黑龙江百姓康健医药连锁有限公司销售劣药醋氯芬酸胶囊（批号：230201）的行为违反了《中华人民共和国药品管理法》第九十八条第一款规定，依据《中华人民共和国药品管理法》第一百一十七条第一款、《中华人民共和国药品管理法》实施条例第七十五条、《黑龙江省药品监督管理局行政处罚裁量适用规则》第十五条第一款的规定予以处罚。

江苏康林贝医疗器械有限公司报告，由于在江苏省局监督抽检中出现一次性使用湿化鼻氧管“还原物质”指标不符合要求，江苏康林贝医疗器械有限公司对其生产的一次性使用湿化鼻氧管主动召回。召回级别为三级。涉及产品的型号、规格及批次等详细信息见《医疗器械召回事件报告表》。

案例一：商丘市查处某药店未从药品上市许可持有人或具有药品生产经营资格的企业购进药品案　　一、案情简介　　根据国家药监局关于开展药品经营环节“清源”行动部署，商丘市市场监督管理局坚持基层导向，坚持以案破局，突出重点，严厉打击药品经营环节违法行为。2025年5月20日，在对辖区内某药店开展检查，通过河南省药品追溯移动APP对该药店经营的药品进行单码追溯查询，经系统查询，复方丹参滴丸、阿托伐他汀钙片、胰激肽原酶肠溶片等药品最终流向终端非本药店，且现场未提供供货方资质及购进票据。商丘市局按照程序依法对上述药品采取扣押强制措施，5月23日对该药店予以立案调查。　　5月20日当天，执法人员询问其购进药品的渠道来源，药店店长以及药店负责人因担心打击报复或者出于其他顾虑没有如实告知执法人员送药人、送药时间、品种、数量等信息。后经执法人员给其讲明从非法渠道购进药品所面临的罚款、人员罚、资格罚等处罚措施后，药店表示全力协助配合执法人员工作，提供了送药时间、送药人进入店内录像视频、车辆信息等。执法人员及时与公安机关联系，查询送药车主信息，并到公安机关作了辨认笔录。市场监管与公安机关执法人员顺藤摸瓜找到了送药人存放药品仓库并将其抓获，送药人涉嫌销售假药罪被公安机关采取刑事拘留强制措施，另外两个同伙被采取取保候审强制措施。　　二、查处情况　　该药店构成了未从药品上市许可持有人或者具有药品生产、经营资格的企业购进复方丹参滴丸等13个品种药品的违法行为，依据《中华人民共和国药品管理法》第一百二十九条“违反本法规定，药品上市许可持有人、药品生产企业、药品经营企业或者医疗机构未从药品上市许可持有人或者具有药品生产、经营资格的企业购进药品的，责令改正，没收违法购进的药品和违法所得，并处违法购进药品货值金额二倍以上十倍以下的罚款；情节严重的，并处货值金额十倍以上三十倍以下的罚款，吊销药品批准证明文件、药品生产许可证、药品经营许可证或者医疗机构执业许可证；货值金额不足五万元的，按五万元计算”的规定。在案件调查过程中，当事人能积极配合调查，如实陈述违法事实并提供证据材料，主动积极配合公安机关和我局追查违法嫌疑人，经案件负责人集体讨论决定，作出减轻处罚，罚款3万元的行政处罚。　　三、主要经验做法　　（一）突出风险研判。以城乡接合部、农村地区为重点区域，强化摸排暗访，以心脑血管病类药物销售价格明显低于市场价的药店为重点检查对象，有的放矢，做到精准打击。　　(二)智慧监管赋能执法。依托河南省药品追溯移动APP实现"一码溯源"，通过数字化手段快速精准锁定药品流向异常，提升执法效能。　　（三）监管稽查联动机制。建立"检查-取证-移交-反馈"闭环体系，业务科室与执法部门形成监管合力，确保违法线索及时查办，形成了监管与稽查部门通力合作、优势互补的格局。　　（四）行刑衔接攻坚模式。针对复杂案件启动公安提前介入机制，成立联合专案组，发挥各自职能技术优势，共同开展案件调查工作，有效破解了线索摸排手段有限、当事人不配合检查、调查等难题。该案的成功办理，就是联合办案的典范。　　四、工作启示　　一是前期进行风险研判，做到精准打击；二是科技赋能推动监管升级，药品追溯系统已成为打击非法渠道购销的关键工具；三是多部门协同作战机制成效显著，市场监管与公安的职能互补形成执法合力；三是强化药品全生命周期监管，从终端销售倒查上游违法环节，实现“清源”效果；四是警示震慑作用凸显，通过典型案例教育引导药品经营企业严守《药品管理法》规定，切实履行主体责任。案例二：新乡市延津县查处某村卫生室非法渠道购进药品案　　2025年5月21日新乡市延津县市场监督管理局接到相关部门问题线索移送函后，对辖区某卫生室药品重复销售及无合法进货票据情况进行现场核查。经查，该村卫生室销售的复方丹参滴丸、阿司匹林肠溶片、左氨氯地平片进货渠道不正规，涉嫌违规购进药品。当事人不能提供进货票据及供货商经营资质。当事人亲属从延津县某医院购买复方丹参滴丸、阿司匹林肠溶片、左氨氯地平片未服用完，又在村卫生室进行销售，以上药品均销售完毕，违法所得共计132.73元。当事人的行为违反了《中华人民共和国药品管理法》第五十五条的规定，依据《中华人民共和国药品管理法》第一百二十九条之规定，责令当事人改正违法行为，处罚如下:1、没收违法所得132.73元;2、罚款人民币20000元;　　通过这起案件，执法人员总结出了一些经验做法。首先，在接到问题线索后能够迅速反应，及时展开调查，这确保了案件能够在较短时间内得到处理，避免了风险的进一步发展。其次，执法人员在调查过程中严格按照法律程序办事，注重证据的收集和分析，保证了案件处理的公正性和合法性。　　这起案件也给我们带来了深刻的工作启示。一方面，药品经营使用单位必须严格遵守药品管理的相关法律法规，提高依法经营意识，规范药品购进渠道，落实质量安全主体责任，防范药品质量安全风险，保障群众用药安全有效。另一方面，市场监管部门要加强同卫生健康、医疗保障等部门的沟通协调，做好案件移送、情况通报、信息共享、联合惩戒等方面的对接工作，积极探索创新综合监管和联合检查，提升风险防范预警和问题发现处置能力，共同营造公平有序的药品经营市场环境。

Delivery Method:Via EmailReference #:320-25-86Product:DrugsRecipient:Mr. Jin Soo BaekManaging DirectorDaewoo Pharmaceutical Co., Ltd.153, Dadae-ro, Saha-guBusan49393South KoreaIssuing Office:Center for Drug Evaluation and Research (CDER)United StatesWarning Letter320-25-86July 2, 2025AMENDED(This letter replaces Warning Letter No. 320-25-86 dated June 26, 2025)Dear Mr. Baek:The United States Food and Drug Administration (FDA) inspected your drug manufacturing facility, Daewoo Pharmaceuticals Co., Ltd., FEI 1000448124, at 153, Dadae-ro, Saha-gu, Busan, from January 6 to 15, 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 product 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 February 12, 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 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)).Inadequate Smoke StudiesSmoke studies showed a lack of unidirectional airflow in your ISO 5 aseptic processing operation. Multiple instances of turbulent airflow in critical areas of filling line(b)(4)were noted, including above the(b)(4). In addition, smoke study videos did not include set-up of the aseptic processing line or filling line interventions that sufficiently represent your commercial manufacturing process.In your response, you commit to repeat smoke studies with defined set-up and interventions. Your response is inadequate as you do not provide details, such as how you will address line deficiencies, when you will perform the smoke studies, and what interventions will be included.Inadequate Media Fill ProgramYour media fills failed to accurately simulate commercial operations. Our inspection found that the aseptic operations simulated during your media fills were not sufficiently representative of aseptic manufacturing operations. We observed significantly more interventions performed during routine batch manufacturing that were either not simulated or reduced in quantity in media fills, as compared to what was observed during production. Notably, a substantial number of these interventions during routine production were unplanned.In addition, the type, frequency, and time of interventions are not routinely documented in production batch records.Your firm also did not require operators to participate in a media fill prior to working in the aseptic processing operation.Your response is inadequate. You commit to documenting routine interventions during manufacturing but fail to evaluate the interventions used in your media fill program and their inadequate representation of routine production. Your operators performed numerous, manually intensive interventions during aseptic operations. As such, the quantity of process simulation interventions and the duration of the media fill should closely resemble the actual manufacturing process. If a media fill program fails to incorporate contamination risk factors and closely simulate actual drug product exposure, the state of process control and assurance of sterility cannot be accurately assessed.Poor Practices in the Aseptic Processing AreasDuring the inspection of your facility, we observed poor practices in ISO 5 areas during the aseptic processing of sterile drug products. These poor practices included, but are not limited to:Exposed skin in the ISO 5 area (e.g., forehead).Use of non-sterile tape on the filling line.Storage of machine tools and spare parts, for use on the filling line, in a(b)(4)of the ISO 5 area.Your response is inadequate because it does not address the lack of oversight of the operators’ aseptic practices and evaluate the insufficiencies in their training. Further, these poor aseptic practices were not evaluated to determine the impact to aseptic processing operations.Insufficient Personnel MonitoringThe personnel monitoring for operators working in the ISO 5 area was not sufficient to assure sterility. For example, the locations chosen for personnel monitoring were not scientifically justified, nor was the practice of using(b)(4)plates for one hand and(b)(4)for the other. In addition, there was no written procedure for gowning qualification.Your response is inadequate, as you fail to conduct a retrospective review of your aseptic personnel monitoring practices.In response to this letter, provide the following:Comprehensive risk assessment of all contamination hazards with respect to your aseptic processes, equipment, and facilities, including an independent assessment that includes, but is not limited to:o All human interactions within the ISO 5 areao Equipment placement and ergonomicso Air quality in the ISO 5 area and surrounding roomo Facility layouto Personnel Flows and Material Flows (throughout all rooms used to conduct and support sterile operations)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.Your plan to ensure appropriate aseptic practices and cleanroom behavior during production. Include steps to ensure routine and effective supervisory oversight for all production batches. Also describe the frequency of quality unit (QU) oversight (e.g., audit) during aseptic processing and its support-operations.A thorough retrospective review and risk assessment that evaluates how poor aseptic technique and cleanroom behavior may have affected the quality and sterility of your drugs.Smoke studies under dynamic conditions, with thorough and complete evaluations of aseptic interventions and operator positioning within the critical filling areas. After you remediate your aseptic operation, provide smoke studies that visualize airflow and critically evaluate unidirectional airflow. Include a video of your dynamic smoke studies.A comprehensive summary of your remediated media fill program that ensures appropriate simulations of worst-case conditions in commercial manufacturing.2. 