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此次医博会由同写意策划，以“发展新质生产力，共享健康新未来”为主题，用全新的视角瞄准国内外医药及大健康产业发展前沿。诚邀海内外医药及大健康各界嘉宾齐聚中国医药城，共赴时代之约。展位/报告火热征集中！ 非临床和临床开发阶段的药物供应是指向研究人员、患者、医疗服务提供者、经销商和开发商提供或供应药物的方式。在非临床开发阶段，药物供应仅限于少数研究人员或实验室。这就需要仔细控制药物的分销，确保药物得到正确的处理、储存和使用。一旦药物进入临床开发阶段，就会通过药房、医院和诊所等各种渠道供应给更多的患者和医疗服务提供者。 医疗产品的临床供应是在临床开发的早期阶段提供给患者和医疗服务提供者的。这包括1期和2期临床试验，它们是评估新药或新疗法在人体中的安全性和有效性的第一步。药物或其他医疗产品一旦成功完成早期临床阶段，并被证明是安全有效的，就可能进入临床开发的后期阶段，如 3 期临床试验，这涉及到更多的患者，并可能涉及到药物或产品的更广泛传播。 1 临床和非临床开发供应 01 临床开发供应链 临床试验中的治疗分配是经过精心策划和控制的，以确保所有参与者以一致的方式接受正确的治疗。这有助于减少试验中可能出现的偏差，并确保试验结果准确反映所研究疗法的有效性。它通常是临床试验中研究的关键变量之一，其分布情况在试验方案中有详细描述。有各种标准和指南（见表12-1）概述了在临床试验中分发材料的适当程序，以确保研究的质量、安全性和完整性。 02 非临床开发供应链 在产品开发中，材料供应指的是采购用于生产药品或其他产品的材料。这可能包括原材料、活性药物成分（API）、辅料以及配制产品所需的其他成分。适当的材料供应是制剂开发的一个重要方面，因为它会影响最终产品的质量、安全性和有效性。必须谨慎选择材料供应商，并对这些材料进行完整的测试和验证，以确保它们符合规定的标准。 除了寻找和采购材料外，制剂开发的材料供应过程还可能涉及储存和处理要求，以 确保材料的稳定性和纯度。一些指导原则和标准（见表12-2）适用于在研究实验室或生产设施等非临床环境中分发材料。在临床或非临床环境中分发材料时，必须遵守这些指导原则和标准，以确保用于产品监管决策的 结果的质量、安全性和完整性。 2 临床试验药物供应 临床供应供应链成功的关键在于供应链领导者（supply chain）与申办者、试验设计团队、项目执行/现场团队、试验的各种运营领导者、包装配送中心、技术专家、家庭保健团队以及监管顾问/专家之间的密切合作。需要使用技术指导对到达患者手中的药物进行清晰的可见性、跟踪、库存管理和监控。需要迅速考虑患者注册人数的变化或研究的变化，以确保药物供应正常，不会出现缺货情况。 因此，提供可视性和可追溯性的实时系统至关重要。确定适当的分销渠道是临床供应战略的另一个方面。确定容器封闭系统的适当性以及持续监控运输和储存条件的温度和湿度也至关重要。另一个关键方面是药物管理，即在整个研究期间管理材料的有效期。 01 临床供应链战略 临床供应链战略（见表12-3）是在新产品的临床开发过程中，向患者和医疗服务提供者分发药品、医疗器械和其他材料的管理计划。这是药物开发的一个重要方面，因为其有助于确保产品在正确的时间和地点以正确的数量供应，以满足临床试验和其他研究的需要。 制定有效的临床供应链战略需要精心策划和协调，以确保在需要的时间和地点提供产品，同时满足质量和安全方面的监管要求和标准。监管机构也在临床开发和供应方面实施明智的战略，以满足患者的需求。 02 新药和仿制药；生物制品和生物类似药 IND即研究性新药申请，是向美国食品药品管理局（FDA）申请开始在人体中测试新药或生物制剂的许可。IND程序旨在确保新药和生物制剂在获准在美国使用前是安全有效的。IND程序的利益相关者包括药物或生物制剂制造商、FDA、医疗保健提供者、患者和权益团体。IND程序旨在确保新药和生物制剂获准在美国使用前经过全面测试和仔细评估。 在其他辖区，它通常是临床试验申请（CTA）。在美国，新药申请（NDA）和仿制药申请（ANDA）涉及小分子药物的上市许可申请，而生物许可申请（BLA）涉及新的生物制剂和生物类似药（见表 12-4）（其他辖区通常使用上市许可申请[MAA]一词）。 另一方面，ANDA仿制药品是一种已在美国获得批准的药品的非专利版本，申请上市许可。ANDA开发与临床活动有几个主要区别。首先，ANDA用于申请仿制药的批准，仿制药是已获FDA批准的专利药（brand-name drug）的复制品。ANDA 一般不要求进行临床试验，因为仿制药的安全性和有效性已经通过专利药的审批程序确定。 因此，ANDA的审批程序比NDA的审批程序要快。不过，ANDA的提交过程可能会涉及一些临床数据，如生物等效性研究，其目的是证明仿制药与品牌药在生物学上等效。生物等效性研究包括给一小群健康志愿者服用仿制药和专利药，并测量其血液中的药物浓度，以确保两者具有可比性。 此外，提交ANDA的过程还可能涉及证明仿制药符合与专利药相同的质量标准。这可能需要进行研究，以证明仿制药具有与专利药相同的纯度、强度和稳定性。特定产品指南由FDA发布，提供有关特定类型药物或产品监管要求的详细信息。特定产品指南可能包括支持ANDA或505(b)(2)申请所需的数据类型信息，以及FDA用于评估药物或产品安全性和有效性的标准信息。 对于经证明与FDA已批准的参照列表药物（RLD）具有生物等效性的仿制药，可给予生物豁免或免除某些监管要求。如果根据适当的体外和/或体内数据证明非专利药与参照列表药物具有生物等效性，则可对某些类型的非专利药（如速释口服固体制剂）给予生物豁免。ANDA由FDA的仿制药办公室（Office of Generic Drugs, OGD）审查，而NDA则由FDA的药物评价与研究中心（Center for Drug Evaluation and Research, CDER）评估。 生物类似药（biosimilar）是一种与参照生物制品相似的生物制品，在安全性、纯度和有效性方面没有临床意义上的差异。生物类似药临床试验通常采用与其他类型药品临床试验类似的流程。这些临床试验旨在提供生物类似药安全性、有效性和质量的证据，是生物类似药审批监管程序的重要组成部分。生物类似药的具体临床试验要求可能因生物类似药开发所在国的具体监管框架而异。 03 绘制供应链图 绘制临床供应链图（见图12-1）有助于识别分销过程中潜在的瓶颈或故障点，并有助于确定可以改进的领域，以优化临床试验机构的研究产品流。这些活动首先由研究产品的生产和分销机构执行，包括生产、分销、中间储存或可能必要的处理步骤。然后是库存管理，用于跟踪研究产品在供应链每个阶段的数量和位置，以及管理有效期和其他特定产品的注意事项。还需要处理不良事件，包括报告和管理临床试验期间可能发生的不良事件的流程，包括收集和分析不良事件的数据，并将这些信息传达给相关各方。 供应链场景必须包含管理研究数据并满足法规遵从性。这包括临床试验数据的收集、存储和分析，以及电子数据系统的管理和供应链中不同各方之间的数据传输。法规遵从性包括确保在临床供应链的每个阶段遵守法规要求的过程，包括向监管机构提交所需的文件。 04 临床试验法规 国际人用药品技术要求协调理事会（ICH）的良好临床实践（GCP）指南和其他指导文件为涉及研究药物的临床试验的设计、实施和报告提供了国际公认的标准，并用于确保临床试验数据的质量和完整性。临床试验法规旨在确保临床试验的安全性和道德性，并保护研究参与者的权利和福利。 在美国，临床试验中的供应链管理由几个不同的机构监管，包括FDA、人类研究保护办公室（OHRP）、和CTRIS计划。IND法规概述了在美国进行研究药物临床试验的要求。临床试验要求申办者和研究人员注册临床试验并提交有关试验的某些信息，包括有关供应链的信息（例如，研究产品的来源和制造商）。 保护人类主体的联邦政策（共同规则）由OHRP管理;它规定了在研究中保护人类受试者的基本伦理原则和要求。通用规则包括与临床试验中研究产品的采购和使用相关的规定，例如要求获得试验受试者的知情同意，并确保研究产品按照协议使用（见表12-5）。 各种发表的参考文献也有助于制定与FDA关于良好临床实践和临床试验的规定相关的最终规则。欧盟的临床试验法规旨在确保临床试验的安全性和道德行为，并保护研究参与者的权利和福利。欧盟一些最重要的临床试验法规包括： 法规(EU) No 536/201439为欧盟临床试验的授权和监督建立了一套单一的规则。它包括与临床试验申请评估、临床试验监督和临床试验结果报告有关的规定。这一规定仍处于过渡阶段，尚未全面实施。 由欧洲药品管理局(EMA)建立的临床试验注册和结果信息提交要求欧盟临床试验的注册和结果报告旨在促进临床研究的透明度和问责制。 通用数据保护条例(GDPR)适用于整个欧盟，建立了保护个人数据的规则，并要求临床试验参与者为临床试验中处理其个人数据提供知情同意。 同时，日本的临床试验法规包括《药事法》及其条例、厚生劳动省（Ministry of Health, Labour and Welfare ，MHLW）运行的临床试验通知（CTN）和临床试验信息（CTI）系统，用于试验目的。在中国，临床试验（包括生物等效性研究）需要事先获得NMPA的批准。获得批准的临床试验应在符合中国 GCP 的认证研究机构内进行。 与此同时，日本的临床试验法规包括《药事法》及其相关法规、由厚生劳动省（MHLW）运营的临床试验通知（CTN）和临床试验信息（CTI）系统。在中国，临床试验（包括生物等效性研究）需要事先获得国家药品监督管理局（NMPA，原中国食品药品监督管理局，简称CFDA）的批准。经批准的临床试验应在符合中国GCP的认证研究机构进行。 在英国，《人用药物(临床试验)条例》为涉及研究性药物和生物制品的临床试验建立了法律框架。它们包括与临床试验的道德行为、临床试验参与者的保护以及向监管机构提交临床试验申请有关的规定。在加拿大，最重要的临床试验法规包括《食品和药品法》及其法规，该法规为涉及研究性药物、生物制剂和医疗器械的临床试验建立了法律框架，《加拿大卫生部临床试验发起人指导文件:临床试验申请》，以及《个人信息保护和电子文件法》（PIPEDA）。 同时，巴西卫生监管局（Brazilian Health Regulatory Agency ，ANVISA）制定了在巴西开展涉及研究药物和生物制剂的临床试验的法律框架。巴西临床试验登记处（ReBec）由ANVISA维护，用于登记临床试验方案和其他相关文件。巴西国家卫生委员会第466/201246号决议规定了在临床试验中保护个人数据的规则。 临床试验供应链管理的监管环境在不断变化，新的法规和指南也在频繁发布。以上只是需要考虑的几项主要临床试验法规。根据临床试验的具体特点，如试验的研究产品类型或试验的资金来源，可能还有其他适用的法规。 05 临床供应材料的可追溯性 作为最佳实践，供应链合作伙伴应按照联邦要求获得许可，并在转让产品所有权时共享信息，以便在产品通过供应链时对其进行跟踪和追溯。可追溯性要求从批次层面延伸到单个包装层面。交易文件和其他药品血统信息可在各实体之间以完全电子化和安全的方式进行交换。商业分销商和第三方物流提供商向FDA提交年度报告，列出其获得许可的州，也可用于临床分销。 制造商应建立系统，以遵守可疑产品的识别和报告要求，包括隔离此类产品，并在适用情况下与临床合作伙伴协调，立即进行调查，以确定材料是否非法。这将包括验证制造商掌握的任何适用的交易历史和交易信息。如果制造商确定产品可疑，则应隔离产品并开展调查。如果证明是合法的，则应完成记录，并将产品记录为已清除。 应使用条形码或序列号等方法对每件研究用产品进行唯一标识和标签。使用数据系统可以对研究用产品进行电子跟踪和追踪，并收集和分析这些产品的移动和使用数据，从而促进可追溯性。为研究用产品的处理和分发制定标准操作程序（SOP），有助于确保以一致和受控的方式处理和分发这些产品。这可以为产品的跟踪和追踪提供明确的指导原则，从而促进产品的可追溯性。 确保参与临床供应链的各方都接受过有关可追溯性重要性的培训和教育--以及跟踪和追踪研究用产品的具体程序和系统--可以确保在整个供应链中保持完整性。临床供应链中的可追溯性是研究用产品在从生产商到临床试验机构的供应链中流动的必要条件。可追踪性在临床试验中非常重要，因为它可以识别和解决分销过程中可能出现的潜在问题，确保研究产品的完整性和质量。 06 临床试验供应链中的潜在问题和缓解计划 临床试验供应链中可能会出现一些问题（见表12-6），这些问题可能会影响向临床试验机构提供研究用产品的能力，并有可能延误或中断临床试验。研究用产品的生产延误或问题（如污染或其他质量问题）会导致向临床试验机构供应这些产品的延误。建立备用生产和分销来源是一种选择，可确保在主要来源出现延误或问题时，研究用产品的持续供应。 研究用产品在运输或储存过程中遇到的物流挑战，如天气或其他不可预见的情况造成的延误，会影响向临床试验机构交付这些产品。实施强大的物流和运输系统可确保及时、可靠地向临床试验机构交付研究产品。跟踪和管理库存方面的库存管理问题，如库存清点不准确或研究用产品过期，会导致供应链出现短缺或其他中断。 开发一个强大的库存管理系统来跟踪和管理研究用产品的供应，包括有效期和其他特定产品的考虑因素，可以缓解这一问题。不遵守这些要求可能会导致研究用产品供应的延误或中断。 因此，有必要确保临床试验供应链的各个阶段都符合监管要求，包括及时向监管机构提交所需文件。为减少这些潜在问题（见图12-2），必须建立健全、计划周密的临床试验供应链，并制定适当的控制措施和应急计划。 3 非临床开发工作的药品供应 01 活性药物成分和辅料的选择与供应 在新药的非临床开发阶段，制药公司需要获得用于临床前试验的原料药供应。原料药是正在开发成药物成品的纯净形式（pure form of the compound），是生产药物成品的原料。原料药由制药公司开发和生产，然后配制成成品剂型。原料药的开发涉及几个步骤。其一是确定和选择化合物的合成路线或生物工艺。 这可以通过各种方法完成，包括合成新化合物、分离天然产物或改造现有化合物。临床前试验用于评估动物实验的安全性和有效性。临床试验确定化合物对人体的安全性和有效性。需要向FDA或EMA等国家监管机构提交药品主文件（DMF）。原料药的开发是一个复杂而耗时的过程，可能需要多年时间和大量投资。 为非临床开发工作获取药物物质供应有多种选择。一些制药公司有能力利用自己的设备在内部合成药物物质。如果公司拥有必要的专业知识和设备，这可能是一种具有成本效益的选择。合同生产组织（CMO）是专门从事原料药和其他药物物质合成与生产的第三方公司。如果公司内部不具备必要的专业知识或设备，制药公司可以将药物开发外包给CMO，这也是一种具有成本效益的选择。 制药公司也可以从供应商处购买药物物质，如化学制造商或专门生产原料药的公司。如果药物物质唾手可得，而公司又不想投资必要的设备和专业知识在内部或通过CMO进行合成，这不失为一种好的选择。原料药供应链非常重要，因为原料药的质量会对成品药的安全性和有效性产生重大影响。在美国，原料药由FDA根据《联邦食品、药品和化妆品 (FD&C) 法》进行监管。在欧盟，原料药由EMA或国家主管当局（NCA）根据GMP原则、欧盟GMP指南和欧盟GMP附件进行监管。 ICH为在适当的质量管理体系下生产活性药物成分（API）提供了GMP指导。其目的还在于帮助确保原料药符合其声称或代表的质量和纯度特征。原料药生产GMP法规对原料药生产设施的设计、运行和维护提出了明确要求。这些规定旨在确保原料药的生产和控制始终如一。 在新药的非临床开发阶段，制药公司需要获得辅料供应，用于药物产品试验批次的非临床开发配方（见表12-7）。 02 原料药和关键成分供应安全 FDA等监管机构已经强调了原料和成分来源等上游的脆弱性。 据该机构称，72%供应美国市场的原料药制造商（见图12-3）都在海外。因此，当这些有限的生产基地发生中断时，无论是自然灾害、地缘政治事件，还是与大流行相关的停产，都会给患者带来后果。全球有数千家制药厂依赖进口。在大流行病等情况下，由于供应链限制外的需求增加，价格上涨是不可避免的。原料药成本是药品生产成本中最重要的组成部分。全球最大的医药市场（美国）和全球最大的非专利药生产国（印度）的决策者们对其依赖性忧心忡忡。 世界银行对原料药进行的一项探索性研究发现，西方原料药制造商的平均工资指数为100，而亚洲则低至8。FDA发现，其他国家的原料药生产基地数量正在增加。因此，在开发周期的后期阶段，美国对外国原料药来源的依赖性越来越大。FDA认为，先进的制造技术可能有助于恢复美国的竞争力，并将国家安全风险降至最低。FDA制定了新的监管准则，鼓励采用流动化学和/或连续生产等新兴技术，因为他们认为传统生产方式永远无法抵消成熟设施所享有的成本优势和生产率。 03 包装材料开发与供应 在开发和鉴定稳健、最佳的一级和二级包装解决方案时，需要考虑科学和数据驱动的方法。有利益相关者（申办者、分销商、CRO、CDMO、材料供应商、运输商）参与的规划是这一过程的重要组成部分，在这一过程中，所有与产品质量相关的要求都会被激发出来。在这一过程中，开发人员可以获取正确的产品参数，如温度、物流、国内和国际运输路线等。风险管理、解决方案开发、配置管理、鉴定和转运研究、技术审查和可追溯性是整个流程的一部分。 制定和选择的解决方案需要考虑供应商的可靠性和技术能力。了解物流功能是设计开发的关键部分。了解配送环境，了解包装物的流向，了解它们是如何成型、处理和储存的，这些都很重要。设计测试和对结果的解释必须成为设计过程的一部分。通过对包装物配送过程的密切观察，可以了解影响所采用的测量机制的变量，并确定振动、跌落、压缩和温度或湿度水平。 冷链包装解决方案（见Figure 12-4）可以说是包装和运输产品的最佳方法，以保持产品在国际或国内运输路线上从头到尾的温度一致，尤其是生物制品。运输生物制品所需的范围和要求非常广泛。因此，冷链工程开发的重要性日益突出，这在一定程度上也是由于 COVID-19 大流行病的关注和在全球范围内运输疫苗的需要。 在美国，除了产品要求外，对冷链解决方案也有监管要求： 美国联邦法规第 21 编第 205.50 部分提到了药品储存和处理的最低要求，并详细说明了温度记录和记录保存的要求； 21 CFR 第 203.32 部分讨论了作为生产规范的一部分，保持药品和条件的稳定性、完整性和有效性的必要性； 21 CFR 第 203.36 部分要求保存表格、报告和记录，以满足保存记录的要求； 《 联邦法规汇编》第 21 卷第 211.150 部分涉及如何分发药品的程序。 21 CFR 第 11 部分提到了该机构认为电子记录和签名可信的法规和标准。 国际安全运输协会（ISTA）制定了测试协议和设计标准，规定了包装在运输过程中应如何保证其内容物得到保护。 04 剂型开发与法规 药物产品开发需要采用基于质量源于设计（QbD）的方法。必须对药物中使用的原料药进行表征。然后将其配制成成品剂型，同时考虑到所需的释放曲线、稳定性、可制造性和患者接受度等因素。进行制剂前研究是为了了解原料药的物理和化学特性，以及它在成品剂型中的表现。在各种储存条件下对成品剂型进行稳定性测试，以确保其稳定和有效。对成品剂型的生产工艺进行开发和优化，以确保能以商业规模进行稳定和可重复的生产。 然后将生产工艺扩大到更大规模，并对成品剂型进行验证，以确保其符合要求的规格。制剂的设计应满足原料药的特定需求，如控制释放曲线、提高稳定性或增强生物利用度。制剂开发应定义质量目标产品特征（QTPP），以确保成品的安全性和有效性，并应在口味、外观和易用性方面为患者所接受。制剂应适合商业规模生产，并应具有可重复性和一致性。 05 潜在问题和缓解计划 药物非临床开发所需的原材料或原料药可能会出现短缺，从而延误开发进程。可以通过建立多个原材料和原料药来源，以及在预计出现短缺之前建立库存来缓解这一问题。原材料或原料药可能存在质量问题，如杂质或效力变化。这会影响成品的安全性和有效性。为减少这一问题，必须仔细评估原材料和原料药的质量，并建立健全的质量控制流程，以确保它们符合规定的规格。成品剂型的生产过程可能存在问题，如生产过程中的变异性或设备问题。 为减少这一问题，必须建立健全的生产流程，并对成品剂型进行全面的测试和验证。材料运输过程中可能会出现延误、损失或损坏，从而影响药物的非临床开发时间表。可通过使用可靠的运输承运商和监控货运状态来缓解这一问题，以确保及时交货。药物的非临床销售过程中可能会出现海关问题，如材料进出口问题或危险品运输问题。为减少此类问题，必须确保海关清关要求，并制定处理此类问题的程序。通过及时发现和解决潜在问题，可以最大限度地减少干扰，确保非临床开发的顺利进行。 06 临床和非临床供应法规：注意事项 制药行业的临床试验支出有所增加。临床试验申办者开展复杂的试验，并希望更快地对试验做出 “开始/不开始 ”的决策（desire a faster “go/no go” decision-making scenario）。临床试验供应链管理对于将新型疗法和治疗方法推向市场至关重要。因此，申办者需要整合专业知识、流程和技术，以支持相关活动。 在许多情况下，临床供应涉及全球供应链。一个临床项目的生命周期从生产开始，到最终核对和销毁结束。