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分析方法生命周期是一个持续的开发过程，其建立在对候选新药的发现、临床前和临床开发过程中使用的每种分析方法的了解之上。分析方法生命周期是分析方法定义、开发、优化、验证、鉴定、确认、转移、维护以及最终报废的流程图。生命周期的综合方法必须确保分析方法从最初的设计和开发发展到商业使用，并且必须在用于商业化道路上的各个临床阶段之前证明适合其预期目的。对分析方法进行评估和选择，以确定药物的具体特征。开发和验证分析测定方法，以根据预先确定的验收标准测试药物和药物产品的具体特征。 分析方法生命周期方法强调，在开发、控制、建立和使用分析程序时，必须有健全的科学流程和质量风险管理。这种方法适用于所有类型的分析方法，所付出的执行程度应与技术的复杂性和所要测量的质量属性的关键性相一致。熟练程度和技术知识是分析方法开发的基本要求，而要构建分析生命周期工作流程以满足预期药物使用的监管要求，则需要深厚的质量和监管知识。图 14-1 表示分析方法生命周期的关键要素及其与产品开发的联系。 1 分析方法定义：选择与优化 方法开发流程的第一步是根据预期用途定义方法的适用范围、目的和目标，以确保方法设计、功能和性能预期保持一致。在此阶段，需要制定协议来定义分析开发计划。分析方法开发的预期用途包括表征、过程测试、常规发布测试、稳定性、生物利用度、原料发布或过程验证支持。 预期用途与产品开发阶段直接相关，从临床前到临床再到商业阶段。在方法定义阶段确定测试样品也很重要。测试样品的例子包括原料药（DS）、制剂（DP）、安慰剂、基质（例如配方缓冲液、生物液体）、活性药物成分、赋形剂、杂质等。检测类别根据国际人用药品技术要求协调委员会（ICH）Q2(R1)指南中关于鉴别、定量杂质、极限测试或检测含量/效力的规定进行定义。分析开发计划的目标可以是正交、表征、可比性、放行、鉴定或鉴定和验证、稳定性或生物利用度研究。建议采用更全面的方法来定义分析方法，以降低方法开发计划与最终方法是否适合其预期用途之间不匹配的风险。 01 分析目标简介：分析方法生命周期结构框架 质量先驱约瑟夫·M·朱兰(Joseph M. Juran)博士提出了“质量源于设计”（Quality by Design (QbD)）的概念。珍妮特·伍德科克博士将高质量药品定义为无污染、能够可靠地向消费者提供标签上承诺的治疗效果的产品。ICH Q8指南强调了QbD概念，即设计最终产品的质量，而不是测试产品。ICH Q8将QbD定义为“一种系统化的开发方法，从预先确定的目标开始，强调基于可靠科学和质量风险管理的对产品和工艺的理解以及过程控制”。FDA鼓励在药品开发、生产和监管中采用基于风险的方法和QbD原则。FDA之所以重视QbD，是因为认识到增加测试并不一定能提高产品质量。质量必须融入产品中（Quality must be built into the product）。QbD要求对药品的预期质量特性进行前瞻性总结。 质量目标产品概况（Quality Target Product Profile ，QTPP）是对药品质量特性的前瞻性总结，在考虑药品的安全性和有效性后，理想情况下应达到这些质量特性，以确保达到预期的质量。QTPP构成了产品设计和开发的基础。QTPP推动了产品质量特性的定义。分析目标概况（Analytical Target Profile ，ATP）是分析方法的同义词。 在确定药品的分析目标概况（ATP）时，必须记录ICH Q2（R1、R2）类别分析方法（analytical methods）、特性（identity）、纯度（purity）、杂质（impurity）和含量（assay）以及性能特征（如准确性、精确性和特异性）的预定义方法参数。ATP中定义的分析测试程序和可报告结果决定了产品的质量属性，并依次为整体控制策略提供关键输入。分析目标概况（ATP）指导着适当分析方法的设计和开发。 分析目标概况（Analytical Target Profile ，ATP）是提供性能标准的基础，用于交付优质产品，并支持分析方法的“符合目的”或“适合预期用途”声明。用于测量关键质量属性（CQA）的分析方法必须足够灵敏、准确和精确，以便对属性进行充分控制，无论该方法用于过程控制还是通过DS或DP的最终产品规格。 定义阶段需要确定ICH Q2(R1)中规定的用于预期用途的纯度、杂质和检测的分析方法，确定关键质量属性（CQAs），确定方法性能的质量属性，根据支持信息确定每个属性的风险分配，以及方法性能的具体可接受性标准，例如系统适用性、检测可接受性、基于生产量的样品可接受性、设备、可转移性、材料和试剂可用性以及检测关键性。 分析方法定义阶段结束后，可以生成一份分析目标概况（Analytical Target Profile ，ATP）报告。根据产品在开发生命周期中的阶段，ATP报告可以是一个独立的交付物，也可以是最终方法开发报告的关键要素。随着新技术的出现、根据法规反馈对方法提出新要求或流程变更，ATP报告可能会被更新并用于指导分析生命周期管理中的进一步方法开发工作。 02 分析方法选择 一旦确定了分析目标概况（Analytical Target Profile ，ATP），分析方法生命周期的下一步就是选择适合目的或预期用途的方法。方法选择应包括对各种技术的评估，这些技术可应用于测试要求并满足产品规格的法规要求。方法的选择基于分析化学，其中包括识别、分离和量化药物化合物化学成分的方法。选择阶段包括选择材料和试剂、样品、设备和实验室。在确定是内部分析还是将分析方法外包给第三方实验室测试以满足法规要求时，用户需求、实验室能力和预算分配起着重要作用。选择阶段需要交付的是符合产品预期用途法规要求的方法选择建议，以及方法开发或方法优化策略的最终确定。 出于记录和存档的目的，可以生成与ATP类似的方法选择和策略报告。该报告可包含以下部分： • 项目名称 • 项目发起人/主要研究者（如适用） • 产品开发阶段（临床前、临床研究性新药（IND）阶段、1期、2期或3期 • 应用（放行、稳定性、in-process、生物利用度） • 产品基质（例如配方缓冲液） • 分析物基质（例如生物液体、配方缓冲液） • 预期用途的法规要求[例如，良好实验室规范GLP、良好临床规范GCP、现行良好生产规范（cGMP）] ICH Q2(R1)规定的分析方法类型 • 拟议规范 • 样品可接受性标准 • 系统适用性标准 • 拟采用的方法及其选择依据 • 替代方法 • 可能出现的短期和长期问题（例如供应链短缺） 03 分析方法的开发与优化 分析方法开发（Analytical method development AMD）是任何药物开发项目不可或缺的组成部分。方法开发是分析方法生命周期中的重要里程碑。分析方法开发的目的是建立分析目标概况（ATP）中规定的药物安全性、特性、强度、纯度和效力的最佳条件。分析方法开发的范围包括选择和优化实验设计以及评估方法性能。方法开发和优化的目标是选择合适的方法参数。交付成果可以是生成开发报告和标准操作程序草案（SOP）。 方法开发提供了关键信息，用于评估该方法是否适合目的，并可根据其预期用途进行方法鉴定或验证。分析开发报告是一份包含方法性能详情、材料和试剂信息、参考标准、对照、系统适用性要求、方法获取和数据分析参数、设备和软件的文档。对于任何开发新药候选物的制药或生物技术公司而言，分析方法开发都是工艺开发的关键支柱。 可采用分阶段的方法来满足法规对方法开发水平的期望。该方法在可靠性和便利性方面进行了优化，可根据其在产品开发阶段的应用情况采用增量开发和优化方法。例如，在产品开发的早期阶段（即临床前和1期），高效液相色谱法可能专注于持续测量目标分析物的含量、纯度和稳定性，但可能无法提供色谱图中所有杂质的特性和响应因子。然而，在产品研发后期（例如2期和3期），同样的方法可以提供这些信息，并将杂质标准纳入分析方法。 方法开发包括优化提取和检测目标分析物的程序和条件。它包括优化以下参数，以确保该方法适用于鉴定或验证(qualification or validation)： • 参考标准(Reference standards) • 关键试剂(Critical reagents) • 校准曲线(Calibration curve) • 质量控制（QC）样品(Quality control (QC) samples) • 选择性和特异性(Selectivity and specificity) • 灵敏度(Sensitivity) • 精确度(Accuracy) • 精确度(Precision) • 回收率(Recovery) • 基质中分析物的稳定性(Stability of the analyte in the matrix) 在分析方法生命周期中，结束方法开发阶段所需的关键成果是方法开发报告和标准操作程序草案。根据公司政策和程序，分析方法开发（Analytical method development AMD）报告的格式可能有所不同，但必须提供所有开发研究、数据、实验和结论的信息，以支持分析方法生命周期的下一步。该报告是建立标准操作程序和鉴定或验证协议目标标准的基石。与AMD报告一起，材料供应商、设备升级、缓冲液体积增加、关键材料属性、历史数据和趋势等信息构成了AMD包。对AMD包进行技术评估，以确定开发数据是否足以支持方法鉴定或方法验证研究。 AMD包可能包含以下可交付成果： • 方法的目的和范围 • 设计和开发历史 • 所选方法的科学原理背景描述 • 评估过的参数和性能 • 开发步骤总结 • 目标样本和基质 • ICH Q2(R1)方法类别 • 纳入开发目标中的ICH Q2(R1)特性 • 压力研究Stress studies（如果在开发阶段进行了初始力衰减研究） • 正在进行的长期研究的稳定性数据 • 系统适用性、方法和样本可接受性标准 • 实现预期用途 • 实现方法策略 • 材料、试剂、标准和对照 • 关键材料属性（critical material attributes，CMA）的识别 • 趋势数据和历史结果 • 实验室对产品预期用途的法规要求 • 操作员资质和培训要求 • 起草标准操作流程 04 分析方法鉴定 分析方法确认（AMQ）是业内公认且广泛接受的方法，用于证明分析方法在科学上合理、符合目的或适合预期用途、一致且能够成功生成可靠的结果。AMQ根据ICH Q2(R1)指南（即准确性、精确性、线性、特异性、范围、检测限/定量限和稳健性）确定与分析方法验证（Analytical Method Validation，AMV）相似的方法性能质量属性，但以阶段适当的方式推进，并与方法的预期用途保持一致。AMQ和AMV都证明了该方法适用于其预期用途，但它们在研究稳健性方面有所不同。 这意味着，与1期研究相比，对方法性能或资格进行更全面的评估可能有助于2期临床试验研究。与阶段相适应的监管指导文件描述了针对最终产品（DS或DP）发布的资格和验证研究的要求，以期用于预期的临床阶段。在分析方法验证（AMV）之前，分析方法确认（AMQ）并非法规要求，但它是ATP中定义的成功验证和方法适用性要求的基础。非营利组织（如肠外药物协会）发布的技术报告为AMQ提供了非约束性指导，并得到制药公司和合同分析测试实验室的广泛认可，以满足临床阶段对基于预期用途的分析方法的适当期望。 在分析方法生命周期中，AMQ可以是流程特性、可比性研究、用于在规格外调查期间确认根本原因的正交特性方法等活动的最终目标，以支持产品放行和产品开发材料的放行 /稳定性测试（即Phase 1和Phase 2临床试验材料）。根据产品所处的阶段以及开发生命周期中的分析方法，可能需要进行部分方法验证或交叉方法验证。方法学验证可作为依据ICH Q2(R1)指南进行完全方法学验证的基础。 监管机构发布了关于提交临床试验研究档案要求的指导方针。这些指导方针并未详细描述临床阶段适用的分析方法要求，但为AMQ对预期产品用途的预期奠定了基础。这些指导文件包括但不限于： • 美国1期和2/3期临床试验的IND申报 • 在欧洲进行临床试验的研究用药品档案提交 随着产品和分析方法在开发周期中的发展，分析方法也会进行科学或技术改进。在对方法进行重大修改后，以及在将其用于临床研究之前，需要评估方法重新认证的必要性。 方法鉴定报告包括结果、评估以及关于方法是否适用于预期用途的结论。AMD数据包附在AMQ报告中。鉴定后分析方法审查的责任对于保持方法的合格状态非常重要。 这些活动包括确保方法的使用符合预期用途，并确保其符合分析生命周期开发和鉴定阶段所定义的目的。鉴定后的变更可能包括新的参考标准或对照样品评估、基于产品开发阶段的范围变更，或将方法的技术转让给其他小组或实验室。 药典方法在使用前不需要进行确认，我们将在本章后面讨论。 AMQ实验和结果的关键交付物在AMQ报告中进行了总结。在AMQ实验完成并起草了鉴定报告后，起草了SOP并将其转移至QC实验室。分析方法鉴定是分析方法和产品开发生命周期中的关键成就。AMQ报告包括： • 设备的校准状态 • 设备软件和版本、采集方法和数据分析 • 材料、试剂、标准品、对照品和样品 • 样品制备和采集方法的描述 • 数据分析和计算方法 • 所有数据文件的参考资料，可清晰追溯到原始数据源 • 每个鉴定协议中预先定义的鉴定要素，以及根据目标标准进行的评估，并附有结论 • 技术评估，以确定每个鉴定要素的验收标准 • 意外结果和降低风险措施 • 关键方法评估（CMA），如确定 • 必要时，确保结果可重复性的关键方法步骤 • 资格鉴定过程中使用的SOP草案或版本的副本 • 根据鉴定结果，对标准操作程序（SOP）的修改建议、说明和理由 • AMD 报告和 ATP（附于 AMQ 报告之后） 2 分析方法验证 分析测试方法验证实验可提供关键数据，支持任何根据法规要求生产的药物的安全性、特性、强度、效力和纯度。测试结果对于确保消费者的健康和安全至关重要。因此，在现行cGMP下用于药品特征分析的方法应在产品生命周期中尽早验证。作为分析方法验证的一部分，所获得的数据提供了书面证据，证明测试程序适用于其预期用途，是方法性能的客观证据，并确保结果的质量和可重复性。 01 法规要求和指导文件 ICH Q2(R1)为分析方法验证（AMV）研究提供了指导并奠定了基础，以确保产品的安全性、有效性和质量。此外，ICH Q7、FDA指导文件、美国和欧盟药典以及技术报告指南对AMV进行了详细描述。 分析方法验证流程因负责药物研发和产品的预期用途的监管机构而异。法规并未对AMV进行详细说明，因此制药公司和合同分析测试实验室需要依靠监管机构和政府当局发布的指南来满足合规性要求。根据《分析程序验证：文本和方法 Q2(R1)中，AMV的关键要素包括准确性、精确度（可重复性、中间精度、可再现性）、特异性、检测限、定量限、线性、范围和稳健性。 监管指南包含不具约束力的建议，但符合监管要求，并提供有关方法验证的官方参考。可用指导文件的示例包括： • 分析程序验证：文本和方法 Q2(R1)，ICH 2005 • 行业指南：药物和生物制剂的分析程序和方法验证，FDA 2015 • 行业指南：生物分析方法验证（指南），FDA 2018 • <1225> 药典程序验证，USP 41-NF 36 • <1226> 药典程序验证，USP 41-NF 36 • <1058> 分析仪器鉴定，USP 41-NF 36 • FDA关于流程验证的指南 • EMA关于流程验证的指南 • ICH M4Q关于通用技术文件（CTD）模块3——质量部分 • ICH Q5C稳定性测试 • ICH Q6 关于测试程序和验收标准 • ICH Q8-11，关于药品开发、风险管理和质量体系 • 欧洲药品质量管理局（EDQM）关于分析程序验证/确认的指南 PA/PH/OMCL (13) 82 R5 • EMA生物分析方法验证指南 • OECD《单一实验室定量分析方法验证指导文件》 分析方法验证（AMV）实验和结果的交付物在验证报告中进行了总结。AMV报告的组成部分与AMQ报告类似，但实验的范围和深度旨在满足适当的预期用途。应在ICH M2电子通用技术文件（eCTD）新药申请（NDA）/生物制品许可申请（BLA）规范中相应部分提交记录完整的AMV报告。在产品生命周期中，随着生产工艺的发展或变化，应考虑采用基于风险的方法对现有分析方法进行重新验证。 当分析方法作为新药申请（NDA）、仿制药申请（ANDA）或生物制品许可申请（BLA）的一部分获得批准/许可时，它就成为FDA批准的已批准产品的分析程序。该分析程序可由FDA认可的来源进行适用性验证，例如美国药典/国家处方集（USP/NF）的规范程序，或由公司作为NDA、ANDA或BLA提交文件的一部分提交并经FDA认可的有效方法。AMV实验和结果在AMV报告中进行了总结。AMV报告完成后，将起草一份SOP并转交给质量控制实验室。分析方法的有效性是分析方法和产品开发生命周期中的关键成就。 02 方法验证的类型 一个完善的分析程序应经过各种类型和级别的验证，以证明方法的可靠性、适用性和目的。根据产品开发阶段和方法的目的，方法验证分为三类：完全验证、部分验证和交叉验证（full validation, partial validation, and cross-validation）。 对于新开发和实施的方法，或者对现有方法的更改对关键成分或程序范围有影响时，需要进行全面验证。 部分验证评估对已验证方法的更改和修改。更改或修改可能涉及检测系统、样品处理、定量范围或基质的组成。部分验证的范围可以从确定日内准确性和精度的范围，到根据更改对方法的可靠性和一致性的影响进行近乎全面的验证。属于部分方法验证的修改或更改包括但不限于以下内容： • 实验室之间的生物分析方法转移 • 分析方法的变化（例如检测系统的变化） • 样本处理程序的变化 • 样本量变化（例如，儿科样本量减少） • 仪器和/或软件平台的变化 • 检测范围的扩展 • 采集生物液体时抗凝剂（而非反离子）的变化（例如从肝素变为EDTA • 物种内基质的改变（例如从人血浆改为人血）或基质内物种的改变（例如从大鼠血浆改为小鼠血浆） • 基质变化（例如脑脊液） • 证明分析物在同时服用药物时的选择性 • 关键试剂的变化（例如批次间变化、试剂变化） 交叉验证用于比较两种或多种生物分析方法的验证参数，以在同一项研究或不同研究中生成数据。例如，当多个合同分析研究实验室参与分析多站点临床试验的样本时，可以执行方法的交叉验证，以确保方法的适用性和实验室间的可靠性。 03 分析方法验证 药典方法，例如已出版的专著、USP/NF、国际官方分析协作协会的官方分析方法、药典（USP和Ph. Eur.）的一般章节或其他公认的标准参考资料，均经过监管机构验证并得到认可。在使用前无需进行全面验证。但是，这些方法需要验证在实际使用条件下的适用性，以确定产品在药典测试中的基质效应。方法适用性或方法验证报告用于记录验证适用性的结果。标准测试（如pH值或灼烧残渣测试）无需进行方法适用性验证。 04 分析方法转移和分析方法可比性 有关分析方法转移（Analytical Method Transfer , AMT）和分析方法可比性（Analytical Method Comparability, AMC）的详细指导，请参阅美国食品和药物管理局（USFDA）的《行业指导：药物和生物制品的分析程序和方法验证》。美国药典（USP）<1224>为可接受的AMT替代策略提供了指导。PDA技术报告第57号：《生物制品的分析方法验证和转移》也提供了有关AMT和AMC的详细指导。 在分析方法和产品开发周期内，随着对工艺的认知加深或新实验室的需求出现，可能会出现方法转移、修改或替换。将分析方法转移至新实验室或实施修改或替代方法的基本实验是相似的。 AMC或AMT的范围在很大程度上取决于产品和方法在开发生命周期中的阶段。例如，在产品开发或毒理学研究阶段，对产品和工艺的整体了解较少，而方法在后期阶段（如Phase 2）是合格的，并且可以获得更大的方法性能信息数据库。因此，在后期阶段开展AMT/AMC研究的风险评估策略可能相当于部分验证，其范围从日内准确性和精度的确定到近乎全面的验证。 4 全球供应链的技术转让 世界卫生组织于2011年发布了附件7指南，其中详细介绍了制药商在药品制造方面的技术转让。虽然世卫组织为在全球范围内销售药品的制造商制定了指导方针，但该组织也参考了ICH Q8、Q9和Q10指南。该指南为全球制造商提供了基础，这些制造商向世界各地具有不同监管要求的国家供应活性药物成分和成品药物。 5 ICH Q14概述：分析程序开发 ICH大会于2018年6月批准了分析程序开发。该指南旨在协调和修订ICH Q2(R1)《分析程序验证指南》中提出的科学方法，同时改善行业与监管机构之间的沟通，以优化审查流程，并采用更健全、基于风险的方法进行上市后变更管理。ICH Q2(R1)中描述的原则将得到更新，以提供一个涵盖Q6A和Q6B范围内产品的框架。更新后的指南还将补充ICH Q8至Q13中的概念。 目前，该指南刚刚完成公众咨询流程，公众意见将提交给ICH，供流程的第三步参考。许多审查员评论说，该指南没有提供改进方法开发方法所建议的好处。其他评论指出Q14是Q2的延伸，但包含了对分析方法开发的生命周期管理方法。有几条评论涉及实时发布测试的方法，该方法在Q6A和Q6B中进行了讨论，并将这些概念纳入Q14。许多审查员质疑，遵循Q14是否允许制造商在批准后对分析测试方法进行更改时拥有更大的灵活性。总体而言，该指南草案令人困惑且范围有限。 ICH Q14将在明年继续发展，包括在2023年5月实施Q2和Q14工作组时采用步骤4。与此同时，制造商可以继续遵循ICH Q2中描述的分析方法开发概念。 6 其他相关指南概览 关于将“分析质量源于设计”（Analytical Quality by Design，AQbD）原则应用于药品药典标准的意见征询期已于2019年8月结束。英国药品和保健产品管理局（MHRA）希望通过这一过程实现其两大首要目标：通过强化系统确保药品安全生产，以及支持和促进创新。为了此次咨询，该机构利用实际案例研究来促进英国药典、良好生产与分销规范（GMDP）监察局和行业专家之间的合作。这种方法包括将“设计质量分析”（AQbd）应用于阿托伐他汀片剂的分析方法研究。制造商捐赠了测定程序，以协助调查。通过这种合作，同行们能够使用ATP定义方法性能，并评估与药典方法的相关性。这个过程有助于从实际的角度定义方法性能参数。这种定义方法性能的合作过程是监管机构与行业领导全球制药创新努力的一个例子。 — 结论 — 分析开发是药品和生物产品开发中一个持续的过程。既往以来，新开发的方法必须进行质量、真实性和有效性（quality, validity, and effectiveness）评估，即使是过去测试过的方法也必须重新检查，以确保其适用于产品。随着知识从过去的经验和方法中建立起来，不断发展的法规和指南塑造了分析开发过程的发展。 参考文献：（上下滑动查看更多） All references verified 10 March 2023. 1. United States Pharmacopeia and National Formulary (USP 41-NF 36). <1220> Analytical procedure life cycle [draft chapter]. Presented at United States Pharmacopeial Convention (USP); 2016. https://www. uspnf.com/sites/default/files/usp_pdf/EN/USPNF/usp-nf-notices/gc-1220-pre-post-20210924.pdf 2. Smith MJ, et al. Technical Report No. 57-2: Analytical method development and qualification for biotechnology products. Parenteral Drug Association; 2015. 3. International Council for Harmonisation. Validation of analytical procedures: Text and methodology Q2(R1). Step 4 version. Dated November 2005. https://database.ich.org/sites/default/files/Q2%28R1%29%20Guideline.pdf 4. Namjoshi S, et al. Quality by design: Development of the quality target product profile (QTPP) for semisolid topical products. Pharmaceutics. Published 23 March 2020. https://pubmed.ncbi.nlm.nih.gov/32210126/ 5. Jackson P, et al. Using the analytical target profile to drive the analytical method lifecycle. Anal Chem. Published 9 January 2019. https://pubs. acs.org/doi/10.1021/acs.analchem.8b04596 6. ter Horst, JP, et al. Implementation of quality by design (QbD) principles in regulatory dossiers of medicinal products in the European Union (EU) Between 2014 and 2019. Ther Innov Regul Sci. Published 13 January 2021. https://doi.org/10.1007/s43441-020-00254-9 7. European Medicines Agency. Quality by design. http://www.ema. europa.eu/ema/index.jsp?curl=pages/regulation/document_listing/ document_listing_000162.jsp. 8. Yu LX, et al. Understanding pharmaceutical quality by design. AAPS J. Published online 23 May 2014. