuing Office:Center for Devices and Radiological HealthUnited StatesWARNING LETTERCMS # 720250December 19, 2025Dear Mr. Sahagun:During an inspection of your firm located in Sarasota, Florida from July 15, 2025, through July 25, 2025, investigators from the United States Food and Drug Administration (FDA) determined that your firm manufactures the Equinoxe Reverse Shoulder Compression Screw along with other accessories of the Equinoxe Reverse Shoulder System. 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.Quality System Regulation ViolationsThis 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 Mathew Collins, Vice President of Quality dated August 15, 2025, along with response updates 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 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). For example, your firm failed to adequately establish production and process control procedures to ensure that devices conform to specifications.A. Your firm failed to define(b)(4)specifications and testing for polymer powder fabricated into UHMWPE molded products to ensure device components meet specified requirements. The document titled, “Ultra-High Molecular Weight Polyethylene (UHMWPE) ETS-0121 Rev. J”, released 02/23/2022 and “Compression Molded UHMW Polyethylene ETS-0122 Rev. L”, released 06/27/2022 call out(b)(4)and(b)(4)(Implants for surgery –(b)(4)–(b)(4)respectively. Your firm has no records of(b)(4)testing for lots of(b)(4)products to verify compliance with required(b)(4)specifications of(b)(4). The Certificate of Conformance values for lots are based on(b)(4)qualification testing of polymer powder fabricated into(b)(4)products rather than actual manufactured products.1. Investigators noted that(b)(4)measurement value of(b)(4), documented on the Certificate of Conformance for part number(b)(4), is not based on testing conducted on molded/fabricated parts. Rather the nominal values documented on this Certificate of Conformance, are based on(b)(4)testing performed on the(b)(4)shipment of(b)(4)raw powder, identified with lot number(b)(4), initially received on or around December 2021. Your firm declares compliance to(b)(4)Implants for surgery –(b)(4)–(b)(4)which notes the physical property requirements of(b)(4)molded products and states in part, “(b)(4).” The qualification testing is documented on Technical Memo TM-2021-1578, with approval dates 01/18-19/2022, and the(b)(4)test result were documented as(b)(4).B. Production and process procedures do not clearly define process controls necessary to ensure conformance to specifications. Your firm failed to adequately document instructions, standard operating procedures, and methods that define and control the manner of production.1. The work instructions do not define and control the manner of production, including in-process inspection of a critical specification and use of the(b)(4)tool. The Equinoxe Reverse Shoulder Torque Screw devices critical specification for break-point dimension inspection ((b)(4)) relies on(b)(4)inspection with significant operator variability. However, Work Instruction titled, Complete and Document Inspection of Machined Product at Sarasota- Machining 701-105-945 Rev. D, also does not clearly or explicitly outline the production and processing controls or provide step-by-step directions for the required, in-process inspections of the Equinoxe Torque Screw device, including specific instructions, equipment needed, process or product parameters or specifications, or inspection requirements.i. FDA investigators noted that an operator was performing this inspection step that required(b)(4)to undergo and pass this in-process inspection step out of a sample size of(b)(4). At the time the investigators observed this in-process inspection being performed, two of the required(b)(4)had undergone and passed this inspection step. The investigators noted that a sample unit, identified the torque screw as passing and meeting the required specification of(b)(4), from point A to B. However, investigators reviewed the measurements and noted that the unit did not pass this(b)(4)inspection test as the unit did not appear to fall completely within the specified(b)(4)lines of the(b)(4)tool image that reflect tolerance limits. Three nonconforming devices were later scrapped as noted on the scrap log and Production Events log.2. Manufacturing procedures do not adequately define process controls, in-process inspections, or equipment specifications. Work Instruction titled, Machine Equinoxe Reverse Shoulder Liner at Sarasota-Machining 701-105-896 Rev. C, released 04/15/2024, does not clearly or explicitly outline the production or processing controls or provide step-by-step directions for the manufacture of the Equinoxe Shoulder Liner device including specific instructions, equipment needed, process or product parameters or specifications, or inspection requirements. Additionally, your firm’s Work Instruction titled, Complete and Document Inspection of Machined Product at Sarasota- Machining 701-105-945 Rev. D, also does not clearly or explicitly outline the production and processing controls or provide step-by-step directions for the required, in-process inspections of the Equinoxe Shoulder Liner device, including specific instructions, equipment needed, process or product parameters or specifications, or inspection requirements. Neither of these Work Instructions document specific instruction on how to perform this inspection test, such as use of the(b)(4)tool, and operator(b)(4)is not addressed. Furthermore, no Operational Qualification was documented for(b)(4)machining processes, of the Equinoxe Polyethylene Shoulder Liner device and devices do not undergo(b)(4)in-process or final testing.Your firm’s responses are not adequate. The responses note that the root causes and contributing factors of the process control deficiencies include inconsistent enforcement of validation requirements, gaps in operator training on comparator-based inspections, and absence of formal inspection method qualification. In addition, the responses note that these deficiencies have systemic implications across your firm’s manufacturing operations and as well design transfer activities. Your firm’s responses describe corrections that include a manufacturing and process hold,(b)(4)inspection of existing inventory during process hold and a Field Action for(b)(4)Humeral Shoulder Liners. Your responses also describe corrective and preventative actions under CAPA 2025-30 that include: validation remediation for relevant manufacturing processes across Sarasota and Gainesville; SOP and work instruction redesign and training; inspection method qualification and retention of coordinate measuring machine reports; develop layered process audit work instructions and integration into QMS trending; SOP update for initial out of specification handing; and design transfer and process validation readiness. Your firm’s responses do not describe, and list remediation activities or products associated to legacy design transfer issues across manufacturing operations at your Sarasota and Gainesville facilities. The activities under CAPA 2025-30 along with the verification of effectiveness criteria, are in progress and extend through March 2026.2) Failure to adequately establish and maintain procedures for corrective and preventative action, as required by 21 CFR 820.100(a). For example:A. The procedure for Corrective and Preventive Actions Procedure, 701-103-137, Rev. AB, dated 6/11/2025 does not identify production events as nonconformities or quality data. A Production Event (PE) is defined as an event generated in(b)(4)utilized for processing electronic device history records, due to a deviation from pre-established product or process specifications. Production Events ((b)(4)documented events) are not analyzed as quality data sources or escalated to CAPAs where appropriate. Investigators noted that from 07/01/2023 to 7/25/2025 there was incomplete documentation maintained or available to demonstrate which Production Event entries were documented and managed as nonconformances. Additionally, no documentation was maintained or available to demonstrate that any Production Events were further assessed or analyzed as quality data sources.B. CAPAs 2023-005 and 2025-005 addressing environmental control specifications for(b)(4)storage were verified as effective and closed, yet environmental monitoring data from March 2024 to current showed your firm continued to exceed allowable temperature and humidity limits. Temperature specifications were changed from(b)(4)to(b)(4)in June 2025 after historical data showed consistent excursions. The pFMEA for the(b)(4)Molding Process, FMEA-000445, Rev A, dated 8/1/2024, discusses product and process impact with high temperatures and humidity, and the potential failures related to air conditioning (HVAC). Specifically, the effect of high moisture in(b)(4)may impact the material strength.Your firm’s responses are not adequate. Your firm’s responses note corrective actions under CAPA 2025-31 that include: CAPA procedural updates for verification of effectiveness; updates to Quality System’s governance and Management Review process adding additional sources of quality data (Production Events, Work in Process Scrap , environmental monitoring data, etc.); updates to software validation to include evaluation for the identification of critical to quality attributes for continuous monitoring; updates to Document Control related to the QMS process change and the determination of quality data outputs for continuous monitoring; and CAPA remediation efforts for verification of effectiveness. Your responses do not describe any retrospective review necessary to assess whether quality data such as Production Events, Work in Process Scrap, etc. or other critical to quality data attributes represent nonconformances or other quality issues that may require the initiation of a CAPA. The activities under CAPA 2025-31 along with the verification of effectiveness criteria, are in progress and extend through March 2026.3) Failure to adequately establish and maintain procedures to control product that does not conform to specified requirements, as required by 21 CFR 820.90(a). For example, your firm failed to identify, document, evaluate nonconforming product including the need for investigation and notification of the persons or organizations responsible.A. There was no written procedure for handling “Production Events (PE)” identified during manufacturing. The Nonconforming Product Handling Procedure, 701-103-013 Rev. AK, dated 9/13/2024, does not include a process to elevate Production Events to a nonconformance, despite the potential for rework may occur. Production Event entries included those for multiple inspection failures found at various stages in the manufacturing process (in-process inspection and QC inspection). For example:1. Failure of product’s dimensional specifications ((b)(4)failure,(b)(4)failure,(b)(4)failure,(b)(4)radius) that may correlate with high scrap rates for dimensional defects.2. Surface quality defects that include those for molding contamination: inclusions on articulating surface and mold marks.3. Machining process issues from setup and tooling that may create recurring dimensional problems (undersize stems on “(b)(4)”, undersized pin head, undersize due to a fixture issue, damaged threads, smooth and inconsistent threads, burrs in threads).4. Packaging issues that include wrinkles on seal, crease in seal, cuts in bag, score mark, seal integrity, loss in vacuum, nonuniform seal, loose fibers and black particles, hair, black particles embedded in bag.B. The WIP Scrap Events Collection procedure does not define threshold levels for when internal WIP scrap should be documented as nonconformances. While supplier receiving inspection has defined thresholds ((b)(4)defect rate), no similar thresholds exist for internal operations. Scrap log includes entries for nonconforming product associated with manufacturing process control deficiencies which include:1. Machining setup issues where numerous entries are labeled as set up, "setup part," "dial in" and tooling/fixture issues labeled as "tool broke," “bad mold tool”, "worn tool," "loose tool” and “wrong offset” resulting in scrap from dimensional and product quality problems (button height, overall thickness, overall length, thread noting dings and dents).2. Molding process issues resulting in scrap from:i. Equipment power issues labeled as “power outage”, “power failure”, “press failure”, “power turned off”;ii. Hydraulic issues (hydraulic Hit/loss, pressure drop);iii. Heating and cooling failure (pumps not turned on);iv. Manufacturing process control issues (“wrong recipes”, “tool not set up”, “missfil”, “not properly blowing out”) resulting in scrap from “flash leakage”, “inclusions on surface” and “under/over” weight product3. Product finishing issues from “over polishing”, “over blasting” and “thread chip wrap” resulting in nonconforming product dispositioned as scrap.4. Operator training issues as “operator error” entries for the machining, molding and finishing manufacturing processes resulting in dimensional and cosmetic nonconforming product dispositioned as scrap.Your firm’s responses are not adequate. Your firm’s responses note that corrective actions under CAPA 2025-31 that included: the coordination of the nonconformance program with the Production Events (PE) and work in process (WIP), and training development. Your firm’s retrospective review of WIP and PE does not include the rationale for timeframes selected. For example, you identified July 2024 through August 2025 for retrospective review; however, FDA investigators reviewed WIP and PE data from 7/01/2023 through 7/25/2025. In addition, we disagree with your investigation that raw data and pivot tables for Production Events and WIP Scrap entries revealed that the vast majority ((b)(4)) of Production Events were benign in nature, and resolved via appropriate mechanisms (e.g.