层析机理建模那些事儿
<div style="max-width:677px;overflow:hidden;"><section style="font-size: 15px;color: rgb(24, 24, 27);letter-spacing: 0px;line-height: 2;" data-mpa-powered-by="yiban.io"><section style="text-align: center;" powered-by="xiumi.us"><br></section><section style="margin-right: 0%;margin-left: 0%;" powered-by="xiumi.us"><section style="display: inline-block;width: 100%;border-width: 1px;border-style: solid;border-color: rgb(0, 136, 111);"><section style="margin-right: 0%;margin-left: 0%;" powered-by="xiumi.us"><section style="border-top: 4px solid rgb(0, 136, 111);"><section><svg viewBox="0 0 1 1" style="float:left;line-height:0;width:0;vertical-align:top;"></svg></section></section><section style="margin-top: 3px;border-top: 1px solid rgb(0, 136, 111);"><section><svg viewBox="0 0 1 1" style="float:left;line-height:0;width:0;vertical-align:top;"></svg></section></section></section><section powered-by="xiumi.us"><section style="justify-content: flex-start;display: flex;flex-flow: row nowrap;"><section style="display: inline-block;width: 100%;vertical-align: top;padding: 10px;align-self: flex-start;flex: 0 0 auto;"><section powered-by="xiumi.us"><p style="white-space: normal;"> 在生物制药行业中，基于层析工艺的开发和表征工作通常是基于统计模型，虽然这些方法易于实现，但是统计模型可能无法预测含复杂成分的蛋白料液在制备色谱中的非线性行为，而机理模型是统计模型的一种替代方案，在早期工艺开发及晚期工艺表征中都有成功的应用案例。</p></section></section></section></section><section style="margin-right: 0%;margin-left: 0%;" powered-by="xiumi.us"><section style="border-top: 1px solid rgb(0, 136, 111);"><section><svg viewBox="0 0 1 1" style="float:left;line-height:0;width:0;vertical-align:top;"></svg></section></section><section style="margin-top: 3px;border-top: 4px solid rgb(0, 136, 111);"><section><svg viewBox="0 0 1 1" style="float:left;line-height:0;width:0;vertical-align:top;"></svg></section></section></section></section></section><section powered-by="xiumi.us"><p style="white-space: normal;"><br></p></section><section powered-by="xiumi.us"><section style="display: flex;flex-flow: row nowrap;margin-top: 12px;margin-right: 0%;margin-left: 0%;text-align: center;justify-content: center;"><section style="display: inline-block;vertical-align: top;width: 14px;flex: 0 0 auto;align-self: flex-start;height: auto;line-height: 0;border-width: 0px;border-style: none;border-color: rgb(62, 62, 62);overflow: hidden;"><section style="transform: rotateZ(20deg);" powered-by="xiumi.us"><section style="justify-content: center;margin: -2px 0% -12px;"><section style="display: inline-block;width: 4px;height: 22px;vertical-align: top;overflow: hidden;background-color: rgb(232, 232, 232);border-width: 0px;border-style: none;border-color: rgb(62, 62, 62);"><section><svg viewBox="0 0 1 1" style="float:left;line-height:0;width:0;vertical-align:top;"></svg></section></section></section></section></section><section style="display: inline-block;vertical-align: top;width: 14px;flex: 0 0 auto;align-self: flex-start;height: auto;line-height: 0;border-width: 0px;border-style: none;border-color: rgb(62, 62, 62);overflow: hidden;margin-left: -6px;"><section style="transform: rotateZ(20deg);" powered-by="xiumi.us"><section style="justify-content: center;margin: -2px 0%;"><section style="display: inline-block;width: 4px;height: 22px;vertical-align: top;overflow: hidden;background-color: rgb(232, 232, 232);border-width: 0px;border-style: none;border-color: rgb(62, 62, 62);"><section><svg viewBox="0 0 1 1" style="float:left;line-height:0;width:0;vertical-align:top;"></svg></section></section></section></section></section><section style="display: inline-block;vertical-align: top;width: auto;min-width: 10%;flex: 0 0 auto;height: auto;align-self: flex-start;background-color: rgb(0, 136, 111);margin-top: 3px;margin-left: -20px;"><section style="margin-right: 0%;margin-left: 0%;justify-content: center;transform: translate3d(4px, 0px, 0px);" powered-by="xiumi.us"><section style="font-size: 17px;color: rgb(255, 255, 255);padding-right: 22px;padding-left: 22px;line-height: 2;text-align: justify;"><p style="white-space: normal;"><strong>层析机理模型是什么</strong></p></section></section></section></section></section><section powered-by="xiumi.us"><p style="white-space: normal;"><br></p></section><section powered-by="xiumi.us"><p style="text-indent: 2em;word-break: break-all;white-space: normal;">层析机理模型是采用计算机模拟的方式，对有限的层析实验图谱及实验结果进行数字模拟。从层析的机理出发，建立的模型可以在计算机端进行大量的相关层析实验的数字模拟，得到预期的实验工艺参数，它大大减少了工艺开发中的实验次数，加深了对层析工艺的理解。