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4070262/ 9. International Council for Harmonisation. Pharmaceutical Development Q8(R2). Step 4 version. Dated August 2009. https:// database.ich.org/sites/default/files/Q8_R2_Guideline.pdf 10. Environmental Protection Agency. Selection and application of an analytical method. In: Multi-agency Radiological Laboratory Analytical Protocols Manual (MARLAP). Dated July 2004. https://www.epa.gov/sites/default/files/2015-05/documents/402-b-04-001a-06-final.pdf 11. Tome T, et al. Development and optimization of liquid chromatography analytical methods by using AQbD principles: Overview and recent advances. Org Process Res Dev. Published 14 August 2019. https://pubs.acs.org/doi/10.1021/acs.oprd.9b00238 12. Food and Drug Administration. Analytical procedures and methods validation for drugs and biologics [guidance]. Current as of 20 April 2020. https://www.federalregister.gov/ documents/2015/07/27/2015-18270/analytical-procedures-andmethods-validation-for-drugs-and-biologics-guidance-for-industry 13. Food and Drug Administration. Bioanalytical method validation guidance for industry [guidance]. Current as of 29 April 2020. https://www.fda.gov/regulatory-information/search-fda-guidance-documents/bioanalytical-method-validation-guidance-industry 14. United States Pharmacopeia and National Formulary (USP 41-NF 36). <1225> Validation of compendial procedures. United States Pharmacopeial Convention (USP); 2016. https://www.ofnisystems. com/wp-content/uploads/2013/12/USP36_1225.pdf 15. United States Pharmacopeia and National Formulary (USP 41-NF 36). <1226> Verification of compendial procedures. United States Pharmacopeial Convention (USP); 2016. https://file.wuxuwang.com/yaopinbz/USP36-NF31/USP36-NF31_01_240.pdf 16. United States Pharmacopeia and National Formulary (USP 41-NF 36). <1058> Analytical Instrument Qualification. United States Pharmacopeial Convention (USP); 2016. https://www.drugfuture. com/Pharmacopoeia/usp35/PDF/0594-0598%20%5B1058%5D%20 ANALYTICAL%20INSTRUMENT%20QUALIFICATION.pdf 17. Food and Drug Administration. Process validation: General principles and practices [guidance]. Current as of 24 August 2018. https://www.fda.gov/regulatory-information/search-fda-guidance-documents/process-validation-general-principles-and-practices 18. European Medicines Agency. Process validation for finished products- Information and data to be provided in regulatory submissions –Scientific guideline. Last updated 21 November 2016. https://www.ema.europa.eu/en/process-validation-finished-products-informationdata-be-provided-regulatory-submissions-scientific 19. International Council for Harmonisation. M4: The Common Technical Document (CTD) M4Q: Quality. https://www.ich.org/ page/ctd 20. International Council for Harmonisation. Quality guidelines. https:// www.ich.org/page/quality-guidelines 21. European Directorate for the Quality of Medicines and Healthcare. Quality management documents: Validation/verification of analytical procedures. Revision in force July 2020. https://www.edqm.eu/en/quality-management-qm-documents 22. European Medicines Agency. Bioanalytical method validation guidance for industry. Dated May 2018. https://www.fda.gov/files/drugs/published/Bioanalytical-Method-Validation-Guidance-for-Industry.pdf 23. Organization for Economic Co-operation and Development.Guidance document for single laboratory validation of quantitative analytical method, No. 204. Dated 14 July 2014. https://www.oecd.org/chemicalsafety/testing/series-testing-assessment-publicationsnumber.htm 24. Briggs RJ, et al. Method transfer, partial validation, and cross validation: Recommendations for best practices and harmonization from the global bioanalysis consortium harmonization team. AAPS J. Published online 5 September 2014. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4389741/#:~:text=Partial%20validations%20are%20 performed%20to,full%20validation%20would%20be%20required 25. United States Pharmacopeia and National Formulary (USP 41- NF 36). <1224> Analytical instrument qualification. United States Pharmacopeial Convention (USP); 2016. 26. World Health Organization. WHO guidelines on transfer of technology in pharmaceutical manufacturing. Dated 2011. https:// extranet.who.int/pqweb/sites/default/files/documents/TRS_961_Annex7_2011.pdf 27. Eglovitch, J. ICH Q14: Pharma groups want clarity on benefits of enhanced approach. Regulatory Focus. Published 4 October 2022. https://www.raps.org/news-and-articles/news-articles/2022/10/ichq14-pharma-groups-want-clarity-on-benefits-of 28. Medicines and Healthcare products Regulatory Agency. Consultation on the application of analytical quality by design concepts to pharmacopeial standards for medicines. Last updated 12 August 2020. https://www.gov.uk/government/consultations/consultation-onthe-application-of-analytical-quality-by-design-aqbd-principles-topharmacopoeial- standards-for-medicines 英文版原文 （上下滑动查看更多） Chapter 14 Analytical Development –Testing and Stability The analytical method lifecycle is a continuous development process that builds on the understanding of the capabilities of each analytical method used throughout the discovery, pre-clinical and clinical development of a new drug candidate. It is a process map of analytical method definition, development, optimization, verification, qualification, validation, transfer, maintenance and finally the retirement of the method. An integrated approach to the lifecycle must ensure that analytical methods evolve from initial design and development to commercial use and must be shown to be fit for their intended purpose before use at the various clinical stages on the way to commercialization. Analytical methods are evaluated and selected to determine specific characteristics of the drug substance. Analytical assays are developed and validated to test specific characteristics of the drug substance and drug products against the predefined acceptance criteria for such characteristics. The analytical method lifecycle approach emphasizes the importance of a robust scientific process and quality risk management for developing, controlling, establishing, and using analytical procedures. It applies to all types of analytical methods, and the extent of effort should be consistent with the complexity of the technique and the criticality of the quality attribute to be measured.1 Proficiency and technical knowledge are fundamental requirements of analytical method development, and profound quality and regulatory knowledge is required to construct an analytical lifecycle workflow to accomplish the regulatory requirements for intended drug use. Figure 14-1 represents key elements of the analytical method lifecycle and its links to product development.2 Analytical Method Definition: Selection and Optimization The first step of the method development process is to define the scope, purpose and objective of the method based on its intended use to ensure the alignment of method design, function, and performance expectations. A protocol is established at this stage to define the analytical development plan. The intended use for the analytical method development could be characterization, in-process testing, routine release testing, stability, bioavailability, raw material release, or process validation support. The intended use is in direct correlation with the product development stage ranging from preclinical to clinical to the commercial phase. It is also important to define the test article during the method definition stage. Examples of test articles are drug substance (DS), drug product (DP), placebo, matrices (e.g., formulation buffer, biological fluids), active pharmaceutical ingredient, excipient, impurity, etc. The assay category is defined per the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use ICH Q2(R1) guideline for identity, quantitative impurity, limit test or assay content/potency.3 The objective of the analytical development plan could be orthogonal, characterization, comparability, release, qualification or both qualification and validation, stability, or bioavailability studies. A more comprehensive approach to defining the analytical method is recommended to reduce the risk of misalignment of the method development plan with the suitability of the final method for its intended use. 1.Analytical Target Profile: Structural Framework for the Analytical Method Lifecycle2,4-7 Quality pioneer Dr. Juran introduced the concept of Quality by Design (QbD). Dr. Janet Woodcock defined a high-quality drug product as a product free of contamination that reliably delivers the therapeutic benefit promised in the label to the consumer.8 ICH Q8 guideline emphasized the QbD concept to design the quality of the final product instead of testing the product. ICH Q8 defines QbD as “A systematic approach to development that begins with predefined objectives and emphasizes product and process understanding and process control based on sound science and quality risk management”.9 The Food and Drug Administration (FDA) encourages risk-based approaches and the adoption of QbD principles in drug product development, manufacturing, and regulation. FDA’s emphasis on QbD began with the recognition that increased testing does not necessarily improve product quality. Quality must be built into the product. QbD requires a prospective summary of the desired quality characteristics of a drug product. A Quality Target Product Profile (QTPP) is defined as a prospective summary of the quality characteristics of a drug product that ideally will be achieved to ensure the desired quality, considering the safety and efficacy of the drug product. QTPP forms the basis for the design and development of the product. QTPP drives the definition of the quality characteristics for the product. Analytical Target Profile (ATP) is an equivalent term for analytical methods. The predefined method parameters for the ICH Q2 (R1, R2) categories of analytical methods, identity, purity, impurity and assay, and performance characteristics such as accuracy, precision and specificity must be documented while defining the ATP for a pharmaceutical product. The analytical testing procedure and reportable results defined in the ATP drive the product’s quality attributes, successively providing critical input to the overall control strategy. ATPs lead the design and development of appropriate analytical methods. The ATPs are the foundation to provide the performance criteria to deliver a quality product and support the “fit for purpose” or “suitable for intended use” statement for an analytical method.An analytical method used to measure critical quality attributes (CQAs) must be sufficiently sensitive, accurate and precise to provide adequate control of the attribute, regardless of whether the method is used for in-process controls or through final productspecifications of DS or DP. A deliverable for the definition phase is a determination of analytical methods for identity, purity, impurity and assay per ICH Q2(R1) for the intended use, measurement of CQAs, identifying quality attributes for method performance, risk allocation of each attribute based on supporting information, and specific acceptability criteria for method performance such as system suitability, assay acceptability, sample acceptability based on throughput, equipment, transferability, material and reagent availability, and assay criticality.An ATP report can be generated to document the conclusion of the analytical method definition stage. ATP reports can be a stand-alone deliverable or a key element of a final method development report, based on the stage of a product in the development lifecycle. The ATP report may be updated and used to guide further method development work during the analytical lifecycle management as new technology becomes available, new requirements for the methods in response to regulatory feedback are put into place, or due to a process change. 