这些活动包括与临床、医疗、第三方物流（3PL）和其他团队协调，以创建、验证和监控临床供应链计划。安全的文件共享、数据完整性和装运跟踪是实现可追溯性的关键。 非临床开发流程通常包括临床前试验、化学、生产和控制（CMC）开发以及监管申请（如IND）等活动。临床前试验包括体外（试管或实验室培养皿）和体内（动物）试验，以评估药物的安全性和有效性。CMC 开发包括开发合成和生产药物的工艺，以及确保药物符合质量标准。监管申请包括向监管机构（如FDA）申请开始人体临床试验的许可。非临床开发的利益相关者包括制药公司、监管机构、分销商、CDMO、测试实验室和原材料供应商。每个利益相关者都有其独特的视角和关注点，因此在整个非临床开发过程中考虑其需求和关注点非常重要。 07 阶段适宜的生产和包装 GMP是一套指导方针和法规，旨在确保药品的生产和控制始终符合最高标准。GMP准则适用于药品生产的各个方面，包括原材料、生产过程和质量控制。GMP标准因药品开发阶段而异。与阶段相适应的GMP是指应用与药物开发阶段相适应的GMP标准。例如，在I期临床试验期间，重点是评估药物的安全性，GMP标准可能不如后期临床试验或上市后的标准严格。随着药物在临床开发过程中取得进展，越来越接近获得上市批准，GMP标准会变得更加严格，以确保最终产品的质量和一致性。必须遵循与阶段相适应的GMP标准，以确保药物的安全性和有效性，并满足监管要求。 例如，在欧盟，2003/94/EC号指令要求将附件13的要求适用于研究用医药产品（Investigational Medicinal Products，IMP）、参照物和非IMP。IMP按照指定市场规定的GMP生产。GMP包括人员、文件管理、质量管理、生产、订购、运输和临床用品的返还。需要指出的是，附件13是对良好临床实践指令的补充。需要指出的是，附件13是对《良好临床实践指令》的补充。 该指令要求IMP生产商对欧盟境内生产的试验用产品以及为试验进口的试验用产品实施GMP。成员国必须确保进口的IMP生产批次是按照至少等同于欧盟GMP的标准生产和检测的。无论是否进口，作为第一步，合格人员（QP）必须对每批用于临床试验的材料（包括进口材料）的放行进行认证。GCP指令要求获得IMP生产许可证，这与人用医药产品的生产许可证不同。要进行比较产品或其他临床试验材料的采购。 临床生产过程还包括生产用于临床试验的安慰剂或对照药物。临床包装也必须符合 GMP标准，以确保药物的安全性和有效性，并满足监管要求。用于临床包装的材料必须是高质量的，并且适合所包装的药物。它们还必须能够承受储存和运输条件。包装设计必须适合所包装的药物和临床试验的要求。包装还应易于使用和处理，并应将药物污染或降解的风险降至最低。临床包装必须包括适当的标签（见图12-5），以提供有关药物的信息，包括名称、强度和剂型，以及任何必要的警告或警示说明。 临床试验中使用盲法是为了确保试验结果客观公正。为确保盲法的有效性，必须精心设计盲法过程，并严格遵守研究药物的包装和标签准则。这可能需要对所有研究药物使用相同的包装和标签，或使用代码来隐藏治疗分配。同样重要的是，要仔细跟踪和记录治疗分配情况，以确保在整个研究过程中始终保持盲法。 08 批发分销规例 FDA最近发布了一项关于为批发分销商和第三方物流公司建立统一许可标准的规则草案。该规则的目的是为供应链参与者提供更大的保证，确保他们有足够的审查和资格来分销处方药，进一步加强供应链。根据拟议的规则，第三方物流必须使用适当的手动，机电或电子温度和湿度记录设备，或日志来记录适当的存储。他们需要确保产品在适当的温度和适当的条件下按照产品标签的要求进行分发，以保持其特性、强度、质量和纯度。 仓库/配送设施必须有确保处方药正确储存的设备，包括冷库、冰箱、温度和湿度装置以及空气处理装置。需要有监控设备，在任何偏离所需储存条件的情况下立即向相关人员发出警报。然而，FDA认为出售或转让的药物临床实验或研究目的一名调查员，定义在21 CFR 312.3（或任何后续监管），一部分在印第安纳州提交给FDA是批发分销的范围之外，因为药物是用于体外，临床、或其他研究目的在印第安纳州。由于这些原因，FDA提出了排除这些类型的交易范围的批发销售。 在欧洲，只有持有批发经销商许可证的人才能储存和运输药品。 09 共性与差异 临床和非临床开发供应链都涉及货物、服务和资源的采购与分配，以支持产品或项目的开发。两者都可能很复杂，涉及多个利益相关者，并在不同且往往具有挑战性的环境中运行，包括原材料、用品、设备和合同服务的货物和服务采购。它们涉及货物和材料的运输和分配，可能涉及当地、国家或国际物流。发展供应链涉及管理和降低风险，如供应链中断、法规变化或质量问题。 临床供应链涉及临床试验材料的管理，包括用于临床试验以评估新药或新疗法的安全性和有效性的研究用医药产品和安慰剂产品。非临床医药开发供应链涉及医药产品早期开发和生产中使用的原材料、供应品和设备的采购与分销，但不涉及临床试验材料。临床供应需要满足额外的监管要求，如GCP指导原则，而非临床医药开发供应链则在必要时遵守特定的数据完整性、QbD和GMP要求。 临床供应主要涉及与临床试验机构协调，并管理向这些机构分发临床试验材料的工作，而非临床医药研发供应链则负责协调研发和生产机构，并管理用于研发目的的原材料、供应品和设备的分发工作。原材料、供应品和设备的储存和处理符合特定要求，但这些要求可能不如临床试验材料的要求严格。 10 大流行病期间临床和非临床开发供应链的复杂性 由于进出口法规、温度偏差和规划不确定性等方面的原因，世界各地的临床试验变得更加复杂。由于COVID-19疫苗等疗法需要快速开发，因此需要尽可能缩短时间。监管机构需要考虑适应以患者为中心的新模式。CRO和申办方公司必须确定采购模式，并明确合作伙伴之间以及全球范围内的责任。COVID-19大流行对全球开发部门的供应链产生了重大影响。研究发现，2020年2月至5月期间，美国启动的研究数量仅为未发 生大流行病时预期数量的57%。发展供应链涉及货物、服务和资源的采购与分销，以支持发展项目和计划，包括中低收入 国家的项目和计划。这些供应链非常复杂，涉及多个利益相关者，在多种多样且往往具有挑战性的环境中运作。 大流行病扰乱了全球贸易和运输网络，增加了获取和运输货物和材料的难度。对个人防护设备（PPE）、包装材料和其他必需品的高需求导致短缺，影响了发展项目对这些物品的供应。各国政府和各组织不得不调整其采购程序，以适应远程工作，遵守社会隔离措施。大流行病增加了管理和监测发展项目的难度，因为旅行和面对面的会议都无法进行。为了应对这些挑战，发展组织必须灵活调整其供应链战略。这包括寻找新的供应来源，使供应商基础多样化，以及利用数字技术促进远程协作和沟通。 — 结论 — 业界发起的临床试验和学术界临床试验都致力于改善医疗服务。然而，它们开展临床研究项目的动机各有不同。为了推销新产品并为公司创造利润，业界需要进行临床试验，以提供新药成功的证据。而在学术界，研究人员的动机则是可以带来的潜在学术和医学影响。由于药物研发需要数年时间，业界往往面临着推出新产品的严格时间压力。当涉及到新研究产品的专利时，情况更是如此。公司越早从受专利保护的产品中获利，对公司就越有利。作为确保产品寿命战略的一部分，公司会开发新的配方、产品线延伸、新的技术平台和新的诉求，这也可能需要进行临床试验。非临床和临床开发阶段的供应链在加快向市场推出价格合理的新疗法方面起着至关重要的作用。 参考文献：（上下滑动查看更多） All references verified 13 March 2023. 1. Food and Drug Administration. What are the different types of clinical research? Current as of 4 January 2018. https://www.fda.gov/patients/clinical-trials-what-patients-need-know/what-are-differenttypes-clinical-research 2. International Council for Harmonisation. Integrated addendum to ICH E6(R1): Guideline for good clinical practice. Step 4 vers. Dated 9 Novemebr 2016. https://database.ich.org/sites/default/files/E6_R2_Addendum.pdf 3. International Council for Harmonisation. Development and manufacture of drug substances (chemical entities and biotechnological/biological entities) Q11. Step 4 vers. Dated 1 May 2012. https://database.ich.org/sites/default/files/Q11%20Guideline.pdf 4. International Council for Harmonisation. Stability testing of new drug substances and products QIA(R2). Step 4 vers. Dated 6 February 2003. https://database.ich.org/sites/default/files/Q1A%28R2%29%20 Guideline.pdf 5. Food and Drug Administration. Digital health technologies for remote data acquisition in clinical investigations [draft guidance]. Current as of 22 December 2021. https://www.fda.gov/regulatory-information/search-fda-guidance-documents/digital-health-technologies-remotedata-acquisition-clinical-investigations 6. Food and Drug Administration. Container closure systems for packaging human drugs and biologics: Chemistry, manufacturing, and controls documentation [guidance]. Dated May 1999. https://www.fda.gov/media/70788/download 7. European Medicines Agency. European medicines agencies network strategy to 2025: Protecting public health at a time of rapid change. Published 2020. https://www.ema.europa.eu/en/documents/report/european-union-medicines-agencies-network-strategy-2025-protecting-public-health-time-rapid-change_en.pdf 8. Food and Drug Administration. IND applications for clinical investigations: Regulatory and administrative components. Current as of 7 March 2022. https://www.fda.gov/drugs/investigationalnew-drug-ind-application/ind-applications-clinical-investigationsregulatory-and-administrative-components 9. Food and Drug Administration. Biologics license applications (BLA) process (CBER). Current as of 27 January 2021. https://www.fda.gov/vaccines-blood biologics/development-approval-process-cber/biologics-license-applications-bla-process-cber 10. Food and Drug Administration. Adaptive designs for clinical trials of drugs and biologics [guidance]. Dated November 2019. https://www. fda.gov/media/78495/download 11. Food and Drug Administration. Generic drugs: Questions & answers. Current as of 16 March 2021. https://www.fda.gov/drugs/frequentlyasked asked-questions-popular-topics/generic-drugs-questions-answers 12. Raines K. A primer on generic drugs and bioequivalence: An overview of the generic drug approval process. https://www.fda.gov/files/about%20fda/published/Generic-Drugs-and-Bioequivalence---Presentation.pdf 13. Food and Drug Administration. Product-specific guidances for generic drug development. Current as of 21 November 2022. https://www.fda. gov/drugs/guidances-drugs/product-specific-guidances-generic-drugdevelopment 14. Food and Drug Administration. Applications covered by section 505(b)(2) [draft]. Dated October 1999. https://www.fda.gov/media/72419/download 15. Food and Drug Administration. M9 biopharmaceutics classification system-based biowaivers [guidance]. Dated May 2021. https://www.fda.gov/media/148472/download 16. Food and Drug Administration. Referencing approved drug products in ANDA submissions. Dated October 2020. https://www.fda.gov/media/102360/download 17. Food and Drug Administration. Office of Generic Drugs. Current as of 5 August 2022. https://www.fda.gov/about-fda/center-drugevaluation-and-research-cder/office-generic-drugs 18. Food and Drug Administration. Center for Drug Evaluation and Research | CDER. Current as of 24 June 2022. https://www.fda.gov/ about-fda/fda-organization/center-drug-evaluation-and-research-cder 19. Food and Drug Administration. Biosimilars guidances. Current as of 5 October 2021. https://www.fda.gov/vaccines-blood-biologics/generalbiologics-guidances/biosimilars-guidances 20. European Medicines Agency. Guideline on similar biological medicinal products. Rev. 1. Effective 30 April 2015. https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-similarbiological-medicinal-products-rev1_en.pdf 21. European Medicines Agency. Guideline on similar biological medicinal products containing biotechnology-derived proteins as active substance: quality issues (revision 1). Effective 1 December 2014. https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-similar-biological-medicinal-products-containingbiotechnology- derived-proteins-active_en-0.pdf 22. European Medicines Agency. Guideline on similar biological medicinal products containing biotechnology-derived proteins as active substance: Non-clinical and clinical issues. Rev. 1. Effective 1 July 2015. https://www.ema.europa.eu/en/documents/scientificguideline/guideline-similar-biological-medicinal-products-containingbiotechnology-derived-proteins-active_en-2.pdf 23. International Council for Harmonisation. ICH E6 (R2) Good clinical practice - Scientific guideline. https://www.ema.europa.eu/en/ich-e6-r2-good-clinical-practice-scientific-guideline 24. Health Canada. Good clinical practices: Guidance documents. Modified 29 September 2022. https://www.canada.ca/en/healthcanada/services/drugs-health-products/compliance-enforcement/good-clinical-practices/guidance-documents.html 25. World Health Organization. Data handbook for good clinical research practice (GCP): guidance for implementation. https://apps-who-int.libproxy1.nus.edu.sg/ iris/bitstream/handle/10665/43392/924159392X_eng.pdf 26. Office for Human Research Protections. Regulations, policy &guidance. Last reviewed 30 June 2020. https://www.hhs.gov/ohrp/ regulations-and-policy/index.html. 