(b)(4),(b)(4)fix, and approved reworks). Additionally, it is not clear from production event logs collected during the inspection how the in process and quality control inspection failures were handled.Your firm notes that although there were gaps in the inconsistent classification and escalation of quality events, that the nonconformances do not indicate a risk to product. FDA disagrees with this assessment in that this does represent a potential risk to distributed product since the FDA inspection and your firm’s investigation identified gaps with QC work instructions and training. Specifically,(b)(4)in-process inspection using manual(b)(4)and(b)(4)lacked formal work instruction to define the method, criteria, or documentation required. This created variability in execution and no documented evidence of consistency or repeatability. Your firm’s CAPA Review Board (CRB) identified this as a systemic breach of regulatory and QMS requirements; however, the assessment noted that it did not require a reportable field action. FDA remains concerned with the potential distribution of nonconforming product.The activities under CAPA 2025-31 along with the verification of effectiveness criteria, are in progress and extend through March 2026.4) Failure to adequately establish and maintain procedures to ensure that environmental conditions do not adversely affect product quality, as required by 21 CFR 820.70(c). For example, your firm failed to adequately establish procedures to ensure your environmental controls are being maintained as specified and that your environmental control systems are adequate and functional.A.(b)(4)Raw Material Storage, QWI-000185, Rev A, dated 4/30/2024 and the current procedure, Rev B, dated 6/10/2025 were not followed for backup environmental monitoring when the(b)(4)system fails in the Sarasota Molding Facility.(b)(4)system graphs from March 2024 to July 2025 of both temperatures and relative humidity levels were commonly and routinely recorded to be outside of the specified, nominal limit levels.B. A Deviation/Change Request, dated 05/27/2025, was “Due to a faulty environmental monitoring sensor ((b)(4)) located in the controlled environment fill room, the sensor will be unplugged, and environmental monitoring will occur using a calibrated data logger for both temperature and humidity”. Only one of(b)(4)poly fill rooms is monitored by the(b)(4)system, with assumption that(b)(4)rooms maintain same conditions despite physical wall separation.The adequacy of your firm’s responses cannot be determined at this time. Your responses note that corrective and preventative actions under CAPA 2025-033 included the environmental monitoring system enhancements; procedural revision to environmental monitoring excursion; training; updates to risk documents; new procedure to be used to document the facility modification; and defining environmental conditions of(b)(4)resin and molded components. The activities under along CAPA 2025-033 with the verification of effectiveness criteria, are in progress and extend through March 20265) Failure to adequately 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. For example, your firm failed to follow the procedures for Supplier Quality Management, 701-103-077, Rev AH, dated 10/31/2023. The FDA investigators noted that(b)(4)., the sole supplier of critical(b)(4)powder, has not received a required on-site audit per Supplier Quality Management Procedure Section 5, Step F, Item 2.C. The last supplier evaluation was conducted in September 2020, with no reevaluation when current procedures were implemented in October 2023. Additionally, there is no signed quality agreement as required per the procedure Section V, Step C, item 4.Your firm’s pFMEAs for the(b)(4)molded products document considers the raw(b)(4)powder, a critical component of the processing and quality of the finished devices. In the Process FMEA Process Failure Mode and Effects Analysis(b)(4)Compression Molding Process, FMEA-000445 Rev. A, DCRTC-00194, dated 8/1/2024 notes that if the(b)(4)is not properly received from the supplier and in conformance with the specifications, this could potentially lead to product impact with quality failures, incorrect traceability, higher product scrap or degraded mechanical characteristics.The FDA inspection noted that there were no records to demonstrate that your(b)(4)powder supplier, has or is maintaining environmental controls and storage conditions of the supplied(b)(4)powder component. The current lot of(b)(4)powder in use by your firm, lot number(b)(4), was first qualified in 2021, and all(b)(4)powder received since then, have been identified with the same lot identification. Documentation demonstrates the initial qualification of lot(b)(4)in 2021; however, your firm has received approximately(b)(4)shipments of the same lot of(b)(4)powder from(b)(4), since 2021 to 7/25/2025.The adequacy of your responses cannot be determined at this time. Your responses note the following activities being handled under CAPA2025-034: Supplier Quality Management SOP revision; the reevaluation of approved suppliers; the integration of supplier checks into design transfer activities; revise On-Site Audits and initiate Quality Agreements and On-Site Audits; and initiate Quality Agreements of(b)(4)powder. Many of the activities under CAPA2025-034 along with the verification of effectiveness criteria, are in progress and extend through June 2026. Therefore, we cannot determine the adequacy at this time.6) Failure to adequately establish procedures for identifying training needs and ensuring that all personnel are trained to adequately perform their assigned responsibilities, as required by 21 CFR 820.25(b). For example, your firm failed to capture the training of employees as described in the Competency and Training Procedure, 701-103-087, Rev. AB, dated 7/9/2024. FDA inspection noted that:A.(b)(4)employees working in manufacturing did not have required QC inspection tools documented in their training records, not meeting the requirement that employees perform all necessary training prior to task execution without oversight.B. The procedure states that all retraining shall be documented and recorded as part of the employee’s training record. In the review of 11 nonconformance reports, 7 nonconformance reports identified operator error as the root cause. Retraining was not identified as an action item in 6 of 7 of the reports reviewed.Your firm’s responses are not adequate. Your responses note the following activities being handled under CAPA 2025-035 include implementation of Task-Level Training Controls; development of work instructions and inspection tools; documented on the job training; the revision of Nonconforming Product Handling Procedure to enforce training; and revision of competency and training procedure. Your firm’s response does not describe any necessary training as part of the design transfer activities associated to a new manufacturing or inspection process. The activities under CAPA 2025-035 along with the verification of effectiveness criteria, are in progress and extend through April 2026.7) Failure to adequately establish procedures for acceptance activities, as required by 21 CFR 820.80(a). For example:A. Your firm failed to identify the correct work instructions that applies to manufacturing personnel when using(b)(4)to produce products for the Truliant Knee 02-029-190-4300 Short Headed Pin For Syringe Pin Puller, Alteon Hip 180-165-20 Alteon 6.5MM Screw, 20MM, and the Equinoxe Shoulder Torque Defining Screws. The work instructions listed did not call out for manufacturing personnel to use the Manufacturing of Product in(b)(4)Work Instruction, 701-105-1121, Rev D, effective date 2/28/2024. The work instructions are:1. Machining of Holding Pins at Sarasota- Machining Work Instruction 701-105-929, Rev. H, effective date 7/15/20252. Machining of 6.5mm Alteon Cancellous Bone Screw at Sarasota-Machining and Finishing Work Instruction, 701-105-964, Rev. C, effective date 6/22/20213. Manufacturing of Torque Defining Screws at Sarasota-Machining and Finishing Work Instruction, 701-105-1071, Rev B, effective date 11/05/2021B. Your firm failed to establish procedures or work instructions for two critical QC inspection tools used for the(b)(4)inspection process for the Equinoxe torque defining screw devices and for the(b)(4)inspection process for the Equinoxe shoulder liner device.The adequacy of your responses cannot be determined at this time. Your responses note that the following activities are being handled under CAPA 2025-036: updates on work instructions that support(b)(4)-controlled tasks and inspection operations; develop inspection tools and work instruction in conjunction with CAPA 2025-35; and work instruction impact review across similar product. The activities under CAPA 2025-036 along with the verification of effectiveness criteria, are in progress and extend through March 2026.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 Melissa Michurski, at CDRHEnforcement@fda.hhs.gov. Please include in the subject line, “CMS Case # 720250” when replying. If you have any questions about the contents of this letter, please contact: Rafael Padilla at Rafael.padilla@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/Barbara C. MarsdenActing DirectorOffice of Regulatory ProgramsOffice of Product Evaluation and QualityCenter for Devices and Radiological HealthCC: Christine Thomas, Chief Quality, Clinical and Regulatory Officer, christine.thomas@advita.com

Delivery Method:Via Electronic Mail - Return Receipt RequestedReference #:320-26-47Product:DrugsRecipient:Mr. M. Jayapal ReddyChief Executive OfficerTentamus India Private Limited3-31/33, Part Sy. No. 123, 124, 125 & 142, KompallyQuthbullapurHyderabad500014TelanganaIndiaIssuing Office:Center for Drug Evaluation and Research (CDER)United StatesWarning Letter320-26-47March 3, 2026Dear Mr. Reddy:The United States Food and Drug Administration (FDA) inspected your contract testing laboratory, Tentamus India Private Limited, FEI 3010960741, at 3-31/33, Part Sy. No. 123, 124,125 & 142, Kompally, Quthbullapur, Hyderabad, Telangana State, from August 14 to 22, 2025.This warning letter summarizes significant violations of Current Good Manufacturing Practice (CGMP) regulations for finished pharmaceuticals. See Title 21 Code of Federal Regulations (CFR), parts 210 and 211 (21 CFR parts 210 and 211).Because your methods, facilities, or controls for manufacturing, processing, packing, or holding do not conform to CGMP, the drug products you tested are adulterated within the meaning of section 501(a)(2)(B) of the Federal Food, Drug, and Cosmetic Act (FD&C Act), 21 U.S.C. 351(a)(2)(B).Furthermore, during the inspection you delayed or limited access to records requested. Due to your delay and limiting access to records during the inspection, the drug products you tested are also deemed adulterated within the meaning of section 501(j) of the FD&C Act, 21 U.S.C. 351(j).We reviewed your September 15, 2025 response to our Form FDA 483 in detail and acknowledge receipt of your subsequent correspondence.During our inspection, our investigator observed specific violations including, but not limited to, the following.1. Your firm’s quality control unit failed to exercise its responsibility to ensure drug products manufactured are in compliance with CGMP, and meet established specifications for identity, strength, quality, and purity (21 CFR 211.22).Your quality unit (QU) failed to ensure that all CGMP records were retained and available for review. Our investigator discovered two garbage bags containing torn analytical records, including chromatographic results, unidentified number lists, and impurity method validation spreadsheets with handwritten notes. For the method validation study, official records contained only handwritten values, while the original data was discarded in the garbage bags. This practice violated your lab documentation standard operating procedure (SOP) which prohibits destroying records or instrument printouts due to errors and requires filing such documents with original data for traceability with proper justification.Additionally, laboratory staff used unofficial personal diaries to record procedures, analytical observations, results, method modifications, and deviation descriptions. Your firm lacked procedures to control the use of these personal diaries and to ensure proper retention of all CGMP data.In your response, you state you opened an investigation and that the validation documents in the garbage bags were not related to drug products destined for the United States. Your response is inadequate. Irrespective of the ultimate use or intended purpose of the validation documents, because your firm operates with a single set of procedures, equipment, and practices for all products tested at your facility, including those destined for the United States, all testing and data must be handled appropriately and in accordance with established procedures. Furthermore, your response fails to describe immediate corrective actions to prevent the destruction of CGMP data or to prevent the use of unofficial diaries to record CGMP data.Reliability of data is compromised when there is a failure to maintain complete records of the conditions and data associated with all tests. Furthermore, the lack of complete data compromises the QU’s ability to exercise its function of ensuring compliance to applicable standards.Your quality system does not adequately ensure the accuracy and integrity of data to support the safety, effectiveness, and quality of the drugs you test. See FDA’s guidance documentData Integrity and Compliance With Drug CGMP: Questions and Answersfor guidance on establishing and following CGMP