</p></section><section powered-by="xiumi.us"><p style="white-space: normal;"><br></p></section><section style="text-align: center;" powered-by="xiumi.us"><section style="vertical-align: middle;display: inline-block;line-height: 0;"></section></section><section powered-by="xiumi.us"><p style="white-space: normal;"><br></p></section><section powered-by="xiumi.us"><p style="text-indent: 2em;white-space: normal;"><strong>建立层析机理模型需要考察以下几个层析方面的参数：</strong></p></section><section powered-by="xiumi.us"><p style="white-space: normal;"><br></p></section><section style="text-align: center;" powered-by="xiumi.us"><section style="vertical-align: middle;display: inline-block;line-height: 0;"></section></section><section style="text-align: center;" powered-by="xiumi.us"><section style="vertical-align: middle;display: inline-block;line-height: 0;"></section></section><section powered-by="xiumi.us"><p style="white-space: normal;"><br></p></section><section powered-by="xiumi.us"><section style="display: flex;flex-flow: row nowrap;margin-right: 0%;margin-bottom: 10px;margin-left: 0%;text-align: left;justify-content: flex-start;"><section style="display: inline-block;vertical-align: top;width: 10%;align-self: flex-start;flex: 0 0 auto;height: auto;"><section style="justify-content: flex-start;" powered-by="xiumi.us"><section style="color: rgb(255, 255, 255);text-align: justify;"><p style="white-space: normal;"><span style="background-color: rgb(0, 136, 111);"> <strong>1</strong> </span></p></section></section></section><section style="display: inline-block;vertical-align: top;width: auto;align-self: flex-start;flex: 100 100 0%;height: auto;"><section style="text-align: justify;" powered-by="xiumi.us"><p style="white-space: normal;">方程中绿色部分系数，即层析柱（填料）相关参数，使用标准样品实验可以测得；</p></section></section></section></section><section powered-by="xiumi.us"><section style="display: flex;flex-flow: row nowrap;margin-right: 0%;margin-bottom: 10px;margin-left: 0%;text-align: left;justify-content: flex-start;"><section style="display: inline-block;vertical-align: top;width: 10%;align-self: flex-start;flex: 0 0 auto;height: auto;"><section style="color: rgb(255, 255, 255);text-align: justify;" powered-by="xiumi.us"><p style="white-space: normal;"><span style="background-color: rgb(0, 136, 111);"> <strong>2</strong> </span></p></section></section><section style="display: inline-block;vertical-align: top;width: auto;align-self: flex-start;flex: 100 100 0%;height: auto;"><section style="text-align: justify;" powered-by="xiumi.us"><p style="white-space: normal;">方程中蓝色部分系数，可通过层析填料参数推导得到；</p></section></section></section></section><section powered-by="xiumi.us"><section style="display: flex;flex-flow: row nowrap;margin-right: 0%;margin-bottom: 10px;margin-left: 0%;text-align: left;justify-content: flex-start;"><section style="display: inline-block;vertical-align: top;width: 10%;align-self: flex-start;flex: 0 0 auto;height: auto;"><section style="color: rgb(255, 255, 255);text-align: justify;" powered-by="xiumi.us"><p style="white-space: normal;"><span style="background-color: rgb(0, 136, 111);"> <strong>3</strong> </span></p></section></section><section style="display: inline-block;vertical-align: top;width: auto;align-self: flex-start;flex: 100 100 0%;height: auto;"><section style="text-align: justify;" powered-by="xiumi.us"><p style="white-space: normal;">方程中黄色部分系数，可通过盐梯度实验测定；</p></section></section></section></section><section powered-by="xiumi.us"><section style="display: flex;flex-flow: row nowrap;text-align: left;justify-content: flex-start;"><section style="display: inline-block;vertical-align: top;width: 10%;align-self: flex-start;flex: 0 0 auto;height: auto;"><section style="color: rgb(255, 255, 255);text-align: justify;" powered-by="xiumi.us"><p style="white-space: normal;"><span style="background-color: rgb(0, 136, 111);"> <strong>4</strong> </span></p></section></section><section style="display: inline-block;vertical-align: top;width: auto;align-self: flex-start;flex: 100 100 0%;height: auto;"><section style="text-align: justify;" powered-by="xiumi.us"><p style="white-space: normal;">方程中红色部分系数，通过拟合实验样品层析图谱和软件图谱得到；</p></section></section></section></section><section powered-by="xiumi.us"><p style="white-space: normal;"><br></p></section><section powered-by="xiumi.us"><section style="display: flex;flex-flow: row nowrap;margin-top: 12px;margin-right: 0%;margin-left: 0%;text-align: center;justify-content: center;"><section style="display: inline-block;vertical-align: top;width: 14px;flex: 0 0 auto;align-self: flex-start;height: auto;line-height: 0;border-width: 0px;border-style: none;border-color: rgb(62, 62, 62);overflow: hidden;"><section style="transform: rotateZ(20deg);" powered-by="xiumi.us"><section style="justify-content: center;margin: -2px 0% -12px;"><section style="display: inline-block;width: 4px;height: 22px;vertical-align: top;overflow: hidden;background-color: rgb(232, 232, 232);border-width: 0px;border-style: none;border-color: rgb(62, 62, 62);"><section><svg viewBox="0 0 1 1" style="float:left;line-height:0;width:0;vertical-align:top;"></svg></section></section></section></section></section><section style="display: inline-block;vertical-align: top;width: 14px;flex: 0 0 auto;align-self: flex-start;height: auto;line-height: 0;border-width: 0px;border-style: none;border-color: rgb(62, 62, 62);overflow: hidden;margin-left: -6px;"><section style="transform: rotateZ(20deg);" powered-by="xiumi.us"><section style="justify-content: center;margin: -2px 0%;"><section style="display: inline-block;width: 4px;height: 22px;vertical-align: top;overflow: hidden;background-color: rgb(232, 232, 232);border-width: 0px;border-style: none;border-color: rgb(62, 62, 62);"><section><svg viewBox="0 0 1 