英文版 （上下滑动看更多） Chapter11 Coordinating Drug Supply for Clinical and Nonclinical Development The supply of a drug during nonclinical and clinical development refers to the way the drug is provided or made available to researchers, patients, healthcare providers, distributors, and developers. During the nonclinical development stage, the supply of a drug is limited to a small number of researchers or laboratories. This involves carefully controlling the distribution of the drug to ensure that it is handled, stored, and administered correctly. Once a drug enters clinical development, it is supplied to a larger number of patients and healthcare providers through various channels, such as pharmacies, hospitals, and clinics. The clinical supplies of medical products are made available to patients and healthcare providers during the early stages of clinical development. This includes Phase 1 and Phase 2 clinical trials, which are the first steps in evaluating the safety and effectiveness of a new drug or treatment in humans.1 Once a drug or other medical product has successfully completed the early clinical stages and has been shown to be safe and effective, it may progress to later stages of clinical development, such as Phase 3 clinical trials, which involve larger numbers of patients and may involve a more widespread distribution of the drug or product. Clinical and Nonclinical Development Supply Clinical Development Supply Chain The distribution of treatment in a clinical trial is carefully planned and controlled to ensure that all participants receive the correct treatment in a consistent manner. This helps to reduce the potential for bias in the trial and to ensure that the results accurately reflect the effectiveness of the treatment being studied. It is typically one of the key variables being studied in a clinical trial, and its distribution is described in detail in the trial protocol. There are various standards and guidelines (see Table 12-1) that outline the appropriate procedures for distributing materials in a clinical trial to ensure the quality, safety, and integrity of the study. Nonclinical Development Supply Chain In the context of product development, material supply refers to the sourcing and procurement of the materials that are used to create a drug or other product. This may include raw materials, Active Pharmaceutical Ingredients (APIs), excipients, and other ingredients needed to formulate the product. Proper material supply is a vital aspect of formulation development, as it can affect the quality, safety, and effectiveness of the final product. Material suppliers must be carefully selected, and these materials must be thoroughly tested and validated to ensure that they meet the required standards.3 The material supply process for formulation development may also be subject to regulatory oversight to ensure that the materials used in the formulation are safe and of high quality. In addition to sourcing and procuring materials, the material supply process for formulation development may also involve storage and handling requirements to ensure the stability4 and purity of the materials. Several guidelines and standards (see Table 12-2) apply to distributing materials in nonclinical settings, such as research labs or manufacturing facilities. It is essential to follow these guidelines and standards when distributing materials in clinical or nonclinical settings to ensure the quality, safety, and integrity of the results to be applied for regulatory decision-making on the product. Drug Supply for Clinical Trials The key to a successful supply chain in clinical supply is the close collaboration of supply chain leads with the sponsor, trial design team, project execution/site team, various  operational leads of the trials, packaging distribution centers, technologists, home healthcare teams, and regulatory consultants/experts. The use of technology5 for clear visibility, tracking, inventory management and monitoring of material reaching the patient is required. Visibility on variations in patient enrollment or changes in the study needs to be swiftly considered to ensure the supply of the material is on track with not out of stock situations. A real-time system to provide visibility and traceability is hence critical. Defining the appropriate distribution channels is another aspect of clinical supply strategy. Determining the adequacy of container closure systems,6 and continually monitoring temperature and humidity transportation and storage conditions are critical. The other key aspect is material management, managing the expiry of the materials throughout the study periods. Clinical Supply Chain Strategy A clinical supply chain strategy (see Table 12-3) is a plan for managing the distribution of drugs, medical devices, and other materials to patients and healthcare providers during the clinical development of a new product. It is an essential aspect of drug development, as it helps to ensure that the product is available in the right quantities, at the right time, and in the right place to meet the needs of clinical trials and other studies. Developing an effective clinical supply chain strategy requires careful planning and coordination to ensure that the product is available when and where it is needed while meeting regulatory requirements and standards for quality and safety. Regulators are also implementing smart strategies in clinical development and supply to meet patient needs. New Drugs and Generics; Biologics and Biosimilars IND, or investigational new drug application,8 is a request to the Food and Drug Administration (FDA) for permission to begin testing a new drug or biologic in humans. The IND process is designed to ensure that new drugs and biologics are safe and effective before they are approved for use in the US. Stakeholders in the IND process include the drug or biologic manufacturer, the FDA, healthcare providers, patients, and advocacy groups. The IND process is designed to ensure that new drugs and biologics are thoroughly tested and carefully evaluated before they are approved for use in the US. In other jurisdictions, it is typically a Clinical Trial Application (CTA). New Drug Applications (NDAs) and Abbreviated New Drug Applications (ANDAs) pertain to marketing authorization applications for small-molecule drugs, while Biological Licence Applications (BLAs)9 pertain to new biologics and biosimilars (see Table 12-4) in the US (other jurisdictions typically use the term marketing authorization application [MAA]). Biologics are complex products that are produced using living cells and are often more difficult to manufacture than small-molecule drugs. As a result, the clinical trial requirements for biologics may be more stringent than those for small-molecule drugs.  The clinical trial design10 for NDAs, ANDAs, and BLAs may differ based on the specific characteristics of the product being tested. For example, the clinical trial design for a small molecule drug may differ from that of a vaccine or a blood product. The size of clinical trials also may vary depending on the specific characteristics of the product being tested. The submission requirements for Biologics may differ in terms of the specific data and information that must be included in the application. ANDA generic drugs, on the other hand, is a request for permission to market a generic version of a drug that is already approved in the US. There are several key differences in ANDA development and clinical activities. Primarily, ANDAs are used to request approval for generic drugs, which are copies of branded drugs that have already been approved by the FDA. ANDAs generally may not require clinical trials to be conducted, as the safety and effectiveness of the generic drug have already been established through the approval process for the brand-name drug. The approval process for ANDAs is, therefore, faster than the approval process for NDAs. However, the ANDA submission process may involve some clinical data, such as bioequivalence studies, which are designed to demonstrate that the generic drug is biologically equivalent to the brand-name drug. Bioequivalence studies involve administering the generic drug and the brand-name drug to a small group of healthy volunteers and measuring the levels of the drug in the blood to ensure that they are comparable. In addition, the ANDA submission process may also involve demonstrating that the generic drug meets the same quality standards as the brand-name drug. This may involve conducting studies to show that the generic drug has the same purity, strength, and stability as the brand-name drug. Product-specific guidance is issued by the FDA to provide detailed information on the regulatory requirements for a specific type of drug or product. Product-specific guidance may include information on the types of data that are needed to support an ANDA or a 505(b)(2) application, as well as information on the criteria that the FDA will use to