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)).Equipment as a Route of ContaminationThe design of the aseptic processing line used to manufacture over-the-counter(b)(4)drug products was inadequate. Line(b)(4)is a traditional filling line consisting of an ISO 5 area(b)(4)and a surrounding ISO 7 area. The line involves manually intensive(b)(4)interventions, and the HEPA filter layout leaves approximately 10-centimeter gaps due to overhead lights in between the filters that appear to affect unidirectional airflow.Furthermore, you did not sterilize direct product contact equipment that holds primary container and closure components for your sterile drug products. These equipment were disinfected with(b)(4), which are not sterilants. You also use(b)(4)approximately(b)(4), which is a decontaminating agent.Your response is inadequate. You commit to turning Line(b)(4)into an(b)(4)restricted access barrier ((b)(4)RAB) filling line. However, you did not provide detailed plans for how you will redesign your filling line and conduct a risk assessment for products currently released to the U.S. Market.Environmental Monitoring (EM)The EM of your aseptic processing operations was inadequate. The locations identified for EM in ISO 5 and ISO 7 areas lacked scientific justification and were not sufficiently located where the aseptic operations are taking place.The consistent and meaningful contamination level in ISO 7, along with frequent manually intensive interventions, posed a high risk to sterile products on your aseptic processing line.Your response is inadequate. You commit to repeating the EM risk assessment and trending EM data but fail to include plans for how you will assess your line after redesign.A vigilant, ongoing EM program is essential to detect and respond to potential product contamination hazards in your manufacturing environment in a timely manner. Loss of environmental control in an aseptic manufacturing facility can ultimately pose a serious hazard to patients.In response to this letter, provide the following:Your corrective action and preventive action (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.An independent assessment of your EM program including, but not limited to, establishing appropriate limits, sampling locations and frequencies, investigating deviations, and trend analysis. Also, ensure the implementation of a comprehensive CAPA plan.3. Your firm failed to establish adequate written procedures for production and process control designed to assure that the drug products you manufacture have the identity, strength, quality, and purity they purport or are represented to possess (21 CFR 211.100(a)).Visual InspectionYour post-fill visual inspection of aseptically filled drug products was insufficient to identify defects which may be present. For example, bottles were only inspected against a(b)(4)background to identify visible defects, particulates, and cloudiness. Individual defect limits were not set. Further, an Acceptable Quality Limit (AQL) sample is not obtained for quality assurance evaluation.In addition, your visual inspector qualification process is inadequate. For example, you lack a procedure for inspector training, and the(b)(4)challenge kit is used for each of(b)(4)runs where it is not required that inspectors identify the correct defect, only the correct bottle.Your response is inadequate. You commit to evaluating the visual inspection program and replacing the(b)(4)process with an(b)(4)one, instead of a(b)(4)inspection methods. Your program should include an appropriate combination of these techniques to ensure detection of the wide array of potential visible product defects.In addition, you fail to provide details regarding the qualification and creation of a defect library, challenge kits, appropriate inspection protocols (including use of a(b)(4)background), and inspector training.In response to this letter, provide the following:A formalized 100% visual inspection program designed to reliably detect particulate contamination and other visible defects. Your program should detail the inspection methods, identify categories of defects and their associated acceptance and rejection limits for each batch, and include inspector training and qualification.A retrospective review of drug product batches released without having undergone a complete and appropriate visual inspection by qualified inspectors.Perform a visual inspection of retain samples for all batches already in distribution and provide the results.4. 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).The QU failed to maintain adequate CGMP oversight. For example:Lack of Written Procedures (211.100)Numerous written procedures were either missing or lacked sufficient detail to ensure consistent repeatability between operators. For example, the following critical processes were not contained in a written procedure: set-up of the filling line, performing interventions on the filling line, personnel monitoring, and how to perform(b)(4)decontamination of aseptic processing rooms.In addition, written procedures lacked sufficient detail, including those for cleaning of the filling line and cleaning of the filling room.Your response is inadequate. You commit to writing procedures for the critical items described above, however you fail to perform a comprehensive review to ensure appropriate procedures are established and followed as part of your quality system. In addition, you did not provide a comprehensive risk assessment of the product impact of the lack of sufficient procedures.Investigations (211.192)We noted multiple instances where thorough investigations were not completed. For example, a viable air monitoring plate dated January 22, 2024, had a significant microbial recovery for the ISO 7 area of Line(b)(4), identified asCladosporium, a mold. The available documentation of theCladosporiumrecovery noted that the same mold was found in multiple areas of the facility. You lacked a meaningful investigation into this trend.Your response is inadequate as you did not commit to opening an investigation to examine this and other potentially adverse trends.Complaint Handling (211.198(a))Your complaint handling and investigation process is inadequate. Retain samples are not always evaluated for sterility unless requested by your distributor, even when the complaint indicates potential contamination. For example, you received a substantial number of complaints for burning or redness but did not perform sterility testing on retain samples until the fourth complaint was received.Your response is inadequate. You commit to reviewing past complaints and updating your current procedure but fail to provide details for how you will incorporate testing, including but not limited to, sterility, into your complaint handling process in the future.Raw Material Testing for(b)(4)(211.84(d)(2))Your incoming raw material sampling and testing plan for(b)(4), which is a component at high-risk of contamination with(b)(4), is inadequate.Your response is inadequate. While you commit to testing each container of every lot moving forward, you did