Mannitol

FDA对2015-2019年收的到263个冻干产品（包括创新药和仿制药）的工艺缺陷进行分类，根据冻干产品的实际生产过程将工艺缺陷分为配制，过滤，灌装和冻干四个大类。下面分别讨论各步骤中常见的缺陷 配制是起始物料的溶解过程，配制应保证原辅料充分溶解和均一。 1.在配制过程中应考虑合适的环境控制（比如温度，相对湿度，，光照），尤其是对高风险，容易降解的原料，应尽可能的采取措施避免原料降解，比如原料使用之前存储在低温环境。 2.在配制过程中如果存在过量投料，必须解释过量投料的原因，过量投料具体的量。 3.根据ICH Q1A(R2)，制剂申报批生产应使用不同批次的API。有些案例将几批原料混合在一起，就无法考察单一批次原料对制剂的影响，也违背了ICH指南的初衷。 4.在配制过程中，原辅料应混合均匀。中间体药液的pH应能使原料的溶解度和稳定性达到最好的状态。因此在配制环节应考察（不限于）：（1）原辅料的加入顺序。（2）原料在不同pH和温度下的溶解度和稳定性。（3）中间体药液在光照和有氧环境下的稳定性。（4）生产条件下原料药的溶解速度。这些研究是制定生产工艺控制的依据。配制环节常见的缺陷是缺乏对这些工艺参数的控制，另外就是缺少批量放大的支持性研究，尤其是对溶解性差，需要较长时间溶解的药物。 5.对于胶体分散液，悬浮液和乳液等非单相溶液，更应该关注原辅料是否能混合均匀。 6.对于处方中含有金属螯合剂或者强酸的产品，所有和药液接触的金属生产设备应满足ASTM 316/316L的要求，以降低元素杂质和表面腐蚀的风险。 配制环节常见的缺陷实例： ①解释申报批中原料3%过量投料的原因，如果过量投料的目的是弥补生产环节中的损失，需要证明不同批次之间的损失量是稳定的，并且成品均符合质量标准。 ②原料溶解性差，申报批中原料溶解的搅拌时间是15h，商业批批量是申报批批量的8倍，但没有研究商业批批量确保原料溶解的措施，需要证明商业批的搅拌参数（比如搅拌速度，搅拌时间等）是能保证原料充分溶解。另外，注意到原料溶解后是浑浊的，因此不能用目检判断是否溶解完全，建议对过滤后药液进行含量检测，作为中控检测项目。 ③产品处方中含有金属螯合剂EDTA，应证明所有和药液接触的金属生产设备满足ASTM 316/316L的要求。 ④中间体药液pH范围制定太宽泛，并且没有制定依据。请收紧pH范围，或者证明原料在这个pH范围内的溶解性和稳定性均能满足要求。 ⑤申报批中没有规定搅拌时间的终点，而是规定为“搅拌至溶解”或者“搅拌时间不少于多长时间”。建议根据研究数据或者申报批生产的数据，规定搅拌时间的上下限。 无菌过滤 原辅料在过滤环节可能会被滤膜或者传送管道吸附，从而影响终产品的含量。尤其是生产前还需要用非药液的液体润湿滤膜，检测滤膜的完整性。因此如果没有确定灌装前的最小排放体积，证明产品的含量或防腐剂浓度满足要求，就会引发缺陷。 另外需要注意的是中间体药液的兼容性测试（比如含量，有关物质，pH）,与中间体药液接触的任何生产设备（比如容器，管道，过滤器和垫片等）需要符合21 CFR 211.65和ICH Q75.1的要求。最常见的缺陷是没有充分评估药液与生产设备接触导致的可提取物和浸出物的风险。推荐参考USP<1163>,<1664>,<87>,<88>,<381>和<661>。 过滤环节常见缺陷实例如下 ①需要规定灌装前最小排放体积，从而确保原辅料不会被滤膜或管道等吸附。 ②证明与药液接触的所有塑料组件符合USP<87>和<88>的要求。 ③处方中使用了高浓度的环糊精来增加原料药的溶解度，但同时也增加了药液与生产设备中塑料组件的浸出风险，请提供单个生产设备生产最差条件的可提取物研究，或者也可以对终产品进行可提取物研究。 ④如果处方中含有有机溶剂，那使用水研究滤膜的可提取物研究是不合适的，需要使用能代表产品的有机溶剂进行滤膜的可提取物研究。 ⑤鼓励对终产品进行可提取研究，确认或消除高于分析评估阈值水平的可提取物或其衍生物。 灌装 ①最大暂存时间研究要有数据支持（比如化学，物理或微生物等），灌装暂停时间研究等。 ②对于冻干产品中间体药液的灌装体积，USP<1151>是不适用的，但USP<1151>对冻干产品的复溶体积是适用的。灌装体积应符合USP<905>的要求。为确保产品能提供跟说明书一致的剂量，申请人应提供以下信息 （1）处方浓度（2）灌装体积范围（3）标签中规定的稀释剂体积（4）复溶产品的总体积（5）考虑到抽取和注射过程的损失，实际注射的药液体积。 ③实际生产中或者能对灌装重量实现100%的在线监测，或者提供一个详细的取样计划（比如取样数量和频率） 灌装过程中常见的缺陷实例 ①请提供根据标签说明产品复溶后的总体积，如果复溶后的总体积不满足USP<1151>的要求，请参照USP<697>进行可抽取体积和注射体积研究，报告可递送体积。 ②根据复溶产品的总体积，只有过量灌装才能保证复溶后药液的浓度是0.5mg/ml，请调整灌装控制策略。 ③提供灌装环节详细的检测灌装体积的中控取样计划。 ④灌装暂停将导致药液升温至室温，申报资料表明原料在室温下容易降解，需要提供灌装暂停时间，以及最小排放体积，并解释这些中控措施的制定依据。 ⑤产品对光照和氧气敏感，需要提供产品在放入冻干机之前的暂存环境控制措施。 冻干 导致冻干产品审评延期的一个重要原因就是申请者对冻干工艺没有充足的认识和理解。研发人员应该对冻干过程中的关键温度有足够的研究，比如产品的玻璃化转变温度，共晶点，塌陷温度，否采取退火等措施。常用的方法是差示热扫描，冻干显微镜等。采取退火操作能降低 1.冻干环节常见的缺陷是没有对一次干燥和二次干燥的终点没有合理的解释。考虑到过早开展二次干燥会导致冷冻块的塌陷或者融化，申请人应对一次干燥终点的制定有充分的理解。 2.值得注意的是申请人很少在商业批的放大计划里监测产品的温度或冻干进度，可能是因为申请人对冻干过程的中控措施没有很好的理解（比如热电偶，皮拉尼表和压力升测试）。 3.干燥不足导致终产品的水分太多，可能会导致产品的保质期缩短，因此申请人应对二次干燥参数进行合理的设置。 4.终产品的水分含量会影响终产品的玻璃化转变温度，应明确终产品的水分含量目标，从而确保终产品的玻璃化转变温度高于产品长期和加速的储存温度。 商业批放大应有科学的取样计划，因为数量变大，冻干机性能差异等都能导致批次间的差异。申请人应明白冻干机设备间的差异，鉴别出所有的关键工艺参数（比如温度，升降温速率，保持时间，各阶段的压力等），也应认识到冻干机满载或部分满载的能力差异。 冻干环节常见的缺陷实例 申报批的冻干工艺参数将用于商业批，无论批量大小，以下主要指批量放大方面的缺陷 1.申报批冻干的关键工艺参数（比如板层温度，升降温速率，腔室压力）适用于商业批，应有科学的解释。 2.批量放大时，应明确每个托盘放多少样品，每个板层放多少托盘，使用几个板层。 3.解释批量放大后，一次干燥的终点是否还合理。 4.干燥是冻干的关键工艺参数，商业批批量放大，冻干机是否满载。 5.提供详细的取样计划，研究冻干机不同板层位置上的终产品关键质量属性是否有差异。 解释冻干工艺参数是如何确定的 1.解释一次干燥的板层温度是如何确定的，跟玻璃化转变温度和塌陷温度的关系，或者提供任何合理的热分析数据。 2.提供冻干过程中详细的温度和压力变化数据，提供压力升数据以合理解释一次干燥和二次干燥终点制定依据。 3.应明确申报批和商业批每个托盘放多少样品，每个板层放多少托盘，使用几个板层。 4.提供详细的取样计划，研究冻干机不同板层位置上的终产品关键质量属性是否存在差异。 5.退火能防止甘露醇结晶导致小瓶在冻干过程中破碎，但是申请者的工艺里并没有退火步骤，那申请者是采取了哪些措施降低小瓶在冻干和储存期间破碎的风险呢。 注：什么是冻干过程中一次干燥的终点 观点：1.瓶子中的游离冰已经全部去除，不用担心二次干燥升温时样品塌陷或者融化。2.冻干过程中耗时最长和花费最多的工艺。3.用牙签插进冻干块的中心，抽出后牙签是干净的。4.实际上并没有什么一次干燥或者二次干燥，冻干过程中板层温度可以一直上升。 除了这些生产环节常见的缺陷以外，另外的缺陷常见生产时间，收率，批量和目检。 生产时间 根据21 CFR 211.111，生产过程的每个环节都应该有时间限制，从原料药投料开始的所有可能的暂停和保持时间都应该有数据支持（比如化学，物理或微生物数据等） 缺陷实例 1.原料药在水中容易降解，应制定从原料药投料开始到冻干开始的最长时间。另外证明中间体药液和生产设备接触后的最差生产条件下，产品的质量仍然符合质量要求。 2.处方中含有有机溶剂，增加了和生产组件中塑料材质的浸出物风险。应确定灌装过程中最长暂停时间，从而限制中间体药液和生产设备的静态接触，并提供最小排放体积，以便从新开始灌装，并证明这些控制措施能降低药液和生产设备接触导致的终产品浸出物风险。 收率 如果未对产品的收率进行控制，那么就会引发缺陷。制定产品收率能够确保当产量出现无法解释的差异后，能去调查那些可能影响药品质量和安全性的问题。经常发现或者不制定收率，或者收率范围特别宽，导致不能反应关键的生产情况。在工艺验证批生产时应该确定收率范围，然而在申报资料递交时，都是根据注册批和稳定性批次制定暂定收率范围。 缺陷实例 1.批记录中没有规定收率，请根据以往生产批次经验，为每个生产步骤规定收率范围。 2.“不少于40%”的收率标准不能正确反映注册批次“98.0%±2.0%”的结果，收进收率范围并制定收率上限。 批量缺陷实例 产品的灌装体积是8ml，建议最小注册批量是8L，但申请者的注册批量是7.5L，并且计划商业批批量放大至75L，我们建议申请者的商业批批量和注册批批量保持一致，并且如果将来批量放大，应提供事前批准补充（PAS）。请参考2014年的FDA工业指南“仿制药：原料药和成品的稳定性检测-问与答”。 目检缺陷实例 1.在批记录中补充100%目检的不合格品率。 2.注册批目检的不合格品率高达12%，解释不合格品率高的原因，并制定在商业批减少不合格品率的控制措施。 以上就是冻干制剂常见的冻干工艺缺陷，希望能对大家的实际研发工作能有些许帮助！ 参考文献： 1.A Regulatory Perspective on Manufacturing Processes Pertaining to Lyophilized Injectable Products

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。 药品开发的目的是设计出高质量的产品及其生产工艺，始终如一地实现产品的预期性能。从药品开发研究和生产经验中获得的信息和知识，可为设计空间、规格和生产控制的建立提供科学依据。从药品开发研究中获得的信息可作为质量风险管理的基础。 重要的注意的是，质量无法通过产品测试；因此，质量应通过设计来实现（quality should be built in by design）。在开发和生命周期管理过程中，处方和生产工艺的变化（Changes in formulation and manufacturing processes）应被视为获得更多信息和进一步支持建立设计空间的机会。同样，从其他间接实验中获得的相关知识纳入其中也很有用。 在开发制剂时，必须确定对成品质量至关重要的属性，同时考虑其预期用途、给药途径和预期患者群体（如儿科、老年病科）的特定需求。所有辅料的选择都应合理。虽然辅料通常是非活性物质，但也应考虑其对目标人群的安全性。应评估活性物质的理化性质（如含水量、溶解度、粒度分布、多晶型或固态型）对成品性能的潜在影响。另一个需要研究的关键问题是活性物质与辅料和容器封闭容器的兼容性。对于组合产品，还应评估设备和/或活性物质之间的兼容性。 从药品开发研究中获得的知识和数据以及从生产数据中获得的经验可用于支持设计空间、规格和生产控制的建立。其他开发概念（即设计质量）可包括使用实验设计（DOE）、质量风险评估和产品整个生命周期质控的研究结果。 1 处方前研究 处方前研究是一组以候选新药的理化性质为重点的研究，这些性质可能会影响药物的性能和剂型的开发，并帮助研究人员选择制剂中应使用的成分（辅料）。 处方前研究可分为几个方面。首先是基本性质的表征，包括了解药物在不同溶剂中的溶解度、解离常数（pKa）、分配系数或分布系数、pH 值、渗透性、固态稳定性、溶液态稳定性等。其次，筛选合适的盐、多晶体、溶胶形式和无定形形式。第三，必须了解衍生的预配方特性，如形态、粒度、体积密度等。处方前研究的最后一项工作是辅料相容性研究，以研究药物在辅料存在时的稳定性。 2 按设计质量原则进行药品开发概述 质量源于设计（Quality by Design, QbD）的开发方法首先要根据患者在用药剂量、便利性和依从性方面的需求，以及预期治疗适应症的市场要求，明确定义目标产品特征（Target Product Profile, TPP）。 产品要求可分为以下三个方面（Figure 13-1）： 1. 产品稳定性，在患者使用前保持一致的产品质量； 2. 可制造性，即生产过程能够生产出质量稳定的药品； 3. 病人使用期间，产品能保持稳定的产品质量。 要满足每个方面的产品要求，需要考虑多种因素。Figure 13-2 概括了这些因素。 01 产品稳定性 产品稳定性主要由分子特性决定，通常在临床候选药物的先导研发过程中对分子特性进行评估和优化。在早期开发过程中会进行制剂前表征研究，以了解与应力条件（stress conditions）和制剂变量（formulation variables）有关的降解途径。例如，pH 值对生物制剂溶液稳定性的影响可能是最重要的因素。 必须平衡化学稳定性、物理稳定性、热稳定性和溶解性，以确定最佳 pH 值范围，从而开发出合适的剂型。如果液体制剂不存在最佳pH值范围，则需要考虑冻干制剂。另外，还可以添加特定的辅料来解决特定的不稳定性问题，从而提高确定最佳 pH 值区域的可能性。 了解产品稳定性的一个重要前提是活性药物成分（API）的关键特性。就生物制剂而言，在原料药工艺开发过程中，可能会出现翻译后修饰，从而导致批次间的巨大差异。对于化学药物，无定形性质和/或结晶形式以及相互转化对于了解最终药物产品的稳定性至关重要。 建立原料药批次历史时间与各种制剂开发研究（如强制降解、预配制、制剂DOE和原型稳定性研究）之间的相关性非常有用。这样就能最大限度地降低原料药关键特性在批次间可能出现重大变化的风险，并在一定程度上保证制剂开发结果具有代表性。用未来的原料药批次制备的药品预计也会有类似的表现。 根据原料药表征结果，初步稳定性风险评估应考虑这些修改对与 TPP 直接相关的关键质量属性的影响以及稳定性增长潜力。初步制剂风险评估的第二个要素是调查制剂参数和条件（如pH值、辅料、痕量金属、光照等）对溶液制剂稳定性可能产生的影响。可以根据强制降解（forced degradation）和处方前研究（pre-formulation study）的结果来确定这些已确定因素中每个因素的关键性，以帮助建立多变量制剂优化研究。 在临床开发的早期阶段，不可能完成全面的处方前表征。合适的早期临床制剂可以通过对分子特性的有限了解来确定，但要辅以平台知识。反过来，在临床试验研究中收集的实时临床和稳定性经验也是确定产品稳定性的一个非常有用的考虑因素。 下一步是针对高风险降解优化关键处方变量，这些高风险降解是通过基于处方前和强制降解研究的风险评估确定的。建立了一个多变量统计DOE研究，以优化化学和物理稳定性方面的关键配方参数。DOE研究的目标是开发出适合商业开发的配方。 特别是，可以根据对结果的统计分析建立一个定量模型。在处方设计空间背景下总结的DOE结果可以让人全面了解关键产品属性的响应与关键配方变量的函数关系。此外，这些信息还为选择具有足够稳健性的商业解决方案配方提供了知识基础，该处方很可能满足保质期稳定性要求。 02 可生产性 不同类型的产品（如化学药物与生物制剂）的制造工艺截然不同。可制造性在很大程度上也是由分子特性决定的。可采用与上述产品稳定性类似的QbD方法来设计和开发生产工艺，以获得质量稳定的产品（图13-3）。 表13-1对主要市场的QbD监管指南进行了综合比较。 03 患者使用 当给患者开处方时，产品在患者使用过程中保持稳定的质量非常重要。对于使用过程可能比较复杂的自服药品（如涉及自动注射器的复方产品），通常会提供详细的分步说明，为患者提供清晰易懂的指导，以促进安全有效地使用药品。由于疾病和治疗的类型不同，说明书的内容也大相径庭，这不在本章的讨论范围之内。 不过，处方药必须符合《联邦法规汇编》第21卷第201.51条规定的标签声明。(g)章节具体说明了内装物数量的声明，必须准确表述包装内装物的数量。此外，对于用于注射的液体药品，其申报应符合《美国药典国家处方集》规定的过量。表13-2对全球市场的容器内容物规定和准则进行了比较。 