evaluate the safety and effectiveness of the drug or product. Biowaivers or exemptions from certain regulatory requirements are granted for generic drugs that are shown to be bioequivalent to a reference-listed drug (RLD) that has already been approved by the FDA. Biowaivers may be granted for certain types of generic drugs, such as those that are immediate-release solid oral dosage forms, if the generic drug can be shown to be bioequivalent to the RLD based on appropriate in vitro and/or in vivo data. ANDAs are reviewed by the FDA’s Office of Generic Drugs (OGD),17 while NDAs are evaluated by the FDA’s Center for Drug Evaluation and Research (CDER).18 Overall, the ANDA process is designed to ensure that generic drugs are safe, effective, and of high quality before they are approved for use. A biosimilar is a biological product that is similar to a reference biologic product and has been shown to have no clinically meaningful differences in terms of safety, purity, and potency. Biosimilar clinical trials typically follow a similar process to clinical trials for other types of pharmaceutical products. To demonstrate this similarity, it is generally necessary to conduct clinical trials in which the biosimilar is compared to the reference product in patients. These clinical trials are designed to provide evidence of the biosimilar’s safety, efficacy, and quality, and are an important part of the regulatory process for the approval of biosimilars. The specific clinical trial requirements for biosimilars may vary depending on the specific regulatory framework in the country where the biosimilar is being developed. Mapping the Supply Chain Mapping the clinical supply chain (see Figure 12-1) can help identify potential bottlenecks or points of failure in the distribution process and can help identify areas where improvements can be made to optimize the flow of investigational products to clinical trial sites. The activities start with the ones performed by manufacturing and distribution sites of investigational products. This includes production, distribution, intermediate storage, or handling steps that may be necessary. Then comes inventory management for tracking the quantity and location of investigational products at each stage of the supply chain, as well as managing expiration dates and other product-specific considerations. There needs to be a handling of adverse events that includes the process for reporting and managing adverse events that may occur during the clinical trial, including the collection and analysis of data on adverse events and the communication of this information to relevant parties. The supply chain scenarios must incorporate managing study data and meet regulatory compliance. This includes the collection, storage, and analysis of data from the clinical trial, as well as the management of electronic data systems and the transfer of data between different parties in the supply chain. Regulatory compliance includes the process of ensuring compliance with regulatory requirements at each stage of the clinical supply chain, including the submission of required documentation to regulatory agencies. Clinical Trial Regulations Good Clinical Practice (GCP) guidelines and other guidance documents23-25 from the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) provide internationally recognized standards for the design, conduct, and reporting of clinical trials involving investigational drugs, and are used to ensure the quality and integrity of clinical trial data. Clinical trial regulations are designed to ensure the safety and ethical conduct of clinical trials and to protect the rights and welfare of study participants. In the US, supply chain management in clinical trials is regulated by several different agencies, including the FDA, the Office for Human Research Protections (OHRP),26 and the CTRIS program. IND regulations outline the requirements for conducting clinical trials of investigational drugs in the US.Clinical trials require sponsors and investigators to register clinical trials and submit certain information about the trial, including information about the supply chain (e.g., the source and manufacturer of investigational products). Federal Policy for the Protec tion of Human Subjects (Common Rule) is administered by the OHRP27; it sets forth basic ethical principles and requirements for the protection of human subjects in research. The Common Rule includes provisions related to the procurement and use of investigational products in clinical trials, such as the requirement to obtain informed consent from trial subjects and to ensure that investigational products are used in accordance with the protocol (see Table 12-5). Various publications also contributed to the development of final rules related to the FDA’s regulations on good clinical practice and clinical trials.28-38 Clinical trial regulations in the EU are designed to ensure the safety and ethical conduct of clinical trials and to protect the rights and welfare of study participants. Some of the most important clinical trial regulations in the EU include: Regulation (EU) No 536/201439 establishes a single set of rules for the authorization and supervision of clinical trials in the EU. It includes provisions related to the assessment of clinical trial applications, the supervision of clinical trials, and the reporting of clinical trial results. This regulation is still in the transition state and is not yet fully implemented. The Clinical Trials Registration and Results Information Submission requirements40 established by the European Medicines Agency (EMA) mandate the registration and results reporting of clinical trials in the EU are designed to promote transparency and accountability in clinical research. The General Data Protection Regulation (GDPR)41 applies throughout the EU, establishes rules for the protection of personal data, and requires that clinical trial participants provide their informed consent for the processing of their personal data in clinical trials. Meanwhile, clinical trial regulations in Japan include the Pharmaceutical Affairs Act and its regulations, the Clinical Trials Notification (CTN) and Clinical Trials Information (CTI) systems run by the Ministry of Health, Labor, and Welfare (MHLW) for the purpose of trials. And in China, clinical trials (including bioequivalence studies) need prior National Medical Products Administration (NMPA, formerly the China Food and Drug Administration, or CFDA) approval. The approved clinical trial should be conducted in a certified research institution that operates in compliance with Chinese GCP. In the UK, the Medicines for Human Use (Clinical Trials) Regulations established the legal framework for the conduct of clinical trials involving investigational drugs and biologics. They include provisions related to the ethical conduct of clinical trials, the protection of clinical trial participants, and the submission of clinical trial applications to regulatory authorities. And in Canada, the most important clinical trial regulations include the Food and Drugs Act and its regulations that establish the legal framework for the conduct of clinical trials involving investigational drugs, biologics, and medical devices, the Health Canada Guidance Document for Clinical Trial Sponsors: Clinical Trial Applications, and the Personal Information Protection and Electronic Documents Act (PIPEDA). Meanwhile, the Brazilian Health Regulatory Agency (ANVISA) establishes the legal framework for conducting clinical trials involving investigational drugs and biologics in Brazil. The Brazilian Clinical Trials Registry (ReBec)45 maintained by ANVISA is used to register clinical trial protocols and other related documents. Brazilian National Health Council Resolution No. 466/201246 establishes the rules for protecting personal data in clinical trials. The regulatory landscape for supply chain management in clinical trials is constantly evolving, and new regulations and guidelines are frequently being issued. These are only a few of the key clinical trial regulations to be considered. There may be additional regulations that apply depending on the specific characteristics of the clinical trial, such as the type of investigational product being tested or the funding source for the trial. Traceability of Clinical Supply Material As a best practice, supply chain partners are to be licensed in accordance with federal requirements and share information when transferring product ownership to permit products to be tracked and traced as they progress through the supply chain. Traceability requirements extend beyond the lot level to the individual package level. Transaction documentation and other pharmaceutical pedigree information can be exchanged among entities in a fully electronic and secure manner. Commercial distributors and third-party logistics providers who submit an annual report to the FDA listing the states in which they are licensed can be used