compliant data integrity practices at https://www.fda.gov/media/119267/download.We acknowledge that you are using multiple independent third-party consultants to audit your operations and assist in meeting FDA requirements.In response to this letter, provide:A comprehensive investigation into the extent of the inaccuracies and omissions in data records and reporting. Your investigation should include:o A detailed investigation protocol and methodology; a summary of all laboratories, manufacturing operations, and systems to be covered by the assessment; and a justification for any part of your operation that you propose to exclude.o Interviews of current and former employees to identify the nature, scope, and root cause of data inaccuracies. We recommend that these interviews be conducted by a qualified third-party.o An assessment of the extent of data integrity deficiencies at your facility. Identify omissions, alterations, deletions, record destruction, non-contemporaneous record completion, and other deficiencies. Describe all parts of your facility’s operations in which you discovered data integrity lapses.o A comprehensive retrospective evaluation of the nature of the testing data integrity deficiencies. We recommend that a qualified third-party with specific expertise in the area(s) where potential breaches were identified should evaluate all data integrity lapses.A current risk assessment of the potential effects of the observed failures on the quality of the drugs you test. Your assessment should include analyses of the risks to patients caused by the release of drugs affected by a lapse of data integrity and analyses of the risks posed by ongoing operations.A management strategy for your firm that includes the details of your global corrective action and preventive action plan. Your strategy should include:o A detailed corrective action plan that describes how you intend to ensure the reliability and completeness of all the data you generate including analytical data, manufacturing records, and all data submitted to FDA.o A comprehensive description of the root causes of your data integrity lapses including evidence that the scope and depth of the current action plan is commensurate with the findings of the investigation and risk assessment. Indicate whether individuals responsible for data integrity lapses remain able to influence CGMP-related or drug application data at your firm.o Interim measures describing the actions you have taken or will take to protect patients and to ensure the quality of your drug testing results, such as notifying your customers, conducting additional testing, recommending additional studies to assure stability, drug application actions, and enhanced complaint monitoring.o Long-term measures describing any remediation efforts and enhancements to procedures, processes, methods, controls, systems, management oversight, and human resources (e.g., training, staffing improvements) designed to ensure the integrity of your company’s data.o A commitment to have a qualified consultant conduct comprehensive annual audits, for at least two years, to assist in evaluating corrective action and preventive action (CAPA) effectiveness after you have executed your data integrity remediation protocol.o Inform FDA if you will be hiring a Chief Integrity Officer who is fully empowered to receive anonymous complaints from employees reporting data integrity concerns and with the authority to ensure any potential breach is promptly investigated (by an independent quality assurance function, along with expertise from outside entities whenever needed).o A status report for any of the above activities already underway or completed.A comprehensive assessment and remediation plan to ensure your QU is given the authority and resources to effectively function. The assessment should also include, but not be limited to:o A determination of whether procedures used by your firm are robust and appropriate.o Provisions for QU oversight throughout your operations to evaluate adherence to appropriate practices.o A complete and final review of each batch and its related information before the QU disposition decision.o Oversight and approval of investigations and discharging of all other QU duties to ensure identity, strength, quality, and purity of all products. Also describe how top management supports quality assurance and reliable operations including, but not limited to, timely provision of resources to proactively address emerging manufacturing/quality issues and to assure a continuing state of control.A list of all method validations performed by your firm since 2022. Provide a third-party assessment of these method validations to determine whether additional development or validation studies are needed. For any method validations requiring revision, provide all correspondence sent to your clients informing them of the need for revisions.2. Your firm failed to thoroughly investigate any unexplained discrepancy or failure of a batch or any of its components to meet any of its specifications, whether or not the batch has already been distributed (21 CFR 211.192).Laboratory DeviationsYou failed to adequately investigate laboratory deviations. An unofficial audit form was used to document laboratory deficiencies found on July 7, 2025, including a discrepancy in which microbiological sample plates could not be located in an incubator despite a logbook entry indicating the plates had been placed there(b)(4)earlier. The audit observations were made approximately six weeks before the inspection, but no CAPAs were listed on the form, and the findings were not included in the QU’s deviation and CAPA tracking program.In your September 15, 2025 response, you stated that the audits were conducted as(b)(4)operational checks to strengthen quality oversight, and you acknowledge the absence of a formal standard operating procedure (SOP) for such practices. You provided an updated SOP that proceduralizes routine process audits and committed to completing CAPAs for the observed items.Your response is inadequate. The updated SOP allows for routine identification and correction of deficiencies outside of the Quality Management System (QMS) without providing guidelines on when personnel must use the QMS framework for identifying and correcting deficiencies. Without QMS tracking and trending of deficiencies and corrections, the QU cannot ensure adequate CAPAs are implemented, potentially allowing operational deficiencies to persist and compromising testing control.Unexplained Out of Specification (OOS) ResultsYou failed to adequately investigate OOS results. On August 31, 2023, you tested(b)(4)for Total Aerobic Microbial Count (TAMC), and on September 11, 2023, reported the results as “Too Numerous to Count (TNTC).” On September 30, 2023 and November 3, 2023, you issued revised test reports for the same sample and test date, listing the TAMC result as passing, with a result of

Delivery Method:VIA EMAIL WITH READ RECEIPTReference #:320-26-48Product:Drugs,Over-the-Counter DrugsRecipient:Mr. Bernard FraisseFounder and CEOFareva Morton Grove1 Avenue President Wilson75016ParisFranceIssuing Office:Center for Drug Evaluation and Research (CDER)United StatesWarning Letter320-26-48March 3, 2026Dear Mr. Fraisse:The United States Food and Drug Administration (FDA) inspected your drug manufacturing facility, Fareva Morton Grove, FEI 1410794, at 6901 Golf Road, Morton Grove, Illinois, from August 4 to 12, 2025.This warning letter summarizes significant violations of Current Good Manufacturing Practice (CGMP) regulations for finished pharmaceuticals. See Title 21, Code of Federal Regulations (CFR), parts 210 and 211 (21 CFR parts 210 and 211).Because your methods, facilities, or controls for manufacturing, processing, packing, or holding do not conform to CGMP, your drug products are adulterated within the meaning of section 501(a)(2)(B) of the Federal Food, Drug, and Cosmetic Act (FD&C Act), 21 U.S.C. 351(a)(2)(B).We reviewed your September 3, 2025, response to our Form FDA 483 in detail, and acknowledge receipt of your subsequent correspondence.During our inspection, our investigators observed specific violations including, but not limited to, the following.1. Your firm failed to use equipment in the manufacture, processing, packing, or holding of drug products that is of appropriate design, adequate size, and suitably located to facilitate operations for its intended use and for its cleaning and maintenance (21 CFR 211.63).Your firm utilizes(b)(4)as a component to manufacture your over-the-counter (OTC) drug products. However, you failed to design and control your(b)(4)to ensure reliable production of(b)(4). The system was unsuitable to ensure both chemical and microbiological quality attributes.For example, your(b)(4)design did not ensure(b)(4). Notably, the system consistently failed to meet the(b)(4)specification. The performance qualification report for your(b)(4)included over(b)(4)of(b)(4)-sampling data, showing that most samples failed USP(b)(4)standards. Despite obtaining failing data, you approved the qualification study in(b)(4). Subsequent(b)(4)data obtained from August 2023 through August 2025 showed that nearly all your(b)(4)samples continued to fail the(b)(4)specification for(b)(4). You used(b)(4)from this(b)(4)in the manufacture of finished drug products.Your(b)(4)also had numerous points within the system that can harbor(b)(4), dead-legs), including some points-of-use located in the drug production area. Your firm was aware of the presence of dead-legs in the system.Deficient(b)(4)design can foster the development of biofilms, resulting in significant sporadic spikes in microbial levels of(b)(4)used for formulation and cleaning. Examples of gram-negative bacteria found in your(b)(4)include Pseudomonas aeruginosa and Serratia marcescens (a familyYersiniaceaemicrobe).In your response, you state that you plan to redesign your(b)(4)to eliminate dead-legs, add(b)(4)equipment, and qualify the system for the production of(b)(4). Your response is inadequate. You do not address your quality unit’s protracted insufficient action to address a long-standing pattern of failing test results of the(b)(4)utilized to make drug products.We acknowledge your commitment to stop using(b)(4)from your(b)(4)to manufacture drug products until the system can be remediated. We also acknowledge your commitment to use purchased(b)(4), in the interim.(b)(4)must be suitable for its intended use. Systems used to produce(b)(4)must be adequately designed, controlled, maintained, and monitored. The monitoring program should include routine testing to ensure that appropriate chemical and microbiological limits are consistently met.In response to this letter, provide:A comprehensive remediation plan for the design, control, and maintenance of the(b)(4), including:o a comprehensive evaluation of vulnerabilities of(b)(4)design and control, and summarize all deficiencies found in the system. The summary should, at a minimum, describe various system characteristics that were assessed for adequacy (for example, system temperature, materials of construction, slope, identified dead-legs, stagnant locations, unsanitary fittings, flow velocity, maintenance requirements).o revised procedures governing your program for ongoing control, maintenance, and monitoring to ensure the remediated system consistently produces(b)(4)that meets(b)(4)monograph specifications and appropriate microbial limits.o a corrective action and preventive action (CAPA) plan that corrects all(b)(4)design and control deficiencies. Include your plans for new system installation, or extensive design remediation (for example, removal of all dead-legs); preparation of a system-validation protocol; and the planned timeline for completion of thorough(b)(4)validation studies.Your plans for improved(b)(4)monitoring, including but not limited to the routine microbial testing of(b)(4)and appropriate limits (objectionable microbes, total count alert/action limits) to ensure the(b)(4)acceptability for use in each batch of drug product produced by your firm. Ensure that your(b)(4)total-count limits are appropriately stringent, in view of the intended use of each of the products produced by your firm.A detailed risk assessment addressing the potential effects of the observed(b)(4)failures on the quality of all drug product batches currently in U.S. distribution. Specify the actions you will take in response to the risk assessment, such as customer notifications and product recalls.2. Your firm failed to conduct appropriate laboratory testing, as necessary, for each batch of drug product required to be free of objectionable microorganisms (21 CFR 211.165(b)).You failed to ensure adequate microbiological testing for each batch of your drug products before release. For example, you failed to follow your procedure SOP L6082, “Identification of Gram-Negative Rod Bacteria and Yeast,” which requires the identification of all gram-negative rods found in your samples. You had not performed the required identification of gram-negative rods recovered from your drug products since January 2025, despite seeing an increase in colony forming units (CFUs) from September 2024 through January 2025.Testing is essential to ensure that the drug products you manufacture conform to all predetermined quality attributes appropriate for their intended use. Because you lacked adequate testing of each batch of your drug products, you do not know whether they conform to all appropriate finished-product specifications and are suitable for release to consumers.In response to this letter, provide:A list of chemical and microbial specifications, including test methods, used to analyze each batch of your drug products before a batch disposition decision.o An action plan and timelines for conducting full chemical and microbiological testing of retain