3 药品开发档案 - 3.2.P.2 CTD组织 通用技术文件（CTD）"模块 3--质量 "的 "药品开发 "部分3.2.P.2，应描述确定所选剂型类型和建议处方适合预期用途的知识。这一部分的每一部分都应包括足够的信息，以便了解药物产品的开发及其生产过程。 4 参考清单药物（RLD）选择注意事项（针对仿制药/复方药）和特征描述 01 美国 FDA法规将上市药品定义为根据相关法规已获得安全性和有效性批准的新药产品。FDA在橙皮书中确定了被指定为参考清单药物（RLD）的上市药品。在橙皮书的活性部分出现的已批准安全性和有效性的上市药物可能有资格成为RLD。 02 欧洲 对于第10(1)条仿制药和第10(3)条混合药的上市许可申请，必须根据 2001/83/EC指令第8(3)、10a、10b或10c条3的规定，在完整卷宗的基础上，参考已经或正在欧盟获得上市许可的参比药品的卷宗。在这种情况下，应确定另一成员国的参比药品，即所谓的 "欧洲参比药品"。仿制药、复方药或仿制药/混合药扩充申请中的试验产品通常与市场上有售的参比药品的相应剂型进行比较。 生物等效性研究中使用的参比产品的选择应基于化验含量和溶出数据，并由申请人负责。除非另有说明，用作试验产品的批次的化验含量与用作参比产品的批次的化验 含量的差异不得超过5%，该含量是根据为试验产品的常规质量检测提出的检测程序确定的。 03 澳大利亚 要在澳大利亚注册一种新的非专利药，必须证明其与澳大利亚参比产品的生物等效性。使用海外参比产品进行生物等效性研究也可以接受，但前提是您必须满足特定条件，证明澳大利亚和海外参比产品之间具有相同性。 04 与RLD比较的考虑因素 与仿制药申请案卷的药品部分内容有关的期望之一是讨论参比产品的选择以及申请产品和参比产品之间的比较和基本相似性证明。 根据第2001/83/EC号指令，非专利药品被定义为活性物质的质量和数量组成与参比药品相同的药品。质量和数量组成相同的要求仅适用于活性物质，而不适用于产品的其他成分。尽管在试验产品的成分中最好使用与参比产品中相似数量的相同辅料，但只要辅料成分的差异不会导致安全性和有效性方面的显著差异，则可以接受。这甚至适用于速释剂型，虽然辅料对高溶解度和完全可吸收的药物物质（如 BCS级I）的生物利用度的影响被认为不太可能，但也不能完全排除。 应确定可能影响生物利用度的辅料（如山梨醇、甘露醇、十二烷基硫酸钠或其他表面活性剂），以及它们可能对胃肠道蠕动、药物渗透性或与膜转运体的相互作用等药效的不同方面产生的影响。可能影响生物利用度的辅料在质量和数量上应与试验产品和参比产品相同。 在任何情况下，都应进一步证明，多来源产品配方中的辅料已明确用于含有该原料药的产品，而且所使用的辅料不会导致参照药和多来源产品在影响吸收的过程（如影响胃肠道蠕动或与转运过程相互作用）方面出现差异，也不会导致改变原料药药代动力学的相互作用。 FDA还指出，根据《联邦法规汇编》（CFR）第 21 条的规定，仿制药（generics）和参照药（reference drugs）具有相同的活性成分、强度、剂型、给药途径和使用条件。如果申请人提供资料证明这些差异不会影响拟议药物产品的安全性或疗效，则法规允许存在制剂差异（formulation differences），即非活性成分（辅料）、杂质和残留溶剂的变化。 此外，药物开发部分应包括对辅料选择的解释说明。应确定辅料与活性物质的相容性，以及在相关情况下与其他辅料的相容性。应根据每种辅料各自的功能，讨论所选辅料、其浓度以及可能影响药物产品性能（如稳定性、生物利用度）或可制造性的特性。 5 容器封闭考虑因素（与剂型的兼容性） 01 一般概念 药品开发的一个重要部分是选择和评估适当的容器封闭系统（container closure system，CCS）。卷宗应描述和讨论商业产品容器封闭系统的选择和理由（见 CTD第3.2.P.7节）。应说明选择主包装材料的理由。讨论应说明为证明容器和封闭装置的完整性而进行的研究。应考虑产品与容器或标签之间可能存在的相互作用。主包装材料的选择应考虑防潮、避光、结构材料与剂型的相容性（包括对容器的吸附和浸出）以及结构材料的安全性。 02 兼容性考虑 FDA《人用药品和生物制品包装工业容器封闭系统指南》强调，与剂型兼容的包装成分不会充分相互作用，导致剂型或包装成分的质量发生不可接受的变化该指南列举了一些相互作用的例子，包括: 由于吸收或吸附活性药物物质而导致药效降低 包装成分中析出的化学物质导致活性药物降解 因吸收导致辅料浓度降低 吸附或浸出引起的降解 药品 pH 值的变化 剂型或包装成分变色 包装成分脆性增加 在对容器封闭系统及其部件进行鉴定研究时，会发现包装部件与剂型之间的某些相互作用。另一些相互作用则可能不会在稳定性研究中出现。因此，在稳定性研究中发现的任何变化，如果可能是由于剂型和包装部件之间的相互作用引起的，都应进行研究并采取适当的措施。表 13-3 总结了常见药物类别的典型包装适宜性注意事项。 加拿大卫生部还确定了证明 容器封闭系统（container closure system，CCS）适宜性所需检查参数的相关性。表13-4总结了常见药品类别的典型包装适用性申报注意事项。 03 提交级别信息 制剂开发过程中收集的数据应在药品开发部分（3.2.P.2.4 容器封闭系统）中列出，以证明所选择的结构材料与药品的稳定性、完整性和相容性、给药方法以及任何灭菌程序（如适用）有关。塑料材料（plastic materials）的具体信息应包括以下细节： 通过萃取和相互作用研究（如适用）和/或毒理学文件（如适用），说明塑料材料与药 品的相容性。 药用产品生产过程对塑料材料的影响（如灭菌条件） 04 浸出物 USP-NF <1664>强调了浸出物管理对药品生产商和监管机构的重要性，因为某些超过特定浓度的浸出物可能会给患者带来安全隐患和/或给药品配方带来兼容性问题。因此，对包装系统和最终药物产品的可提取物和可浸出物的（management of both extractables and leachables）已成为许多剂型的药品开发和像监管递交的重要组成部分，尤其是那些被认为与包装系统发生剂型相互作用的风险相对较高的剂型（relatively high risk for dosage form interaction with the packaging system），以及基于给药途径的安全风险相对较高的剂型。 其余风险相对较高的剂型包括：吸入气雾剂和溶液、注射剂和注射混悬液、眼药以及透皮软膏和贴剂。但必须注意的是，即使是低风险剂型也存在一定的风险，适当严格的可浸出物评估对于低风险剂型类别（如外用药和口服剂型等）中的特定药物产品可能非常重要（表13-5）。 根据FDA目前对注射剂和眼科药物产品中可浸出杂质的建议，眼科和注射剂产品中的可浸出物： 可源于主要容器封口 可通过半透容器迁移 可来自树脂（包括添加剂和基础聚合物）、粘合剂、油墨和次级包装 就其性质和特性而言，可浸出物包括 存在于软塑料薄膜和软管中的化学品 印刷油墨（直接印在容器上的标签） 标签中的粘合剂 外包装（软质容器） 弹性封口（硬质小瓶） 玻璃成分（小瓶、瓶子、注射器） 图13-4举例说明了用于包装无菌溶液的塑料瓶可能产生的浸出物。 6 兼容性研究的基本考虑因素 欧洲药品管理局 (EMA) 总结了与兼容性研究策略有关的基本注意事项。有两种类型：萃取和相互作用。萃取研究的目的是确定制剂或活性物质在与材料接触时可能萃取的材料添加剂。对于用于口服和外用（眼科除外）非固体活性物质和非固体剂型的容器封闭系统的塑料材料，如果该材料既未在欧洲药典或成员国药典中描述，也未被批准用于食品包装，则有必要进行萃取研究。对于用于吸入、肠外或眼科给药的非固体药物的容器封闭系统的非药典塑料材料，即使已被批准用于食品包装，也必须进行萃取研究。 在评估所选塑料包装材料是否适合预期用途时，应证明该材料与活性物质或药物的相容性。测试可通过使用塑料材料、塑料部件或容器本身来进行。相互作用研究的程度和设计分别取决于活性物质和药物剂型的物理状态： 对于固体活性物质和固体剂型，相互作用的风险较低，一般不需要进行含量/ 容器相互作用研究。 用于吸入或非肠道使用的固体剂型，如冻干产品，可能需要进行包装材料与制剂成分之间的相互作用研究。 对于非固体活性物质和液体剂型，需要针对每种活性物质/剂型进行全面、适当的相互作用风险研究。 研究应评估容器/给药系统的关键功能特性，并应确保不会发生导致活性物质或药 品质量下降的重大变化。相互作用研究可包括： 迁移研究，以监测物质从塑料材料沥滤到制剂/活性物质中的情况，和/或 吸附研究，用于评估吸附或吸收效应可能导致的药物质量下降。 01 溶出度开发注意事项（固体剂型） 拟用作速释药物产品常规控制测试的溶出程序应具有稳健性、可重复性和鉴别性， 以确保产品质量的一致性，并检测产品质量属性，因为这些属性一旦改变，可能会影响体内性能。原则上，在开发研究中应考虑以下几个方面： 应在考虑药物物质的pH溶解度曲线和 pKa 的基础上开发药物产品的溶出特性。 选择合适的溶解介质（成分、容量）应基于活性物质的物理化学特性以及药物产品和待测制剂的预期剂量范围。根据FDA的观点，常规溶出度测试不必严格遵守胃肠道环境。测试条件应基于药物的物理化学特性和口服后剂型可能暴露的环境条件。 一般来说，应使用水介质，pH 值应首先在生理pH值范围内进行评估。在使用表面活性剂的情况下，表面活性剂的浓度应尽可能低，并提供相关的溶解度和溶解数据以及科学讨论。值得注意的是，根据ANVISA RDC 31/2010号指南中关于溶出试验条件选择的规定，通过提供实验数据证明所选表面活性剂的浓度尽可能低，对于证明溶出方法的鉴别力具有重要意义。 溶出仪的选择由申请人自行决定，并应充分说明理由。最常用的溶出试验方法是：(1) 篮法（仪器 1）；(2) EMA、FDA和ANVISA 一般推荐的桨法。 开发使用桨式仪器的方法时，搅拌速度应从每分钟50转开始。在有适当理由的情况下，可采用更高的搅拌速度。 根据 FDA 的指导，一般来说，溶出度测试期间应保持温和的搅拌条件，以获得最大的分辨力，并检测出体内性能较差的产品。 开发使用篮式仪器的方法时，搅拌速度应从每分钟 100 转开始。在有适当理由的情况下，可采用更高的搅拌速度或不同的篮网尺寸。由于流体动力效应（如锥形）或其他因素（如药片粘连），在较低转速下观察到的结果变异性较大，因此可以采用较高的搅拌速度。然而，众所周知，提高搅拌速度的方法可能区分度较低。应避免仅仅为了降低结果的可变性或在更短的时间内获得完全溶解而牺牲鉴别力来提高搅拌速度。 应讨论并证明其鉴别力，或以其他方式证明其合理性。FDA强调，从质量保证的角度看，最好采用鉴别力更强的溶出方法， 因为在体内性能受到影响之前，试验就能显示出产品质量可能发生的变化。 7 不同卫生机构的溶出度控制考虑因素 01 溶出度标准 溶出度标准是指在规定时间内溶出的活性物质的数量，以产品标签上标明的含量的百分比表示。溶出度测试以及溶出度药物产品规格是针对配方和药物产品的测试。 表13-6列出了不同代表性主管卫生机构对溶出度标准的要求。 02 FDA制定非专利产品溶出度规格的方法 为仿制药产品制定溶出度规格的方法可分为三类，具体取决于是否存在药物产品的官方药典测试，以及参照上市药物所采用的溶出度测试的性质。如果有美国药典（USP）溶出度测试要求，所有获批的新药产品都应符合这些要求。这三个类别是： 可用的USP药物产品溶出度测试：质量控制溶出度测试是 USP 中描述的测试。仿制药办公室生物等效性部门还建议使用USP方法，以15分钟或更短的时间间隔为测试产品和参比产品（各12个单位）提取溶出度曲线。 未提供 USP 药物产品溶出度测试；已公开提供 NDA 参考药物产品溶出度测试：建议使用批准用于参比上市产品的方法，以15分钟间隔对受试产品和参比产品（各12个单位）进行溶出度曲线测试。如果有科学依据，生物等效性部门也可要求提交额外的溶出度测试数据，作为批准条件。 未提供USP药物产品溶出度测试；未公开提供NDA参考列表药物产品的溶出度测试：建议使用测试产品和参比产品在各种测试条件下进行比较溶出度测试。在任何情况下，都应按之前的建议生成曲线。溶出度规格是根据现有的生物等效性数据和其他数据制定的。 8 生物豁免考虑因素 生物豁免是在新药和仿制药开发中免除体内生物利用度（BA）和/或生物等效性（BE）研究监管要求的重要工具，建议将支持生物豁免的相关文件作为药品开发部分的一个组成部分，即使根据递交文件结构，可以或必须在不同位置进行描述。采用这种方法的好处如下： - 简化审批程序、缩短开发时间，从而降低产品总成本 - 避免不必要的人体试验 有三种主要的生物豁免类型： - Strength biowaiver（规格豁免） - 基于生物药剂学分类系统( biopharmaceutical classification system,BCS)的生物豁免 - Well-established use application（完善的使用申请） 01 规格生物豁免 如果申请的试验产品有多种规格，则只需确定一种或两种规格的生物等效性即可，这取决于不同规格之间的成分比例以及下文所述的其他产品相关问题。 评估的规格类型取决于活性物质药代动力学的线性关系。如果生物等效性已在检测产品间潜在差异最敏感的一种或几种规格上得到证实，则可免于对其他规格进行体内生物等效性研究。 申请额外规格豁免必须满足以下一般要求： 药品的生产工艺相同 不同规格的质量成分相同 不同规格的成分在量上成正比，即所有剂型中每种辅料的用量与活性物质用量的比例相同（对于速释产品，包衣成分、胶囊壳、着色剂和香料不需要遵守这一规则）；如果成分在量上成正比方面有一些偏差，但如果以下条件 i) 和 ii) 或 i) 和 iii) 适用于生 物等效性研究中使用的规格和考虑规格的剂型，则仍可认为符合条件 活性物质的含量低于片芯重量、胶囊重量的 5%。 不同片芯辅料或胶囊内容物的含量在相关强度下相同，仅活性物质的含量有变化。 改变填充剂的用量，以反映活性物质用量的变化。其他核心辅料或胶囊内容物的用量应与相关强度的相同。 适当的体外溶出度数据应证实放弃额外的体内生物等效性试验的充分性。 02 基于生物药剂学分类系统（BCS）的生物豁免（BCS-based Biowaiver） 生物药剂学分类系统（BCS）是一个科学框架，根据药物的水溶性和肠道渗透性将药物分为四类（如表13-7所示）。BCS结合药物产品的溶解度，考虑了影响速释口服固体制剂吸收速度和程度的几个关键因素： 在以下情况下，基于BCS的生物豁免可适用于速释药物产品： 已证明药物具有高溶解度和完全吸收（BCS I级）；以及 考虑到具体要求，已证明试验药品和参照品的体外溶出特性非常快（>85%在15分钟内）或同样快（85%在30分钟内）；以及 可能影响生物利用度的辅料在质量和数量上相同。一般来说，最好使用相同的辅料，且辅料用量相近（即辅料用量不超过参照产品辅料用量的 ± 10%）。 03 既定用途申请 根据第2001/83/EC号指令第10a条的规定，如果能够证明某种药品的活性物质在欧盟范围内已确定用于医疗用途至少10年，并具有公认的疗效和可接受的安全性，则可以通过详细引用已发表的科学文献（可在公共领域获得的信息）来替代临床前和临床试验的结果。应考虑以下标准来证明这种既定用途的使用： - 该物质在患者中常规使用的时间;物质使用的数量方面，考虑到该物质在实践中使用的程度、按地域使用的程度以及通过药物警戒或其他方法监测该物质使用的程度 - 科学界对该物质使用的关注程度（反映在已发表的科学文献中）以及科学评估的一致性。 04 特定剂型的生物豁免考虑因素 原则上，对于非速效释放剂型，只要满足特定条件，并特别注意可能对体内产生影响的辅料相互作用，就可以适用生物豁免研究。表13-8列出了特定剂型的考虑因素，表13-9总结了各种剂型接受生物豁免的可行性。 9 给药途径 药物可通过多种途径进入人体： - 口服 - 静脉注射（静脉注射）、肌肉注射（肌肉注射）或皮下注射（皮下注射） - 置于舌下（舌下含服）或牙龈与脸颊之间（颊含服） - 插入直肠（经直肠）或阴道（经阴道） - 放入眼内（眼部途径）或耳内（耳部途径） - 喷入鼻腔，通过鼻膜吸收（鼻腔途径） - 吸入肺部，通常通过口腔（吸入途径） - 涂抹于皮肤（皮肤），产生局部（局部）或全身（全身）效应 - 通过皮肤贴片（透皮）给药，产生全身效果 每种途径都有特定的目的、优点和缺点，如表13-10所示。 10 多剂量剂型的其他注意事项 多剂量单位药物剂型的使用证明，容器封闭系统的渗透可能会导致药物产品的微生物污染。微生物能够快速增殖；因此，如果药物产品有利于微生物生长，受污染产品的微生物质量可能会在很短的时间内下降。FDA强烈建议，成品储存条件和相关的保存期应针对具体产品并有科学数据支持。