2.Analytical Method Selection2,4-7,10-13 Once the ATP is defined, the next step in the analytical method lifecycle is selecting methods that are fit for purpose or suitable for the intended use. Method selection should include an assessment of various technologies that could be applied to the testing requirement and meet the regulatory requirements for the product specification. A method is selected based on analytical chemistry, which includes methodologies to identify, separate, and quantify the chemical components of medicinal compounds. The selection phase includes the selection of materials and reagents, samples, equipment, and laboratory. The user requirements, the laboratory’s capacity, and budget allocation play a significant role in the determination of in-house versus outsourcing the analytical methods to third-party laboratory testing to meet the regulatory requirement. The deliverables for the selection phase are a proposal for the choice of methods that meet regulatory requirements for the product’s intended use and the finalization of method development or method optimization strategy. A method selection and strategy report similar to ATP can be generated for documentation and record-keeping purposes. The report could contain the following sections: • Project name • Project sponsor/principal investigator (if applicable) • Product development phase [preclinical, Investigational New Drug (IND)-enabling, Phase 1, Phase 2, or Phase 3] • Application (release, stability, in-process, bioavailability) • Product matrices (e.g., formulation buffer) • Analyte matrix (e.g., biological fluids, formulation buffer) • Regulatory requirements for intended use [e.g., good laboratory practice, good clinical practice, current good manufacturing practice (cGMP)] • Analytical method type per ICH Q2(R1) • Proposed specification • Sample acceptability criteria • System suitability criteria • Proposed choice of methods and selection rationale • Alternative methods • Possible short-term and long-term concerns (e.g., supply chain shortages) 3.Analytical Method Development and Optimization2,4-7, 10-13 Analytical method development (AMD) is integral for any drug development program. Method development is the major milestoneof the lifecycle of analytical methods. The purpose of analyticalmethod development is to establish optimal conditions definedin the ATP for drug safety, identity, strength, purity, and potency.The scope of analytical method development can include selectingand optimizing experimental design and evaluating methodperformance. The objective of method development and optimizationis selection of appropriate method parameters. The deliverablecould be the generation of a development report and draftstandard operating procedure (SOP). The method developmentpackage provides critical information to evaluate if the method isfit for purpose and can be progressed to method qualification orvalidation based on its intended use. An analytical developmentreport is a document containing the details of the method performance,information on materials and reagents, reference standards,controls, system suitability requirements, method acquisition anddata analysis parameters, equipment, and software. Analyticalmethod development is the critical pillar of process developmentfor any pharmaceutical or biotechnology company developing new drug candidates. A phased approach can be used to capture the regulatory expectations for the level of method development. The method is optimized for its reliability and convenience, and the incremental development and optimization approach can be used depending on its application in the product development phase. For example, during the early stages of product development (i.e., preclinical and Phase 1), a high-performance liquid chromatography method may focus on consistently measuring the analyte of interest for content, purity, and stability, but may not be able to provide the identity and response factors of all impurities in the chromatogram. However, the same method may provide this information at a later stage of product development (e.g., Phase 2 and Phase 3) and incorporate impurity standards in the analytical method. Method development involves optimizing the procedures and conditions involved with extracting and detecting the analyte of interest. It includes the optimization of the following parameters to ensure that the method is suitable for qualification or validation: • Reference standards • Critical reagents • Calibration curve • Quality control (QC) samples • Selectivity and specificity • Sensitivity • Accuracy • Precision • Recovery • Stability of the analyte in the matrix The key deliverables needed to conclude the method development phase during the analytical method lifecycle are the method development report and draft SOPs. Depending on the company policy and procedures, the format of an AMD report may vary but must deliver information on all development studies, data, experiments, and conclusions to support the next step in the analytical method lifecycle. This report is cornerstone for the establishment of the SOP and target criteria in the qualification or validation protocol. Together with the AMD report, information for the addition of material vendors, equipment upgrades, scale-up buffer volumes, critical material attributes, historical data and trending forms the AMD package. The AMD package is technically evaluated to determine whether the development data are sufficient to support method qualification or method validation studies. An AMD package could contain the following deliverables: • Purpose and scope of method • Design and development history • Background description of scientific rationale for selected method • Evaluated parameters and performance • Summary of development steps • Target samples and matrices • ICH Q2(R1) category of method • ICH Q2(R1) characteristics included in targets for development • Stress studies (if an initial force degradation study during development phase is conducted) • Stability data for ongoing long-term studies • System suitability and method and sample acceptability criteria • Accomplish intended use • Fulfill method strategy • Materials, reagents, standards, and controls • Identification of critical material attributes (CMAs) • Trend data and historical results • Regulatory requirements for laboratory for the intended use of the product • Operator qualification and training requirements • Draft SOPs 4.Analytical Method Qualification2,4-7,10-13 Analytical Method Qualification (AMQ) is the industry-recognized and widely acceptable approach for demonstrating that an analytical method is scientifically sound, fit for purpose or suitable for intended use, consistent and successfully able to generate reliable results. AMQ identifies the similar quality attributes for method performance as Analytical Method Validation (AMV) per ICH Q2(R1) guidance (i.e., accuracy, precision, linearity, specificity, range, limit of detection/limit of quantitation, and robustness) but progresses in a phase-appropriate manner and in alignment with the intended use of the method. AMQ and AMV both prove that method is suitable for its intended use, but they differ in terms of robustness of the studies. This means that a more thorough evaluation of method performance or qualification may be conducted to support a Phase 2 clinical trial study than was used for the Phase 1 study. The phase-appropriate regulatory guidance documents describe the requirement for the qualification and validation studies intended for the final product (DS or DP) release for the intended clinical phase. AMQ is not a regulatory requirement prior to the AMV but forms the basis for successful validation and method suitability requirement defined in ATP. Technical reports issued by nonprofit groups such as Parenteral Drug Association provide nonbinding guidelines for the AMQ and are widely accepted by the pharmaceutical companies and contract analytical testing laboratories to meet clinical phase appropriate expectations for the analytical method based on intended use. AMQ can be an end goal in the analytical method lifecycle for activities such as process characterization, comparability studies, orthogonal characterization methods used for confirmation of root cause during an out-of-specification investigation to support the release of product and release/stability tests of product development material (i.e., Phase 1 and 2 clinical trial material).2 Partial method validation or cross-method validation may be warranted depending on the stage of a product and analytical method in the development lifecycle. Qualification of methods can be foundation for full method validation per ICH Q2(R1) guideline. The regulatory agencies publish guidelines on requirements to submit the dossier for clinical trial studies. These guidelines do not describe the clinical-phase-appropriate analytical methods requirement in detail but form the basis for the AMQ expectations for intended product use. These guidance documents include but are not limited to: • IND submission for Phase 1 and for Phase 2/3 in the US • Investigational medicinal product dossier submission for clinical trials in Europe Scientific or technical improvements in the analytical method are exercised as the product and analytical method evolve in the development lifecycle. The need for the requalification of the method is assessed after significant changes are made to the method and before its use for the clinical study. A method qualification report is generated to include results, evaluation, and conclusion for the method suitability for the intended