samples to determine the quality of all batches of drug product distributed to the United States that are within expiry as of the date of this letter.o A summary of all results obtained from testing retain samples from each batch. If such testing reveals substandard-quality drug products, take rapid corrective actions, such as notifying customers and product recalls.A comprehensive assessment and remediation plan to ensure your QU is given the authority and resources to effectively function. The assessment should also include but not be limited to:o A determination of whether procedures used by your firm are robust and appropriateo Provisions for QU oversight throughout your operations to evaluate adherence to appropriate practiceso A complete and final review of each batch and its related information before the QU disposition decisiono Oversight and approval of investigations and discharging of all other QU duties to ensure identity, strength, quality, and purity of all products3. Your firm failed to ensure that laboratory records included complete data derived from all tests necessary to ensure compliance with established specifications and standards (21 CFR 211.194(a)).You failed to accurately document drug product microbiology testing results. Specifically, you did not contemporaneously record negative results for sample plates on which no microbiological growth was observed. Your procedure required positive plates to be entered contemporaneously, while blank entries were later automatically documented as zero values. Our inspection of the laboratory revealed a plate that had been counted and found to contain 20 CFUs. However, your firm had discarded the plate without recording the microbial levels.You were also unable to provide complete(b)(4)microbial sampling results from the(b)(4). Results existed in mixed formats (for example, paper-based and electronic entries), with some data missing.Collectively, these deficiencies indicate a significant risk of systematic underreporting of microbial findings.Reliability of data is fundamentally compromised when there is a failure to record data or to maintain complete and accurate records of test results. Furthermore, the lack of reliable data compromises the ability of your quality unit (QU) to exercise its function of ensuring compliance to applicable standards.In your response, you commit to retraining your microbiology staff to require microorganism identification, as well as accurate and contemporaneous recording of CGMP activities.Your response is inadequate in that you do not adequately address the major flaws in your laboratory system. Your response also lacks steps to systemically address your inadequate oversight of data integrity, including but not limited to improving your quality-assurance function.In response to this letter, provide:A comprehensive, independent assessment of your laboratory practices, procedures, methods, equipment, documentation, analyst competencies, and management oversight. Based on this review, provide a detailed plan to remediate and evaluate the effectiveness of your laboratory system.Your(b)(4)often result in high counts, ranging from(b)(4)CFUs/(b)(4)mL. Explain how your firm characterizes these counts and define when you would deem a sample result to be Too Numerous To Count (TNTC). Also describe how your method ensures accurate and precise expression of test results in a “per ml” measurement.A complete, independent assessment of documentation systems used throughout your manufacturing and laboratory operations to determine where documentation practices are insufficient. Include a detailed CAPA plan that comprehensively remediates your firm’s documentation practices to ensure you retain attributable, legible, complete, original, accurate, and contemporaneous records throughout your operation.Your quality system does not adequately ensure the accuracy and integrity of data to support the safety, effectiveness, and quality of the drugs you manufacture. See FDA’s guidance document Data Integrity and Compliance With Drug CGMP: Questions and Answers for guidance on establishing and following CGMP compliant data-integrity practices at https://www.fda.gov/media/119267/download.We strongly recommend that you retain a qualified consultant to assist in your remediation. In response to this letter, provide:A comprehensive investigation into the extent of the inaccuracies in data records and reporting, including all microbial-results data pertaining to drugs distributed to the United States. Include a detailed description of the scope and root causes of your data-integrity lapses.A current risk assessment of the potential effects of the observed failures on the quality of your drugs. Your assessment should include analyses of the risks to patients caused by the release of drugs affected by a lapse of data integrity, and analyses of the risks posed by ongoing operations.A management strategy for your firm that includes the details of your global CAPA plan. The detailed corrective-action plan should describe how you intend to ensure the reliability and completeness of all data generated by your firm, including microbiological and analytical data, manufacturing records, and all data submitted to FDA.Cosmetics Manufactured for Distribution in the United StatesIn addition, some of the products you manufacture may be regulated as cosmetics, as defined in section 201(i) of the FD&C Act (21 U.S.C. 321(i)). Any cosmetics you manufacture must comply with applicable statutory and regulatory requirements, including the FD&C Act. We note that under section 301(a) of the FD&C Act (21 U.S.C. 331(a)), it is a prohibited act to introduce or deliver for introduction into interstate commerce a cosmetic that is adulterated or misbranded.We also note that the Modernization of Cosmetics Regulation Act of 2022 (MoCRA) provides new requirements with which facilities that manufacture cosmetic products must comply. You may find the FD&C Act, MoCRA, and FDA’s regulations through links on FDA’s website at www.fda.gov.ConclusionThe violations cited in this letter are not intended to be an all-inclusive list of violations that exist at your facility. You are responsible for investigating and determining the causes of any violations and for preventing their recurrence or the occurrence of other violations.Correct any violations promptly. Failure to promptly and adequately address this matter may result in regulatory or legal action without further notice including, without limitation, seizure and injunction. Unresolved violations may also prevent other Federal agencies from awarding contracts.Failure to address violations may also cause FDA to withhold issuance of Export Certificates. FDA may withhold approval of new applications or supplements listing your firm as a drug manufacturer until any violations are completely addressed and we confirm your compliance with CGMP. We may re-inspect to verify that you have completed corrective actions to address any violations.This letter notifies you of our findings and provides you an opportunity to address the above deficiencies. After you receive this letter, respond to this office in writing within 15 working days. Specify what you have done to address any violations and to prevent their recurrence. In response to this letter, you may provide additional information for our consideration as we continue to assess your activities and practices. If you cannot complete corrective actions within 15 working days, state your reasons for delay and your schedule for completion.Send your electronic reply to CDER-OC-OMQ-Communications@fda.hhs.gov. Identify your response with FEI 1410794 and ATTN: Carlos Gonzalez.Sincerely,/S/Francis GodwinDirectorOffice of Manufacturing QualityOffice of ComplianceCenter for Drug Evaluation and Research

Delivery Method:Via EmailProduct:DrugsRecipient:Ryan NapierskiChief Executive OfficerNSE Products, Inc. DBA Nu Skin Enterprises, Inc.75 West Center StreetProvo,UT84601United Statesrnaperski@nuskin.comIssuing Office:Center for Drug Evaluation and Research (CDER)United StatesWARNING LETTERMarch 2, 2026RE: 3093 (CMS 722667)Ryan Napierski:This letter concerns your firm’s drug listing information provided to FDA’s electronic Drug Registration and Listing System (eDRLS) for your drug products, “AP-24 Fluoride,” NDC 62839-1151; “AP-24,” NDC 62839-1152; and “AP-24 Whitening,” NDC 62839-1155.1Your firm has not fulfilled its listing obligations under section 510(j) of the Federal Food, Drug, and Cosmetic Act (FD&C Act), 21 U.S.C 360(j). Failure to provide listing information for a drug in accordance with 510(j) of the FD&C Act is prohibited under section 301(p) of the FD&C Act, 21 U.S.C. 331(p). These violations are described in more detail below.Drug Listing ViolationsSection 510(j) of the FD&C Act, 21 U.S.C. 360(j), and 21 CFR 207 set forth the requirements for the listing of drugs. In accordance with section 510(j)(2) of the FD&C Act, 21 U.S.C 360(j)(2), and 21 CFR 207.57(b), registrants must review and update their drug listing information each June and December. Furthermore, under 21 CFR 207.57(b)(1)(iv), registrants must submit any material changes in any information previously submitted including, per 21 CFR 207.49(a)(12), manufacturing establishment information. The drug listings stated above reference a manufacturing establishment,(b)(4), that has confirmed that it has not been involved in the manufacturing of these drugs for more than five years, yet they continue to be cited in your listings with no end marketing date. Therefore, your firm has not fulfilled its listing obligations under section 510(j) of the FD&C Act, 21 U.S.C. 360(j). Failure to provide listing information for a drug in accordance with 510(j) of the FD&C Act is prohibited under section 301(p) of the FD&C Act, 21 U.S.C. 331(p).Additionally, your firm has 61 drug listings that have not been updated or certified as required and therefore have been inactivated by FDA. Please update the listing information for these drugs to reflect their current status. If you no longer manufacture and distribute these drugs, then the drugs must be discontinued by adding an end marketing date.Complete, accurate, and up-to-date establishment registration and drug listing information is essential to promote and protect patient safety. FDA relies on establishment registration and drug listing information for several key programs, including drug establishment inspections, supply chain security, and post-market surveillance. Establishment registration and drug listing information is also widely used outside FDA for purposes such as electronic prescribing and electronic health records, insurance reimbursement, and patient education. We note that this warning letter only addresses establishment registration and drug listing issues associated with your products.ConclusionThis letter is not intended to be an all-inclusive statement of violations that may exist in connection with your products. You are responsible for investigating and determining the causes of any violations and for preventing their recurrence or the occurrence of other violations. It is your responsibility to ensure that your firm complies with all requirements of federal law, including FDA regulations.This letter notifies you of our concerns and provides you an opportunity to address them. Failure to adequately address this matter may result in legal action including, without limitation, seizure and injunction.Please notify FDA in writing, within 15 working days of receipt of this letter, of the specific steps you have taken to correct any violations. Include an explanation of each step being taken to prevent the recurrence of violations, as well as copies of related documentation. 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. If you cannot complete corrective action within 15 working days, state the reason for the delay and the time within which you will complete the correction. In absence of a corrective action, the deficient listing data will not be available for certification under 21 CFR 207.57(b)(2) requirements and will be ultimately inactivated by FDA.2If you believe that your products are not in violation of the FD&C Act, include your reasoning and any supporting information for our consideration.Your response should be sent to U.S. Food and Drug Administration, Center for Drug Evaluation and Research/Office of Compliance/Office of Unapproved Drugs and Labeling Compliance by e-mail to eDRLS@fda.hhs.gov. Please be aware that a manual override may be required for certain types of revisions made to an existing drug listing file. If you receive a validation error or have any questions regarding the contents of this letter, please contact us at eDRLS@fda.hhs.gov for further assistance. Include the case identification numbers (3093) (CMS 722667) on all correspondence.Sincerely,/S/Tina Smith, M.S.Captain, U.S. Public Health ServiceDirectorOffice of Unapproved Drugs and Labeling ComplianceOffice of ComplianceCenter for Drug Evaluation and ResearchU.S. Food and Drug Administration___________________1On December 10, 2025, we sent your firm a drug listing deficiency letter describing the observed listing deficiencies in the information your firm submitted. In addition, we followed up on December 11, 2025, December 19, 2025, and January 16, 2026, to various points of contact. On January 24, 2026, we sent your firm a data removal notification email informing you of a data removal action. As stated in that email, the continued deficiencies resulted in your products’ data removal from FDA’s Online NDC Directory. FDA sends data deficiency letters and data removal notifications to the contact person found in the labeler code SPL submitted by your firm to FDA. If this information has changed, it is your responsibility to update this within 30 days of any change, under 21 CFR 207.33(c).2See 84 FR 40417.