制药公司应使用风险评估方法来证明产品标签中描述的制备和储存条件不会使最终药物产品面临对患者造成微生物不安全的重大风险。表13-11列出了一些机构的多剂量表述指南。 — 结论 — 药品研发是一项复杂的多学科研究，对任何新药的成功开发都至关重要。其目的是开发生产安全有效药物的流程和方法。从药品开发研究和生产经验中获得的知识为建立设计空间、规格和工艺控制（design space, specifications, and process controls）提供了科学依据。 更系统化的开发方法被定义为 "质量源于设计"（quality by design），其可以考虑在产品的整个生命周期中纳入先前的知识、使用实验设计的研究结果（design of experiments）、使用质量风险评估（use of quality risk assessment）以及使用知识管理（use of knowledge management）。虽然医药开发往往处于临床开发的驱使之下，但其推动了重要的改进，有助于加快药物开发、开创尖端制药技术，设计新的药物递送形式，使疾病“可治疗”（“druggable,”），优化开发成本，提高患者依从性，扩大未得到充分治疗的人群的可及性。 参考文献：（上下滑动查看更多） All references verified 14 March 2023. 1. Chaurasia G. A review on pharmaceutical preformulation studies in formulation and development of new drug molecules. Int J Pharm Sci Res. Published 1 June 2016. https://ijpsr.com/bft-article/a-reviewon-pharmaceutical-preformulation-studies-in-formulation-anddevelopment-of-new-drug-molecules/ 2. European Commission Health and Food Safety Directorate-General.Volume 2A Procedures for marketing authorization chapter 1 Marketing authorisation. Dated July 2019. https://health.ec.europa.eu/ system/files/2019-07/vol2a_chap1_en_0.pdf 3. EurLex. Directive 2001/83/EC of the European Parliament and of the Council of 6 November 2001 on the community code relating to medicinal products for human use. Published 26 July 2019.https://eur-lex.europa.eu/legal-content/EN/TXT/PDF/?uri=CELEX:02001L0083-20190726&from=EN 4. European Medicines Agency. Guideline on the investigation of bioequivalence. Dated 20 January 2010. https://www.ema.europa. eu/en/documents/scientific-guideline/guideline-investigationbioequivalence-rev1_en.pdf 5. Food and Drug Administration. Container closure systems for packaging human drugs and biologics [guidance]. https://www. fda.gov/regulatory-information/search-fda-guidance-documents/ container-closure-systems-packaging-human-drugs-and-biologics 6. Health Canada. Guidance document: Quality (chemistry and manufacturing) guidance: New drug submissions (NDSs) and abbreviated new drug submissions (ANDSs). https://www.canada. ca/en/health-canada/services/drugs-health-products/drug-products/applications-submissions/guidance-documents/chemical-entityproducts- quality/guidance-document-quality-chemistrymanufacturing- guidance-new-drug-submissions-ndss-abbreviatednew- drug-submissions.html 7. European Medicines Agency. Guideline on plastic immediate packaging materials. Dated 19 May 2005. https://www.ema.europa. eu/en/documents/scientific-guideline/guideline-plastic-immediatepackaging-materials_en.pdf 8. United States Pharmacopeia and the National Formulary. USPNF <1664> Assessment of drug product leachables associated with pharmaceutical packaging/delivery systems. Current as of 3 April 2020. https://latam-edu.usp.org/wp-content/uploads/2021/01/USP%20 NF%201664.pdf 9. Lewis DB. Current FDA perspective on leachable impurities in parenteral and ophthalmic drug products. Presented at: AAPS Workshop on Pharmaceutical Stability – Scientific and Regulatory Considerations for Global Drug Development and Commercialization. 22-23 October 2011. https://www.dalton.com/Content/files/FDAExtractable-Leachable.pdf 10. Food and Drug Administration. Dissolution testing of immediate release solid oral dosage forms [guidance]. Current as of 17 October 2019. https://www.fda.gov/regulatory-information/search-fdaguidance-documents/dissolution-testing-immediate-release-solidoral-dosage-forms 11. European Medicines Agency. Reflection paper on the dissolution specification for generic solid oral immediate release products with systemic action. Dated 10 August 2017. https://www.ema.europa. eu/en/documents/scientific-guideline/reflection-paper-dissolutionspecification-generic-solid-oral-immediate-release-products-systemic_ en.pdf 12. International Council for Harmonisation. Biopharmaceutics classification system-based biowaivers M9. Adopted 20 November 2019.https://database.ich.org/sites/default/files/M9_Guideline_Step4_2019_1116.pdf 13. European Medicines Agency. Guideline on quality of oral modified release products. Dated 20 March 2014. https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-quality-oral-modifiedrelease-products_en.pdf 14. Food and Drug Administration. Route of administration. Current as of 14 November 2017. https://www.fda.gov/drugs/data-standardsmanual-monographs/route-administration 英文原文版 （上下滑动查看更多） Chapter 13 Pharmaceutical Development Studies and Manufacturing Experience The aim of pharmaceutical development is to design a quality product, as well as its manufacturing process, to consistently deliver the intended performance of the product. The information and knowledge gained from pharmaceutical development studies and manufacturing experience provide scientific understanding to support the establishment of the design space, specifications, and manufacturing controls. Information from pharmaceutical development studies can be a basis for quality risk management. It is important to recognize that quality cannot be tested into products; therefore, quality should be built in by design. Changes in formulation and manufacturing processes during development and lifecycle management should be looked upon as opportunities to gain additional knowledge and further support establishment of the design space. Similarly, inclusion of relevant knowledge gained from experiments giving unexpected results can also be useful. When developing a formulation, it is important to identify attributes critical to the finished product’s quality, taking into consideration its intended usage, route of administration and the specific needs of the intended patient population, e.g., pediatrics,geriatrics. All excipient choices should be justified. Although excipients usually are inactive substances, their safety for the target population should be considered. The potential effect of the active substance’s physicochemical properties (e.g., water content,solubility, particle size distribution, polymorphic or solid-state form) on the finished product’s performance should be evaluated. Another key issue to be investigated is the active substance’s compatibility with excipients, and container closure systems. For combination products, the compatibility of the devices and/or active substances with each other also should be evaluated. The knowledge and data acquired from pharmaceutical development studies and experience gained from manufacturing data may be used to support the establishment of the design space, specifications, and manufacturing controls. Other development concepts (namely, quality by design) can include the results of studies using design of experiments (DOE), quality risk assessment and manufacturing controls throughout the lifecycle of the product. Pre-formulation Pre-formulation is a group of studies that focus on the physicochemical properties of a new drug candidate that could affect the drug performance and the development of a dosage form and helps researchers choose what ingredients (excipients) should be used in the preparation.1 Formulation studies aim to develop a drug preparation which is both stable, safe and acceptable to the patient. Pre-formulation