not commit to testing of finished products that previously used these raw materials to verify that(b)(4)are not present above specified levels.The use of ingredients contaminated with(b)(4)has resulted in various lethal poisoning incidents in humans worldwide. See FDA’s guidance document Testing of(b)(4)to help you meet the CGMP requirements when manufacturing drugs containing ingredients at high-risk for(b)(4)contamination at(b)(4).In response to this letter, provide:A commitment to provide(b)(4)test results, no later than 30 calendar days from the date of this letter, from testing retains for all lots of high-risk drug components used in the manufacture of drug products. Alternatively, if a retain of a component lot is unavailable, perform retain sample testing of all implicated finished drug product batches for the presence of(b)(4).A full risk assessment for drug products that are within expiry which contain any ingredient at risk for(b)(4)contamination (including, but not limited to,(b)(4)). Take prompt and appropriate actions to determine the safety of all lots of the component(s) and any related drug product that could contain(b)(4), including customer notifications and product recalls for any contaminated lots. Identify additional appropriate CAPAs that secure supply chains in the future, including, but not limited to, ensuring that all incoming raw material lots are from fully qualified manufacturers and free from unsafe impurities. Detail these actions in your response to this letter.A description of how you will test each component lot for conformity with all appropriate specifications for identity, strength, quality, and purity. If you intend to accept any results from your supplier’s certificate of analysis instead of testing each component lot for strength, quality, and purity, specify how you will robustly establish the reliability of your supplier’s results through initial validation as well as periodic revalidation. In addition, include a commitment to always conduct at least one specific identity test for each incoming component lot. In the case of(b)(4), and certain additional high-risk components we note that this includes the performance of parts(b)(4)of the United States Pharmacopeia (USP) monograph.The chemical quality control specifications you use to test each incoming lot of high-risk drug components to determine acceptability for use in manufacturing.A comprehensive, independent review of your material system to determine whether all suppliers of components, containers, and closures, are each qualified and the materials are assigned appropriate expiration or retest dates. The review should also determine whether incoming material controls are adequate to prevent use of unsuitable components, containers, and closures.A comprehensive, independent assessment of your overall system for investigating deviations, discrepancies, complaints, out-of-specification (OOS) results, and failures. Provide a detailed action plan to remediate this system. Your action plan should include, but not be limited to, significant improvements in investigation competencies, scope determination, root cause evaluation, CAPA effectiveness, QU oversight, and written procedures. Address how your firm will ensure all phases of investigations are appropriately conducted.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.5. Your firm failed to establish and follow adequate written procedures for cleaning and maintenance of equipment (21 CFR 211.67(b)).Your cleaning procedures lack sufficient detail to ensure repeatability between operators. We observed cleaning deficiencies and variability between operators, including wiping technique, using the same cleaning cloths for multiple areas, and failure to clean on top of the overhead light casings of the filling line.Further, the disinfection efficacy studies for(b)(4)did not adequately address all materials of the filling line, including but not limited to,(b)(4)(filling equipment),(b)(4)and(b)(4), and(b)(4)hose).In addition, your(b)(4)room decontamination validation is deficient (e.g., biological indicator locations are not adequately justified).Your response is inadequate. You commit to conduct a comprehensive review and assessment of cleaning and disinfection practices; however, you fail to investigate the impact on the products in the U.S. Market. In addition, a retrospective review for only extraneous chromatographic peaks is not sufficient to determine if deficient cleaning practices contribute to finished product that does not meet established specifications.In response to this letter, provide the following:A CAPA plan, based on the retrospective assessment of your cleaning and disinfection program, that includes appropriate remediations to your cleaning and disinfection processes and practices, and timelines for completion. Provide a detailed summary of vulnerabilities in your process for lifecycle management of equipment cleaning and disinfection. Describe improvements to your cleaning and disinfection program, including enhancements to cleaning and disinfection effectiveness; improved ongoing verification of proper cleaning and disinfection execution for all products and equipment; and all other needed remediations.Additional Guidance on Aseptic ProcessingSee 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.Quality SystemsYour firm’s quality systems are inadequate. For guidance on establishing and maintaining CGMP-compliant quality systems, see FDA’s guidances: Q9 Quality Risk Management at https://www.fda.gov/media/167721/download and Q10 Pharmaceutical Quality System at https://www.fda.gov/media/71553/download.Drug Production SuspendedWe acknowledge your commitment to suspend production of all drugs and that you deregistered your facility as a drug manufacturer. In response to this letter, clarify whether you intend to resume manufacturing drugs for the U.S. market at this facility in the future.If you plan to resume any manufacturing operations regulated under the FD&C Act, notify this office before resuming your drug manufacturing operations. If your firm intends to resume manufacturing drugs, you should engage a consultant qualified as set forth in 21 CFR 211.34 to evaluate your operations to assist your firm in meeting CGMP requirements. Your use of a consultant does not relieve your firm’s obligation to comply with CGMP. Your firm’s executive management remains responsible for resolving all deficiencies and systemic flaws to ensure ongoing CGMP compliance. In your notification to the Agency, provide a summary of your remediations to demonstrate that you have appropriately completed all CAPAs.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. 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 Daewoo Pharmaceutical Co. Ltd, 153, Dadae-ro, Saha-gu, Busan, 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 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 1000448124 and ATTN: Sarah Rhoades.Sincerely,/S/Francis GodwinDirectorOffice of Manufacturing QualityOffice of ComplianceCenter for Drug Evaluation and Research