Delivery Method:VIA UPSReference #:320-26-49Product:DrugsRecipient:Franco NegronChief Executive OfficerSimtra BioPharma SolutionsBuilding C, Suite 270, 2nd Floor400 Interpace ParkwayParsippany,NJ07054United Statesfrnegron@simtra.comIssuing Office:Center for Drug Evaluation and Research (CDER)United StatesWarning Letter320-26-49March 3, 2026Dear Mr. Negron:The United States Food and Drug Administration (FDA) conducted an unannounced inspection of your drug manufacturing facility, Simtra Deutschland GmbH, formerly Baxter Oncology GmbH, FEI 3002806419, at Kantstr. 2, 33790 Halle/Westphalia, Germany, from September 18 to 26, 2025.This warning letter summarizes significant violations of Current Good Manufacturing Practice (CGMP) regulations for finished pharmaceuticals. See Title 21 Code of Federal Regulations (CFR), parts 210 and 211 (21 CFR parts 210 and 211).Because your methods, facilities, or controls for manufacturing, processing, packing, or holding do not conform to CGMP, your drug products are adulterated within the meaning of section 501(a)(2)(B) of the Federal Food, Drug, and Cosmetic Act (FD&C Act), 21 U.S.C. 351(a)(2)(B).We reviewed your October 20, 2025 response to our Form FDA 483 in detail and acknowledge receipt of your subsequent correspondence.During our inspection, our investigators observed specific violations including, but not limited to, the following.1. Your firm failed to perform operations within specifically defined areas of adequate size and to have separate or defined areas or such other control systems necessary to prevent contamination or mix-ups in aseptic processing areas (21 CFR 211.42(c)(10)).Significant deficiencies were identified with aseptic processing controls in your(b)(4)and restricted access barrier system (RABS) processing lines used to aseptically manufacture sterile drug products for the U.S. market.Cleaning and DisinfectionYou used(b)(4)extensively to rinse critical, interior surfaces and aseptic processing equipment in your(b)(4)and RABS lines after production. This(b)(4)was fed from(b)(4)cleaning use points inside your(b)(4)and RABS through excessively long (up to approximately(b)(4)) deadlegs from your(b)(4)loop. Deadlegs in(b)(4)systems are known to cause stagnation of(b)(4)and excessive microbial growth.Between June 2023 and September 2025, routine testing of(b)(4)cleaning use points in your ISO 5(b)(4)and RABS resulted in at least 47 microbial recoveries, including 14 that exceeded your action limit. Your routine monitoring samples repeatedly recovered gram-negative, biofilm-forming,(b)(4)organisms includingSphingomonas, Methylobacterium, Bradyrhizobium, andRalstoniaspecies. Investigations for at least two incidents associated with microbial recoveries identified the design of your(b)(4)cleaning use point piping as the most likely root cause. However, your corrective action and preventive action (CAPA) plans have failed to comprehensively address the identified deficiencies in your(b)(4)system design.Furthermore, post-production environmental monitoring (EM) samples taken within your ISO 5(b)(4)and RABS between June 2023 and September 2025 have resulted in repeated recoveries of gram-negative(b)(4)organisms includingSphingomonas, Methylobacterium, andCupriavidusspecies.This sampling identified a worrisome adverse trend in your RABS in late 2023 in which(b)(4)gaskets and(b)(4)were found to be contaminated with gram negative microbes. Significantly, too-numerous-to-count (TNTC) levels were present on RABS(b)(4)gaskets in multiple instances during this period. Your investigations acknowledged that equipment design (including(b)(4)gaskets) and maintenance, in combination with cleaning (e.g., residual(b)(4)from cleaning), caused the deviation.You failed to sufficiently address the underlying cause of residual(b)(4)in a timely manner, instead relying on personnel to(b)(4)dry any observed moisture.In your response, you commit to corrective actions including(b)(4)sanitization of(b)(4)cleaning use point piping and(b)(4)of the(b)(4)used in ISO 5 cleaning. Additionally, you explain your process of(b)(4)-drying your(b)(4)and RABS with(b)(4)drying of residual(b)(4)during visual inspection by operators. You also commit to implementing(b)(4)disinfection of the(b)(4)in your(b)(4)and RABS.Your response is inadequate because your corrective actions fail to address the fundamental, self-identified design flaw in your(b)(4)supply lines” that lead to each of your(b)(4)and RABS processing lines for cleaning. You also fail to holistically address residual(b)(4)from cleaning your(b)(4)and RABS units across your site. The residual(b)(4)issue poses a significant risk to barrier/(b)(4)system control (e.g., interference with decontamination cycle efficacy) and can potentially lead to drug product contamination.(b)(4)Integrity TestingYou failed to adequately maintain equipment to assure aseptic conditions. Your(b)(4)integrity testing program for(b)(4)was found to be deficient. For example:Your(b)(4)integrity testing program for(b)(4)permitted(b)(4)to fail acceptance criteria during pressure decay testing(b)(4)times before requiring replacement. Your translated procedure states, “All(b)(4)that fail the leak test (pressure drop test) may be retested. If the(b)(4)fails more than(b)(4)times, it must be replaced.”When(b)(4)failed leak testing, retesting was often not performed the same day but at a later date. As a result, you manufactured drug products using(b)(4)that had failed leak testing without confirming their integrity. For example,(b)(4)on line(b)(4)failed to meet acceptance criteria on July 1, 2025, and did not pass testing until July 19, 2025. In the 18-day period between these tests, your production schedule indicated you manufactured at least(b)(4)batches of drug products.You lacked raw(b)(4)testing data. During the inspection, you were unable to locate raw(b)(4)integrity testing data from(b)(4)for line(b)(4).Instead of reviewing raw(b)(4)testing data, your quality assurance unit relied on forms containing transcribed information.In your response, you commit to enhancing your(b)(4)integrity testing program through procedural updates requiring additional quality oversight, defining actions following test failures including not permitting production to proceed “following an invalid or failed test,” and implementing quality review of visual and(b)(4)testing results.You indicate that inappropriate acceptance criteria programmed into your(b)(4)integrity testing device caused many of the failures. You also assert, “[T]here has been no impact to any released batches or the overall control of sterility assurance at the site.”Furthermore, your response states that in your operators’ experience, pressure decay failures are generally not indicative of non-integral(b)(4), and they instead relied upon visual inspection.Your response calls into question the reliability of your(b)(4)integrity testing program. Visual inspections, on their own, are insufficient to monitor(b)(4)integrity. Visual(b)(4)examinations provide far lower detectability than, and cannot be substituted for,(b)(4)integrity testing devices. It is essential that your firm use(b)(4)integrity testing devices that are capable of reliably detecting sub-visible breaches in(b)(4)integrity.You also failed to perform retrospective evaluation of potentially impacted products and processes. In response to the uninvestigated(b)(4)integrity failures, you concluded there was no quality impact to released batches or overall contamination risk at the site. However, you appear to have limited your review only to examples cited during the inspection.Additionally, you failed to assess equipment management across your site to identify other potentially impacted critical equipment that may affect aseptic conditions. You should give continual attention to the integrity of critical equipment. This includes comprehensive maintenance procedures that establish adequate integrity testing and proactive replacement before breakdown.Protective Equipment MaterialsYou failed to implement other adequate equipment control systems to prevent contamination during aseptic processing. Our investigators observed particles shedding from(b)(4)material in aseptic areas. For example, loose, visible fibers were observed on and dislodging from(b)(4)covers during(b)(4)installation within critical aseptic filling areas. Fibers also were observed on tubing in two locations in line(b)(4). Subsequently, unused(b)(4)covers were inspected and observed to have loose fibers indicating the material itself was the source of contamination. You use the material is used to protect(b)(4)and the end of sterile tubing.Furthermore, this is an ongoing issue. Your customer reported your previous non-pharmaceutical grade(b)(4)material as a source of particulate contamination. In response, you introduced your current(b)(4)material across your(b)(4)and RABS processing lines without evaluating its particle generating characteristics.In your response, you explain the(b)(4)seams on the(b)(4)are the apparent source of visible fibers and they appear to be statically charged. You also indicate you are working with your supplier to address this issue while taking interim controls including awareness training, visual checks of equipment at risk of fibers, removal of observed fibers with sterile lint-free wipes, and the exchange of equipment when fibers are observed attached to product contact surfaces.Your response is inadequate. You limited your retrospective batch review to only the two batches observed to be exposed to loose fibers during the inspection. Your response also fails to assess the particles generated by the(b)(4)material to determine their characteristics (e.g., size). Additionally, your response fails to support the adequacy of visual inspection as an interim control or to review quality indicators for particle related issues (e.g., complaints, deviations). Finally, your response did not address your failure to evaluate particle generation in the replacement material when you implemented a change control for(b)(4)in response to a particle generation complaint. This is a quality oversight failure.Aseptic processing operations should be designed and executed to minimize exposure of sterile articles to potential contamination hazards in the manufacturing operation. Flaws in the design of cleanrooms and aseptic processing lines or improper execution of aseptic operations can enable entry of contaminants into the critical (ISO 5) processing area and lead to product contamination.