studies can be classified into several aspects. First, there is the characterization of fundamental properties, which includes understanding the solubility in different solvents, dissociation constant (pKa), partition or distribution coefficient, pH, permeability, solid state stability, solution state stability, etc. Second, screening of an appropriate salt, polymorph, solvate forms and amorphous form occurs. Third, an understanding of the derived pre-formulation properties like morphology, particle size, bulk density, etc., must be gained. The last activity performed in pre-formulation studies is the excipients compatibility studies, to investigate the stability of the drug substance in the presence of the excipients. Overview of Pharmaceutical Development via Quality by Design Principle The Quality by Design (QbD) development approach starts with a clear definition of the Target Product Profile (TPP) in accordance with patient needs related to dosing, convenience, and compliance, as well as marketing requirements for the intended therapeutic indication. The product requirements can be divided into the following three aspects (Figure 13-1): 1.Product stability that maintains consistent product qualities before patient use; 2.Manufacturability that the process is capable to yield a drug product with consistent product quality; 3.Patient use during which the product maintains consistent product qualities. There are a variety of factors that need to be considered to meet the product requirement for each aspect. These factors are summarized in Figure 13-2. Product Stability Product stability is largely determined by the molecular properties, which are usually assessed and possibly optimized during lead generation for clinical candidates. Pre-formulation characterization studies are conducted during early development to understand the degradation pathway with respect to stress conditions, as well as formulation variables. For example, the effect of pH on solution stability in the case of biologics is probably the most important factor. It is critical to balance chemical stability, physical stability, thermal stability and solubility in order to identify the optimal pH range for proper dosage form development. If an optimal pH region does not exist for a feasible solution formulation, a freeze-dried formulation needs to be considered. Alternatively, specific excipients can be added to address particular instability issues and therefore enhance the probability of identifying an optimal pH region. A critical prerequisite to understand product stability are the critical properties of the active pharmaceutical ingredient (API). In the case of biologics, there could be post-translational modifications that contribute to large lot-to-lot variability during API process development. In the case of chemical drugs, the amorphous nature and/or crystalline form along with interconversion are critical to understanding the final drug product stability. It is extremely useful to establish a correlation between the timing of API lot history and the various formulation development studies, such as forced degradation, pre-formulation, formulation DOE and prototype stability studies. As a result, the risk of potentially significant lot-to-lot variability of API critical properties is minimized and provides some assurance that formulation development results are representative. Drug products prepared from future API lots would be expected to perform similarly. Based on API characterization results, a preliminary stability risk assessment should consider the impact of these modifications on the critical quality attributes directly linked to the TPP, as well as the stability growth potential. A second element of the initial formulation risk assessment is investigation of possible impact of formulation parameters and conditions, such as pH, excipients, trace metals, light, etc., on solution formulation stability. The criticality of each of these identified factors can be determined based on forced degradation and pre-formulation study results to help set up the multivariate formulation optimization study. A comprehensive pre-formulation characterization is not likely to have been completed during the early stage of clinical development. A suitable early phase clinical formulation can be defined by the somewhat limited understanding of molecular properties but supplemented by platform knowledge. In turn the real time clinical and stability experience gathered during clinical trial studies can be an extremely useful consideration to define product stability. The next step is to optimize the critical formulation variables with respect to those degradations of high risk, which are identified via risk assessment based on pre-formulation and forced degradation studies. A multivariate statistical DOE study is set up to optimize the key formulation parameters with respect to chemical and physical stability. The goal of the DOE study is to develop a formulation suitable for commercial development. In particular, a quantitative model can be developed based on statistical analysis of the results. The DOE results summarized in the context of formulation design space provide a comprehensive understanding of the response of the critical product attributes as a function of the critical formulation variables. Furthermore, this information forms the knowledge base for selection of a commercial solution formulation with sufficient robustness that will likely meet the shelf life stability requirements. Manufacturability Different types of products (e.g., chemical drugs versus biologics) are manufactured by very different processes. Manufacturability is again largely determined by the molecular properties. A similar QbD approach as described above for product stability can be utilized to design and develop a manufacturing process that yields a product with consistent quality (Figure 13-3). A comprehensive comparison of QbD regulatory guidance in major markets is summarized in Table 13-1. Patient Use When a drug is prescribed to patients, it is important that the product maintains consistent quality during patient use. For a self-administered drug that may have a complicated process (e.g., a combination product where an auto-injector is involved), detailed step-by-step instructions are usually provided to give directions that are clear and understandable for patients to promote safe and effective use of the drug. The instructions vary significantly depending on the types of diseases and therapy, which is beyond the scope of this chapter. However, the prescribed drugs must meet the label claims under 21 CFR 201.51. Section (g) specifically describes the declaration of net quantity of contents, which shall express an accurate statement of the quantity of contents of the package. Furthermore, in the case of a liquid drug intended for injection the declaration shall comply with the excess volume prescribed by the National Formulary of the US Pharmacopeia. A comparison of the container content regulations and guidelines among the global markets