use. The AMD data package is appended to the AMQ report. Accountability for the post-qualification analytical method review is important to maintain the qualified state of the method. The activities include assurance of intended use versus current use of the method and ensure that it meets the purpose defined during the development and qualification phases of the analytical lifecycle. Post-qualification changes may include new reference standards or control sample evaluation, a change of scope based on the product development phase, or a technical transfer of the method to another group or laboratory. Compendial methods do not require qualification prior to use, and will be discussed later in this chapter. The key deliverable for AMQ experiments and results are summarized in the AMQ report. An SOP is drafted and transferred to the QC laboratory after the AMQ experiments are complete and the qualification report is drafted. The qualified state of an analytical method is a key accomplishment in the analytical method and product development lifecycle. The AMQ report includes: • Calibration status of equipment • Software and versions for equipment, acquisition methods and data analysis • Materials, reagents, standards, controls, and samples • Description for sample preparation and acquisition methods • Data analysis and calculation methods • References to all data files generated with clear traceability to primary sources of data • Predefined qualification elements per qualification protocol and assessment against target criteria with conclusion • Technical assessment to define the acceptance criteria for each qualification element • Unexpected outcomes and actions to mitigate their risks • CMA, if identified • Critical method steps for the reproducibility of the results, if needed • Copy of draft SOP or version of SOP used during the qualification process • Suggestions for the changes, instructions, and justifications for the revision to the SOP based on qualification • AMD report with ATP (appended to AMQ report) Analytical Method Validation Analytical test method validation experiments deliver the critical data supporting the safety, identity, strength, potency, and purity of any pharmaceutical drug manufactured according to regulatory requirements. The test results are crucial to ensure the health and safety of consumers. Therefore, an analytical method applied to pharmaceutical product characterization under current cGMPs should be validated as early as possible in the product lifecycle. Data obtained as part of analytical method validation provides documented evidence, demonstrating that the test procedure is suitable for its intended use and is objective evidence of the method’s performance and ensures quality and reproducibility of results. 1.Regulatory requirements and guidance documents ICH Q2(R1) guides and sets a foundational base for AMV studies to ensure product safety, efficacy, and quality. Additionally, AMV is well described in ICH Q7, FDA guidance documents, US and EU compendia and technical reports guides. The analytical method validation process varies depending on the regulatory bodies governing drug development and the product’s intended use. The regulations do not provide detailed descriptions of AMV, so pharmaceutical companies and contract analytical testing laboratories rely on guidelines published by regulatory and government authorities to meet compliance expectations. According to Validation of Analytical Procedures: Text and Methodology Q2(R1), the key elements for the AMV are accuracy, precision (repeatability, intermediate precision, reproducibility), specificity, detection limit, quantitation limit, linearity, range, and robustness.3 The regulatory guidelines have non-binding recommendations but conform to the regulatory requirements and provide official references regarding method validation. Examples of available guidance documents are: • Validation of Analytical Procedures: Text and Methodology Q2(R1), ICH 20053 • Guidance for Industry: Analytical Procedures and MethodsValidation for Drugs and Biologics, FDA 201512 • Guidance for Industry: Bioanalytical Method Validation (Guidance), FDA 201813 • <1225> Validation of Compendial Procedures, USP 41-NF 3614 • <1226> Verification of Compendial Procedures, USP 41-NF 3615 • <1058> Analytical Instrument Qualification, USP 41-NF 3616 • FDA’s guidelines on process validation 17 • EMA’s guidelines on process validation18 • ICH M4Q on common technical document (CTD) module 3 – quality section19 • ICH Q5C on stability testing20 • ICH Q6 on test procedures and acceptance criteria20 • ICH Q8–11 on pharmaceutical development, risk management, and quality systems20 • EDQM’s guideline on Validation/Verification of Analytical Procedures PA/PH/OMCL (13) 82 R521 • EMA’s guideline on bioanalytical method validation22 • OECD’s Guidance Document for Single Laboratory Validation of Quantitative Analytical Method23 The deliverables for AMV experiments and results are summarized in the validation report. The components of the AMV reports are similar to the AMQ report, but the extent and depth of the experiment is designed to meet the suitable intended use. A fully documented AMV report should be submitted in the corresponding sections of the applications in the ICH M2 Electronic Common Technical Document (eCTD) Specification for the New Drug Application (NDA)/Biologic License Application (BLA). As the manufacturing process evolves or changes during the product’s lifecycle, a risk-based approach should be taken into consideration for revalidation of existing analytical methods. When an analytical method is approved/licensed as part of the NDA, Abbreviated New Drug Application (ANDA), or BLA, it becomes the FDA-approved analytical procedure for the approved product. This analytical procedure may be verified for suitability from FDA-recognized sources such as a compendial procedure from the United States Pharmacopeia/National Formulary (USP/NF) or a validated method submitted by a company as part of an NDA, ANDA, or BLA submission package and was determined acceptable by FDA. The key deliverable for AMV experiments and results are summarized in the AMV report. Once the AMV report is finalized, an SOP is drafted and transferred to the QC laboratory. The validated state of an analytical method is a key accomplishment in the analytical method and product development lifecycle. 2.Types of Method Validation12,13,22-24 A developed analytical procedure should undergo one of the various types and levels of validation to demonstrate the reliability of the method’s performance, suitability of intended use and the purpose of the method. Depending on the product development stage and the purpose of the method, the method validation falls into three categories: full validation, partial validation, and cross-validation. Full validation is warranted for newly developed and implemented methods or when changes applied to the existing method have an impact on critical components or the scope of the procedure. Partial validation evaluates changes and modifications to already validated methods. Changes or modifications can vary from changes in detection system, sample processing, quantitation range or composition of matrix. The scope of partial validation can range from one intra-day accuracy and precision determination to a nearly full validation based on the nature of the change could have on the method’s reliability and consistency.21 The modifications or changes that fall into the category of partial method validation include, but are not limited to, the following:10,17 • Bioanalytical method transfers between laboratories • Changes in analytical methodology (e.g., a change in detection systems) • Changes in sample processing procedures • Changes in sample volume (e.g., the smaller volume of pediatric samples) • Changes in instruments and/or software platforms • Extensions of the assay range • Changes in the anticoagulant (but not changes in the counterion) in harvesting biological fluids (e.g., heparin to EDTA) • Changes in the matrix within species (e.g., switching from human plasma to human blood) or changes to the species within the matrix (e.g., switching from rat plasma to mouse plasma) • Changes to the matrices (e.g., cerebrospinal fluid) • Demonstrating the selectivity of an analyte in the presence of concomitant medications • Changes in critical reagents (e.g., lot-to-lot changes, changes in reagents) Cross-validation is performed to compare validation parameters of two or more bioanalytical methods to generate the data within the same study or across different studies. For example, when multiple contract analytical research laboratories are involved to analyze samples from multisite clinical trials, cross-validation of methods may be performed to ensure method suitability and interlaboratory reliability. 3.Analytical Method Verification24 Compendial methods, such as published monographs, USP/NF, the official methods of analysis of Association of Official Analytical Collaboration International, general chapters of Pharmacopeias (USP and Ph. Eur.), or other recognized standard references, are validated and accepted by the regulatory agencies. They do not require full validation prior to use. However, they are verified for suitability under actual conditions of use to identify any matrix effects of a product in the compendial test. A method suitability or method verification report is generated to document the verification of suitability for use. Method verification for suitability is not required for standard tests, such as those for pH or residue on ignition. 4.Analytical Method Transfer and Analytical Method Comparability The detailed guidance for the Analytical Method Transfer (AMT) and Analytical Method Comparability (AMC) can be found in Guidance for Industry: Analytical Procedures and Methods Validation for Drugs and Biologic of the USFDA.13 USP <1224> gives guidance for acceptable alternative strategies for AMT.25 PDA Technical Report No. 57: Analytical Method Validation and Transfer for Biotechnology Products also provides detailed guidance on AMT and AMC. During the analytical method and product development lifecycle, method transfers, modifications, or replacement may occur as more knowledge is obtained for the processes or the need for a new laboratory arises. The fundamental experiments to carry out an analytical method transfer to a new laboratory or for implementing a modified or alternative method are similar. The scope of AMC or AMT is highly dependent on the phase of a product and method in the development lifecycle. For example, during product development or toxicological studies phase, the overall knowledge for the product and process is less, whereas methods are qualified at the later stage, such as Phase 2, and a larger database of method performance information is available. Therefore, the risk assessment strategy to develop AMT/AMC studies in this later stage could be equivalent to a partial validation and can range from one intra-day accuracy and precision determination to a nearly full validation. 