Delivery Method:VIA UNITED PARCEL SERVICE AND VIA E-MAILReference #:25-HFD-45-06-02Product:DrugsRecipient:Mark J. Savant, M.D2435 Ocean AvenueSan Francisco,CA94127United StatesIssuing Office:Center for Drug Evaluation and Research (CDER)United StatesWARNING LETTERFDA Ref. No.: 25-HFD-45-06-02Dear Dr. Savant:This Warning Letter informs you of objectionable conditions observed during the U.S. Food and Drug Administration (FDA) inspection conducted at your clinical site between April 9 and April 17, 2024. Investigator Dustin R. Abaonza, representing FDA, reviewed your conduct of a clinical investigation (Protocol(b)(4), “(b)(4)”) of the investigational drugs(b)(4), performed for the(b)(4).This inspection was conducted as a part of FDA’s Bioresearch Monitoring Program, which includes inspections designed to evaluate the conduct of research and to help ensure that the rights, safety, and welfare of human subjects have been protected.At the conclusion of the inspection, Investigator Abaonza presented and discussed with you the Form FDA 483, Inspectional Observations. We acknowledge receipt of your May 8, 2024, written response to the Form FDA 483.From our review of the FDA Establishment Inspection Report, the documents submitted with that report, and your written response dated May 8, 2024, it appears that you did not adhere to the applicable statutory requirements in the Federal Food, Drug, and Cosmetic Act (FD&C Act) and applicable regulations contained in Title 21 of the Code of Federal Regulations, part 312 (21 CFR 312) governing the conduct of clinical investigations and the protection of human subjects. We wish to emphasize the following:1. You failed to ensure that the investigation was conducted according to the investigational plan [21 CFR 312.60].As a clinical investigator, you are required to ensure that your clinical studies are conducted in accordance with the investigational plan. The investigational plan for Protocol(b)(4)required you to calculate the volume of the investigational product (IP) administered to enrolled subjects according to the subjects’ body weight. The protocol also required you to ensure that subjects met all eligibility requirements before enrollment. You failed to adhere to these requirements. Examples of these failures include but are not limited to the following:a. The investigational plan for Protocol(b)(4)required the volume of the(b)(4), for intravenous infusion to be calculated according to the subjects’ body weight in kilograms (kg). You failed to adhere to this requirement. Specifically, Subject(b)(6)’s body weight was documented as 68.9 kg at study entry. However, on January 19, 2022, Subject(b)(6)received a calculated volume of IP according to a body weight of 152 kg instead of 68.9 kg. As a result, the final volume of(b)(4)received by Subject(b)(6)was more than two times the amount of IP that the subject should have received, according to the protocol.In your May 8, 2024, written response to the Form FDA 483, you stated that Subject(b)(6)’s body weight was incorrectly documented by the clinical research coordinator on the IP prescription provided to the pharmacist as 152 kg rather than 152 lb. You also stated that you signed the prescription electronically, but that you: (1) failed to ensure that the subject’s weight was documented correctly, (2) failed to review the source documents before the treatment visit, and (3) failed to ensure that the study coordinator was adequately trained on the protocol.b. The investigational plan for Protocol(b)(4)required you to ensure that study subjects met all inclusion criteria before enrollment. The subjects who were randomized to receive(b)(4)were required to meet the additional eligibility criteria found in the investigational agent-specific appendix of the protocol. You failed to adhere to this requirement. Specifically:i. The investigational plan for Protocol(b)(4), Appendix XV, required you to ensure that subjects of reproductive potential had a negative serum or urine pregnancy test within 48 hours before study entry. Subject(b)(6), a 37-yearold female, was documented as being capable of birthing potential on the subject’s Day 0/Study Entry case report form dated January 19, 2022. However, this case report form indicates that the pregnancy test was not applicable, and no negative serum or urine pregnancy test was documented within 48 hours of study entry. Despite her not meeting this inclusion criterion, Subject(b)(6)was randomized on the study and received the IP on January 19, 2022.ii. The investigational plan for Protocol(b)(4), Appendix XV, required you to ensure that subjects in phase III of the protocol met the protocol definition of being at “higher” risk of progression to hospitalization or death before enrollment in the study.1If subjects did not meet the protocol’s definition of “higher” risk, including subjects who had received at least one dose of a(b)(4), they were considered to be at “lower” risk of progression to hospitalization or death, according to the protocol. However, two subjects did not meet the protocol definition of being at “higher” risk of progression to hospitalization or death. Specifically:(a) According to study records, Subject(b)(6)did not meet the protocol’s definition for “higher” risk of progression to hospitalization or death. However, on January 17, 2022, this subject was randomized to phase III of the protocol, with the risk of progression indicated as being “high.”(b) According to study records, Subject(b)(6)was documented to have received two(b)(4), which met the protocol’s definition of “lower” risk for progression to hospitalization or death. However, on January 19, 2022, this subject was randomized to phase III of the protocol, with the risk of progression indicated as being “high.”In your May 8, 2024, written response to the Form FDA 483, you stated that you did not adequately review the inclusion/exclusion criteria; instead, you relied on the clinical research coordinator to provide you with all the eligibility information, and you made the determination based on the information provided. You further stated that site-created source documents were insufficient; that they lacked inclusion of critical assessments; and that they lacked collection of data required at subject visits, such as the required pregnancy tests at screening/Day 0, and an inclusion/exclusion criteria checklist. You also stated that you failed to ensure that the clinical research coordinator was trained adequately on the protocol.In addition, in your written response, you detailed the corrective and preventive actions that you and your site have taken or plan to take, including: (1) reporting the protocol deviations to the IRB; (2) requiring investigators to personally write prescriptions and review all source documents to ensure that subjects are given the correct dose of IP; (3) implementing quality checks of all source documents to ensure that the source documents are accurate and complete; (4) including a visit checklist on source documentation for all future studies, to ensure that all required assessments are completed and documented properly; (5) creating a detailed inclusion and exclusion criteria checklist for all future studies, to ensure that eligibility requirements are met; and (6) implementing an onboarding/training plan for all current and new site staff.We emphasize that as the clinical investigator, it is your responsibility to ensure that studies are conducted in accordance with the investigational plan, both to protect the rights, safety, and welfare of subjects and to ensure the integrity of study data. Your failure to conduct the clinical study in accordance with the protocol resulted in an overdose of the investigational product to a subject, as well as the enrollment of subjects who did not meet all eligibility requirements. This conduct raises significant concerns about your protection of the study subjects enrolled at your site, and raises concerns about the validity and integrity of the data collected at your site.2. You failed to obtain informed consent in accordance with the provisions of 21 CFR part 50 [21 CFR 312.60 and 21 CFR 50.20].As a clinical investigator, you