is summarized in Table 13-2. Pharmaceutical development dossier - 3.2.P.2 CTD organization The Pharmaceutical Development Section 3.2.P.2 of the Module 3 -Quality of the Common Technical Document (CTD) should describe the knowledge that establishes that the type of dosage form selected and the formulation proposed are suitable for the intended use. This section should include sufficient information in each part to provide an understanding of the development of the drug product and its manufacturing process. Reference List Drug (RLD) Selection Considerations (for Generics/Hybrids) and Characterization  US Food and Drug Administration (FDA) regulations define a listed drug as a new drug product that has been approved for safety and effectiveness under the relevant regulations. FDA identifies in the Orange Book listed drugs that have been designated as RLDs. A listed drug approved for safety and effectiveness that appears in the Active Section of the Orange Book may be eligible to be an RLD. Europe For Article 10(1) generic and 10(3) hybrid marketing authorization applications reference must be made to the dossier of a reference medicinal product for which a marketing authorization is or has been granted in the Union on the basis of a complete dossier in accordance with Articles 8(3), 10a, 10b or 10c of Directive 2001/83/EC.3 According to Article 10(1), third subparagraph of Directive 2001/83/EC a generic application can also be submitted in a Member State even if the reference medicinal product has never been authorized in that Member State. In that case, a reference medicinal product in another Member State should be identified, a so-called “European reference medicinal product.” Test products in an application for a generic or hybrid product or an extension of a generic/hybrid product are normally compared with the corresponding dosage form of a reference medicinal product, if available on the market. The selection of the reference product used in a bioequivalence study should be based on assay content and dissolution data and is the responsibility of the applicant.4 Unless otherwise justified, the assayed content of the batch used as test product should not differ more than 5% from that of the batch used as reference product determined with the test procedure proposed for routine quality testing of the test product. Australia To register a new generic medicine in Australia, you must demonstrate bioequivalence against the Australian reference product. A bioequivalence study using an overseas reference product may be acceptable, provided you can demonstrate identicality between the Australian and overseas reference products by fulfilling specific conditions. Comparison to RLD Considerations One of the expectations related to the pharmaceutical section content of a dossier of an abridged application is the discussion on the reference product choice and the comparison and essential similarity proof between the applied and reference products. Based on Directive 2001/83/EC a generic medicinal product is defined as a medicinal product which has the same qualitative and quantitative composition in active substances as the reference medicinal product. The same qualitative and quantitative composition requirement extends only to the active substance(s) and not to the other ingredients of the product. Though it is advisable to use similar amounts of the same excipients in the composition of test like in the reference product, differences in excipient composition are accepted provided that they do not lead to significant differences as regards safety and efficacy. This is applicable even in the case of immediate release dosage forms, for which although the impact of excipients on bioavailability of highly soluble and completely absorbable drug substances (e.g., BCS-class I) is considered rather unlikely, it cannot be completely excluded. Excipients that might affect bioavailability ( e.g. sorbitol, mannitol, sodium lauryl sulfate or other surfactants) should be identified, as well as their possible impact on different aspects of pharmaceutical effect like the gastrointestinal motility, drug permeability or interaction with membrane transporters. Excipients that might affect bioavailability should be qualitatively and quantitatively the same in the test product and the reference product. In all cases it should be further demonstrated that the excipients included in the formulation of the multisource product are well established for use in products containing that API and that the excipients used will not lead to differences between the comparator and multisource product with respect to processes affecting absorption (e.g., by effects on gastro-intestinal motility or interactions with transport processes) or which might lead to interactions that alter the pharmacokinetics of the API. FDA also states that, based on section 21 of the Code of Federal Regulations (CFR), generics and their reference drugs have the same active ingredient(s), strength, dosage form, route of administration and condition of use. The regulations allow for formulation differences, i.e., changes in inactive ingredients (excipients), impurities and residual solvents, if applicants provide information demonstrating that these differences do not affect the safety or efficacy of the proposed drug product. In addition, the pharmaceutical development section should include an explanation of the choice of the excipient(s). Compatibility of the excipients with active substances and, where relevant, with other excipients, should be established. The excipients chosen, their concentration, and the characteristics that can influence the drug product performance (e.g., stability, bioavailability) or manufacturability should be discussed in relation to the respective function of each excipient. Container Closure Considerations (Compatibility with Dosage Form)  General concepts An essential part of the pharmaceutical development is the choice and evaluation of the appropriate container closure system (CCS). A dossier should describe and discuss the choice and rationale for selection of the container closure system for the commercial product (described in section 3.2.P.7 of the CTD). The choice of materials for primary packaging should be justified. The discussion should describe studies performed to demonstrate the integrity of the container and closure. A possible interaction between product and container or label should be considered. The choice of primary packaging materials should consider protection from moisture and light, compatibility of the materials of construction with the dosage form (including sorption to container and leaching), and safety of materials of construction. Compatibility considerations FDA Guidance for Industry Container Closure Systems for Packaging Human Drugs and Biologics highlights that packaging components that are compatible with a dosage form will not interact sufficiently to cause unacceptable changes in the quality of either the dosage form or the packaging component.5 The guideline present examples of interactions