for clinical distribution as well. A manufacturer should have systems to comply with a suspect product’s identification and reporting requirements, including quarantining such product and promptly investigating in coordination with clinical partners, as applicable, to determine whether the material is illegitimate. This will include validating any applicable transaction history and transaction information in possession of the manufacturer. If the manufacturer determines a product to be suspect, the product should be quarantined, and an investigation conducted. If proven legitimate, the records should be completed, and the product should be documented as cleared. Each unit of the investigational product should be uniquely identified and labeled using methods such as barcodes or serial numbers. The use of data systems can facilitate traceability by allowing the electronic tracking and tracing of investigational products, as well as the collection and analysis of data on the movement and use of these products. Establishing standard operating procedures (SOPs) for the handling and distribution of investigational products can help ensure that these products are handled and distributed in a consistent and controlled manner. This can facilitate traceability by providing clear guidelines for the tracking and tracing of products. Ensuring that all parties involved in the clinical supply chain are trained and educated on the importance of traceability – as well as specific procedures and having systems in place for tracking and tracing investigational products – can ensure that integrity is maintained throughout the supply chain. Traceability in the clinical supply chain is required for the movement of investigational products through the supply chain from the manufacturer to the clinical trial site. It is important in clinical trials because it allows for the identification and addressing of potential issues or problems that may arise during the distribution process, ensuring the integrity and quality of the investigational product. Potential Issues and Mitigation Plans in Clinical Trial Supply Chain Several issues can arise in the clinical trial supply chain (see Table 12-6), which can impact the ability to deliver investigational products to clinical trial sites and potentially delay or disrupt the clinical trial. Manufacturing delays or issues with the production of investigational products, such as contamination or other quality issues, can lead to delays in supplying these products to clinical trial sites. Establishing backup manufacturing and distribution sources is an option to ensure a continuous supply of investigational products in case of delays or issues with the primary source. Logistical challenges with the transportation or storage of investigational products, such as delays due to weather or other unforeseen circumstances, can impact the delivery of these products to clinical trial sites. Implementing robust logistics and transportation systems can ensure the timely and reliable delivery of investigational products to clinical trial sites. Inventory management issues with tracking and managing inventory, such as incorrect stock counts or expiration of investigational products, can lead to shortages or other disruptions in the supply chain. Developing a robust inventory management system to track and manage the supply of investigational products, including expiration dates and other product-specific considerations, can mitigate this issue. Failure to comply with these requirements can lead to delays or disruptions in the supply of investigational products. Ensuring regulatory compliance at all stages of the clinical trial supply chain, including submitting required documentation to regulatory agencies in a timely manner, is therefore necessary. To mitigate these potential issues (see Figure 12-2), it is essential to have a robust and well-planned clinical trial supply chain with appropriate controls and contingency plans in place. Drug Supply for Nonclinical Development Work Selection and Supply of Active Pharmaceutical Ingredients and Excipients During the nonclinical development phase of a new medication, pharmaceutical companies need to obtain a supply of the API for use in preclinical testing. The drug substance is the pure form of the compound that is being developed into medication and is the source material to produce the finished drug product. They are developed and manufactured by pharmaceutical companies and are then formulated into finished dosage forms. Development of the API involves several steps. Identification and selection of the synthetic route or biological process for a compound are one. This can be done through various methods, including the synthesis of new compounds, isolation of natural products, or modification of existing compounds. Preclinical testing is performed to evaluate the safety and effectiveness in animals. Clinical trials determine the safety and efficacy of the compound in humans. Regulatory Drug Master File (DMF) submission at a national regulatory agency such as the FDA or the EMA is required. The development of APIs is a complex and time-consuming process that can take many years and require significant investment. There are several options for obtaining a supply of drug substances for nonclinical development work. Some pharmaceutical companies have the capability to synthesize the drug substance in-house using their own facilities. This can be a cost-effective option if the company has the necessary expertise and equipment. Contract Manufacturing Organizations (CMOs) are third-party companies that specialize in the synthesis and manufacture of APIs and other drug substances. Pharmaceutical companies can outsource the development of the drug substance to a CMO, which can also be a cost-effective option if the company does not have the necessary expertise or equipment in-house. Pharmaceutical companies can also purchase the drug substance from a supplier, such as a chemical manufacturer or a company that specializes in the production of APIs. This can be a good option if the drug substance is readily available, and the company does not want to invest in the necessary equipment and expertise to synthesize it in-house or through a CMO. The API supply chain is important because the quality of the API can have a significant impact on the safety and effectiveness of the finished medication. In the US, APIs are regulated by the FDA under the Federal Food, Drug, and Cosmetic (FD&C) Act. In the EU, APIs are regulated by the EMA or by National Competent Authorities (NCAs) under the principles of GMP, as well as the EU GMP guidelines and the EU GMP annexes. The ICH provides GMP guidance48 for the manufacturing of active pharmaceutical ingredients (APIs) under an appropriate system for managing quality. It is also intended to help ensure that APIs meet the quality and purity characteristics that they purport, or are represented, to possess. GMP regulations for the manufacture of APIs lay bare the requirements for the design, operation, and maintenance of API manufacturing facilities. The regulations are intended to ensure that APIs are consistently manufactured and controlled. During the nonclinical development phase of a new medication, pharmaceutical companies need to obtain a supply of excipients for use in the nonclinical development formulation (see Table 12-7) of test batches of the drug product. API and Key Ingredient Supply Security The upstream vulnerabilities, like sources of raw materials and ingredients, have been highlighted by regulators such as the FDA.  According to the agency, 72% of API manufacturers (see Figure 12-3) supplying the US market are overseas.49 As a result, when disruptions occur at those limited sites, whether from natural disasters, geopolitical events, or pandemic-related shutdowns,patients suffer the consequences. There are thousands of pharmaceutical manufacturing plants across the world dependent on imports. A price increase is unavoidable due to the increased demand out of the supply chain restrictions such as in pandemic conditions. The cost of the API is the most significant component of the pharmaceutical cost of production. Policymakers at the world’s largest pharmaceutical market (the US) and the world’s largest generics producer (India)50 are worried about their dependency. An exploratory study on API by The World Bank found that Western API manufacturers have an average wage index of 100, while in Asia, it is as low as eight. The FDA identified that the number of API manufacturing sites is increasing in other countries. The reliance of the US on foreign sources of API in later stages of the development cycle is therefore growing. The FDA believes that advanced manufacturing technologies may help regain US competitiveness and minimize national security risks. There are new regulatory guidelines to encourage emerging technologies such as flow chemistry and/or continuous manufacturing, as they