三、Technology Transfer for Global Supply Chain The World Health Organization issued Annex 7 guidance in 2011 which detailed instructions for manufacturers on the transfer of technology in pharmaceutical manufacturing. Although WHO develops their own guidance for manufacturers distributing pharmaceutical products globally, they also rely on ICH Q8, Q9, and Q10 guidance in their framework. This guidance serves as a basis for global manufacturers who are supplying active pharmaceutical ingredients and finished drug products to various countries around the world with varying regulatory requirements. Overview of ICH Q14: Analytical Procedure Development Analytical procedure development was endorsed by the ICH Assembly in June 2018.27 This guideline seeks to harmonize and revise scientific approaches set forth in ICH Q2(R1) Guideline on Validation of Analytical Procedures while improving regulatory communication between industry and regulators to optimize the review process and a sounder, risk-based approach to post-marketing change management. Principles described in ICH Q2(R1) will be updated to provide a framework that covers products in scope of Q6A and Q6B. The updated guideline will also compliment concepts in ICH Q8 to Q13. Currently, the guideline just finished the public consultation process and comments will be provided to ICH for Step 3 of the process. Many reviewers commented that the guidance didn’t provide the benefits that an enhanced method development approach suggests. Additional comments stating that Q14 is an extension of Q2 but included a lifecycle management approach to analytical method development. There were several comments about the approach to real-time release testing, which is discussed in Q6A and Q6B, and incorporating these concepts into Q14.Many reviewers questioned whether following Q14 would permit manufacturers more flexibility in making post-approval changes to analytical testing methods. There is an overall impression that the draft guideline is confusing and limited in scope. ICH Q14 will continue to evolve over the next year, including the adoption of Step 4 to begin in May 2023 with the implementation of the Q2 and Q14 Working Group. In the meantime, manufacturers can continue to follow concepts described in ICH Q2 for analytical method development. Overview of Other Relevant Guidelines The consultation period for comments on the application of Analytical Quality by Design (AQbD) principles to pharmacopeial standards for medicines closed in August 2019. The Medicines and Healthcare products Regulatory Agency set to align two of its top priorities through this process: to ensure the safe production of medicines through enhanced systems and to support and enhance innovation.28 For this consultation, the agency used an actual case study to foster collaboration among the British Pharmacopoeia, Good Manufacturing and Distribution Practice (GMDP) Inspectorate and industry experts. This approach included applying analytical Quality by Design or AQbd to an investigation of the analytical methodology used for Atorvastatin tablets. The manufacturer donated the assay procedure to assist with the investigation. Through this collaboration, the counterparts were able to define method performance using an ATP and assess the relevance compared to compendial methodology. This process helped define the method performance parameters from a practical standpoint. This collaborative process for defining method performance is one example of regulators and industry leading the global effort in pharmaceutical innovation. Conclusion Analytical development is a continuous process in pharmaceutical and biologic product development. While it is obvious that newly developed methods must be evaluated for quality, validity, and effectiveness, even methods that have been tested in the past must be re-examined to ensure that they are appropriate for the product. Continually evolving regulations and guidances shape the evolution of the analytical development process as knowledge is built from past experience and methodologies. 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↓↓↓

同写意20岁庆！中国医药创新未来之路！“意”同创新，穿越周期，赢得未来。7月中旬，苏州金鸡湖畔，让我们与“新药写意人”一起为中国医药创新“同写意”！本章重点介绍当前国际上的医药产品监管环境，包括全面概述国际人用药品技术要求协调理事会（ICH）和世界卫生组织（WHO）的关键作用，后者是联合国（UN）领导全球卫生生态系统倡议与合作的唯一机构。本章还讨论了致力于协调和持续改进全球监管流程以提高效率的国际组织。1历史遗产与法规对医药产品的监管源于使用不安全的产品以及由此引发的公共健康风险和悲剧。15世纪英国颁布的《药剂师器皿、药品和物品法》是早期颁布便于允许检查医药产品的生产来合法管制药品的典型例子。在美国，1902年的《生物制品管制法》（又称《病毒毒素法》）授权美国政府卫生实验室（美国国立卫生研究院的前身）监管生物制品（包括血清和疫苗）的生产。随后，1906年又颁布了《纯净食品和药品法》，禁止在州际贸易中对食品、饮料和药品进行掺假和掺杂。美国农业部化学局被授权执行这项法律，并于1930年更名为食品药品监督管理局（FDA）。1938年的《联邦食品、药品和化妆品法》（FD&C）规定，新药在上市前必须经证明安全有效，并扩大了FDA的权限，使其有权监管医疗器械和化妆品。在这些法律颁布之前，消费者面临着潜在的不安全、无效和掺假产品的风险。公共卫生悲剧，包括1937年美国的Elixir Sulfanilamide事件以及20世纪50年代欧盟和加拿大的沙利度胺悲剧，加速了现代有效法规的实施。根据1938年《食品药品管制法》，生物制剂（或生物制品）被视为药物，虽然该法的某些部分适用于生物制剂，但该法并未修改或取代最初的1902年《生物制品管制法》的规定；因此，这两部法律的规定都被用于监管生物制剂，监管权力由FDA和卫生实验室/NIH分担。1972年，包括疫苗和血清在内的生物制剂的监管工作由NIH移交给FDA。2监管机构的作用虽然不同地区和市场目前的发展水平（发达、发展中或新兴）可能会有不同的监管规定，但监管机构的作用始终如一：保护公众健康。监管机构的责任声明说明了这一点，下面举几个例子：印度中央药品标准控制组织 (CDSCO)：通过确保药品、化妆品和医疗器械的安全性、有效性和质量，保障并提高公众健康水平。澳大利亚治疗用品管理局（TGA）：通过有效、及时地监管治疗用品，保障并提高澳大利亚社会的健康水平。日本药品和医疗器械管理局 (PMDA)：通过确保药品和医疗器械的安全性、有效性和质量，保护公众健康。中国国家药品监督管理局 (NMPA)：负责药品（包括中药和民族药）、医疗器械和化妆品的安全监管。3药物尽管各个市场/地区的申报要求各不相同，但监管机构一般要求申办方提交数据和资料，表明研究疗法具有合理、令人满意的效益-风险比，以便获得市场批准。就非专利药而言，生产商必须提供证据，证明拟议产品与其前身创新药具有相同的疗效、安全性和性能特征。生产商必须能够满足其计划在其销售产品的每个国家的个别监管要求。其还必须遵守上市后的监控要求，以确保根据药品的风险概况对关键问题进行评估，并根据要求采取相应的行动。对药品的风险概况进行评估，并按要求采取行动。世卫组织将药物警戒（PV）定义为 "与检测、评估、了解和预防不良反应或任何其他药品/疫苗相关问题有关的科学和活动"。ICH药物警戒E2E准则也引用了这一定义，该准则指出，药物警戒 "描述了一种总结已确定的药物重要风险、重要的潜在风险和重要的缺失信息的方法，包括潜在的高危人群和可能使用该产品但尚未进行批准前研究的情况"。该指南还建议 "应对所有药物产品进行常规药物警戒"，并建议除特定地方要求外，还应满足常规药物警戒的要求：制定标准系统和流程，确保以可获取的方式收集和整理并向相关人员报告的所有可疑不良反应信息。为监管机构准备报告。快速报告药品不良反应。定期更新安全更新报告（PSUR）持续监测已批准产品的安全性概况，包括信号检测、问题评估、更新标签以及与监管机构联络。4生物制品生物制剂或生物产品是一类从生物体中提取的治疗产品。在生物制剂的生产过程中，这些原生生物/原液是通过生物反应器中的大规模细胞培养进行培育和纯化的。起源生物可以是病毒、细菌、酵母、植物细胞或动物细胞。生物制品比药品用途更广，可用于开发复杂的疗法，如疫苗、生长因子、免疫调节剂、单克隆抗体以及从人血和血浆中提取的产品。FDA将人体细胞、组织以及细胞和组织类产品（HCT/P's）区分为由其器械和放射卫生中心（CDRH）作为医疗器械监管的产品和由其生物制品评估与研究中心（CBER）监管的产品。5国际协调理事会（ICH）国际药品协调理事会成立于1990年，其宗旨是 "就如何进一步协调药品注册技术指南和要求的解释和应用提出建议，从而减少或避免在研究和开发人类新药过程中进行重复试验"。监管协调为全球监管机构和制药业保护公众健康带来了诸多益处。这种协调效应的主要好处包括：在不影响安全性和有效性的前提下，防止重复进行人体临床试验，最大限度地减少动物试验的使用；简化新药申请的监管评估程序；缩短药物开发时间，减少药物开发资源。这进一步强调了向全球利益相关者发出的关键和重要信息，即有必要开发安全有效的高效疗法，使患者能够获得治疗。ICH 的创始成员是来自美国、欧盟和日本等发达国家的监管机构和制药业代表。成员已扩大到许多其他国家和具有观察员地位的组织（见Table 3-1） 。ICH将其协调工作的透明度作为建立和维护公众信任的优先事项。ICH大会和管理委员会努力确保ICH过程保持透明，并认识到所有利益相关者都应了解有关重要决策的最新信息以及ICH指南制定的实时进展情况。2005年和2012年，该委员会分别采取措施，确保指南制定过程的所有部分都能尽快、清晰地在其网站上公开反映。ICH协调活动分为四类：正式的ICH程序（formal ICH procedures）、问答程序（Q&A procedures）、修订程序（revision procedures）和维护程序（maintenance procedures）。每项活动都可能需要一份概念文件（concept paper）和/或业务计划（business plan）（见Figure 3-1）。正式的ICH程序包括五个步骤。所有新的ICH主题的协调都遵循该程序。成立一个专家工作组（expert working group ,EWG），负责实施以下步骤和程序。步骤 1：达成共识• 工作小组根据概念文件中确定的目标，编写技术文件的共识草案。步骤 2a：确认关于技术文件的共识• 当大会根据EWG报告一致认为有足够的科学共识可使技术文件进入下一阶段的监管磋商时，即进入该步骤。步骤 2b：监管成员通过准则草案• 在技术文件的基础上，ICH监管成员将采取其认为必要的行动来制定准则草案。• 监管成员批准准则草案。步骤 3：监管磋商和讨论• 包括三个不同阶段৹ 阶段 I - 适用于区域监管磋商阶段。৹ 第 II 阶段--适用于在从咨询过程中获得所有意见后对区域咨询意见的讨论。৹ 第三阶段--是步骤3专家指南草案的定稿阶段。步骤3专家指南草案经监管EWG 签名后，提交给大会监管成员，请求通过。步骤 4：通过 ICH 协调准则• 大会一致认为已就指南草案达成充分共识。ICH监管成员通过步骤4的最终文件，将其作为ICH指南。步骤 5：实施• 按照适用于ICH对其他地区监管准则和要求的相同国家/地区程序实施。指导方针一旦进入正式程序的第5步，即由各自国家或地区的ICH监管成员和观察员实施。监管成员应根据ICH章程实施所有ICH指南/准则。监管观察员是ICH的无表决权成员；执行某些ICH指南是成为监管成员的先决条件。总体而言，ICH指南根据适用的国家、地区和/或地方规则实施，所有ICH指南的实施阶段也取决于成员或观察员加入ICH的时间。此外，ICH还对监管成员和观察员国家/地区进行调查，以了解ICH指南的实施和遵守水平及其适用性。ICH 指南主题分为四类，每类都有一个字母代码：1. Quality Guidelines (Q) 质量指南涉及稳定性研究的开展、杂质测试相关阈值的定义，以及基于现行良好生产规范（cGMP）风险管理的更灵活的药品质量方法。2.   Safety Guidelines (S) 安全指南 旨在通过体内和体外动物研究，揭示潜在的风险，如致癌性、遗传毒性和生殖毒性。3.    Efficacy Guidelines (E)疗效指 涉及人体临床试验的设计、实施、安全性和报告。这些指南还包括生物技术过程中产生的新型药物，以及利用药物遗传学/基因组学技术生产更有针对性的药物。4.   Multidisciplinary Guidelines (M) 多学科指南 为不完全或单一属于质量、安全和疗效类别的交叉主题提供指导。这些多学科指南包括ICH医学术语 （MedDRA）、通用技术文件（CTD），以及监管信息传输电子标准（ESTRI）的制定。全球数据协调工作ICH工作取得的一项具有里程碑意义的重要成就是，各方同意将所有与质量、安全性和有效性相关的数据信息以一种名为 "通用技术文件"（CTD）的标准格式进行整合。CTD在很大程度上消除了向不同ICH监管机构提交信息时重新格式化的需要。在许多国家，已被ICH监管成员接受的CTD可作为在相应市场审查研究产品的先例。CTD分为五个模块：- 模块1 针对特定地理区域，包括行政管理信息。- 模块2 包括质量、非临床和临床数据摘要。- 模块3 包括质量（CMC）数据。- 模块4 包括非临床数据。- 模块5 包括临床数据。ICH M4指导方针为提交纸质CTD提供指导，而M8指导方针则为提交电子CTD要求提供指导。2003年7月，CTD成为欧盟和日本新药申请的强制格式，并被强烈推荐用于提交给美国FDA的新药申请（NDA）。6世界卫生组织世界卫生组织（世卫组织，World Health Organization (WHO)）成立于1948年。世卫组织是联合国（United Nations， UN）唯一的机构，它将全球各国、合作伙伴和人民联系在一起，以促进健康，同时维护世界安全，为弱势群体服务，确保世界人口获得最高水平的健康。WHO的使命是围绕全球公共卫生提供全球领导和指导，并维护全球卫生生态系统。目前，世卫组织有194个成员国。世卫组织秘书处包括专家、工作人员和外勤人员，设在瑞士日内瓦。世卫组织在150多个国家设有区域办事处，这些办事处分布在以下全球区域：- 非洲- 美洲- 东地中海- 欧洲- 东南亚- 西太平洋世卫组织计划《第十三个工作总规划》（The Thirteenth General Programme of Work (GPW 13)）确定了世卫组织2019-2023年五年期战略。该方案侧重于实现三个十亿目标，以便在国家一级对人民健康产生可衡量的影响。基于COVID-19全球大流行对公共卫生造成的破坏，世卫组织将GPW 13延长至2025年。世卫组织参与了意义重大、影响深远的全球和区域公共卫生倡议。最近的一个例子是2020年4月启动的ACT（获取COVID-19工具）加速器伙伴关系。该伙伴关系是一项 "具有里程碑意义的合作，旨在加快COVID-19疫苗、诊断和治疗方法的开发、生产和公平分配"，汇集了十个主要的公共卫生和发展机构以及各国政府和非政府组织，以应对不断发展的大流行病形势。7国际组织、合作协议和伙伴关系下文概述了几个地区的国际和地区合作努力。药品检查合作计划药品检查合作计划（Pharmaceutical Inspection Co-operation Scheme (PIC/S)）成立于1995年，是1970年《药品检查公约》（PIC）的延伸。它是监管机构之间在人用或兽用医药产品良好生产规范（GMP）领域的一种不具约束力的非正式合作安排。PIC/S的主要任务是 "在国际范围内领导制定、实施和维护统一的药品生产质量管理规范（GMP）标准和检查机构的质量体系"。作为一个先驱组织，PIC/S在药品检查和GMP领域处于领先地位。自成立以来，PIC/S已成功地适应了不断变化的环境，特别是全球化环境，目前仍是全球唯一专门从事GMP工作的组织。自2023年起，PIC/S的任务将扩展到non-good practice（GxP，主要侧重于培训和标准领域的良好生产工艺 (GMDP)），这也符合PIC/S的新使命，即通过统一标准和为全球监管检查员提供世界一流的培训，领导制定和实施人用和兽用药品检查框架，努力改善公众健康。PIC/S愿意与全球任何拥有类似GMP检查系统的监管机构开展合作。目前，PIC/S有50多个全球监管机构参与。国际药品监管机构计划国际药品监管机构计划（International Pharmaceutical Regulators Programme (IPRP)）成立于2018年，旨在促进人用药品监管方法的趋同。IPRP的宗旨是为其监管成员和观察员创造一个环境，就共同关心的问题交流信息，促成合作，促进人用医药产品监管方法的趋同。其目标侧重于协助最大限度地提高潜在效率，以应对日益复杂的全球监管环境，促进ICH和其他国际协调的人用医药产品技术准则的实施。IPRP为其成员和观察员提供实实在在的好处，并致力于促进信息共享与合作，以推动公共卫生事业的发展，促进药品的获取，并应对共同关心的新出现的监管挑战。IPRP成员包括世卫组织和多个全球监管机构（见表 3-2）。国际药品监管机构联盟国际药品监管机构联盟 (International Coalition of Medicines Regulatory Authorities (ICMRA)）是一个由世界各个地区的主要监管机构自愿组成的行政级别联盟。它为药品监管机构提供全球战略焦点，并在共同的监管问题和挑战方面发挥战略领导作用。ICMRA的成立旨在应对全球当前和新出现的监管和安全挑战。国际制药商协会联合会国际制药商协会联合会（International Federation of Pharmaceutical Manufacturers and Associations (IFMPA)）是一家位于瑞士日内瓦的全球性非营利组织，代表以研究为基础的制药公司和协会。该组织与联合国有正式关系，并提供行业专业知识，帮助全球卫生界找到改善全球健康的解决方案。经济合作与发展组织经济合作与发展组织（Organisation for Economic Co-operation and Development (OECD)）成立于1961年，是一个拥有37个成员国的政府间经济组织，旨在促进经济进步和世界贸易。经合组织与各国政府、政策制定者和公民一起，致力于建立以证据为基础的国际标准，并为一系列社会、经济和环境挑战寻找解决方案。它为数据和分析、经验交流、最佳做法分享以及公共政策和国际标准制定方面的建议提供了一个独特的论坛和知识中心。伊斯兰合作组织伊斯兰合作组织（Organisation of Islamic Cooperation (OIC)）的前身是伊斯兰会议组织，是一个成立于1969年的国际组织，由57个成员国组成，其中49个是穆斯林占多数的国家。伊斯兰合作组织是 "穆斯林世界的集体声音"，致力于 "本着促进国际和平与和谐的精神，捍卫和保护穆斯林世界的利益"。8美洲泛美药品监管协调网络泛美药品监管协调网络 (Pan American Network for Drug Regulatory Harmonization）成立于1999年，并于2000年获得泛美卫生组织（PAHO）的正式认可。PANDRH的使命是 "促进药品质量、安全和疗效各方面的药品监管协调，为提高美洲成员国公民的生活质量和医疗保健水平做出贡献"。其协调工作包括处方药和非处方药（OTC）、非专利产品、类似生物制品、疫苗和草药。PANDRH 目前的成员包括泛美卫生组织所有成员国的药品监管机构、地区制药行业协会（ALIFAR、FIFARMA）、学术界、消费者团体和专业协会的代表。美洲五个次区域贸易一体化集团，如安第斯共同体、加共体（加勒比共同体）、中美洲一体化体系（中美洲）、南方共同市场（南美洲/南方共同市场）和北美自由贸易协定（北美自由贸易协定）的代表也加入了 PANDRH"。