are required to obtain informed consent in accordance with 21 CFR part 50. FDA’s regulations at 21 CFR 50.20 state that, except as provided in 21 CFR 50.23 and 21 CFR 50.24, no investigator may involve a human being as a subject in research covered by the regulations unless the investigator has obtained the legally effective informed consent of the subject or the subject’s legally authorized representative.Protocol(b)(4), the “Phase III Main Informed Consent Form,” which was approved by the IRB on August 11, 2021, stated that subjects would receive information about specific study drugs being tested in a separate consent form. This separate consent form, “Informed Consent Form Addendum for Study Drugs,” which was also approved by the IRB on August 11, 2021, was used to inform potential subjects about all the study drugs they might receive in the study, including the associated risks of the study drugs.You failed to obtain legally effective informed consent for two subjects before their enrollment in Protocol(b)(4). Specifically, Subjects(b)(6)and(b)(6)signed the “Phase III Main Informed Consent Form” on January 17, 2022; however, neither subject signed the “Informed Consent Form Addendum for Study Drugs.”In your May 8, 2024, written response to the Form FDA 483, you stated that you failed to read the full IRB approval letter and were therefore unaware of the requirement to obtain informed consent from subjects using the additional “Informed Consent Form Addendum for Study Drugs.” You also detailed the corrective and preventive actions that you and your site have taken or plan to take, including: (1) submitting the deviation to the IRB; (2) contacting the subjects to come onsite to obtain the missed consent; (3) updating site informed consent standard operating procedures (SOPs) to include the use of a study-specific informed consent checklist and process document, as well as providing staff training on the updated SOPs; and (4) hiring a quality-control professional to manage IRB approval notifications and implementation.We emphasize that as the clinical investigator, you are responsible for ensuring that legally effective informed consent is obtained from subjects before their enrollment. Your failure to obtain informed consent in accordance with 21 CFR part 50 before involving subjects in research jeopardizes the safety and welfare of subjects by denying them an opportunity to fully assess the risks and benefits of their participation in the clinical investigation.While we acknowledge the corrective and preventive actions that you and your site have taken and plan to take, your response is inadequate because you have not provided sufficient details about your corrective action plan. For example, you did not provide sufficient details about the policies, procedures, and training plan being implemented at your site to prevent similar violations in the future.We emphasize that as the clinical investigator, you are ultimately responsible for compliance with all applicable FDA regulations governing the conduct of clinical investigations and the protection of human subjects, both to protect the rights, safety, and welfare of subjects and to ensure the integrity of study data. Your failure to conduct the clinical study in accordance with the protocol, your failure to obtain the legally effective informed consent before involving subjects in research, and your lack of oversight and supervision of the clinical study, raise significant concerns about your protection of study subjects enrolled at your site and raise concerns about the validity and integrity of the data collected at your site.This letter is not intended to be an all-inclusive list of deficiencies with your clinical study of an investigational drug. 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 any ongoing or future studies comply with FDA regulations.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 that 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-Communications@fda.hhs.gov. Your written response and any pertinent documentation should be addressed to:Brittany L. Garr-Colón, MPHBranch ChiefCompliance Enforcement BranchDivision of Enforcement and Post-marketing SafetyOffice of Scientific InvestigationsOffice of ComplianceCenter for Drug Evaluation and ResearchU.S. Food and Drug AdministrationBuilding 51, Room 535210903 New Hampshire AvenueSilver Spring, MD 20993Sincerely yours,{See appended electronic signature page}David C. Burrow, Pharm.D., J.D.DirectorOffice of Scientific InvestigationsOffice 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 BURROW06/26/2025 06:42:31 AM_____________________1The protocol considered the following subjects at “higher” risk of progression to hospitalization or death as long as the subject did NOT receive any doses of a(b)(4): (1) ≥ 65 years of age; (2) ≥ 55 years of age and satisfying at least one of the following: history of cardiovascular disease (for example, myocardial infarction, stroke, heart failure), hypertension with at least one medication recommended or prescribed, or chronic obstructive pulmonary disease (COPD) or other chronic respiratory disease requiring daily prescribed therapy; (3) ≥ 18 years of age and satisfying at least one of the following: body mass index ≥ 35 kg/m2, chronic kidney disease requiring hemodialysis or peritoneal dialysis, Type 1 or Type 2 diabetes, or exogenous or endogenous immunosuppression (that is, HIV infection or receiving corticosteroids equivalent to prednisone ≥ 20 mg daily for at least 14 consecutive days, within 30 days before study entry); or (4) treatment with biologics, immunomodulators, or chemotherapy within 90 days before study entry.

Delivery Method:Via EmailProduct:Drugs\Over-the-Counter DrugsRecipient:Tom FreyneCEOScope Health Inc79 Madison Ave, Fl 8New York,NY10016United Stateshello@optase.comIssuing Office:Center for Drug Evaluation and Research (CDER)United StatesWARNING LETTERJuly 9, 2025RE: 695085Dear Mr. Freyne:This letter is to advise you that on August 28, 2024 the U.S. Food and Drug Administration (FDA) reviewed your product labeling, including on your website at the internet address optase.com where your ophthalmic drug products are available for purchase in the United States without a prescription.Based on our review, your MGD Advanced Dry Eye Drops, Dry Eye Intense Drops (multi-use bottle and single dose), Allegro Eye Drops, HYLO Night Eye Ointment, Tea Tree Oil Eyelid Wipes, Tea Tree Oil Eyelid Gel, and Protect Eyelid Cleansing Spray drug products are unapproved new drugs introduced or delivered for introduction into interstate commerce in violation of sections 505(a) and 301(d) of the Federal Food, Drug, and Cosmetic Act (FD&C Act), 21 U.S.C. 355(a) and 331(d). In addition, your Dry Eye Intense Drops (multi-use bottle) product is misbranded under section 502(f)(2) of the FD&C Act, 21 U.S.C. 352(f)(2), and your Allegro Eye Drops, MGD Advanced Dry Eye Drops, Dry Eye Intense Drops (multi-use bottle and single dose), and HYLO Night Eye Ointment products are misbranded under section 502(ee) of the FD&C Act, 21 U.S.C. 352(ee). Introduction or delivery for introduction of misbranded products into interstate commerce is prohibited under sections 301(d) and (a) of the FD&C Act, 21 U.S.C. 331(d) and (a). These violations are described in more detail below.Unapproved New Drug and Misbranded Drug ViolationsMGD Advanced Dry Eye Drops, Dry Eye Intense Drops (multi-use bottle and single dose), Allegro Eye Drops, HYLO Night Eye Ointment, Tea Tree Oil Eyelid Wipes, Tea Tree Oil Eyelid Gel, and Protect Eyelid Cleansing Spray are “drugs” as defined by section 201(g)(1)(B) of the