which include: Loss of potency due to absorption or adsorption of the active drug substance Degradation of the active drug substance induced by a chemical entity leached from a packaging component Reduction in the concentration of an excipient due to absorption Adsorption or leachable-induced degradation Changes in drug product pH Discoloration of either the dosage form or the packaging component Increase in brittleness of the packaging component Some interactions between a packaging component and dosage form will be detected during qualification studies on the container closure system and its components. Others may not show up except in the stability studies. Therefore, any change noted during a stability study that may be attributable to interaction between the dosage form and a packaging component should be investigated and appropriate action taken. Table 13-3 summarizes typical packaging suitability considerations for common classes of drug products. Health Canada has also established the correlation of the parameters required to be checked to prove the suitability of the CCS.6 Table 13-4 summarizes typical packaging suitability submission considerations for common classes of drug products. Submission Level Information The data collected during the development of a preparation should be presented in the section on pharmaceutical development (3.2.P.2.4 Container Closure System) to justify the choice of the material(s) of construction in relation to the stability, integrity and compatibility of the medicinal product, to the method of administration and to any sterilization procedures, if applicable. Specific information for plastic materials should include details on: The compatibility of the plastic material with the medicinal product by performing extraction and interaction studies, where appropriate, and/or toxicological documentation, where applicable. The influence of the manufacturing process of the medicinal product on the plastic material, where applicable (e.g., sterilization conditions)7 Leachables USP-NF <1664> highlights that management of leachables is important to pharmaceutical product manufacturers and regulatory authorities because certain leachables above specific concentrations can present safety concerns for patients and/or compatibility issues for drug product formulations.8 During the 1980s, the FDA began to formally and comprehensively address leachables in drug products after findings of patient sensitivity induced by leachables and other potential safety concerns related to leachables. Since then, management of both extractables and leachables for packaging systems and final drug products has become an important part of pharmaceutical development and regulatory submissions for many dosage form types, particularly for those deemed of relatively high risk for dosage form interaction with the packaging system, along with a relatively high safety risk based on the route of administration. Remaining relatively high-risk dosage forms include: inhalation aerosols and solutions, injectables and injectable suspensions, ophthalmic, and transdermal ointments and patches. It is important to note, however, that even low-risk dosage forms present some risk and that appropriately rigorous leachables assessments can be important to particular drug products in lower risk dosage form categories (e.g., topicals and oral dosage forms, etc.) (Table 13-5). Based on Current FDA Perspective on Leachable Impurities in Parenteral and Ophthalmic Drug products,9 leachables in ophthalmic and parenteral products: Can originate from primary container closure Can migrate through semi-permeable containers Can originate from resins (including additives and base polymers), adhesives, inks, and secondary packaging In terms of their nature and identity leachables can be: Chemicals present in flexible plastic films and tubing Printing inks (labeling stamped directly on containers) Adhesive from labels Overwrapping (flexible containers) Elastomeric closures (rigid vials) Components of glass (vials, bottles, syringes) An illustrative presentation of the possible leachables from a plastic bottle intended for the packaging of a sterile solution is provided in Figure 13-4.9 Basic Considerations for Compatibility Studies The European Medicines Agency (EMA) summarizes the basic points needed to be taken into consideration related to the compatibility studies strategy. There are two types: extraction and interaction. The aim of extraction studies is to determine those additives of the material that might be extracted by the preparation or the active substance in contact with the material. Extraction studies are considered necessary for plastic material used for container closure systems of non-solid active substances and non-solid dosage forms for oral and topical (except ophthalmic) use if the material is neither described in the European Pharmacopoeia nor in the pharmacopoeia of a Member State, nor has been approved for foodstuff packaging. For non-compendial plastic material used for container closure systems for non-solid medicinal products intended for inhalation, parenteral or ophthalmic administration, extraction studies are required even when approved for use in food packaging. When evaluating the suitability of the selected plastic packaging material for the intended use, the compatibility of the material with the active substance or the medicinal product should be demonstrated. Testing may be performed by use of the plastic material, the plastic component, or the container itself. The extent and design of interaction studies depend on the physical state of the active substance and the dosage form of the medicinal product, respectively: For solid active substances and solid dosage forms, the risk of interaction is low and generally does not require a content/container interaction study. Solid dosage forms intended for inhalation or parenteral use, e.g., lyophilized products, may need interaction studies between the packaging material and the components of the formulation. For non-solid active substances and liquid dosage forms, the risk of interaction requires comprehensive and suitable studies specific for each active substance/formulation. The studies should evaluate the critical functional characteristics of the container/delivery system and should ensure that no significant alterations occur leading to a lesser quality of the active substance or the medicinal product. Interaction studies may include: Migration studies to monitor the leaching of substances from the plastic material into the formulation/active substance, and/or Sorption studies to evaluate a possible loss of drug quality due to adsorption or absorption effects. Dissolution Development Considerations (for Solid Dosage Forms) A dissolution procedure intended to be used as a routine control test for immediate release drug products should be robust, reproducible and discriminatory in order to assure a consistent product quality and to detect product quality attributes, which, if altered, may affect the in vivo performance.10 As such, a