1" style="float:left;line-height:0;width:0;vertical-align:top;"></svg></section></section></section></section></section><section style="display: inline-block;vertical-align: top;width: auto;min-width: 10%;flex: 0 0 auto;height: auto;align-self: flex-start;background-color: rgb(0, 136, 111);margin-top: 3px;margin-left: -20px;"><section style="margin-right: 0%;margin-left: 0%;justify-content: center;transform: translate3d(4px, 0px, 0px);" powered-by="xiumi.us"><section style="font-size: 17px;color: rgb(255, 255, 255);padding-right: 22px;padding-left: 22px;line-height: 2;text-align: justify;"><p style="white-space: normal;"><strong>层析机理模型的应用阶段</strong></p></section></section></section></section></section><section powered-by="xiumi.us"><p style="white-space: normal;"><br></p></section><section powered-by="xiumi.us"><p style="word-break: break-all;text-indent: 2em;white-space: normal;"><span style="color: rgb(0, 136, 111);"><strong>层析机理建模可以用在产品生命周期的任意阶段，贯穿从临床前研究到商品化生产</strong></span>，都可以将更多实验数据输入到机理模型中，以提高其预测能力，包括工艺开发阶段、工艺放大阶段、工艺表征阶段及商业化后偏差分析阶段。</p></section><section powered-by="xiumi.us"><p style="white-space: normal;"><br></p></section><section style="text-align: center;" powered-by="xiumi.us"><section style="vertical-align: middle;display: inline-block;line-height: 0;"></section></section><section powered-by="xiumi.us"><p style="white-space: normal;"><br></p></section><section powered-by="xiumi.us"><section style="display: flex;flex-flow: row nowrap;margin-top: 12px;margin-right: 0%;margin-left: 0%;text-align: center;justify-content: center;"><section style="display: inline-block;vertical-align: top;width: 14px;flex: 0 0 auto;align-self: flex-start;height: auto;line-height: 0;border-width: 0px;border-style: none;border-color: rgb(62, 62, 62);overflow: hidden;"><section style="transform: rotateZ(20deg);" powered-by="xiumi.us"><section style="justify-content: center;margin: -2px 0% -12px;"><section style="display: inline-block;width: 4px;height: 22px;vertical-align: top;overflow: hidden;background-color: rgb(232, 232, 232);border-width: 0px;border-style: none;border-color: rgb(62, 62, 62);"><section><svg viewBox="0 0 1 1" style="float:left;line-height:0;width:0;vertical-align:top;"></svg></section></section></section></section></section><section style="display: inline-block;vertical-align: top;width: 14px;flex: 0 0 auto;align-self: flex-start;height: auto;line-height: 0;border-width: 0px;border-style: none;border-color: rgb(62, 62, 62);overflow: hidden;margin-left: -6px;"><section style="transform: rotateZ(20deg);" powered-by="xiumi.us"><section style="justify-content: center;margin: -2px 0%;"><section style="display: inline-block;width: 4px;height: 22px;vertical-align: top;overflow: hidden;background-color: rgb(232, 232, 232);border-width: 0px;border-style: none;border-color: rgb(62, 62, 62);"><section><svg viewBox="0 0 1 1" style="float:left;line-height:0;width:0;vertical-align:top;"></svg></section></section></section></section></section><section style="display: inline-block;vertical-align: top;width: auto;min-width: 10%;flex: 0 0 auto;height: auto;align-self: flex-start;background-color: rgb(0, 136, 111);margin-top: 3px;margin-left: -20px;"><section style="margin-right: 0%;margin-left: 0%;justify-content: center;transform: translate3d(4px, 0px, 0px);" powered-by="xiumi.us"><section style="font-size: 17px;color: rgb(255, 255, 255);padding-right: 22px;padding-left: 22px;line-height: 2;text-align: justify;"><p style="white-space: normal;"><strong>层析机理模型的流程</strong></p></section></section></section></section></section><section powered-by="xiumi.us"><p style="white-space: normal;"><br></p></section><section powered-by="xiumi.us"><p style="text-indent: 2em;white-space: normal;"><strong>层析机理建模的核心流程大致包括以下5个方面：</strong></p></section><section style="text-align: center;" powered-by="xiumi.us"><section style="vertical-align: middle;display: inline-block;line-height: 0;"></section></section><section powered-by="xiumi.us"><p style="white-space: normal;"><br></p></section><section powered-by="xiumi.us"><section style="display: flex;flex-flow: row nowrap;margin-right: 0%;margin-bottom: 10px;margin-left: 0%;text-align: left;justify-content: flex-start;"><section style="display: inline-block;vertical-align: top;width: 10%;align-self: flex-start;flex: 0 0 auto;height: auto;"><section style="justify-content: flex-start;" powered-by="xiumi.us"><section style="color: rgb(255, 255, 255);text-align: justify;"><p style="white-space: normal;"><span style="background-color: rgb(0, 136, 111);"> <strong>1</strong> </span></p></section></section></section><section style="display: inline-block;vertical-align: top;width: auto;align-self: flex-start;flex: 100 100 0%;height: auto;"><section style="text-align: justify;" powered-by="xiumi.us"><p style="white-space: normal;"><strong>系统表征：</strong>采用含1%丙酮和1 M NaCl的溶液进行系统死体积的表征；</p></section></section></section></section><section powered-by="xiumi.us"><section style="display: flex;flex-flow: row nowrap;margin-right: 0%;margin-bottom: 10px;margin-left: 0%;text-align: left;justify-content: flex-start;"><section style="display: inline-block;vertical-align: top;width: 10%;align-self: flex-start;flex: 0 0 auto;height: auto;"><section style="color: rgb(255, 255, 255);text-align: justify;" powered-by="xiumi.us"><p style="white-space: normal;"><span style="background-color: rgb(0, 136, 111);"> <strong>2</strong> </span></p></section></section><section style="display: inline-block;vertical-align: top;width: auto;align-self: flex-start;flex: 100 100 0%;height: auto;"><section style="text-align: justify;" powered-by="xiumi.us"><p style="white-space: normal;"><strong>层析柱表征：</strong>包括层析柱体积、填料孔隙率、轴向扩散系数、配基密度等，一般采用盐溶液作为非吸附的孔穿透标记物，用葡聚糖作为非孔穿透标记物进行孔隙率的测定；轴向扩散系数通过葡聚糖峰进行测定；配基密度采用酸碱滴定的方式进行测定。