FD&C Act, 21 U.S.C. 321(g)(1)(B), because they are intended for use in the diagnosis, cure, mitigation, treatment, or prevention of disease, and/or under section 201(g)(1)(C) of the FD&C Act, 21 U.S.C. 321(g)(1)(C), because they are intended to affect the structure or any function of the body.Examples of claims from the products’ labeling, including on your website listed above, that provide evidence of the intended use (as defined in 21 CFR 201.128) of these products as drugs include, but may not be limited to, the following:MGD Advanced Dry Eye Drops“OPTASE® MGD Advanced Drops provide a preservative free combination of ingredients designed to relieve dry eye symptoms . . . An Advanced Lipid-based drop for Evaporative Dry Eye & MGD Symptoms . . .” [from your product website at https://optase.com/product/mgd-advanced-dry-eye/]Dry Eye Intense Drops (multi-use bottle and single dose)“The special formulation of OPTASE® Intense provides comfort from moderate to severe dry eye including dry eye post operatively. . . .” [from your product websites at https://optase.com/product/dry-eye-intense-drops/ and https://optase.com/product/dryeye-intense-drops-sdu/]Allegro Eye Drops“Optase® Allegro Eye Drops is a preservative free lubricant that acts as a first line of defense to stop environmental irritants in their tracks . . . by creating a more protective tear film and strengthening the ocular mucosa. This unique formulation . . . creates a water rich shield to protect epithelial cells from environmental irritants” [from the product website at https://optase.com/product/allegro-eye-drops/]HYLO Night Eye Ointment“How It Works . . . OPTASE® HYLO Night™ relieves night-time symptoms of burning, sore, dry eyes by forming a comfortable long-lasting protective film on the eyes. . . .” [from your product website at https://optase.com/product/hylo-night/]Tea Tree Oil Eyelid Wipes“Cleaning your eyelids daily will help remove debris, bacteria and oils that can often lead to Blepharitis, MGD or Dry Eye symptoms. . . . FORMULATED WITH NATURAL INGREDIENTS FOR SENSITIVE SKIN . . . Anti-Inflammatory Tea Tree Leaf Oil . . .” [from your product website https://optase.com/product/tea-tree-oil-wipes/]Tea Tree Oil Eyelid Gel“OPTASE® Tea Tree Oil Gel . . . can be used as part of the recommended management regimen for Blepharitis . . . GENTLE FORMULA ENRICHED WITH NATURAL INGREDIENTS . . . Anti-Inflammatory Tea Tree Leaf Oil . . .” [from your product website https://optase.com/product/tea-tree-oil-gel/]Multiple products“About Meibomian Gland Dysfunction (MGD) . . . MGD is a chronic condition which occurs when the glands in the eyelids don’t produce enough oil, or the oil that is produced is of poor quality. . . . How to manage MGD . . . Cleanse . . . maintain clean eyelids and lashes to ensure there is nothing that can block oils from reaching the surface of the eye. . . . Hydrate . . . If you suffer from severe MGD you may require an eye drop that can supplement the oily layer in your tear film to reduce tear evaporation. . . . Addressing the root cause of MGD . . . can also lead to a reduction of symptoms in related conditions such as Dry Eye Disease (DED) and Blepharitis. . . . Products To Relieve Symptoms . . . MGD Advanced Dry Eye Drops . . . Dry Eye Intense Drops . . . Single Dose Dry Eye Intense Drops . . . HYLO Night Eye Ointment” [from your website at https://optase.com/about-mgd/]“About Blepharitis . . . What is Blepharitis . . . There are two main types of Blepharitis: . . . Anterior Blepharitis . . . This is where the inflammation affects the skin around the base of your eyelashes . . . Posterior Blepharitis . . . This is where the inflammation affects your eyelid glands. Meibomian Gland Dysfunction (MGD) can occur when the eyelid glands become clogged. . . . How to manage Blepharitis . . . Daily lid hygiene is key to the management of Blepharitis and other conditions of the eye such as Meibomian Gland Dysfunction (MGD) and Styes. . . . Products To Relieve Symptoms . . . Tea Tree Oil Eyelid Wipes . . . Tea Tree Oil Eyelid Gel . . . Protect Eyelid Cleansing Spray” [from your website at https://optase.com/about-blepharitis/]Unapproved New Drug ViolationsBased on the above labeling evidence, your MGD Advanced Dry Eye Drops, Dry Eye Intense Drops (multi-use bottle and single dose), Allegro Eye Drops, HYLO Night Eye Ointment, Tea Tree Oil Eyelid Wipes, Tea Tree Oil Eyelid Gel, and Protect Eyelid Cleansing Spray products are intended for use as topical ophthalmic drug products. As described below, these products are unapproved new drugs marketed in violation of sections 505(a) and 301(d) of the FD&C Act, 21 U.S.C. 355(a) and 331(d).A drug product is a “new drug” within the meaning of section 201(p) of the FD&C Act, 21 U.S.C. 321(p), if it is not generally recognized as safe and effective (GRASE) for use under the conditions prescribed, recommended, or suggested in its labeling. Your above-referenced topical ophthalmic drug products are not generally recognized as safe and effective (GRASE) for their above referenced uses1and, therefore, are “new drugs” under section 201(p) of the FD&C Act, 21 U.S.C. 321(p). With certain exceptions not applicable here, a new drug may not be legally introduced or delivered for introduction into interstate commerce without an approved application from the FDA in effect, as described in sections 301(d) and 505(a) of the FD&C Act, 21 U.S.C. 331(d) and 355(a). There are no FDA-approved applications in effect for any of the products identified above.In addition, under section 505G of the FD&C Act, certain nonprescription drugs marketed without an approved application—commonly referred to as “over-the-counter (OTC) monograph drugs”—may be legally marketed if they meet applicable requirements. With respect to nonprescription ophthalmic drug products, in order to be GRASE and not new drugs, the products must, among other things, conform to the conditions in the applicable OTC monograph, Over-the-Counter Monograph M018, Ophthalmic Drug Products for Over-the-Counter Human Use (hereinafter M018).2However, your nonprescription ophthalmic drug products MGD Advanced Dry Eye Drops, Dry Eye Intense Drops (multi-use bottle and single dose), Allegro Eye Drops, and HYLO Night Eye Ointment do not conform to the conditions specified in M018 for the reasons described below, and thus cannot be legally marketed under section 505G.Ophthalmic Demulcent ProductsYour MGD Advanced Dry Eye Drops, Dry Eye Intense Drops (multi-use bottle and single dose), and Allegro Eye Drops are demulcent products formulated with several active ingredients that are not permitted for OTC monograph ophthalmic demulcent drug products. Specifically, according to your products’ labeling, your MGD Advanced Dry Eye Drops product is formulated with the active ingredients glycerin, sacha inchi seed oil, trehalose, and sodium hyaluronate. Your Dry Eye Intense Drops products are formulated with glycerin and sodium hyaluronate and your Allegro Eye Drops product is formulated with hydroxyethyl cellulose and Ectoin®.However, sacha inchi seed oil, trehalose, sodium hyaluronate, and Ectoin® are not active ingredients permitted for ophthalmic demulcent drug products under M018.12. We note that, although you identify these ingredients as inactive ingredients on the product label, statements on your website show that they are active ingredients in their respective products because they are intended to furnish pharmacological activity for the treatment of a disease or condition.3Examples of these statements include, “Contains Sacha inchi seed oil, Trehalose and Hyaluronic Acid which combine to strengthen