comprehensive development of the dissolution method should be included within the pharmaceutical development section. In principle, the following aspects should be considered in the context of this development study: The dissolution characteristics of the drug product should be developed based on consideration of the pH solubility profile and pKa of the drug substance. The selection of a suitable dissolution medium (composition, volume) should be based on the physico-chemical characteristics of the active substance(s) and the intended dose range of the drug product and the formulation to be tested. Based on FDA’s point of view, strict adherence to the gastrointestinal environment need not be used in routine dissolution testing. The testing conditions should be based on physico-chemical characteristics of the drug substance and the environmental conditions the dosage form might be exposed to after oral administration. In general, an aqueous medium should be used and the pH should first be evaluated in the physiological pH range. In case of use of surfactants the concentration of the surfactant should be as low as possible and be justified by relevant solubility and dissolution data and an accompanying scientific discussion. As per ANVISA guidance RDC 31/2010 regarding selection of dissolution test conditions, it is noteworthy that demonstration that the concentration of the chosen surfactant is the lowest possible through the presentation of experimental data is of great relevance to prove the discriminative power of the dissolution method. The selection of the dissolution apparatus is up to the applicant and should be sufficiently justified. The dissolution test methods most commonly used are (1) the basket method (Apparatus 1) and (2) the paddle method as generally recommended by EMA, FDA and ANVISA. The development of methods using the paddle apparatus should start with a stirring speed of 50 rpm. Higher stirring speeds may be applied with an appropriate justification. Based on FDA guidance, in general, mild agitation conditions should be maintained during dissolution testing to allow maximum discriminating power and to detect products with poor in vivo performance. The development of methods using the basket apparatus should start with a stirring speed of 100 rpm. Higher stirring speeds or different basket mesh sizes may be applied with an appropriate justification. A higher stirring speed may be justified by high variability of the results observed at lower speed rates due to hydrodynamic effects (e.g., coning) or other factors (e.g., tablet sticking). However, it is known that methods with increased stirring speeds may be less discriminatory. Increasing the stirring speed at the expense of the discriminatory power simply to reduce variability of the results or to obtain complete dissolution in a shorter time should be avoided. The discriminatory power should be discussed and demonstrated or otherwise justified. The FDA highlights that from a quality assurance point of view, a more discriminative dissolution method is preferred, because the test will indicate possible changes in the quality of the product before in vivo performance is affected. Dissolution Control Considerations Among Various Health Authorities Dissolution specification The dissolution specification is expressed in terms of the quantity of active substance dissolved in a specified time, expressed as a percentage of the content stated on the product label.11 Dissolution testing and therefore dissolution drug product specifications are formulation- and drug-product-specific tests. The expectations related to the dissolution specification per different representative competent health authorities is presented in Table 13-6. FDA Approaches for Setting Dissolution Specifications for Generic Products The approaches for setting dissolution specifications for generic products fall into three categories, depending on whether an official compendial test for the drug product exists and on the nature of the dissolution test employed for the reference listed drug. All approved new drug products should meet current US Pharmacopeia (USP) dissolution test requirements, if they exist. The three categories are: 1USP Drug Product Dissolution Test Available: The quality control dissolution test is the test described in the USP.The Division of Bioequivalence, Office of Generic Drugs, also recommends taking a dissolution profile at 15-minute intervals or less using the USP method for test and reference products (12 units each). 2USP Drug Product Dissolution Test Not Available; Dissolution Test for Reference Listed NDA Drug Product Publicly Available: A dissolution profile at 15-minute intervals of test and reference products (12 units each) using the method approved for the reference listed product is recommended. The Division of Bioequivalence may also request submission of additional dissolution testing data as a condition of approval, when scientifically justified. 3USP Drug Product Dissolution Test Not Available; Dissolution Test for Reference Listed NDA Drug Product Not Publicly Available: Comparative dissolution testing using test and reference products under a variety of test conditions is recommended. In all cases, profiles should be generated as previously recommended. The dissolution specifications are set based on the available bioequivalence and other data. Biowaiver Considerations The biowaiver is an important tool for waiving the regulatory requirement for in vivo bioavailability (BA) and/or bioequivalence (BE) studies in both new and generic drug development and the relevant documentation which support this is proposed to be an integral part of the pharmaceutical development section, even if based on the dossier structure it can or must be described at different locations. The advantages of applying it are the following: Simplification of approval process reduction of development time and therefore overall product costs Avoidance of unnecessary human testing  There are three major biowaiver types: Strength biowaiver Biopharmaceutics classification system (BCS)-based biowaiver Well-established use application Strength Biowaiver If several strengths of a test product are applied for, it may be sufficient to establish bioequivalence at only one or two strengths, depending on the proportionality in composition between the different strengths and other product-related issues described below. The type or types of strength to evaluate depends on the linearity in pharmacokinetics of the active substance. If bioequivalence has been demonstrated at the strength(s) most sensitive to detect a potential difference between products, in vivo bioequivalence studies for the other strength(s) can be waived. The following general requirements must be met to claim a waiver for additional strengths: 1The pharmaceutical products are manufactured by the same manufacturing process 2The qualitative composition of the different strengths is the same 3The composition of the strengths is quantitatively proportional, i.e., the ratio between the amount of each excipient to the amount of active substance(s) is the same for all strengths (for immediate release products coating components, capsule shell, color agents and flavors are not required to follow this rule); if there is some deviation from quantitatively proportional composition, condition c) is still considered fulfilled if condition i) and ii) or i) and iii) below apply to the strength used in the bioequivalence study and the strength(s) for which a waiver is considered: a.The amount of the active substance(s) is less than 5% of the tablet core weight, the weight of the capsule content. b.The amounts of the different core excipients or capsule content are the same for the concerned strengths and only the amount of active substance is changed. c.The amount of a filler is changed to account for the change in amount of active substance. The amounts of other core excipients or capsule content should be the same for the concerned strengths. 