Cytiva推出商品化的用于机理建模的预表征f(x)层析柱，方便使用。</p></section></section></section></section><section powered-by="xiumi.us"><section style="display: flex;flex-flow: row nowrap;margin-right: 0%;margin-bottom: 10px;margin-left: 0%;text-align: left;justify-content: flex-start;"><section style="display: inline-block;vertical-align: top;width: 10%;align-self: flex-start;flex: 0 0 auto;height: auto;"><section style="color: rgb(255, 255, 255);text-align: justify;" powered-by="xiumi.us"><p style="white-space: normal;"><span style="background-color: rgb(0, 136, 111);"> <strong>3</strong> </span></p></section></section><section style="display: inline-block;vertical-align: top;width: auto;align-self: flex-start;flex: 100 100 0%;height: auto;"><section style="text-align: justify;" powered-by="xiumi.us"><p style="white-space: normal;"><strong>蛋白实验：</strong>根据实验目的的不同，选择进行3~10个实验用于模型的校准；</p></section></section></section></section><section powered-by="xiumi.us"><section style="display: flex;flex-flow: row nowrap;margin-right: 0%;margin-bottom: 10px;margin-left: 0%;text-align: left;justify-content: flex-start;"><section style="display: inline-block;vertical-align: top;width: 10%;align-self: flex-start;flex: 0 0 auto;height: auto;"><section style="color: rgb(255, 255, 255);text-align: justify;" powered-by="xiumi.us"><p style="white-space: normal;"><span style="background-color: rgb(0, 136, 111);"> <strong>4</strong> </span></p></section></section><section style="display: inline-block;vertical-align: top;width: auto;align-self: flex-start;flex: 100 100 0%;height: auto;"><section style="text-align: justify;" powered-by="xiumi.us"><p style="white-space: normal;"><strong>模型校准：</strong>在GoSilico软件上进行层析机理模型的建立，求得方程中相关参数；</p></section></section></section></section><section powered-by="xiumi.us"><section style="display: flex;flex-flow: row nowrap;text-align: left;justify-content: flex-start;"><section style="display: inline-block;vertical-align: top;width: 10%;align-self: flex-start;flex: 0 0 auto;height: auto;"><section style="color: rgb(255, 255, 255);text-align: justify;" powered-by="xiumi.us"><p style="white-space: normal;"><span style="background-color: rgb(0, 136, 111);"> <strong>5</strong> </span></p></section></section><section style="display: inline-block;vertical-align: top;width: auto;align-self: flex-start;flex: 100 100 0%;height: auto;"><section style="text-align: justify;" powered-by="xiumi.us"><p style="white-space: normal;"><strong>模型验证：</strong>机理模型建立完成后，需要同时在软件和实验室进行特定工艺条件的实验，对比实验结果进行模型的验证；</p></section></section></section></section><section powered-by="xiumi.us"><p style="white-space: normal;"><br></p></section><section powered-by="xiumi.us"><section style="display: flex;flex-flow: row nowrap;margin-top: 12px;margin-right: 0%;margin-left: 0%;text-align: center;justify-content: center;"><section style="display: inline-block;vertical-align: top;width: 14px;flex: 0 0 auto;align-self: flex-start;height: auto;line-height: 0;border-width: 0px;border-style: none;border-color: rgb(62, 62, 62);overflow: hidden;"><section style="transform: rotateZ(20deg);" powered-by="xiumi.us"><section style="justify-content: center;margin: -2px 0% -12px;"><section style="display: inline-block;width: 4px;height: 22px;vertical-align: top;overflow: hidden;background-color: rgb(232, 232, 232);border-width: 0px;border-style: none;border-color: rgb(62, 62, 62);"><section><svg viewBox="0 0 1 1" style="float:left;line-height:0;width:0;vertical-align:top;"></svg></section></section></section></section></section><section style="display: inline-block;vertical-align: top;width: 14px;flex: 0 0 auto;align-self: flex-start;height: auto;line-height: 0;border-width: 0px;border-style: none;border-color: rgb(62, 62, 62);overflow: hidden;margin-left: -6px;"><section style="transform: rotateZ(20deg);" powered-by="xiumi.us"><section style="justify-content: center;margin: -2px 0%;"><section style="display: inline-block;width: 4px;height: 22px;vertical-align: top;overflow: hidden;background-color: rgb(232, 232, 232);border-width: 0px;border-style: none;border-color: rgb(62, 62, 62);"><section><svg viewBox="0 0 1 1" style="float:left;line-height:0;width:0;vertical-align:top;"></svg></section></section></section></section></section><section style="display: inline-block;vertical-align: top;width: auto;min-width: 10%;flex: 0 0 auto;height: auto;align-self: flex-start;background-color: rgb(0, 136, 111);margin-top: 3px;margin-left: -20px;"><section style="margin-right: 0%;margin-left: 0%;justify-content: center;transform: translate3d(4px, 0px, 0px);" powered-by="xiumi.us"><section style="font-size: 17px;color: rgb(255, 255, 255);padding-right: 22px;padding-left: 22px;line-height: 2;text-align: justify;"><p style="white-space: normal;"><strong>层析机理模型的应用场景</strong></p></section></section></section></section></section><section powered-by="xiumi.us"><p style="white-space: normal;"><br></p></section><section powered-by="xiumi.us"><section style="margin-right: 0%;margin-left: 0%;text-align: left;justify-content: flex-start;display: flex;flex-flow: row nowrap;"><section style="display: inline-block;vertical-align: middle;width: auto;background-color: rgba(255, 255, 255, 0);line-height: 0;align-self: center;flex: 0 0 auto;"><section style="text-align: center;opacity: 1;" powered-by="xiumi.us"><section style="display: inline-block;width: 17px;height: 17px;vertical-align: top;overflow: hidden;background-color: rgb(0, 136, 111);"><br></section></section><section style="text-align: center;opacity: 1;margin-top: -8px;margin-right: 0%;margin-left: 0%;transform: translate3d(6px, 0px, 0px);" powered-by="xiumi.us"><section style="display: inline-block;width: 12px;height: 12px;vertical-align: top;overflow: hidden;background-color: rgb(204, 231, 226);"><br></section></section></section><section style="display: inline-block;vertical-align: middle;width: auto;background-color: rgba(255, 255, 255, 0);line-height: 0;letter-spacing: 0px;padding-right: 10px;padding-left: 10px;align-self: center;flex: 0 0 auto;"><section powered-by="xiumi.us"><section style="justify-content: flex-start;display: flex;flex-flow: row nowrap;"><section style="display: inline-block;width: 100%;vertical-align: top;border-width: 0px;border-style: none;border-color: rgb(62, 62, 62);line-height: 1;letter-spacing: 0px;align-self: flex-start;flex: 0 0 auto;"><section style="margin-right: 0%;margin-bottom: 4px;margin-left: 0%;" powered-by="xiumi.us"><section style="font-size: 16px;color: rgb(0, 136, 111);padding-right: 5px;padding-left: 5px;text-align: justify;"><p style="white-space: normal;"><strong>工艺开发模型</strong></p></section></section></section></section></section></section></section></section><section powered-by="xiumi.us"><p style="white-space: normal;"><br></p></section><section powered-by="xiumi.us"><p style="text-indent: 2em;word-break: break-all;white-space: normal;"><strong><span style="color: rgb(0, 136, 111);">Roche公司采用GoSilico软件进行单克隆抗体阳离子层析实验的机理建模</span></strong>，项目背景如表1所示：</p></section><section powered-by="xiumi.us"><p style="white-space: normal;"><br></p></section><section style="margin-bottom: 10px;" powered-by="xiumi.us"><section style="font-size: 12px;color: rgb(139, 139, 141);text-align: center;line-height: 1.6;"><p>表1. 背景信息</p></section></section><section style="text-align: center;margin-top: 10px;margin-bottom: 10px;" powered-by="xiumi.us"><section style="vertical-align: middle;display: inline-block;line-height: 0;"></section></section><section powered-by="xiumi.us"><p style="white-space: normal;"><br></p></section><section powered-by="xiumi.us"><p style="text-indent: 2em;white-space: normal;"><span style="letter-spacing: 0px;">通过层析系统及层析柱表征、蛋白实验、模型校准计算得到相关参数如下表2所示：</span></p></section><section powered-by="xiumi.us"><p style="white-space: normal;"><br></p></section><section style="margin-bottom: 10px;" powered-by="xiumi.us"><section style="font-size: 12px;color: rgb(139, 139, 141);text-align: center;line-height: 1.6;"><p><span style="letter-spacing: 0px;">表2. 模型参数</span></p></section></section><section style="text-align: center;" powered-by="xiumi.us"><section style="vertical-align: middle;display: inline-block;line-height: 0;"></section></section><section powered-by="xiumi.us"><p style="white-space: normal;"><br></p></section><section powered-by="xiumi.us"><p style="text-indent: 2em;word-break: break-all;white-space: normal;"><span style="letter-spacing: 0px;">从图1中层析图谱的叠加结果可以看出，实验数据（点图）与计算机模拟数据（线图）吻合度很高，进一步进行了上样量为80 mg/ml的湿端实验，实验结果（表3）显示对于Protein 1、Protein 2及Protein 3模型预测值与实验测定值有高度的一致性，均在95%置信区间内。</span></p></section><section powered-by="xiumi.us"><p style="white-space: normal;"><br></p></section><section style="text-align: center;" powered-by="xiumi.us"><section style="vertical-align: middle;display: inline-block;line-height: 0;"></section></section><section style="margin-top: 10px;" powered-by="xiumi.us"><section style="font-size: 12px;color: rgb(139, 139, 141);text-align: center;line-height: 1.6;"><p>图1 实验参数与模型预测性</p></section></section><section powered-by="xiumi.us"><p style="white-space: normal;"><br></p></section><section style="margin-bottom: 10px;" powered-by="xiumi.us"><section style="font-size: 12px;color: rgb(139, 139, 141);text-align: center;line-height: 1.6;"><p>表3 模型验证结果</p></section></section><section style="text-align: center;" powered-by="xiumi.us"><section style="vertical-align: middle;display: inline-block;line-height: 0;"></section></section><section powered-by="xiumi.us"><p