(b)(4)technology represents a significant advance over traditional operational designs. However, all technologies have failure modes that require ongoing, vigilant monitoring and maintenance to ensure a state of control, including(b)(4). A strong quality system is essential to oversee design and construction of aseptic processing lines and supporting utilities, and to ensure ongoing proper operational control to safeguard against contamination hazards throughout the facility lifecycle.See FDA’s guidance documentSterile Drug Products Produced by Aseptic Processing—Current Good Manufacturing Practiceto help you meet the CGMP requirements when manufacturing sterile drugs using aseptic processing at https://www.fda.gov/media/71026/download.In response to this letter, provide the following:A comprehensive assessment of your(b)(4)system design, control, and maintenance including, but not limited to:o Identification of deadlegs and any other insanitary elements of your(b)(4)system.o A comprehensive remediation plan and detailed CAPA timeline for improving design, control, and maintenance of your(b)(4)system. Include re-piping and modifications to eliminate deadlegs, removal of insanitary fittings, assurance of appropriately designed recirculating loops, and completion of all other needed remediations to ensure sanitary systems. Place special emphasis on identifying and eliminating any deadlegs that feed(b)(4), RABS, or other sterile production equipment.o The validation report for the(b)(4)system after all identified design issues have been fully corrected and any maintenance repairs have been completed. Include the system validation protocol, the complete test results, and the final validation report. Include the summary of all improvements made to system design, as well as the program for ongoing control and maintenance.A comprehensive, independent retrospective assessment of your cleaning effectiveness to evaluate the scope of potential contamination from residual moisture after cleaning. For each production line, assess(b)(4)cleaning and(b)(4)drying cycles, identify specific equipment parts which remain within the(b)(4)and RABS after cleaning, and address the potential for(b)(4)to remain stagnant within equipment between production operations. The assessment should identify any inadequacies of cleaning procedures and practices, and encompass each piece of manufacturing equipment used to manufacture products intended to be sterile.Based upon the cleaning effectiveness assessment, provide a CAPA detailing improvements to your cleaning and disinfection program including enhancements to cleaning effectiveness, improved ongoing verification of proper cleaning and disinfection execution for all products and equipment, and all other needed remediations.A comprehensive assessment of the design and control of your firm’s manufacturing operations with a detailed and thorough review of all microbiological hazards.Your CAPA plan to implement routine, vigilant operations management oversight of facilities and equipment. This plan should ensure, among other things, prompt detection of equipment/facilities performance issues, effective execution of repairs, adherence to appropriate preventive maintenance schedules, timely technological upgrades to the equipment/facility infrastructure, and improved systems for ongoing management review.A comprehensive evaluation of your ongoing(b)(4)maintenance program.o Address elements including, but not limited to, frequency of integrity tests (e.g., at least(b)(4)),(b)(4)testing procedure and methodology, and appropriate practices to reduce the occurrence of invalid tests.o Conduct an analysis of the various failure scenarios that have occurred during your(b)(4)leak testing (e.g., device set-up problems, failure to meet initial pressure, employee interference). Also include further clarity on whether supervisors will be notified immediately, prior to initiation of a retest, of any instance of a(b)(4)integrity test failure.o Include a product impact assessment.o Provide associated CAPA.A comprehensive risk assessment of all contamination hazards with respect to your aseptic processes, equipment, and facilities. A detailed remediation plan with timelines to address the findings of the contamination hazards risk assessment. Describe specific tangible improvements to be made to aseptic processing operation design and control. Specify actions you will take in response to the risk assessment, such as customer notifications and product recalls.A risk assessment addressing the use of shedding material within your critical ISO 5 production areas. Include a detailed summary of how you determined that your interim controls are adequate to prevent the contamination of products. Include details of your investigation such as evaluation of particle generation, particle size distribution, and the likelihood of detection by visual inspection. Discuss your investigation into potentially impacted lots of product including your evaluation of quality indicators such as complaints and deviations. Specify actions you will take in response to the risk assessment, such as customer notifications and product recalls.2. Your firm failed to establish and follow appropriate written procedures that are designed to prevent microbiological contamination of drug products purporting to be sterile, and that include validation of all aseptic and sterilization processes (21 CFR 211.113(b)).Your(b)(4)cycles were inadequately validated to ensure that they were capable of consistently decontaminating all interior surfaces of your(b)(4)and multiple RABS lines in preparation for aseptic production.Biological Indicator RecoveriesInadequacies in your(b)(4)process were demonstrated through a trend of routine recoveries of biological indicator (BI) growth at completion of validation cycles executed in your(b)(4)since 2022.Notably, your acceptance criteria were inappropriate in that they allowed routine recovery of multiple BI survivors. For example, positive BIs (upwards of 8 recoveries) were identified in nearly all validation cycles ((b)(4)of(b)(4)) between 2022 and 2025 on your lines(b)(4)lines. These positive BIs occurred at various locations within each line. However, based upon your inappropriate acceptance criteria, only two of the(b)(4)validation cycles were found to be unacceptable.Furthermore, you attributed recent validation failures in 2025 to “rogue” phenomenon in a BI lot, but this fails to recognize the multiple positive BIs that occurred with other BI lots in the same year. You also failed to acknowledge your long-term trend of routine BI positives in most of your(b)(4)validation studies.Inadequate(b)(4)ValidationYour(b)(4)validation did not demonstrate reliable decontamination cycle capability. For example:(b)(4)were not(b)(4)during the(b)(4)validation cycles such that(b)(4)were present in the(b)(4). Your validation instruction, PPVA VA 48074e/03, appears to permit(b)(4)to rest on the bottom of(b)(4), creating an occluded surface which undermines the ability of(b)(4)to decontaminate this critical location.You did not document or adequately specify each location of BI placement. You also lacked scientific evidence to support the triplicate BIs being representative of each location.You allowed repetition of validation cycles without proper investigation in each instance of observed BI growth. Your(b)(4)validation cycle was repeated in your(b)(4)after initially failing to meet its acceptance criteria for positive BIs ((b)(4)out of(b)(4)).In your response, you committed to assessing your(b)(4)for surface exposure and implementing remediations based on your findings where possible, increasing BIs in(b)(4)with(b)(4)for(b)(4)decontamination process validation, updating your procedures to address failed validation cycles, reducing the allowable BI growth, implementing investigational requirements for any BI growth, and optimizing the(b)(4)cycle in your(b)(4).Your response is inadequate. You failed to address multiple years of consistent recoveries of positive BIs across multiple locations within your(b)(4)during previous validation cycles. Recurrent failures are indicative of poor cycle robustness and require further investigation. Furthermore, your commitment to increase the number of BIs in(b)(4)does not address setup and configuration adaptations that can ensure consistent exposure of all interior surfaces to(b)(4).Incomplete exposure of interior surfaces to(b)(4)compromises decontamination effectiveness and places the(b)(4)and RABS environment at risk. Furthermore, as discussed above, the inconsistent removal of residual moisture prior to(b)(4)treatment of your(b)(4)and RABS could further compromise(b)(4)decontamination efficacy.In response to this letter, provide:A detailed summary of your validation program for ensuring a state of control throughout the product lifecycle, along with associated procedures. Describe your program for process performance qualification and ongoing monitoring of variation to ensure a continuing state of control.A comprehensive, independent review of the adequacy of(b)(4)cycles. Place special attention on(b)(4)cycle stages including(b)(4). Provide a timeline for a detailed report on the findings of the independent review and associated CAPA activities (e.g., cycle parameter changes such as an increased decontamination phase duration; optimized airflow; improved surface exposure).A detailed program for designing, validating, maintaining, controlling and monitoring each of your decontamination cycles that includes vigilant monitoring to ensure an ongoing state of control. Also, include your program for assuring ongoing state of control throughout your facility and equipment infrastructure.Procedures to ensure residual(b)(4)is appropriately removed from RABS and(b)(4)units before execution of(b)(4)cycles.Request for a Meeting with FDAAfter you submit your response to this warning letter, we recommend you reach out to this office to arrange for a teleconference to discuss your corrective actions and preventive actions in detail. Please direct your request to Patricia Warren at patricia.warren@fda.hhs.gov and cc: CDER-OC-OMQ-Communications@fda.hhs.gov.ConclusionThe violations cited in this letter are not intended to be an all-inclusive list of violations that exist at your facility. You are responsible for investigating and determining the causes of any violations and for preventing their recurrence or the occurrence of other violations.If you are considering an action that is likely to lead to a disruption in the supply of drugs produced at your facility, FDA requests that you contact CDER’s Drug Shortages Staff immediately, at drugshortages@fda.hhs.gov, so that FDA can work with you on the most effective way to bring your operations into compliance with the law. Contacting the Drug Shortages Staff also allows you to meet any obligations you may have to report discontinuances or interruptions in your drug manufacture under 21 U.S.C. 356C(b). This also allows FDA to consider, as soon as possible, what actions, if any, may be needed to avoid shortages and protect the health of patients who depend on your products.Correct any violations promptly. FDA may withhold approval of new applications or supplements listing your firm as a drug manufacturer until any violations are completely addressed and we confirm your compliance with CGMP. We may re-inspect to verify that you have completed corrective actions to any violations.Failure to address any violations may also result in the FDA refusing admission of articles manufactured at Simtra Deutschland GmbH located at Kantstr. 2, 33790 Halle/Westphalia, Germany, into the United States under section 801(a)(3) of the FD&C Act, 21 U.S.C. 381(a)(3). Articles under this authority that appear to be adulterated may be detained or refused admission, in that the methods and controls used in their manufacture do not appear to conform to CGMP within the meaning of section 501(a)(2)(B) of the FD&C Act, 21 U.S.C. 351(a)(2)(B).This letter notifies you of our findings and provides you an opportunity to address the above deficiencies. After you receive this letter, respond to this office in writing within 15 working days1. Specify what you have done to address any violations and to prevent their recurrence. In response to this letter, you may provide additional information for our consideration as we continue to assess your activities and practices If you cannot complete corrective actions within 15 working days, state your reasons for delay and your schedule for completion.Send your electronic reply to CDER-OC-OMQ-Communications@fda.hhs.gov. Identify your response with FEI 3002806419 and ATTN: Samantha Bradley.Sincerely,/S/Francis GodwinDirectorOffice of Manufacturing QualityOffice of ComplianceCenter for Drug Evaluation and ResearchCC:Rémi HelmigSite DirectorSimtra Deutschland GmbHKantstr. 233790 Halle/WestphaliaGermanyrhelmig@simtra.com_____________________1Under program enhancements for the Generic Drug User Fee Amendments (GDUFA) reauthorization for fiscal years (FYs) 2023-2027, also known as the GDUFA III Commitment Letter, your facility may be eligible for a Post-Warning Letter Meeting to obtain preliminary feedback from FDA on the adequacy and completeness of your corrective action plans.