and replenish your tear film, and protect your eyes. . . .” (MGD Advanced Dry Eye Drops); “INACTIVE INGREDIENT: Sodium hyaluronate . . . Binds to eye surface with comfortable, soothing properties” (Dry Eye Intense Drops); and “This unique formulation includes . . . Ectoin® which creates a water rich shield to protect epithelial cells from environmental irritants . . .” (Allegro Eye Drops). Thus, these ingredients are active ingredients and, because they are not active ingredients permitted under M018.12, the MGD Advanced Dry Eye Drops, Dry Eye Intense Drops, and Allegro Eye Drops products do not conform with the conditions for lawful marketing of an OTC ophthalmic demulcent product as set forth in M018.Ophthalmic Emollient ProductsYour HYLO Night Eye Ointment product is an emollient product formulated with the active ingredient vitamin A. However, vitamin A is not an active ingredient that is permitted for ophthalmic emollient drug products under M018.14. We note that, although you identify this ingredient as an inactive ingredient on the product label, statements on your website show that it is an active ingredient in the product because it is intended to furnish pharmacological activity for the treatment of a disease or condition.4For example, your product website states, “OPTASE® HYLO Night™ is a soft and consistent ointment, containing Vitamin A . . . to help improve the tear film and protect the surface of the eye.” Thus, this is an active ingredient that is not permitted under M018.14, therefore your HYLO Night Eye Ointment product does not conform with the conditions for lawful marketing of an OTC ophthalmic emollient product as set forth in M018.For the above reasons, your above-referenced products MGD Advanced Dry Eye Drops, Dry Eye Intense Drops (multi-use bottle and single dose), Allegro Eye Drops, HYLO Night Eye Ointment, Tea Tree Oil Eyelid Wipes, Tea Tree Oil Eyelid Gel, and Protect Eyelid Cleansing Spray are unapproved new drugs. The introduction or delivery for introduction into interstate commerce of these unapproved new drug products violates sections 505(a) and 301(d) of the FD&C Act, 21 U.S.C. 355(a) and 331(d).Misbranded Drug ViolationsFurther, your Dry Eye Intense Drops (multi-use bottle) product is misbranded under section 502(f)(2) of the FD&C Act because its labeling does not “[bear]…such adequate warnings against use in those pathological conditions or by children where its use may be dangerous to health, or against unsafe dosage or methods or duration of administration or application, in such manner and form, as are necessary for the protection of users…”. Here, the warning described in M018.60, “If solution changes color or becomes cloudy, do not use”, is required for ophthalmic demulcent drug products, such as your Dry Eye Intense Drops (multi-use bottle) product, to be legally marketed under section 505G of the FD&C Act. This monograph warning also falls within the scope of the warnings described in section 502(f)(2) of the FD&C Act. Thus, omission of this monograph warning from the product labeling renders the product misbranded under section 502(f)(2).Additionally, your Allegro Eye Drops, MGD Advanced Dry Eye Drops, Dry Eye Intense Drops, (multi-use bottle and single dose), and HYLO Night Eye Ointment products are misbranded under section 502(ee) of the FD&C Act, 21 U.S.C. 352(ee), because these products are nonprescription drugs subject to section 505G of the FD&C Act, 21 U.S.C. 355h, but do not comply with the requirements for marketing under that section (as described above) and are not the subject of an application approved under section 505 of the FD&C Act, 21 U.S.C. 355.The introduction or delivery for introduction of a misbranded drug into interstate commerce violates section 301(a) of the FD&C Act, 21 U.S.C. 331(a).ConclusionThe violations cited in this letter are not intended to be an all-inclusive list 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.Your response should be sent to U.S. Food and Drug Administration, CDER/OC/Office of Unapproved Drugs and Labeling Compliance by email to FDAAdvisory@fda.hhs.gov. Please include your firm name and the unique identifier “695085” in the subject line of your email.Sincerely,/S/Tina Smith, M.S.Captain, U.S. Public Health ServiceDirectorOffice of Unapproved Drugs & Labeling ComplianceOffice of ComplianceCenter for Drug Evaluation and ResearchU.S. Food and Drug Administration_____________________________1FDA is not aware of any adequate and well-controlled clinical trials in the published literature that support a determination that your above-referenced topical ophthalmic drug products are GRASE for use under the conditions prescribed, recommended, or suggested in their labeling.2M018 reflects the conditions as set forth in the relevant final orders established and in effect under section 505G; see Order OTC000023, available at FDA’s website OTC Monographs @ FDA, https://dps.fda.gov/omuf.3See 21 CFR 201.66(b)(2), which defines an active ingredient as “any component that is intended to furnish pharmacological activity or other direct effect in the diagnosis, cure, mitigation, treatment, or prevention of disease, or to affect the structure or any function of the body of humans.”4Id.

Delivery Method:Via EmailProduct:Drugs、Over-the-Counter DrugsRecipient:Susan K. BentonPresidentThea Pharma, Inc.303 Wyman Street, Suite 205Waltham,MA02451United States(b)(6), (b)(7)(C)Issuing Office:Center for Drug Evaluation and Research (CDER)United StatesWARNING LETTERJuly 9, 2025RE: 712416Dear Ms. Benton:This letter is to advise you that on August 29, 2024 the U.S. Food and Drug Administration (FDA) reviewed your product labeling, including on your website at the internet address www.ivizia.com and your Amazon storefront at https://www.amazon.com/iVIZIA-Lubricant-Preservative-Free-Moisturizing-Friendly/dp/B09TD27BR5?th=1 where your IVIZIA sterile lubricant eye drops product is available for purchase in the United States without a prescription.Based on our review, your IVIZIA sterile lubricant eye drops product is an unapproved new drug introduced or delivered for introduction into interstate commerce in violation of sections 505(a) and 301(d) of the Federal Food, Drug, and Cosmetic Act (FD&C Act,) 21 U.S.C. 355(a) and 331(d). In addition, this product is misbranded under section 502(ee) of the FD&C Act, 21 U.S.C. 352(ee). Introduction or delivery for introduction of such products into interstate commerce is prohibited under sections 301(d) and (a) of the FD&C Act, 21 U.S.C. 331(d) and (a). These violations are described in more detail below.Unapproved New Drug and Misbranded Drug ViolationsYour IVIZIA sterile lubricant eye drops is a “drug” as defined by section 201(g)(1)(B) of the FD&C Act, 21 U.S.C. 321(g)(1)(B), because it is intended for use in the diagnosis, cure, mitigation, treatment, or prevention of disease, and/or under section 201(g)(1)(C) of the FD&C Act, 21 U.S.C. 321(g)(1)(C), because it is intended to affect the structure or any function of the body.Examples of claims from the product labeling and your website that provide evidence of the intended use (as defined in 21 CFR 201.128) of this product as a drug include, but may not be limited to, the following:IVIZIA sterile lubricant eye drops“Use???? For use as a lubricant to prevent further irritation or to relieve dryness of the eye” [from the Drug Facts panel on product carton labeling]“iVIZIA for Dry Eyes . . . made with hydrating polymers, sodium hyaluronate, and trehalose, iVIZIA’s unique multi-moisturizing formula improves eye comfort during computer work . . .” [from your website https://www.ivizia.com/]“Instant and long-lasting relief of dry eye symptoms for up to 8 hours…UNIQUE FORMULA…POVIDONE (active ingredient) …A hydrating polymer that significantly decreases dry eye discomfort…. made with revitalizing hyaluronic acid and trehalose…HYALURONIC ACID “HA” (inactive)…one of the most water-loving molecules…described as “nature’s moisturizer”. It can bind 1000 times its weight in water… TREHALOSE (inactive)… synthetized by plants such as the Rose of Jericho…can survive extreme dehydration thanks to trehalose.”