9欧洲欧亚经济联盟欧亚经济联盟（Eurasian Economic Union，EAEU/EEU）由白俄罗斯共和国、哈萨克斯坦共和国和俄罗斯联邦成立，旨在建立 "一个经济联盟，提供货物、服务、资本和劳动力的自由流动，并在联盟内由文件和国际协定确定的部门奉行协调、统一和单一的政策"。自2014年成立以来，欧亚经济联盟的成员已扩大到亚美尼亚共和国和吉尔吉斯共和国。欧亚经济联盟的协调工作正在取得进展。10亚太地区日本制药工业协会日本制药工业协会（JPMA）是一个自愿组织，目前拥有71家研发型制药公司会员。JPMA成立于1968年，以 "实现患者参与的医疗 "为宗旨，通过开发创新型新药为全球医疗保健事业做出了贡献。JMPA的目标是开发多方面的项目，重点解决影响制药行业的共同问题，加深对制药的理解，促进国际合作。作为ICH的创始行业成员，JMPA非常活跃。该集团还领导着亚洲制药协会会议（APAC）。东南亚国家联盟东南亚国家联盟Association of Southeast Asian Nations (ASEAN)（东盟）由印度尼西亚、马来西亚、菲律宾、新加坡和泰国的外交部长于1967年成立，此后又增加了以下成员国：文莱、柬埔寨。东盟在文化、经济和政治发展方面开展合作，包括监管协调方面的工作。东盟医药产品工作组（PPWG）成立于1999年，旨在制定 "东盟成员国医药法规协调计划， 以补充和促进[东盟自由贸易区]目标的实现"。该倡议特别注重消除法规对贸易造成的技术壁垒，同时不影响药品的质量、疗效和安全"。PPWG致力于新化学实体（NCE）生物制品、主要和次要变异产品以及非专利药品的协调工作。亚太经济合作组织亚太经济合作组织（Asia-Pacific Economic Cooperation (APEC)）成立于 1989年，由来自澳大利亚、文莱、加拿大、印度尼西亚、日本、韩国、马来西亚、新西兰、菲律宾、新加坡、泰国和美国的代表组成。目前，亚太经合组织成员包括澳大利亚、文莱达鲁萨兰国、加拿大、智利、中华人民共和国、中国香港、印度尼西亚、日本、韩国、马来西亚、墨西哥、新西兰、巴布亚新几内亚、秘鲁、菲律宾、俄罗斯联邦、新加坡、中国台北、泰国和美国以及越南。亚太经合组织的主要目标是 "支持亚太地区的可持续经济增长和繁荣"。亚太经合组织生命科学创新论坛（APEC Life Sciences Innovation Forum）成立于 2002 年，旨在引领医疗保健和健康科学创新。亚太经合组织生命科学创新论坛有来自政府、行业和学术界的代表参与。一年后，亚太经合组织LSIF监管协调指导委员会（RHSC）成立，目的是 "到2020年实现医疗产品监管审批程序的区域趋同。"LSIF是一个三方论坛，由来自政府最高行政级别、行业和学术界的代表共同参与，为生命科学创新创造正确的政策环境。目前，它有三个主要目标：1. 与国际标准和医疗服务相协调2. 促进经济和技术合作，包括能力建设3. 探索促进公私部门在生命科学创新方面合作的途径。目前正在亚太经合论坛 LSIF 和区域健康服务中心下实施的项目之一是 "促进多区域临床试验（MRCT）路线图"。在日本的倡导下，多区域临床试验路线图旨在 "促进多区域临床试验（MRCT）以及监管机构接受这些临床试验结果的审查"。亚洲协调工作组亚洲协调工作组（Asian Harmonization Working Party (AHWP)）成立于1996-97年，旨在加强亚洲地区的监管协调。AHWP的目标是 "研究和建议协调亚洲和其他地区医疗器械法规的方法，并与全球医疗器械监管论坛、亚太经合组织和其他相关国际组织协调工作，以建立统一的要求、程序和标准"。AHWP目前由来自31个成员经济体的监管机构和医疗器械行业的代表组成。最近，继2020年3月发布预公告之后，AHWP领导层正准备将亚洲协调工作组（AHWP）转变为全球协调工作组（Global Harmonization Working Party (GHWP)）。11非洲非洲药品监管协调组织许多非洲国家法律基础薄弱，缺乏专业技术知识，无法支持适当或有效的监管审查。因此，非洲药品监管协调组织（African Medicines Regulatory Harmonisation(AMRH)）应运而生，"以建立和完善与非洲人口安全、优质药品的监管和获取相关的标准和要求"。自2014年以来，非洲药品监管协调组织一直由非洲各国卫生部长领导，旨在通过监督 "选定药品清单的注册和协调非洲大陆的区域协调系统 "来实现其目标。西非国家经济共同体 西非国家经济共同体（Economic Community of West African States (ECOWAS)）由位于西非地区的15个成员国组成。它于1975年通过《拉各斯条约》成立。西非经共体的使命是促进成员国所有活动领域的经济一体化。西非经共体的愿景是建立一个无国界地区，在这个地区，人民可以获得丰富的资源，并能够在可持续的环境下通过创造机会利用这些资源。西非经共体成员国包括贝宁、布基纳法索、佛得角、科特迪瓦、冈比亚、加纳、几内亚、几内亚比绍、利比里亚、马里、尼日尔、尼日利亚、塞内加尔、塞拉利昂和多哥。— 结论 —  全球监管立法和法规影响着制药和医疗保健行业，也影响着患者对新兴和创新疗法的获取。近几十年来，监管框架和要求进一步发展，以保护公众健康，防止不安全产品的出现。世界各地的监管规定因多种因素而异，包括产品类别/类型、风险概况和分类以及当地监管体系的成熟度。监管要求和差异继续给驾驭监管环境带来挑战，并增加了对更好的监管框架和全球统一性的需求。加强和完善协调有助于降低成本，缩短上市时间，促进贸易，加强研发，使患者能够获得安全有效的产品。由政府、行业和学术界代表组成的几个小组和组织已经成立，以启动和继续实现协调目标。在进入自由化和全球化时代之后，发展中经济体的愿望集中于确保进入其市场的产品的安全和性能，这意味着全球统一的法规或基准将成为加强这一目标的重要工具。世界各国政府和监管机构都有责任不断审查本国的法规、监管立法、框架和程序，以确保其能有效促进本国人民的经济和社会福祉，保护公众健康。总之，除了确保患者获得高质量的医疗保健服务外，全球医疗保健、监管流程和协调工作中引入更新和创新疗法的全球基准仍是当务之急。这需要全球监管机构和组织以一致和快速的方式不断努力。英文原文（上下滑动查看更多）Chapter 3. International Harmonization via ICH, WHO, and other Global InitiativesThis chapter focuses on the current international environments for the regulation of medicinal products, including a comprehensive overview of the critical roles of the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) and the World Health Organization (WHO,) which is the sole United Nations (UN) agency leading the initiatives and collaborations for the global health ecosystem. The chapter also discusses international organizations focused on harmonization and continuous improvements for efficiencies in the global regulatory processes.Historical Legacy and RegulationsThe regulation of medicinal products derives from the use of unsafe products and the resultant public health risks and tragedies. The Apothecary Wares, Drugs and Stuffs Act, enacted in 15th century England, is a classic example of an early effort to legally control medicines by allowing the inspection of medicinal product manufacturing.In the US, the Biologics Control Act of 1902, also known as the Virus-Toxin Law, provided the authority to the US government’s Hygienic Laboratory (a precursor of the National Institutes of Health) to regulate the manufacture of biological products, including serums and vaccines. It was followed in 1906by the Pure Food and Drugs Act, prohibiting misbranded and adulterated foods, drinks, and drugs in interstate commerce. Authority to enforce this law was given to the US Department of Agriculture’s Bureau of Chemistry, which became the Food and Drug Administration (FDA) in 1930. The Federal Food, Drug, and Cosmetic (FD&C) Act of 1938 required that new drugs must be proven to be safe and effective before marketing and extended the FDA’s authority, giving it purview over the regulation of medical devices and cosmetics.Prior to the enactment of those laws, consumers were exposed to risks from potentially unsafe, ineffective, and adulterated products. Public health tragedies, including the 1937 Elixir Sulfanilamide incident in the US and the thalidomide tragedy in the EU and Canada in the 1950s, fast-tracked the implementation of modern and effective regulations.Under the FD&C Act of 1938, a biologic (or biological product) was considered to be a drug, and while some parts of the law were applicable to the biologics, the law did not modify or supersede the provisions of the original Biologics Control Act of 1902; therefore, provisions of both laws were used to regulate biologics, and regulatory authority was split between FDA and the Hygienic Laboratory/NIH. Regulation of biologics, including vaccines and serums, was transferred from NIH to FDA in 1972.Role of RegulatorsWhile regulations may vary by region and by a market’s current level of development (developed, developing, or emerging), the role of the regulator remains the same: To protect the public health. This is illustrated in the statements of responsibility by regulators, as presented with a few examples below:• India’s Central Drugs Standard Control Organization (CDSCO): To safeguard and enhance the public health by assuring the safety, efficacy, and quality of drugs, cosmetics, and medical devices.• Australia’s Therapeutic Goods Administration (TGA): Safeguards and enhances the health of the Australian community through effective and timely regulation of therapeutic goods.• Japan’s Pharmaceuticals and Medical Devices Agency (PMDA): Protects the public health by assuring the safety, efficacy, and quality of pharmaceuticals and medical devices.• China’s National Medical Products Administration (NMPA): To supervise the safety of drugs (including traditional Chinese medicines [TCMs] and ethno-medicines), medical devices, and cosmetics.DrugsAlthough the individual market/region submission requirements vary, regulatory authorities generally require the sponsors to submit data and information indicating that the investigational therapy has a reasonable and satisfactory benefit-risk ratio for its market approval. In the case of generic drugs, the manufacturers must provide evidence that the proposed product has the same therapeutic efficacy, safety, and performance characteristics as its predecessor innovator drug.Manufacturers must be able to meet the individual regulatory requirements of each country in which they intend to market the product. They also must comply with postmarket monitoring requirements to ensure critical issues are assessed against thedrug’s risk profile and actioned, as required. WHO defines pharmacovigilance (PV) as “the science and activities relating to the detection, assessment, understanding, and prevention of adverse effects or any other medicine/vaccine-related problem.” This definition is also referenced in the ICH Pharmacovigilance E2E guideline, which notes that PV “describes a method for summarizing the important identified risks of a drug, important potential risks, and important missing information, including the potentially at-risk populations and situations where the product is likely to be used that have not been studied pre-approval.”The guideline also advises that “routine pharmacovigilance should be conducted for all medicinal products” and recommends that the requirements for routine PV, in addition to any local requirements:• Systems and processes to ensure information about all suspected adverse reactions reported to company personnel are collected and collated in an accessible manner.• Preparing reports for regulatory authorities.• Expedited Adverse Drug Reaction Reports.• Periodic Safety Update Reports (PSURs)• Continuous monitoring of approved products’ safety profile, including signal detection, issue evaluation, updating labeling, and liaising with regulatory authorities.BiologicsBiologics or biological products are a class of therapeutic products derived from living organisms. In the biologics manufacturing process, these origination organisms are grown and then purified using large-scale cell cultures in bioreactors. Originating organisms may be viruses, bacteria, yeasts, plant cells, or animal cells. Biologics are more versatile than pharmaceuticals and can be used to develop complex therapies such as vaccines, growth factors, immune modulators, monoclonal antibodies, as well as products derived from human blood and blood plasma. The FDA distinguishes between the human cells, tissues, and cellular and tissue-based products (HCT/P’s) that are regulated by its Centerfor Devices and Radiological Health (CDRH) as medical devices and those that are regulated by its Center for Biologics Evaluation and Research (CBER).International Council for HarmonisationEstablished in 1990, ICH aims “to make recommendations toward achieving greater harmonization in the interpretation and application of technical guidance and requirements for pharmaceutical product registration, thereby reducing or obviating duplication of testing carried out during the research and development for new human medicines.”Regulatory harmonization offers many benefits to both the global regulatory authorities and the pharmaceutical industry for protecting public health. The key benefits of this harmonization effects include the prevention of duplication of clinical trials in humans and minimizing the use of animal testing without compromising safety and effectiveness, streamlining the regulatory assessment process for new drug applications, and reducing the development times and resources for drug development. This further emphasizes the critical and vital message to the global stakeholders regarding the need for developing safe and effective efficiency in allowing patient access to therapies.Founding members of ICH were regulatory and pharmaceutical industry representatives from developed nations including the US, EU, and Japan. Membership has expanded to many other countries and organizations holding observer status (See Table 3-1).ICH prioritizes transparency regarding its harmonization work as one way to build and maintain public trust. The ICH Assembly and Management Committee works to ensure that the ICH process remains transparent and has recognized that all stakeholders should have current information on the important decisions and real-time progress of ICH guideline development. In 2005 and again in 2012, the council took measures to ensure all parts of the guideline development process were reflected publicly on its website as quickly and clearly as possible.ICH harmonization activities fall into four categories: formal ICH procedures, Q&A procedures, revision procedures, and maintenance procedures. For each activity, a concept paper and/or a business plan may be required (see Figure 3-1).The formal ICH procedure consists of five steps. It is followed for the harmonization of all new ICH topics. An expert working group (EWG) is established, which works on the following steps and procedures for implementation.Step 1: Consensus building• The EWG prepares a consensus draft of the technical document based on the objectives set out in the concept paper.Step 2a: Confirmation of consensus on the technical document• This step is approached when the assembly agrees, per the EWG report, that there is sufficient scientific consensus for the technical document to proceed to the next stage of regulatory consultation.Step 2b: Adoption of the draft guideline by regulatory members• Based on the technical document, the ICH regulatory members will take the actions they deem necessary to develop the draft guideline.