Delivery Method:VIA UNITED PARCEL SERVICE AND VIA E-MAILReference #:26-HFD-45-03-01Product:DrugsRecipient:Mr. David S. MoorePresidentNovo Nordisk Inc.800 Scudders Mill RoadPlainsboro,NJ08536United StatesIssuing Office:Center for Drug Evaluation and Research (CDER)United StatesWARNING LETTERMr. David S. Moore FDA Ref. No.: 26-HFD-45-03-01PresidentNovo Nordisk Inc.800 Scudders Mill RoadPlainsboro, New Jersey 08536Dear Mr. Moore:This Warning Letter informs you of objectionable conditions observed during the U.S. Food and Drug Administration (FDA) inspection conducted at your firm, Novo Nordisk Inc. (hereinafter referred to as NNI), between January 13 and February 7, 2025. The investigators representing FDA reviewed your compliance with postmarketing adverse drug experience (PADE) regulations. The inspection revealed serious violations of PADE reporting requirements found in section 505(k) of the Federal Food, Drug, and Cosmetic Act (FD&C Act) [21 U.S.C. 355(k)] and Title 21, Code of Federal Regulations (21 CFR) 314.80. Failure to comply with section 505(k) is a prohibited act under section 301(e) of the FD&C Act [21 U.S.C. 331(e)].This inspection was conducted as a part of FDA’s Bioresearch Monitoring Program, which includes inspections designed to ensure that accurate, reliable, and timely safety data are submitted to FDA for the monitoring of product safety, and to ensure compliance with PADE regulations.At the conclusion of the inspection, the investigators presented and discussed with you the Form FDA 483, Inspectional Observations. We acknowledge receipt of your written response to the Form FDA 483 dated March 3, 2025, and your subsequent correspondence dated April 11, 2025; May 2, 2025; June 6, 2025; July 11, 2025; September 19, 2025; October 31, 2025; and January 15, 2026.From our review of the FDA Establishment Inspection Report, the documents submitted with that report, and your written response and correspondence dated March 3, 2025; April 11, 2025; May 2, 2025; June 6, 2025; July 11, 2025; September 19, 2025; October 31, 2025; and January 15, 2026, it appears that you did not adhere to the applicable statutory requirements in the FD&C Act and applicable regulations contained in 21 CFR part 314.We wish to emphasize the following:Failure to develop written procedures for the surveillance, receipt, evaluation, and reporting of postmarketing adverse drug experiences (ADEs) to FDA as required by 21 CFR 314.80(b).As an application holder of products with active ingredients including semaglutide, liraglutide, nedosiran sodium, and estradiol, NNI is required to develop written procedures for the surveillance, receipt, evaluation, and reporting of postmarketing adverse drug experiences (ADEs) to FDA. You developed written procedures that failed to ensure that you, and your contractor acting on your behalf, complied with all applicable PADE regulations for the surveillance, receipt, evaluation, and reporting of ADEs.Examples of this failure include but are not limited to the following:1. You failed to develop written procedures, as required under 21 CFR 314.80(b), that ensured that you, and your contractor acting on your behalf, reported all serious and unexpected ADEs to FDA within 15 calendar days, in accordance with 21 CFR 314.80(c)(1)(i). PADE regulations require the applicant to report each ADE that is both serious and unexpected, whether foreign or domestic, no later than 15 calendar days from the initial receipt of the information by the applicant (21 CFR 314.80(c)(1)(i)). Specifically:a. Your written procedure Q014048, “Handling of Adverse Events and Other Safety Information” (Ver: 28.0, Effective Date: 03 Oct 2024), allowed ADEs reported to NNI to be rejected or cancelled (and therefore not to be reported to FDA) if the ADE was considered by the reporter to be unrelated to the product. Specifically, Q014048 excludes reports from the definition of “adverse reaction” if “the reporters specifically state that they believe the events to be unrelated or that a causal relationship can be excluded.” This definition is inconsistent with FDA regulations, which define an ADE as “[a]ny adverse event associated with the use of a drug in humans, whether or not considered drug-related.” FDA’s regulations require applicants to develop written procedures for, among other things, the reporting of ADEs regardless of whether the event is considered causally related to the product. An ADE that is determined to be both serious and unexpected must be reported to FDA no later than 15 days from the date of initial receipt. Based on your written procedure, your staff or contractor cancelled or rejected serious and unexpected ADEs that were required to be reported within 15 calendar days because they documented these events as being unrelated to the product. For example, Argus1Case #1331385 involves a consumer who was disabled after experiencing a stroke, which is a serious and unexpected ADE, while receiving liraglutide. The consumer reported that the stroke was not related to liraglutide; therefore, you rejected this case. As a result, you failed to report serious and unexpected ADEs to FDA within 15 calendar days, as required by PADE regulations.During the inspection, you stated that you opened deviation DV0166369 in April 2024 after discovering that not all reportable serious and unexpected ADEs were submitted to FDA because the ADEs were cancelled or rejected by your staff or contractor and were documented as being “incidental” or “incidental and unrelated.” You identified your written procedures, including Q014048 (both the current and prior versions), as a root cause for this deviation, because both the current and prior versions allowed ADEs reported to NNI to be rejected or cancelled based on the reporter’s assessment of a lack of causality of the event to the product. The root-cause analysis noted that while the exclusion of certain ADEs from reporting as described in the written procedures was consistent with foreign regulatory authority regulations, it was not consistent with U.S. regulations. Although you closed deviation DV0166369 in December 2024, you did not ensure that your corrective and preventive actions were effectively implemented to resolve the existing issues and to prevent recurrence of the noncompliance. Specifically, while you ensured that prior versions of Q014048 were no longer in use, you did not update the definition of “adverse reactions” to remove references to relatedness and causality in the current version of Q014048. Additionally, you closed deviation DV0166369 without confirming the completion of your corrective action to submit all reportable serious and unexpected ADEs to FDA. Although you stated in your written response that you submitted these ADEs to FDA after the investigators discussed them with you during this inspection, you did not provide the case numbers and dates submitted to FDA for all cases with serious and unexpected ADEs that were identified as part of deviation DV0166369. As a result, FDA cannot verify that all serious and unexpected ADEs identified in this deviation were submitted to FDA. Furthermore, you did not provide sufficient information regarding how you will implement the corrective and preventive actions identified in this deviation to ensure that all serious and unexpected ADEs are reported to FDA.In your written response dated March 3, 2025, and in subsequent correspondence, you described corrective actions including but not limited to: (1) revising procedures and other documents to remove certain terminology that created ambiguity and led to serious and unexpected ADEs not being reported to FDA; (2) updating definitions and documentation of the term “spontaneous cases”; and (3) performing a retrospective review of cases to ensure that all valid cases were submitted to FDA. Further, you stated that all cases that were identified as 15-day Alert reports as part of deviation DV0166369 had been submitted to FDA as of February 6, 2025.While we acknowledge the corrective and preventive actions you have taken or plan to take, your written response and subsequent correspondence are inadequate because you did not provide sufficient details for the Agency to determine whether your actions effectively resolved the existing issues and will prevent similar violations in the future. Specifically, you did not provide sufficient details about how your updated procedures, guidance, and training materials will ensure future compliance with reporting serious and unexpected ADEs to FDA in a timely manner.b. Your written procedure Q014048, “Handling of Adverse Events and Other Safety Information” (Ver: 28.0, Effective Date: 03 Oct 2024), states that the minimum criteria for Individual Case Safety Reports (ICSRs) to qualify for submission in an expedited manner are: (1) one or more identifiable reporters; (2) a single identifiable patient; (3) a suspected NNI product; and (4) a suspected adverse reaction. However, your written procedure did not ensure that you, and the call-center contractors acting on your behalf, correctly received, reviewed, and processed ADE information, which resulted in the failure to submit serious and unexpected ADEs that were required to be reported to FDA within 15 calendar days.Specifically, you and your contractors inappropriately invalidated 15-day Alert reports because of a lack of patient identifiers; however, during the inspection, FDA identified valid patient identifiers in source documents for these reports. These reports were not submitted to FDA until they were discussed with you during the inspection. For example, Argus Case #1342548 includes a consumer reporting a death for a male patient who received semaglutide; however, you invalidated the case because you failed to capture the patient identifier. During the inspection, FDA found the patient identifier in the source documents for this case. As a result of this erroneous invalidation, you failed to report serious and unexpected ADEs to FDA within 15 calendar days, as required.We note that you identified this issue when(b)(4)served as your call-center contractor between May 12 and October 12, 2023. You later terminated your contract with(b)(4)⁽ᵇ⁾ ⁽⁴⁾ and switched your call-center contractor to(b)(4), starting on October 13, 2023. You also opened deviation DV0155511 in December 2023 in response to issues observed with(b)(4). Although you switched your call-center contractor to(b)(4)and completed corrective and preventive actions as part of deviation DV0155511, you continued to invalidate cases of ADEs for lack of a patient identifier, despite the patient identifiers’ being available in accordance with written procedure Q014048 and the cases’ otherwise qualifying as reportable. Therefore, you did not ensure that your corrective and preventive actions (for example, review and creation of training resources and content for vendors) were effectively implemented to resolve the existing issues and to prevent recurrence of the noncompliance.In your March 3, 2025, written response and in subsequent correspondence, you stated proposed corrective actions, including but not limited to: (1) conducting retrospective reviews of cases to ensure that all valid cases were submitted to FDA; (2) drafting work instructions related to ICSR quality checks and verification, including source data verification; (3) planning a phased approach to transition safety case intake from the contracted call-center agents to dedicated insourced patient safety agents, who are health care professionals; (4) performing an assessment of the vendor management program; and (5) creating a Vendor Management team, a Vendor Quality team, and a Training team dedicated to your U.S. Patient Safety team, to ensure adequate vendor training and oversight.While we acknowledge the corrective and preventive actions you have taken or plan to take, your written response is inadequate because you did not provide information about whether your proposed actions will prevent similar violations in the future. For example, you did not provide specific information about how you will ensure that vendors acting on your behalf correctly receive, review, and process ADE information, including how you will maintain oversight related to delegated functions. Specifically, you did not provide sufficient details about how your Vendor Management, Quality, and