[from your website under Product-Dry Eye Drops https://www.ivizia.com/ivizia-dry-eye-drops/ (last visited December 2024)]“Scientifically formulated to moisturize and lubricate dry eyes…Hyaluronic Acid (enhancer)…can hold 1000x its weight in moisture…Trehalose (enhancer)…works with hyaluronic acid to resist drying longer.” [from the website directly linked from IVIZIA.com product page which direct consumers to purchase IVIZIA sterile lubricant eye drops without a prescription under the “BUY NOW” button https://www.amazon.com/iVIZIALubricant-Preservative-Free-Moisturizing-Friendly/dp/B09TCZRG1K?ref_=ast_sto_dp (last visited December 2024]Unapproved New Drug ViolationsBased on the above evidence of intended use, your IVIZIA sterile lubricant eye drops product is intended for use as an ophthalmic demulcent (lubricant) drug product. As described below, this drug product is an unapproved new drug marketed in violation of sections 505(a) and 301(d) of the FD&C Act, 21 U.S.C. 355(a) and 331(d).A drug product is a “new drug” within the meaning of section 201(p) of the FD&C Act, 21 U.S.C. 321(p), if it is not generally recognized as safe and effective (GRASE) for use under the conditions prescribed, recommended, or suggested in its labeling. With certain exceptions not applicable here, a new drug may not be introduced or delivered for introduction into interstate commerce without an approved application from FDA in effect, as described in section 505(a) of the FD&C Act, 21 U.S.C. 355(a). No FDA-approved applications pursuant to section 505 of the FD&C Act, 21 U.S.C. 355, are in effect for your IVIZIA sterile lubricant eye drops drug product.Your drug product is marketed as an ophthalmic demulcent drug product and is subject to section 505G of the FD&C Act, 21 U.S.C. 355h, which generally governs nonprescription drugs marketed without an approved application. Under section 505G of the FD&C Act, certain nonprescription drugs marketed without an approved application —commonly referred to as “over-the-counter (OTC) monograph drugs”—may be legally marketed if they meet applicable requirements. With respect to nonprescription ophthalmic drug products, such as your IVIZIA sterile lubricant eye drops, in order to be GRASE and not a new drug, the product must, among other things, conform to the conditions in the applicable OTC monograph, here Over-the-Counter (OTC) monograph M018: Ophthalmic Drug Products for Over-the-Counter Human Use (hereinafter M018).1However, your IVIZIA sterile lubricant eye drops drug product does not conform to the conditions specified in M018 for the reasons described below.Your IVIZIA sterile lubricant eye drops is a demulcent product formulated with several active ingredients that are not permitted for OTC monograph ophthalmic demulcent drug products. Specifically, according to your products labeling, your IVIZIA sterile lubricant eye drops is formulated with the active ingredients hyaluronic acid and trehalose.However, hyaluronic acid and trehalose are not active ingredients permitted for ophthalmic demulcent drug products under M018. 21. We note that, although you identify these ingredients as inactive ingredients on the product label, statements on your website show that they are active ingredients because they are intended to furnish pharmacological activity for the treatment of a disease or condition2. Example of these statements include, “made with hydrating polymers, sodium hyaluronate, and trehalose, iVIZIA’s unique multi-moisturizing formula improves eye comfort during computer work . . .” Furthermore, claims such as “can hold 1000x its weight in moisture” and “nature’s moisturizer,” are associated with the ingredient hyaluronic acid and claims such as “can survive extreme dehydration thanks to trehalose,” and “works with hyaluronic acid to resist drying longer” are associated with the ingredient trehalose. Thus, these ingredients are active ingredients and, because they are not active ingredients permitted under M018.12, your IVIZIA sterile lubricant eye drops product does not conform with the conditions for lawful marketing of an OTC ophthalmic demulcent drug product as set forth in M018.Thus, your IVIZIA sterile lubricant eye drops product does not comply with the applicable conditions specified in M018 and has not otherwise been found GRASE.3Accordingly, this product is a new drug within the meaning of section 201(p) of the FD&C Act, 21 U.S.C. 321(p), and there is no basis under section 505G of the FD&C Act under which this product would be legally marketed without an approved application. Because there is no approved application in effect for this product, this product is an unapproved new drug. The introduction or delivery for introduction into interstate commerce of this unapproved new drug product violates sections 505(a) and 301(d) of the FD&C Act, 21 U.S.C. 355(a) and 331(d).Misbranded Drug ViolationsAdditionally, your IVIZIA sterile lubricant eye drops is misbranded under section 502(ee) of the FD&C Act, 21 U.S.C. 352(ee), because this product is a nonprescription drug subject to section 505G of the FD&C Act, 21 U.S.C. 355h, but does not comply with the requirements for marketing under that section and is not the subject of an application approved under section 505 of the FD&C Act, 21 U.S.C. 355.The introduction or delivery for introduction of a misbranded drug into interstate commerce violates section 301(a) of the FD&C Act, 21 U.S.C. 331(a).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 fifteen 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 fifteen working days, state the reason for the delay and the time within which you will complete the correction.Your response should be sent to U.S. Food and Drug Administration, CDER/OC/Office of Unapproved Drugs and Labeling Compliance by email to FDAADVISORY@fda.hhs.gov. Please include your firm name and the unique identifier “712416” in the subject line of the email.Sincerely,/S/Tina Smith, M.S.Captain, U.S. Public Health ServiceDirectorOffice of Unapproved Drugs and LabelingComplianceOffice of ComplianceCenter for Drug Evaluation and ResearchFood and Drug Administrationcc: Chrysoula Koukoutsis, Director, Global Regulatory Affairs, Vice President of Regulatory Affairs___________________________1M018 reflects the conditions as set forth in the relevant final orders established and in effect under section 505G; see Order OTC000023, available at FDA’s website OTC Monographs@FDA, https://dps.fda.gov/omuf.2See 21 CFR 201.66(b)(2), which defines an active ingredient as “any component that is intended to furnish pharmacological activity or other direct effect in the diagnosis, cure, mitigation, treatment, or prevention of disease, or to affect the structure or any function of the body of humans.”3FDA is not aware of any adequate and well-controlled clinical trials in the published literature that support a determination that IVISIA lubricant eye drops product is GRASE for use under the conditions prescribed, recommended, or suggested in its labeling, nor has FDA determined this drug product to be GRASE pursuant to an order issued under section 505G(b).