concluded that traditional manufacturing can never offset the cost advantages and productivity that established facilities enjoy. Packaging Material Development and Supply A science and data-driven approach needs to be considered in developing and qualifying robust and optimal primary and secondary packing solutions. Planning with stakeholder (sponsor, distributor, CRO, CDMO, material vendor, transporter) involvement, where all the product quality-related requirements are elicited, is a vital part of the process. This process of engagement allows the developer capturing correct product parameters, such as temperature, logistics, and domestic and international transit routes. Risk management, solution development, configuration management, qualification and transit studies, technical reviews, and traceability are performed as part of the process. The solution developed and selected needs to take into consideration supplier reliability and technical capabilities. The understanding of logistics functions is a critical part of the design development. Knowing the distribution environment, understanding the flow of packages as to how they are shaped, handled, and stored is important. Design tests and interpretation of the results need to be part of the process. Close observation of the package distribution process allows for understanding the variables that impact the mechanisms of measurement to be employed and determines vibration, drop, compression and temperature or humidity levels. A cold-chain packing solution (see Figure 12-4) can be best described as the method of packaging and shipping a product to maintain a consistent temperature from end to end within a transit route, be it international or domestic in nature, especially for biologics. The range and requirements needed to ship biologics is broad. The significance of cold-chain engineering development has hence taken prominence, also in part due to focus on the COVID-19 pandemic and the need for shipment of vaccines around the world. In the US, apart from product requirements, there are also regulatory requirements for cold-chain solutions: 21 CFR Part 205.50 refers to the minimum requirements for the storage and handling of drugs and details the requirement for temperature recording and recordkeeping; 21 CFR Part 203.32 discusses the need to maintain the drugs and conditions to maintain stability, integrity, and effectiveness as part of manufacturing specifications; 21 CFR Part 203.36 calls for maintaining forms, reports, and records to meet requirements for recordkeeping; 21 CFR Part 211.150 refers to the procedure of how drugs are to be distributed. 21 CFR Part 11 refers to the regulations and criteria in which the agency considers electronic records and signatures trustworthy. The International Safe Transit Association (ISTA) develops testing protocols and design standards that define how packages should be to guarantee protection for their content during the transportation cycle. Dosage Form Development and Regulations A based approach based on Quality by Design (QbD) is required for the drug product development.52 The API used in the medication must be characterized. It is then formulated into a finished dosage form, taking into consideration factors such as the desired release profile, stability, manufacturability, and patient acceptability.  Pre-formulation studies are conducted to understand the physical and chemical properties of the API and how it will behave in the finished dosage form. Stability testing of the finished dosage form is evaluated under various storage conditions to ensure that it remains stable and effective over time. The manufacturing process of the finished dosage form is developed and optimized to ensure that it can be consistently and reproducibly manufactured at a commercial scale. The manufacturing process is then scaled up to a larger scale, and the finished dosage form is validated to ensure that it meets required specifications. The formulation should be designed to meet the specific needs of the API, such as controlling the release profile, improving stability, or enhancing bioavailability. The formulation development should define Quality Target Product Profile (QTPP) to ensure the safety and effectiveness of the finished product and should be acceptable to patients in terms of taste, appearance, and ease of use. It should be amenable for manufacture at a commercial scale and should be reproducible and consistent. Potential Issues and Mitigation Plans There can be shortages of the raw materials or APIs needed for the nonclinical development of the medication, which can delay the development process. This issue can be mitigated by establishing multiple sources for raw materials and APIs, and by building up inventory in advance of anticipated shortages. There may be quality issues with the raw materials or APIs such as impurities or variations in potency. This can impact the safety and effectiveness of the finished product. To mitigate this issue, it is important to carefully evaluate the quality of raw materials and APIs and to establish robust quality control processes to ensure they meet the required specifications. There may be issues with the manufacturing process for the finished dosage form, such as variability in the production process or problems with equipment. To mitigate this issue, it is important to establish robust manufacturing processes and conduct thorough testing and validation of the finished dosage form. There may be delays or losses, or damages in the shipping of materials, which can impact the timeline for the nonclinical development of the medication. This issue can be mitigated by using reliable shipping carriers and by monitoring the status of shipments to ensure timely delivery. There may be customs issues that arise during the nonclinical distribution of a medication, such as problems with the import or export of materials or issues with the transportation of hazardous materials. To mitigate this issue, it is important to ensure customs clearance requirements and to establish procedures for handling such issues as they arise. By identifying and addressing potential issues in a timely manner, it is possible to minimize disruptions and ensure the smooth progress of nonclinical development. Clinical and Nonclinical Supply Regulations: Points to Consider Clinical trial spending in the pharmaceutical industry has increased. Clinical trial sponsors run complex trials and desire a faster “go/no go” decision-making scenario on their trials. Clinical trial supplies chain management is critical in bringing novel therapies and treatments to market. For that reason, sponsors need to align expertise, processes, and technology to support the activities. Clinical supply involves a global supply chain in many cases. A clinical project lifecycle starts from manufacturing and ends with the final reconciliation and destruction. The activities include coordination with clinical, medical, and third-party logistics (3PL) and other teams to create, validate and monitor the clinical supply chain plan. Secure document sharing, data integrity, and shipment tracking are key for traceability.  Monitoring of product expiry and inventory is also critical. A successful clinical project starts with developing plans to manage the regulatory requirements and regulations for importation and distribution. The process of completing CTA or IND applications is a critical step. The valuation of adequate funding for the activities and appropriate costing estimations are required for smooth project execution. Clinical trial documents, pharmacy manuals, or laboratory testing manuals to ensure GCP compliance is needed. Product designs or formulations tailored to the needs of clinical trials, as well as ensuring subject compliance, are key factors. A nonclinical development process typically involves activities such as preclinical testing, chemistry, manufacturing, and controls (CMC) development, and regulatory application (e.g., an IND). Preclinical testing includes in vitro (test tube or lab dish) and in vivo (animal) testing to evaluate the safety and effectiveness of the drug. CMC development involves developing the process for synthesizing and producing the drug, as well as ensuring that the drug meets quality standards. The regulatory application includes an application to a regulatory agency (e.g., the FDA) to request permission to begin clinical testing in humans. The stakeholders in the nonclinical development include the pharmaceutical company, regulatory agencies, distributors, CDMO, testing labs, and raw material vendors. Each of these stakeholders has a unique perspective and set of focus, and it is important to consider the needs and concerns throughout the nonclinical development process. Phase-Appropriate Manufacturing and Packaging GMPs are a set of guidelines and regulations that are designed to ensure that pharmaceuticals are consistently produced and controlled to the highest