Training teams will operate, what their activities will be, or how these teams will ensure that contractors acting on your behalf will accurately and completely capture ADEs, perform quality check activities, and comply with all applicable PADE requirements. In addition, you did not describe how the “insourced” call center will operate, nor did you provide adequate information to ensure that your insourced call center will comply with PADE requirements in the future.c. Your written procedure Q040018, “Handling Individual Safety Cases in the Global Safety Database” (Ver 43.0, Effective Date: 17 May 2024), states that most serious adverse reactions should enter medical review by calendar day 9 following the awareness date, and they should complete medical review by calendar day 10 following the awareness date. However, your written procedure failed to ensure that cases completed “medical review” within the timelines specified in your written procedure. Rather, cases remained in “medical review” status longer than specified in your written procedure, resulting in your failure to submit 15-day Alert reports to FDA within the required time frame. During the inspection, FDA identified and made you aware of serious and unexpected ADEs that were not submitted to FDA because they remained in “medical review” status beyond the timeline specified in your written procedures. For example, in Argus Case #1334278, you received information on December 9, 2024, from a consumer who reported suicidal ideation while taking semaglutide. This case entered “medical review” status on December 16, 2024; however, medical review was not performed until February 3, 2025, after being identified during FDA’s inspection, and the case was submitted to FDA on February 5, 2025. As a result, you failed to report serious and unexpected ADEs to FDA within 15 calendar days, as required by PADE regulations.In your March 3, 2025, written response and your April 11, 2025, correspondence, you stated that your corrective actions included but were not limited to a requirement for daily review of patient safety cases across each workflow state. However, your written response is inadequate because you did not provide any information about whether your proposed actions will prevent similar violations in the future. For example, you did not provide sufficient details regarding the root cause of this violation, including why these cases remained in “medical review” status beyond the time frames specified in your written procedure. You also have not provided an assessment of whether, and to what extent, this issue implicates the timely reporting of other cases in your product portfolio.2. You failed to develop written procedures that ensured all ADEs that are the subject of 15-day Alert reports were promptly investigated in accordance with 21 CFR 314.80(c)(1)(ii). PADE regulations require that the applicant must promptly investigate all ADEs that are the subject of postmarketing 15-day Alert reports (21 CFR 314.80(c)(1)(ii)).Your written procedure Q0360683, “Case Management Workflow at Novo Nordisk Inc. Patient Safety” (Ver: 7.0, Approved Date: 04 Nov 2024), stated that you did not require follow-up on reported ADEs if consent was not obtained from the reporter and if the reporter was a non-health care professional. Based on this written procedure, you, and your contractor acting on your behalf, failed to promptly investigate ADEs that were subject to 15-day Alert reporting because you did not follow up with reporters to request additional information unless you explicitly obtained consent from the reporter. PADE regulations do not require the obtaining of consent to acquire additional information. As a result, you failed to investigate serious and unexpected ADEs as required by PADE regulations.For example, Argus Case #1171264 includes a non-health care professional reporting the death of a patient receiving semaglutide; however, you failed to promptly investigate because consent was not obtained from the reporter and the reporter was a non-health care professional, as stated in your written procedure. This case was closed without your reporting it to FDA.Procedure Q0360683 also required that NNI perform two follow-up attempts for serious cases in which a death is reported, to obtain relevant safety information for reporting to FDA. However, you failed to promptly investigate Argus Case #1079792, in which a physician reported to your company representative that a patient taking semaglutide was depressed and committed suicide. Youfailed todocument any attempt to obtain additional information from the reporter, including patient identifiers. As of the date of issuance of this letter, this case has not been submitted to FDA.In your written response dated March 3, 2025, you attributed the failure to promptly investigate serious and unexpected ADEs to a procedural gap that required unnecessary consent from the reporter. In your written response and in subsequent correspondence, you described corrective actions including but not limited to: (1) revising local and global SOPs and trainings to remove the requirement to obtain consent from reporters for follow-up; (2) removing fields requiring reporters’ consent from local IT platforms; (3) sending a communication to all vendors and revising safety data exchange agreement (SDEA) templates to clarify that consent is not a predicate requirement to collecting information from a reporter; and (4) conducting a retrospective review of cases to assess that appropriately timed and documented follow-up attempts with reporters were conducted. However, your written response is inadequate because you did not provide information about how your proposed or completed corrective actions would prevent similar violations in the future. For example, you did not provide sufficient details about your quality-control activities, including how you will maintain oversight of vendors with whom you contract to fulfill any of your ADE responsibilities.Additionally, your written response did not specifically address how you will conduct appropriate follow-up, as required by 21 CFR 314.80(c)(1)(ii), for 15-day Alert reports that were not submitted at the time of the inspection.In your March 3, 2025, written response, and in subsequent correspondence, you described corrective actions including but not limited to your engagement with a consultant to perform reviews of your pharmacovigilance processes and associated interfaces, as well as your deviation system and your corrective and preventive action system, to ensure that all cases have been reported to FDA and all deviations have been handled adequately. You also stated that your consultant is engaged in a retrospective review of all closed pharmacovigilance-related deviations dating back to June 2017, and that you have created a deviation review board. We acknowledge that your retrospective review of deviations is complete and that you have received the final report. For each major deviation that may affect compliance with PADE regulations and that has a Quality Assurance approval date after 01 Jan 2021, including those listed on the Deviations Handling request provided to the investigators during the inspection, you should submit a description of the deviation, date of identification, current status, the root-cause analysis, an assessment of the impact, the status of all corrective and preventive actions, and the timeline and results for effectiveness checks.While we acknowledge the corrective and preventive actions your firm has taken since our inspection, your response is inadequate because you did not provide sufficient details to determine whether your actions will effectively prevent similar violations in the future. Your explanations, when taken into consideration with the violations described above and your failure to adequately address your noncompliance, suggest systemic failures with your surveillance, receipt, evaluation, and reporting of ADEs to FDA. In addition, your failure to identify and assess the root cause(s) of deficiencies discussed in this letter raises concerns about your firm’s ability to monitor the safety of your products, including through oversight of vendors with whom you contract to fulfill any of your ADE responsibilities. While this inspection focused on NNI’s compliance with PADE regulations for a sample of NNI’s products, including semaglutide, liraglutide, nedosiran sodium, and estradiol, based on the nature of the inspection’s findings and your written response and correspondence, we have serious concerns about the scope and impact of these violations on your entire product portfolio.FDA relies on the complete, accurate, and timely submission of ADEs to monitor a product’s safety profile and uphold FDA’s mission to protect and promote public health. Reporting ADEs to FDA within the required time frames is necessary for the ongoing monitoring of drug safety profiles. Failure to report and investigate ADEs may limit the safety information that FDA may need when monitoring potential safety signals.We emphasize that as an application holder, it is your responsibility to ensure that you comply with all applicable PADE requirements, including when you contract with a vendor to fulfill any of your ADE responsibilities. Your failure to develop procedures that ensure the submission of 15-day Alert reports and the prompt investigation of ADEs that were the subject of 15-day Alert reports raises significant concerns about your ability to accurately and completely report product safety information to the FDA in accordance with PADE requirements.This letter is not intended to be an all-inclusive list of deficiencies that exist at NNI. It is your responsibility to ensure adherence to each requirement of the law and relevant FDA regulations. You should address any deficiencies and establish procedures to ensure that you comply with FDA regulations.If you are considering an action that is likely to lead to a disruption in the supply of drugs produced at your facility, FDA requests that you contact CDER’s Drug Shortages Staff immediately, at drugshortages@fda.hhs.gov, so that FDA can work with you on the most effective way to bring your operations into compliance with the law. Contacting the Drug Shortages Staff also allows you to meet any obligations you may have to report discontinuances or interruptions in your drug manufacture under 21 U.S.C. 356C(b) and allows FDA to consider, as soon as possible, what actions, if any, may be needed to avoid shortages and protect the health of patients who depend on your products.This letter notifies you of our findings and provides you with an opportunity to address the deficiencies noted above. Within 15 business days of your receipt of this letter, you should notify this office in writing of the actions you have taken to prevent similar violations in the future. Failure to address this matter adequately may lead to regulatory action. If you believe you have complied with the FD&C Act and relevant regulations, please include your reasoning and any supporting information for our consideration.Should you have any questions or concerns regarding this letter or the inspection, please email FDA at CDER-OSI-ADE@fda.hhs.gov. Your written response and any pertinent documentation should be addressed to:Dipti Kalra R.Ph., M.S., MBA Branch ChiefPostmarketing Safety BranchDivision of Enforcement and Postmarketing Safety Office of Scientific InvestigationsOffice of ComplianceCenter for Drug Evaluation and ResearchU.S. Food and Drug Administration Building 51, Room 534310903 New Hampshire Avenue Silver Spring, MD 20993-0002Sincerely,{See appended electronic signature page}David C. Burrow, Pharm.D., J.D. DirectorOffice of Scientific Investigations Office of ComplianceCenter for Drug Evaluation and ResearchU.S. Food and Drug Administration--------------------------------------------------------------------------------------------This is a representation of an electronic record that was signed electronically. Following this are manifestations of any and all electronic signatures for this electronic record.--------------------------------------------------------------------------------------------/s/------------------------------------------------------------DAVID C BURROW03/05/2026 08:24:50 AM______________________1Argus is NNI’s drug safety database.