• Regulatory members endorse the draft guideline.Step 3: Regulatory consultation and discussion• Comprised of three distinct stages৹ Stage I – This applies to the regional regulatory consultation stage.৹ Stage II – This applies to the discussion of regional consultation comments after ৹ btaining all comments from the consultation process.৹ Stage III – This is the finalization of Step 3 expert draft guideline. The Step 3 expert draft guideline with regulatory EWG signatures is submitted to the regulatory members of the assembly to request adoption.Step 4: Adoption of an ICH Harmonised Guideline• The assembly agrees that there is sufficient consensus on the draft guideline. The ICH regulatory members adopt the Step 4 final document as an ICH harmonised guideline.Step 5: Implementation• Implementation s carried out according to the same national/regional procedures that apply to other regional regulatory guidelines and requirements in the ICH regions.ICH Guidelines Implementation Once a guideline has reached Step 5 of the formal procedure, it is implemented by ICH regulatory members and observers in their respective country or region. Regulatory members are expected to implement all ICH guidelines based on the ICH Articles of Association. Regulatory observers are non-voting members of ICH; implementation of certain ICH guidelines is a prerequisite to becoming a regulatory member.Overall, ICH Guidelines are implemented under the applicable national, regional, and/or local rules, with the stage of implementation of all ICH Guidelines also being dependent on when a member or observer joined ICH. Further, ICH surveys the regulatory member and observer countries/regions to understand the level of implementation and adherence to the ICH guidelines and their applicability.ICH guidance topics are divided into four categories, and each is assigned a letter code:1.Quality Guidelines (Q) address the conduct of stability studies, define relevant thresholds for impurities testing, and foster a more flexible approach to pharmaceutical quality based on current good manufacturing practice (cGMP) risk management.2.Safety Guidelines (S) seek to uncover potential risks such as carcinogenicity genotoxicity, and reproductive toxicity in animal studies at both in vivo and in vitro levels.3.Efficacy Guidelines (E) are concerned with the design, conduct, safety, and reporting of human clinical trials. These guidelines also cover the novel types of medicines derived from biotechnological processes and the use of pharmacogenetics/genomics techniques to produce better-targeted medicines.4.Multidisciplinary Guidelines (M) provide guidance on the cross-cutting topics which do not entirely or uniquely fit into one of the Quality, Safety, and Efficacy categories. These multidisciplinary guidelines include the ICH medical terminology (MedDRA), the Common Technical Document (CTD), and the development of Electronic Standards for the Transfer of Regulatory Information (ESTRI).Global Data Harmonization EffortAn important and landmark achievement stemming from ICH efforts is the agreement to assemble all Quality, Safety, and Efficacy related data information in a standard format called the Common Technical Document (CTD).22 The CTD submission process has revolutionized the regulatory review processes, reduced time, and has led to harmonized electronic submission acceptance and good review practices. The CTD has largely eliminated the need to reformat the information for submission to the different ICHregulatory authorities. In many countries, a CTD that has been accepted by an ICH regulatory member can serve as precedent for the review of investigational products in the respective marketThe CTD is organized into five modules:• Module 1 is geographic region specific and includes administrative information.• Module 2 includes quality, non-clinical, and clinical data summaries.• Module 3 includes quality data.• Module 4 includes non-clinical data.• Module 5 includes clinical data.The ICH M4 guideline provides guidance on the paper submission of a CTD, whereas the M8 guideline provides guidance on the electronic CTD submission requirements.In July 2003, the CTD became the mandatory format for new drug applications in the EU and Japan and is strongly recommended for new drug applications (NDA) submitted to the US FDA.World Health OrganizationThe World Health Organization (WHO) was founded in 1948. WHO is the United Nations (UN) sole agency that connects global nations, partners, and people to promote health while keeping the world safe and serving the vulnerable to ensure that the world population has access to attain the highest level of health.WHO’s mission is to provide global leadership and guidance around global public health and to maintain the global health ecosystem. Currently, WHO includes 194 member states. The WHO Secretariat includes experts, staff, and field workers and is in Geneva, Switzerland. WHO operates regional offices in more than 150 countries, organized into the following global regions:• Africa• Americas• Eastern Mediterranean• Europe• South-East Asia• Western PacificWHO ProgrammeThe Thirteenth General Programme of Work (GPW 13) defines WHO’s strategy for the five-year period, 2019-2023. This programme focuses on triple billion targets to achieve measurable impacts on people’s health at the country level. Based on public health disruptions from the COVID-19 global pandemic, WHO extended GPW 13 to 2025.WHO has engaged in significant and impactful global and regional public health initiatives. A recent example is the ACT (Access to COVID-19 Tools) Accelerator partnership, launched in April 2020. The partnership, a “landmark collaboration to accelerate the development, production, and equitable distribution of vaccines, diagnostics, and therapeutics for COVID-19,” brought together ten leading public health and development agencies, as well as national governments, non-governmental organizations, in response to the developing pandemic situation. International Organizations, Cooperation Agreements, and PartnershipsThe following section outlines international and regional collaboration efforts in several regions.Pharmaceutical Inspection Co-operation SchemePharmaceutical Inspection Co-operation Scheme (PIC/S) was established in 1995 as an extension to the Pharmaceutical Inspection Convention (PIC) of 1970. It is a non-binding, informal cooperative arrangement between regulatory authorities in the field of good manufacturing practice (GMP) of medicinal products for human or veterinary use. The PIC/S primary mission is “to lead the international development, implementation, and maintenance of harmonised good manufacturing practice (GMP) standards and quality systems of inspectorates in the field of medicinal products”.As a pioneer organization, PIC/S leads in the field of pharmaceutical inspections and GMP. Since its establishment, PIC/S has successfully adapted to a constantly changing environment, particularly globalization, and it remains the sole organization worldwide that exclusively deals with GMP. PIC/S’ mandate from 2023 will be expanded to GxP with a primary focus on good manufacturing process (GMDP) in the field of training and standards, in line with the PIC/S new mission to strive to improve public health by leading the development and implementation of inspection frameworks for human and veterinary medicines, through harmonization of standards and offering world-class training to the regulatory inspectors around the globe.The PIC/S is open to collaborating with any global regulatory authority which has a comparable GMP inspection system. Currently, the PIC/S presently comprises more than 50 participating global regulatory authorities.International Pharmaceutical Regulators ProgrammeInternational Pharmaceutical Regulators Programme (IPRP) was established in 2018 to promote the convergence of regulatory approaches for pharmaceutical medicinal products for human use. The purpose of IPRP is to create an environment for its regulatory members and observers to exchange information on issues of mutual interest, enable cooperation and promote convergence of regulatory approaches for pharmaceutical medicinal products for human use. Their aim focuses on assisting in maximizing potential efficiencies in addressing the increasingly complex global regulatory environment to facilitate the implementation of ICH and other internationally harmonized technical guidelines for pharmaceutical products intended for human use. IPRP offers tangible benefits for its members and observers and is committed to promoting information sharing and collaboration to advance public health, facilitate access to medicines, and address emerging regulatory challenges of mutual interest.  