standards. GMP guidelines apply to all aspects of drug production, including raw materials, production process, and quality control. GMP standards vary depending on the stage of drug development. Phase-appropriate GMP refers to the application of GMP standards that are appropriate for the stage of drug development. For example, during Phase I clinical trials, the focus is on evaluating the safety of the drug, and the GMP standards may be less stringent than they would be during later-phase clinical trials or postmarketing. As the drug progresses through clinical development and moves closer to market approval, GMP standards become more stringent to ensure the quality and consistency of the final product. It is important to follow phase-appropriate GMP standards to ensure the safety and effectiveness of the drug, as well as to meet regulatory requirements. For example, in the EU, Directive 2003/94/EC requires applying the requirements of Annex 13 to Investigational Medicinal Products (IMPs), comparators and non-IMPs. IMPs are manufactured as per GMPs as defined in the designated markets. The GMPs include personnel, document management, quality management, production, ordering, shipping and return of clinical supplies. It needs to be noted that Annex 13 is in addition to the Good Clinical Practice Directive. That directive requires IMP manufacturers to apply GMPs for investigational products manufactured within the EU as well as those investigational products imported for trials. Member states must ensure that the imported IMP production batch is manufactured and tested in accordance with standards at least equivalent to EU GMPs. Imported or not, as a first step, the Qualified Person (QP) must certify the release of each batch of material for clinical trials, including imported material. The GCP directive requires an IMP manufacturing licence, which is different from a manufacturing licence for medicinal products for human use. The sourcing of comparator products or other clinical trial materials is to be performed. The clinical manufacturing process also involves the production of placebo or control drugs for use in clinical trials. Clinical packaging must also meet GMP standards to ensure the safety and effectiveness of the drug, as well as to meet regulatory requirements. The materials used for clinical packaging must be of high quality and suitable for the drug being packaged. They must also be able to withstand the conditions of storage and transport. The packaging design must be suitable for the drug being packaged and the requirements of the clinical trial. It should also be easy to use and handle and should minimize the risk of contamination or degradation of the drug. Clinical packaging must include appropriate labeling (see Figure 12-5) to provide information about the drug, including the name, strength, and dosage form, as well as any necessary warning or cautionary statements.  Blinding is used in clinical trials to ensure that the results are objective and unbiased. To ensure the effectiveness of blinding, it is important to carefully design the blinding process and follow strict guidelines for packaging and labeling the study drugs. This may involve using identical packaging and labelling for all study drugs or using codes to conceal the treatment assignment. It is also important to carefully track and record the treatment assignments to ensure that the blinding remains in place throughout the study. Wholesale Distribution Regulations The US FDA recently released a draft rule53 on establishing uniform licensing standards for wholesale distributors and 3PLs. The purpose of the rule is to provide greater assurance that supply chain participants are sufficiently vetted and qualified to distribute prescription drugs, further strengthening the supply chain. As per the proposed rule, the 3PL must use appropriate manual, electromechanical, or electronic temperature and humidity recording equipment, or logs to document proper storage. They need to ensure that products are distributed at appropriate temperatures and are under appropriate conditions in accordance with the requirements in the product’s labeling to preserve their identity, strength, quality, and purity. The warehouse/distribution facilities must have equipment that ensures prescription drugs are properly stored, including cold storage, refrigerators, temperature and humidity devices, and air-handling units. There needs to be monitoring equipment that immediately alerts appropriate personnel of any deviations from the required storage conditions. However, the FDA considers the sale or transfer of a drug for investigational or research purposes to an investigator, as defined in 21 CFR Part 312.3 (or any successor regulation), under an IND submitted to the FDA to be outside the scope of wholesale distribution because the drug is used for in vitro, clinical, or other research purposes under an IND. For these reasons, the FDA has proposed to exclude these types of transactions from the scope of wholesale distribution. And in Europe, only a wholesale dealer licence holder can store and transport drugs. Commonalities and Differences Both clinical and nonclinical development supply chains involve the procurement and distribution of goods, services, and resources to support the development of products or programs. Both can be complex, involving multiple stakeholders and operating in diverse and often challenging environments, including procurement of goods and services for raw materials, supplies, equipment, and contracted services. They involve the transportation and distribution of goods and materials, which may involve local, national, or international logistics. Development supply chains involve managing and mitigating risks, such as disruptions to the supply chain, changes in regulations, or quality issues. Clinical supply chains involve the management of clinical trial materials, including investigational medicinal products and placebo products, which are used in clinical trials to assess the safety and efficacy of new drugs or treatments. Nonclinical pharmaceutical development supply chains involve the procurement and distribution of raw materials, supplies, and equipment used in the early development and production of pharmaceutical products, but do not involve clinical trial materials. Clinical supply needs to meet additional regulatory requirements, such as GCP guidelines, while nonclinical pharmaceutical development supply chains adhere to specific data integrity, QbD, and GMP requirements, where required. While clinical supply primarily involves coordinating with clinical trial sites and managing the distribution of clinical trial materials to these sites, the nonclinical pharmaceutical development supply chains coordinate development and manufacturing sites and manage the distribution of raw materials, supplies, and equipment for development purposes. The storage and handling of raw materials, supplies, and equipment are in accordance with specific requirements, but these may not be as stringent as those for clinical trial materials. Clinical and Nonclinical Development Supply Chain Complexities During a Pandemic Clinical trials around the world have become more complex due to aspects such as import, and export regulations, temperature excursions, and planning uncertainties. The need for rapid development of therapies such as the COVID-19 vaccines supports the need to have shorter timelines where possible. The regulator’s drive to accommodate new patient-centric modalities needs to be considered. It is critical for the CRO and sponsor companies to identify sourcing models and define responsibilities between partners and across the globe. The COVID-19 pandemic had a significant impact on development sector supply chains around the world. It was found that the number of studies initiated in the US from February –May 2020 was only 57% of what would have been expected had the pandemic not occurred.54 Development supply chains involve the procurement and distribution of goods, services, and resources to support development projects and programs, including for lowand middle-income countries. These supply chains are complex, involving multiple stakeholders and operating in diverse and often challenging environments. The pandemic disrupted global trade and transportation networks, making it more difficult to obtain and transport goods and materials. High demand for Personal Protective Equipment (PPE), packaging materials, and other essential supplies led to shortages, which affected the availability of these items for development projects. Governments and organizations had to adjust their procurement processes to accommodate remote work to comply with social distancing measures. The pandemic made it more difficult to manage and monitor development projects, as travel and in-person meetings were not possible. To address these challenges, development organizations had to be flexible and adapt their supply chain