4Appropriate in vitro dissolution data should confirm the adequacy of waiving additional in vivo bioequivalence testing. BCS-based Biowaiver BCS is a scientific framework for classifying drug substances into one of four classes (as presented in Table 13-7) based on their aqueous solubility and intestinal permeability. When combined with the dissolution of the drug product, BCS considers several key factors governing the rate and extent of absorption from immediate release solid oral dosage forms: A BCS-based biowaiver may apply for an immediate release drug product if: The drug substance has been proven to exhibit high solubility and complete absorption (BCS class I); and Either very rapid (>85% within 15 minutes) or similarly rapid (85% within 30 minutes) in vitro dissolution characteristics of the test and reference product has been demonstrated considering specific requirements; and Excipients that might affect bioavailability are qualitatively and quantitatively the same. In general, the use of the same excipients in similar amounts is preferred (i.e., within ± 10% of the amount of excipient in the reference product or less). A BCS-based biowaiver is also applicable for an immediate release drug product if: The drug substance has been proven to exhibit high solubility and limited absorption (BCS class III); and Very rapid (>85% within 15 min) in vitro dissolution of the test and reference product has been demonstrated considering specific requirements; and Excipients that might affect bioavailability are qualitatively and quantitatively the same and other excipients are qualitatively the same and quantitatively very similar (i.e., within ± 10% of the amount of excipient in the reference product or less). Well-established Use Application According to Article 10a of Directive 2001/83/EC it is possible to replace results of pre-clinical and clinical trials by detailed references to published scientific literature (information available in the public domain) if it can be demonstrated that the active substances of a medicinal product have been in well-established medicinal use within the EU for at least 10 years, with recognized efficacy and an acceptable level of safety. The following criteria for the demonstration of such well-established use should be taken into account: The time over which a substance has been used with regular application in patients; quantitative aspects of the use of the substance, considering the extent to which the substance has been used in practice, the extent of use on a geographical basis and the extent to which the use of the substance has been monitored by pharmacovigilance or other methods The degree of scientific interest in the use of the substance (reflected in the published scientific literature) and the coherence of scientific assessments. Biowaiver Considerations for Specific Dosage Forms In principle waiver of BE studies for other than immediate release dosage forms can apply provided that specific conditions are met with special note to the possible excipient interactions that may have in vivo impact. Considerations for specific dosage forms are presented in Table 13-8, and Table 13-9 summarizes the feasibility of biowaiver acceptance per various dosage forms. Route of Administration Drugs are introduced into the body by several routes.14 They may be: Taken by mouth (orally) Given by injection into a vein (intravenously), into a muscle (intramuscularly) or beneath the skin (subcutaneously) Placed under the tongue (sublingually) or between the gums and cheek (buccally) Inserted in the rectum (rectally) or vagina (vaginally) Placed in the eye (by the ocular route) or the ear (by the otic route) Sprayed into the nose and absorbed through the nasal membranes (nasally) Breathed into the lungs, usually through the mouth (by inhalation) Applied to the skin (cutaneous) for a local (topical) or bodywide (systemic) effect Delivered through the skin by a patch (transdermally) for a systemic effect Each route has specific purposes, advantages, and disadvantages, as presented in Table 13-10. Other Considerations for Multidose Presentation The use of multiple dose unit drug dosage forms has proven that penetration of the container closure system may result in microbial contamination of the drug product. Microorganisms are able to proliferate at a rapid rate; therefore, if the drug product is conducive to microbial growth the microbiological quality of the contaminated product may be diminished in a very short period of time. FDA strongly recommends that finished product storage conditions and related holding periods should be product-specific and supported by scientific data. Pharmaceutical companies should use a risk assessment approach to demonstrate that the preparation and storage conditions which are described in the product label do not put the final drug product at significant risk to be microbiologically unsafe to the patient. Table 13-11 lists some agency multidose presentation guidelines. Conclusion Pharmaceutical development is a complex multidisciplinary function critical to the successful development of any new medicinal product. Its purpose is to develop processes and methods for producing safe and effective drugs. The knowledge gained from pharmaceutical development studies and manufacturing experience offer scientific understanding to support the establishment of the design space, specifications, and process controls. A more systematic approach to development, defined as quality by design, can consider the incorporation of prior knowledge, results of studies using design of experiments, use of quality risk assessment, and use of knowledge management throughout the lifecycle of the product. Though often in the shadow of clinical development, pharmaceutical development drives important improvement, helping to accelerate drug development, pioneer cutting-edge pharmaceutical technologies, devise new pharmaceutical forms of drug delivery that make conditions “druggable,” optimize development cost, increase patient adherence, and broaden access for undertreated populations. 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↓↓↓