style="white-space: normal;"><br></p></section><section powered-by="xiumi.us"><section style="margin-right: 0%;margin-left: 0%;text-align: left;justify-content: flex-start;display: flex;flex-flow: row nowrap;"><section style="display: inline-block;vertical-align: middle;width: auto;background-color: rgba(255, 255, 255, 0);line-height: 0;align-self: center;flex: 0 0 auto;"><section style="text-align: center;opacity: 1;" powered-by="xiumi.us"><section style="display: inline-block;width: 17px;height: 17px;vertical-align: top;overflow: hidden;background-color: rgb(0, 136, 111);"><br></section></section><section style="text-align: center;opacity: 1;margin-top: -8px;margin-right: 0%;margin-left: 0%;transform: translate3d(6px, 0px, 0px);" powered-by="xiumi.us"><section style="display: inline-block;width: 12px;height: 12px;vertical-align: top;overflow: hidden;background-color: rgb(204, 231, 226);"><br></section></section></section><section style="display: inline-block;vertical-align: middle;width: auto;background-color: rgba(255, 255, 255, 0);line-height: 0;letter-spacing: 0px;padding-right: 10px;padding-left: 10px;align-self: center;flex: 0 0 auto;"><section powered-by="xiumi.us"><section style="justify-content: flex-start;display: flex;flex-flow: row nowrap;"><section style="display: inline-block;width: 100%;vertical-align: top;border-width: 0px;border-style: none;border-color: rgb(62, 62, 62);line-height: 1;letter-spacing: 0px;align-self: flex-start;flex: 0 0 auto;"><section style="margin-right: 0%;margin-bottom: 4px;margin-left: 0%;" powered-by="xiumi.us"><section style="font-size: 16px;color: rgb(0, 136, 111);padding-right: 5px;padding-left: 5px;text-align: justify;"><p style="white-space: normal;"><strong>工艺放大模型</strong></p></section></section></section></section></section></section></section></section><section powered-by="xiumi.us"><p style="white-space: normal;"><br></p></section><section powered-by="xiumi.us"><p style="text-indent: 2em;word-break: break-all;white-space: normal;">GoSilico建立的机理模型除了可以作为工艺开发的模型工具，还可以有效地指导工艺放大。<span style="color: rgb(0, 136, 111);"><strong>Boehringer Ingelheim Pharma建立了这样的机理模型成功用于层析工艺的放大指导</strong></span>，具体实验背景如表4所示。</p></section><section powered-by="xiumi.us"><p style="white-space: normal;"><br></p></section><section style="margin-bottom: 10px;" powered-by="xiumi.us"><section style="font-size: 12px;color: rgb(139, 139, 141);text-align: center;line-height: 1.6;"><p>表4. 背景信息</p></section></section><section style="text-align: center;" powered-by="xiumi.us"><section style="vertical-align: middle;display: inline-block;line-height: 0;"></section></section><section powered-by="xiumi.us"><p style="white-space: normal;"><br></p></section><section powered-by="xiumi.us"><p style="text-indent: 2em;white-space: normal;"><span style="letter-spacing: 0px;">通过层析系统及层析柱表征、蛋白实验、模型校准计算得到相关参数如表5所示，部分的模型校准参数及模型校准层析图谱如表5及图2所示，从层析图谱可以看出，机理模型建立的四种蛋白的层析图谱（实线）与实际湿端实验的数据（点图）的吻合度很高。</span></p></section><section powered-by="xiumi.us"><p style="white-space: normal;"><br></p></section><section style="margin-bottom: 10px;" powered-by="xiumi.us"><section style="font-size: 12px;color: rgb(139, 139, 141);text-align: center;line-height: 1.6;"><p>表5. 模型校准参数列表</p></section></section><section style="text-align: center;" powered-by="xiumi.us"><section style="vertical-align: middle;display: inline-block;line-height: 0;"></section></section><section powered-by="xiumi.us"><p style="white-space: normal;"><br></p></section><section style="text-align: center;" powered-by="xiumi.us"><section style="vertical-align: middle;display: inline-block;line-height: 0;"></section></section><section style="margin-top: 10px;" powered-by="xiumi.us"><section style="font-size: 12px;color: rgb(139, 139, 141);text-align: center;line-height: 1.6;"><p> 图2. 机理模型与蛋白实验结果对比（点图：实验数据；线图：模型模拟数据）</p></section></section><section powered-by="xiumi.us"><p style="white-space: normal;"><br></p></section><section powered-by="xiumi.us"><p style="text-indent: 2em;white-space: normal;">两种规模的湿端实验用于模型的验证，一种是实验室规模的层析实验，采用10 mm柱直径，20.2 cm柱高的层析柱，另一种是放大规模的层析实验，采用140 mm柱直径，20.5 cm柱高的层析柱。结果显示，采用湿端实验得到的数据和采用机理建模建立的模型得到的数据一致性非常吻合。</p></section><section powered-by="xiumi.us"><p style="white-space: normal;"><br></p></section><section style="text-align: center;" powered-by="xiumi.us"><section style="vertical-align: middle;display: inline-block;line-height: 0;"></section></section><section style="margin-top: 10px;" powered-by="xiumi.us"><section style="font-size: 12px;color: rgb(139, 139, 141);text-align: center;line-height: 1.6;"><p>图3. 