IPRPmembers include WHO and multiple global regulatory authorities (see Table 3-2).Table 3-2. Members and Observers of the International Pharmaceutical Regulators ProgrammeInternational Coalition of Medicines Regulatory AuthoritiesThe International Coalition of Medicines Regulatory Authorities (ICMRA) is a voluntary, executive-level coalition of key regulators from every region in the world. It provides a global strategic focus for medicines regulators and gives strategic leadership on shared regulatory issues and challenges. ICMRA was created to address current and emerging regulatory and safety challenges globally.International Federation of Pharmaceutical Manufacturers and AssociationsThe International Federation of Pharmaceutical Manufacturers and Associations (IFMPA) is a global non-profit organization in Geneva, Switzerland, representing research-based pharmaceutical companies and associations. The group has official relations with the UN and contributes industry expertise to help the global health community find solutions that improve global health.Organisation for Economic Co-operation and DevelopmentThe Organisation for Economic Co-operation and Development (OECD) is an intergovernmental economic organization with 37 member countries, founded in 1961 to stimulate economic progress and world trade. Together with governments, policymakers, and citizens, the OECD works on establishing evidence-based international standards and finding solutions to a range of social, economic, and environmental challenges. It provides a unique forum and knowledge hub for data and analysis, exchange of experiences, best-practice sharing, and advice on public policies and international standard-setting.Organisation of Islamic CooperationThe Organisation of Islamic Cooperation (OIC), formerly the Organisation of the Islamic Conference, is an international organization founded in 1969, consisting of 57 member states, 49 of which are Muslim-majority countries. OIC is “the collective voice of the Muslim world” and works to “safeguard and protect the interests of the Muslim world in the spirit of promoting international peace and harmony.”The AmericasPan American Network for Drug Regulatory HarmonizationPan American Network for Drug Regulatory Harmonization (PANDRH) was established in 1999 and officially recognized by the Pan American Health Organization (PAHO) in 2000.PANDRH’s mission is to “promote drug regulatory harmonization for all aspects of quality, safety, and efficacy of pharmaceutical products as a contribution to the quality of life and health care of the citizens of the Member Countries of the Americas. Their harmonization efforts include prescription and over-the-counter (OTC) medicines, generic products, similar biologics, vaccines, and herbal medicines.The current PANDRH members are pharmaceuticals regulatory authorities of all PAHO member states, representatives of the regional pharmaceutical industry associations (ALIFAR, FIFARMA), academia, consumer groups, and professional associations. They are joined by representatives from the five sub-regional trade integration groups within the Americas, such as the Andean Community, CARICOM (Caribbean Community), SICA (Central America), MERCOSUR (South America/ Southern Common Market), and NAFTA (North American Free Trade Agreement).”EuropeEurasian Economic UnionEurasian Economic Union (EAEU/EEU) was established by the Republic of Belarus, the Republic of Kazakhstan, and the Russian Federation to create “an economic union that provides free movement of goods, services, capital, and labor and pursues coordinated, harmonized, and single policy in the sectors determined by the document and international agreements within the Union.” Since its establishment in 2014, the membership of the EAEU has expanded to include the Republic of Armenia and the Kyrgyz Republic. EAEU harmonization efforts are in progress.Asia-Pacific RegionJapan Pharmaceutical Manufacturers AssociationJapan Pharmaceutical Manufacturers Association (JPMA) is a voluntary organization with 71 research- and development-oriented pharmaceutical company members currently. Established in 1968, JPMA has contributed to global healthcare through the development of innovative new drugs under the motto of “realizing patient-participating medicine.” The JMPA aims to develop multifaceted projects focused on solving common problems affecting the pharmaceutical industry, deepening the understanding of pharmaceuticals, and fostering international cooperation. JMPA is active as a founding industry member of ICH. The group also leads the Asian Pharmaceutical Association Conference (APAC).Association of Southeast Asian NationsThe Association of Southeast Asian Nations (ASEAN) was established in 1967 by the Foreign Ministers of Indonesia, Malaysia, Philippines, Singapore, and Thailand and has since expanded to include the following additional member states: Brunei, Cambodia,Laos, Myanmar, and Vietnam. ASEAN collaborates in cultural, economic, and political development, including work in regulatory harmonization.36The ASEAN Pharmaceutical Product Working Group (PPWG) was established in 1999 to develop “harmonisation schemes of pharmaceutical regulations of the ASEAN member countries to complement and facilitate the objective of [ASEAN Free Trade Area]. The initiative was particularly focused on the elimination of technical barriers to trade posed by regulations, without compromising on drug quality, efficacy, and safety.” PPWG works on harmonization efforts for new chemical entities (NCEs) biotechnological products, major and minor variation products, and generic pharmaceutical products.Asian-Pacific Economic CooperationAsia-Pacific Economic Cooperation (APEC) was founded in 1989 by representatives from Australia, Brunei, Canada, Indonesia, Japan, South Korea, Malaysia, New Zealand, the Philippines, Singapore, Thailand, and the US. Currently, the APEC membershipincludes Australia; Brunei Darussalam; Canada; Chile; People’s Republic of China; Hong Kong, China; Indonesia; Japan; South Korea; Malaysia; Mexico; New Zealand; Papua New Guinea; Peru; the Philippines; the Russian Federation; Singapore; Chinese Taipei; Thailand; and the US; Vietnam. APEC’s primary goal “is to support sustainable economic growth and prosperity in the Asia-Pacific region.”The APEC Life Sciences Innovation Forum (APEC LSIF) was formed in 2002 to lead healthcare and health sciences innovation. APEC LSIF engages representatives from government, industry, and academia. A year later, the APEC LSIF Regulatory Harmonization Steering Committee (RHSC) was established to “achieve regionalconvergence on regulatory approval procedures for medical products by 2020.”The LSIF is a tripartite forum that engages representatives from the highest administrative levels of government, industry, and academia to create the right policy environment for life sciences innovation. Currently, it has three main objectives:1. Harmonization with international standards and health services2. To promote economic and technical cooperation, including capacity building3. To explore avenues to promote public-private sector collaboration in life sciences innovation.One of the projects currently being implemented under APEC LSIF and RHSC is the Roadmap to Promote Multi-Regional Clinical Trial (MRCT). Championed by Japan, MRCT aims to “facilitate multi-regional clinical trials (MRCT) and the acceptanceof these clinical trial results for review by regulatory authorities.”Asian Harmonization Working PartyThe Asian Harmonization Working Party (AHWP) was formed in 1996–97 to achieve greater regulatory harmonization in Asia. AHWP’s goals are “to study and recommend ways to harmonize medical device regulations in the Asian and other regions and to work in coordination with the GHTF, APEC, and other related international organizations aiming for establishing harmonized requirements, procedures, and standards.” AHWP currently is comprised of representatives from regulatory authorities and the medical device industry from 31 member economies. Most recently, following the pre-announcement issued in March 2020, the AHWP leadership is preparing the transformation of the Asian Harmonization Working Party (AHWP) into the GlobalHarmonization Working Party (GHWP).AfricaAfrican Medicines Regulatory Harmonisation Many African countries have insufficient legal foundations and lack the technical expertise to support adequate or efficient regulatory reviews. Therefore, African Medicines Regulatory Harmonisation (AMRH) was created “to establish and improve standards and requirements related to the regulation of and access to safe, high-quality medicines for the African population.” AMRH, which has been led by African health ministers since 2014, aims to achieve its objective by overseeing “the registration of a selected list of medicines and coordinate regional harmonization systems on the continent.” Economic Community of West African States The Economic Community of West African States (ECOWAS) is made up of 15 member countries located in the Western African region. It was established in 1975 via the treaty of Lagos. The ECOWAS mission is to promote economic integration in all fields of activity of the constituting countries. Its vision is the creation of a borderless region where the population has access to its abundant resources and is able to exploit the same through the creation of opportunities under a sustainable environment. The ECOWAS Member States include Benin, Burkina Faso, Cabo Verde, Côted’Ivoire, the Gambia, Ghana, Guinea, Guinea Bissau, Liberia, Mali, Niger, Nigeria, Senegal, Sierra Leone, and Togo. ConclusionGlobal regulatory legislation and statutes impact the pharmaceutical and healthcare industries and patient access to newer and innovative therapies. In recent decades, the regulatory framework and requirements have evolved further to protect public health and protect against unsafe products. Regulations vary worldwide based upon several factors, including product category/type, risk profile and classification, and maturity of the local regulatory system. Regulatory requirements and variations continue to create challenges in navigating the regulatory environment and increase the demand for a better regulatory framework and harmonization globally.Greater and well-integrated harmonization could help reduce cost and market time, facilitate trade, enhance research and development, and allow patient access to safe and efficacious products. Several groups and organizations comprising representatives fromgovernment, industry, and academia have been established to initiate and continue the harmonization objectives.After the era of liberalization and globalization, the desires of developing economies have been focused on ensuring the safety and performance of the product brought to their markets, which signifies that a globally harmonized regulation or benchmark would be an important tool for strengthening the same. All governments and regulatory authorities worldwide have a constant responsibility to review their country regulations, regulatory legislations, frameworks, and processes to ensure that they promote efficiently and effectively the economic and social well-being of their people and the protection of public health.In summary, the need for global benchmarks in global healthcare, regulatory processes, and harmonized efforts in bringing newer and innovative therapies apart from ensuring patient access to quality healthcare remains at the forefront. It requires continuous efforts from global regulatory authorities and organizations in a consistent and expedited manner.参考文献：（上下滑动查看更多）All references verified 31 January 2023.1.van Boxtel CJ, Santoso B, Edwards IR. Drug Regulation: History, Present and Future. In: Drug Benefits and Risks: International Textbook of Clinical Pharmacology, Revised 2nd Ed. IOS Press and Uppsala Monitoring Centre, 2008: 6 –77.2.Food and Drug Administration. 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