strategies. This involved finding new sources of supplies, diversifying the supplier base, and leveraging digital technologies to facilitate remote collaboration and communication. Conclusion Industry-initiated and academic clinical trials strive to improve healthcare. However, they have their own motivations for pursuing clinical research projects. To market a new product and generate profit for the company, the industry needs clinical trials for the purpose of providing evidence of a successful new drug. Whereas in academia, researchers are motivated by the potential academic and medical impact they can impart. Since drug development takes years, the industry is often under strict timeline pressure to launch a new product. This is especially true when a patent for a new investigational product is involved. The sooner the company can profit from a patent-protected product, the better it is for the company. As part of the strategies to ensure product longevity,companies develop a novel formulation, line extensions, new technology platforms, and new claims, which may also call for clinical trials.55 Pharmaceutical and medical corporations serve the shareholders, who want to see profitability with a quick turnaround time. The nonclinical and clinical development phases supply chain has a critical role to play in bringing new and affordable therapies to market at a faster pace. The identification and mitigation of potential clinical and nonclinical supply risks, the standardization of supply chain processes, the coordination between regulatory bodies, and the adoption of supply chain technology solutions are a few elements to consider to be successful with supply chain security for the patient critical development materials. The segment continues to garner pharmaceutical industry interest. 声明：原英文原文版权归美国法规事务协会（RAPS）所有，本译文供参考，如有任何建议，请联系我们。 同写意媒体矩阵，欢迎关注↓↓↓

WARRINGTON, Pa., Oct. 23, 2024 (GLOBE NEWSWIRE) -- Windtree Therapeutics, Inc. (“Windtree” or the “Company”) (NasdaqCM: WINT), a biotechnology company focused on advancing early and late-stage innovative therapies for critical conditions and diseases, today announced that the Company has completed national phase filings of patent applications around the world, including in the United States, Germany, France, Italy, Japan and China. The istaroxime patent is entitled, “ISTAROXIME-CONTAINING INTRAVENOUS FORMULATION FOR THE TREATMENT OF PRE-CARDIOGEN1C SHOCK AND CARDIOGENIC SHOCK”, is No. PCT/US2023/018998 and was assigned application No. 18/858,086. “Windtree continues to prepare for the potential of istaroxime in treating cardiogenic shock patients by expanding and strengthening our patent estate,” said Craig Fraser, Chairman and Chief Executive Officer of Windtree. “Unique aspects of istaroxime are utilized in our strategy for intellectual property and positive clinical development has helped bring these aspects to light.” About IstaroximeIstaroxime is a first-in-class dual-mechanism therapy designed to improve both systolic and diastolic cardiac function. Istaroxime is designed as a positive inotropic agent that increases myocardial contractility through inhibition of Na+/K+- ATPase with a complimentary mechanism that facilitates myocardial relaxation through activation of the SERCA2a calcium pump on the sarcoplasmic reticulum enhancing calcium reuptake from the cytoplasm. Data from multiple Phase 2 studies in patients with early cardiogenic shock or acute decompensated heart failure have demonstrated that istaroxime infused intravenously significantly improves cardiac function and blood pressure without increasing heart rate or the incidence of cardiac rhythm disturbances. About Windtree Therapeutics, Inc.Windtree Therapeutics, Inc. is a biotechnology company focused on advancing early and late-stage innovative therapies for critical conditions and diseases. Windtree’s portfolio of product candidates includes istaroxime, a Phase 2 candidate with SERCA2a activating properties for acute heart failure and associated cardiogenic shock, preclinical SERCA2a activators for heart failure and preclinical precision aPKCi inhibitors that are being developed for potential in rare and broad oncology applications. Windtree also has a licensing business model with partnership out-licenses currently in place. Forward Looking StatementsThis press release contains statements related to the potential clinical effects of istaroxime; the potential benefits and safety of istaroxime; the clinical development of istaroxime; and our research and development program for treating patients in early cardiogenic shock due to heart failure. Such statements constitute forward-looking statements within the meaning of The Private Securities Litigation Reform Act of 1995. The Company may, in some cases, use terms such as “predicts,” “believes,” “potential,” “proposed,” “continue,” “estimates,” “anticipates,” “expects,” “plans,” “intends,” “may,” “could,” “might,” “will,” “should” or other words that convey uncertainty of future events or outcomes to identify these forward-looking statements. Such statements are based on information available to the Company as of the date of this press release and are subject to numerous important factors, risks and uncertainties that may cause actual events or results to differ materially from the Company’s current expectations. Examples of such risks and uncertainties include, among other things: the Company’s ability to secure significant additional capital as and when needed; the Company’s ability to achieve the intended benefits of the aPKCi asset acquisition with Varian Biopharmaceuticals, Inc.; the Company’s risks and uncertainties associated with the success and advancement of the clinical development programs for istaroxime and the Company’s other product candidates, including preclinical oncology candidates; the Company’s ability to access the debt or equity markets; the Company’s ability to manage costs and execute on its operational and budget plans; the results, cost and timing of the Company’s clinical development programs, including any delays to such clinical trials relating to enrollment or site initiation; risks related to technology transfers to contract manufacturers and manufacturing development activities; delays encountered by the Company, contract manufacturers or suppliers in manufacturing drug products, drug substances, and other materials on a timely basis and in sufficient amounts; risks relating to rigorous regulatory requirements, including that: (i) the U.S. Food and Drug Administration or other regulatory authorities may not agree with the Company on matters raised during regulatory reviews, may require significant additional activities, or may not accept or may withhold or delay consideration of applications, or may not approve or may limit approval of the Company’s product candidates, and (ii) changes in the national or international political and regulatory environment may make it more difficult to gain regulatory approvals and risks related to the Company’s efforts to maintain and protect the patents and licenses related to its product candidates; risks that the Company may never realize the value of its intangible assets and have to incur future impairment charges; risks related to the size and growth potential of the markets for the Company’s product candidates, and the Company’s ability to service those markets; the Company’s ability to develop sales and marketing capabilities, whether alone or with potential future collaborators; the rate and degree of market acceptance of the Company’s product candidates, if approved; the economic and social consequences of the COVID-19 pandemic and the impacts of political unrest, including as a result of geopolitical tension, including the conflict between Russia and Ukraine, the People’s Republic of China and the Republic of China (Taiwan), and the evolving events in Israel and Gaza, and any sanctions, export controls or other restrictive actions that may be imposed by the United States and/or other countries which could have an adverse impact on the Company’s operations, including through disruption in supply chain or access to potential international clinical trial sites, and through disruption, instability and volatility in the global markets, which could have an adverse impact on the Company’s ability to access the capital markets. These and other risks are described in the Company’s periodic reports, including its Annual Report on Form 10-K, Quarterly Reports on Form 10-Q and Current Reports on Form 8-K, filed with or furnished to the Securities and Exchange Commission and available at www.sec.gov. Any forward-looking statements that the Company makes in this press release speak only as of the date of this press release. The Company assumes no obligation to update forward-looking statements whether as a result of new information, future events or otherwise, after the date of this press release. Contact Information:Eric Curtisecurtis@windtreetx.com