机理模型的验证（点图：实验数据；线图：模型模拟数据）</p></section></section><section powered-by="xiumi.us"><p style="white-space: normal;"><br></p></section><section powered-by="xiumi.us"><section style="margin-right: 0%;margin-left: 0%;text-align: left;justify-content: flex-start;display: flex;flex-flow: row nowrap;"><section style="display: inline-block;vertical-align: middle;width: auto;background-color: rgba(255, 255, 255, 0);line-height: 0;align-self: center;flex: 0 0 auto;"><section style="text-align: center;opacity: 1;" powered-by="xiumi.us"><section style="display: inline-block;width: 17px;height: 17px;vertical-align: top;overflow: hidden;background-color: rgb(0, 136, 111);"><br></section></section><section style="text-align: center;opacity: 1;margin-top: -8px;margin-right: 0%;margin-left: 0%;transform: translate3d(6px, 0px, 0px);" powered-by="xiumi.us"><section style="display: inline-block;width: 12px;height: 12px;vertical-align: top;overflow: hidden;background-color: rgb(204, 231, 226);"><br></section></section></section><section style="display: inline-block;vertical-align: middle;width: auto;background-color: rgba(255, 255, 255, 0);line-height: 0;letter-spacing: 0px;padding-right: 10px;padding-left: 10px;align-self: center;flex: 0 0 auto;"><section powered-by="xiumi.us"><section style="justify-content: flex-start;display: flex;flex-flow: row nowrap;"><section style="display: inline-block;width: 100%;vertical-align: top;border-width: 0px;border-style: none;border-color: rgb(62, 62, 62);line-height: 1;letter-spacing: 0px;align-self: flex-start;flex: 0 0 auto;"><section style="margin-right: 0%;margin-bottom: 4px;margin-left: 0%;" powered-by="xiumi.us"><section style="font-size: 16px;color: rgb(0, 136, 111);padding-right: 5px;padding-left: 5px;text-align: justify;"><p style="white-space: normal;"><strong>缩小模型的建立</strong></p></section></section></section></section></section></section></section></section><section powered-by="xiumi.us"><p style="white-space: normal;"><br></p></section><section powered-by="xiumi.us"><p style="word-break: break-all;margin-bottom: 15px;text-indent: 2em;white-space: normal;">Boehringer Ingelheim Pharma在实验室规模建立12.3 ml柱体积的阳离子层析机理模型，并应用在指导200 L，2000 L及12000 L商业化规模，考察产品关键质量属性CQA和关键层析表现（KPI）。通过对比模型建立200 L，2000 L及12000 L的相关数据，发现此模型可以精确的预测不同规模的层析行为，进一步证实了建立的机理模型参数的可靠性。</p><p style="word-break: break-all;text-indent: 2em;white-space: normal;"><span style="color: rgb(0, 136, 111);"><strong>Boehringer Ingelheim Pharma分别考察了机理模型和实验室缩小模型（SDM）与生产规模实验数据的等效型</strong></span>，TOST检验结果显示，机理模型可以作为数字端的缩小模型用于工艺表征实验，避免了实验室缩小模型在不同规模下的变异性，是实验室SDM模型的一个有效的替代。</p></section><section powered-by="xiumi.us"><p style="white-space: normal;"><br></p></section><section style="text-align: center;" powered-by="xiumi.us"><section style="vertical-align: middle;display: inline-block;line-height: 0;"></section></section><section style="margin-top: 10px;" powered-by="xiumi.us"><section style="font-size: 12px;color: rgb(139, 139, 141);text-align: center;line-height: 1.6;"><p> 图4. 缩小模型等效性评价</p></section></section><section powered-by="xiumi.us"><p style="white-space: normal;"><br></p></section><section powered-by="xiumi.us"><section style="margin-right: 0%;margin-left: 0%;text-align: left;justify-content: flex-start;display: flex;flex-flow: row nowrap;"><section style="display: inline-block;vertical-align: middle;width: auto;background-color: rgba(255, 255, 255, 0);line-height: 0;align-self: center;flex: 0 0 auto;"><section style="text-align: center;opacity: 1;" powered-by="xiumi.us"><section style="display: inline-block;width: 17px;height: 17px;vertical-align: top;overflow: hidden;background-color: rgb(0, 136, 111);"><br></section></section><section style="text-align: center;opacity: 1;margin-top: -8px;margin-right: 0%;margin-left: 0%;transform: translate3d(6px, 0px, 0px);" powered-by="xiumi.us"><section style="display: inline-block;width: 12px;height: 12px;vertical-align: top;overflow: hidden;background-color: rgb(204, 231, 226);"><br></section></section></section><section style="display: inline-block;vertical-align: middle;width: auto;background-color: rgba(255, 255, 255, 0);line-height: 0;letter-spacing: 0px;padding-right: 10px;padding-left: 10px;align-self: center;flex: 0 0 auto;"><section powered-by="xiumi.us"><section style="justify-content: flex-start;display: flex;flex-flow: row nowrap;"><section style="display: inline-block;width: 100%;vertical-align: top;border-width: 0px;border-style: none;border-color: rgb(62, 62, 62);line-height: 1;letter-spacing: 0px;align-self: flex-start;flex: 0 0 auto;"><section style="margin-right: 0%;margin-bottom: 4px;margin-left: 0%;" powered-by="xiumi.us"><section style="font-size: 16px;color: rgb(0, 136, 111);padding-right: 5px;padding-left: 5px;text-align: justify;"><p style="white-space: normal;"><strong>工艺表征</strong></p></section></section></section></section></section></section></section></section><section powered-by="xiumi.us"><p style="white-space: normal;"><br></p></section><section powered-by="xiumi.us"><p style="text-indent: 2em;word-break: break-all;margin-bottom: 15px;white-space: normal;">层析机理模型可以作为数字端的缩小模型，那么就可以在数字端进行QbD理念下的生物药工艺表征的相关研究。<span style="color: rgb(0, 136, 111);"><strong>Boehringer Ingelheim Pharma建立了抗体工艺中阳离子层析机理模型，用于工艺表征。</strong></span>图5为层析机理模型进行工艺表征的流程：</p><p style="text-indent: 2em;word-break: break-all;margin-bottom: 15px;white-space: normal;">首先明确层析工艺的参数及产品质量标准的可接受范围，通过OFAT的模式进行单变量实验确定相关参数PAR值；</p><p style="text-indent: 2em;word-break: break-all;margin-bottom: 15px;white-space: normal;">其次，对于确定为CPP或KPP的工艺参数，进行多变量实验确定边界条件，并通过湿端实验来进行验证。</p><p style="text-indent: 2em;word-break: break-all;white-space: normal;">最后，进行1000次的蒙特卡洛模拟，样品来源及工艺参数作为输入变量，收率及产品相关杂质作为输出变量，结果（图6）显示模拟后收率及产品质量数据均在可接受的标准范围内。</p></section><section powered-by="xiumi.us"><p style="white-space: normal;"><br></p></section><section style="text-align: center;" powered-by="xiumi.us"><section style="vertical-align: middle;display: inline-block;line-height: 0;"></section></section><section style="margin-top: 10px;" powered-by="xiumi.us"><section style="font-size: 12px;color: rgb(139, 139, 141);text-align: center;line-height: 1.6;"><p> 图5 层析机理模型进行工艺表征的流程</p></section></section><section powered-by="xiumi.us"><p style="white-space: normal;"><br></p></section><section style="text-align: center;" powered-by="xiumi.us"><section style="vertical-align: middle;display: inline-block;line-height: 0;"></section></section><section style="margin-top: 10px;" powered-by="xiumi.us"><section style="font-size: 12px;color: rgb(139, 139, 141);text-align: center;line-height: 1.6;"><p>图6 . 层析机理模型进行工艺表征结果</p></section></section><section powered-by="xiumi.us"><p style="white-space: normal;"><br></p></section><section powered-by="xiumi.us"><section style="display: flex;flex-flow: row nowrap;margin-top: 12px;margin-right: 0%;margin-left: 0%;text-align: center;justify-content: center;"><section style="display: inline-block;vertical-align: top;width: 14px;flex: 0 0 auto;align-self: flex-start;height: auto;line-height: 0;border-width: 0px;border-style: none;border-color: rgb(62, 62, 62);overflow: hidden;"><section style="transform: rotateZ(20deg);" powered-by="xiumi.us"><section style="justify-content: center;margin: -2px 0% -12px;"><section style="display: inline-block;width: 4px;height: 22px;vertical-align: top;overflow: hidden;background-color: rgb(232, 232, 232);border-width: 0px;border-style: none;border-color: rgb(62, 62, 62);"><section><svg viewBox="0 0 1 1" style="float:left;line-height:0;width:0;vertical-align:top;"></svg></section></section></section></section></section><section style="display: inline-block;vertical-align: top;width: 14px;flex: 0 0 auto;align-self: flex-start;height: auto;line-height: 0;border-width: 0px;border-style: none;border-color: rgb(62, 62, 62);overflow: hidden;margin-left: -6px;"><section style="transform: rotateZ(20deg);" powered-by="xiumi.us"><section style="justify-content: center;margin: -2px 0%;"><section style="display: inline-block;width: 4px;height: 22px;vertical-align: top;overflow: hidden;background-color: rgb(232, 232, 232);border-width: 0px;border-style: none;border-color: rgb(62, 62, 62);"><section><svg viewBox="0 0 1 1" style="float:left;line-height:0;width:0;vertical-align:top;"></svg></section></section></section></section></section><section style="display: inline-block;vertical-align: top;width: auto;min-width: 10%;flex: 0 0 auto;height: auto;align-self: flex-start;background-color: rgb(0, 136, 111);margin-top: 3px;margin-left: -20px;"><section style="margin-right: 0%;margin-left: 0%;justify-content: center;transform: translate3d(4px, 0px, 0px);" powered-by="xiumi.us"><section style="font-size: 17px;color: rgb(255, 255, 255);padding-right: 22px;padding-left: 22px;line-height: 2;text-align: justify;"><p style="white-space: normal;"><strong>总结</strong></p></section></section></section></section></section><section powered-by="xiumi.us"><p style="white-space: normal;"><br></p></section><section powered-by="xiumi.us"><p style="text-indent: 2em;white-space: normal;">层析机理模型已成功应用在抗体药物生命周期的各个阶段，大大节省了工艺开发相关的时间和成本，相信未来会有更多的实际应用得以实现。</p></section><section powered-by="xiumi.us"><p style="white-space: normal;"><br></p></section><section powered-by="xiumi.us"><section style="margin-right: 0%;margin-bottom: 5px;margin-left: 0%;justify-content: flex-start;display: flex;flex-flow: row nowrap;"><section style="display: inline-block;width: auto;vertical-align: top;min-width: 10%;flex: 0 0 auto;height: auto;border-bottom: 4px solid rgba(0, 136, 111, 0.35);border-bottom-right-radius: 0px;align-self: flex-start;"><section style="line-height: 1.5;" powered-by="xiumi.us"><p style="white-space: normal;"><strong>参考文献：</strong></p></section></section></section></section><section style="font-size: 12px;color: rgb(139, 139, 141);line-height: 1.6;" powered-by="xiumi.us"><p style="word-break: break-all;white-space: normal;"><span style="letter-spacing: 0px;">1. Prediction uncertainty assessment of chromatography models using Bayesian inference</span></p><p style="word-break: break-all;white-space: normal;">2. Good modeling practice for industrial chromatography; Mechanistic modeling of ion exchange chromatography of a bispecific antibody</p><p style="word-break: break-all;white-space: normal;">3. Cross-scale quality assessment of a mechanistic cation exchange chromatography model</p><p style="word-break: break-all;white-space: normal;">4. In silico process characterization for biopharmaceutical development following the quality by design concept</p></section><section style="text-align: center;margin-right: 0%;margin-left: 0%;" powered-by="xiumi.us"><br></section></section>
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