Microscopic visualization of virus removal by dedicated filters used in biopharmaceutical processing: Impact of membrane structure and localization of captured virus particles

Adan‐Kubo Jun; Tsujikawa Muneo; Takahashi Kadue; Hongo‐Hirasaki Tomoko; Sakai Kaoru

摘要

Abstract >Virus filtration with nanometer size exclusion membranes (“nanofiltration”) is effective for removing infectious agents from biopharmaceuticals. While the virus removal capability of virus removal filters is typically evaluated based on calculation of logarithmic reduction value (LRV) of virus infectivity, knowledge of the exact mechanism(s) of virus retention remains limited. Here, human parvovirus B19 (B19V), a small virus (18–26?nm), was spiked into therapeutic plasma protein solutions and filtered through Planova? 15N and 20N filters in scaled‐down manufacturing processes. Observation of the gross structure of the Planova hollow fiber membranes by transmission electron microscopy (TEM) revealed Planova filter microporous membranes to have a rough inner, a dense middle and a rough outer layer. Of these three layers, the dense middle layer was clearly identified as the most functionally critical for effective capture of B19V. Planova filtration of protein solution containing B19V resulted in a distribution peak in the dense middle layer with an LRV 4, demonstrating effectiveness of the filtration step. This is the first report to simultaneously analyze the gross structure of a virus removal filter and visualize virus entrapment during a filtration process conducted under actual manufacturing conditions. The methodologies developed in this study demonstrate that the virus removal capability of the filtration process can be linked to the gross physical filter structure, contributing to better understanding of virus trapping mechanisms and helping the development of more reliable and robust virus filtration processes in the manufacture of biologicals. </abstract> </span> <span class="z_kbtn z_kbtnclass hoverxs" style="display: none;">展开▼</span> </div> <div class="translation abstracttxt"> <span class="zhankaihshouqi fivelineshidden" id="abstract"> <span>机译：</span><Abstract Type =“Main”XML：Lang =“en”> <标题类型=“main”>抽象</ title> >具有纳米尺寸排除膜（“纳米滤乱”）的病毒过滤对于从生物制药中除去感染剂的有效。虽然病毒去除过滤器的病毒去除能力通常基于病毒感染性的对数减少值（LRV）的计算来评估，但病毒保留的确切机制的知识仍然有限。在这里，人对病毒B19（B19V），一种小病毒（18-26〜NM）掺入治疗血浆蛋白溶液中并通过Planova过滤？缩小制造过程中的15N和20N滤波器。通过透射电子显微镜观察Planova中空纤维膜的总结构（TEM）显示Planova滤光片微孔膜具有粗糙的内部，致密的中间和粗糙的外层。在这三层中，清楚地鉴定为有效捕获B19V的最有效的中间层。含有B19V的蛋白质溶液的Planova过滤导致致密中间层中的分布峰，LRV＆ 4，展示过滤步骤的有效性。这是第一份报告，以便在实际制造条件下进行的过滤过程中同时分析病毒去除过滤器的总结构和可视化病毒夹带。本研究开发的方法表明，过滤过程的病毒去除能力可以与毛物理滤波器结构相关联，有助于更好地理解病毒捕获机制，并帮助开发在制造中的更可靠和更强的病毒过滤过程生物学。</ p> </摘要> </span> <span class="z_kbtn z_kbtnclass hoverxs" style="display: none;">展开▼</span> </div> </div> <div class="record"> <h2 class="all_title" id="enpatent33" >著录项</h2> <ul> <li> <span class="lefttit">来源</span> <div style="width: 86%;vertical-align: text-top;display: inline-block;"> <a href='/journal-foreign-15005/'>《Biotechnology Progress》</a> <b style="margin: 0 2px;">|</b><span>2019年第6期</span><b style="margin: 0 2px;">|</b><span>共11页</span> </div> </li> <li> <div class="author"> <span class="lefttit">作者</span> <p id="fAuthorthree" class="threelineshidden zhankaihshouqi"> <a href="/search.html?doctypes=4_5_6_1-0_4-0_1_2_3_7_9&sertext=Adan‐Kubo Jun&option=202" target="_blank" rel="nofollow">Adan‐Kubo Jun;</a> <a href="/search.html?doctypes=4_5_6_1-0_4-0_1_2_3_7_9&sertext=Tsujikawa Muneo&option=202" target="_blank" rel="nofollow">Tsujikawa Muneo;</a> <a href="/search.html?doctypes=4_5_6_1-0_4-0_1_2_3_7_9&sertext=Takahashi Kadue&option=202" target="_blank" rel="nofollow">Takahashi Kadue;</a> <a href="/search.html?doctypes=4_5_6_1-0_4-0_1_2_3_7_9&sertext=Hongo‐Hirasaki Tomoko&option=202" target="_blank" rel="nofollow">Hongo‐Hirasaki Tomoko;</a> <a href="/search.html?doctypes=4_5_6_1-0_4-0_1_2_3_7_9&sertext=Sakai Kaoru&option=202" target="_blank" rel="nofollow">Sakai Kaoru;</a> </p> <span class="z_kbtnclass z_kbtnclassall hoverxs" id="zkzz" style="display: none;">展开▼</span> </div> </li> <li> <div style="display: flex;"> <span class="lefttit">作者单位</span> <div style="position: relative;margin-left: 3px;max-width: 639px;"> <div class="threelineshidden zhankaihshouqi" id="fOrgthree"> <p>Central Research LaboratoryJapanese Blood Products OrganizationKobe Hyogo Prefecture Japan;</p> <p>Central Research LaboratoryJapanese Blood Products OrganizationKobe Hyogo Prefecture Japan;</p> <p>Central Research LaboratoryJapanese Blood Products OrganizationKobe Hyogo Prefecture Japan;</p> <p>Technology Development Department Bioprocess DivisionAsahi Kasei Medical Co. Ltd.Nobeoka Miyazaki Prefecture Japan;</p> <p>Central Research LaboratoryJapanese Blood Products OrganizationKobe Hyogo Prefecture Japan;</p> </div> <span class="z_kbtnclass z_kbtnclassall hoverxs" id="zhdw" style="display: none;">展开▼</span> </div> </div> </li> <li > <span class="lefttit">收录信息</span> <span style="width: 86%;vertical-align: text-top;display: inline-block;"></span> </li> <li> <span class="lefttit">原文格式</span> <span>PDF</span> </li> <li> <span class="lefttit">正文语种</span> <span>eng</span> </li> <li> <span class="lefttit">中图分类</span> <span><a href="https://www.zhangqiaokeyan.com/clc/15.html" title="生物科学">生物科学;</a></span> </li> <li class="antistop"> <span class="lefttit">关键词</span> <p style="width: 86%;vertical-align: text-top;"> <a style="color: #3E7FEB;" href="/search.html?doctypes=4_5_6_1-0_4-0_1_2_3_7_9&sertext=downstream processing&option=203" rel="nofollow">downstream processing;</a> <a style="color: #3E7FEB;" href="/search.html?doctypes=4_5_6_1-0_4-0_1_2_3_7_9&sertext=material science&option=203" rel="nofollow">material science;</a> </p> <div class="translation"> 机译：下游加工;材料科学; </div> </li> </ul> </div> </div> <div class="literature cardcommon" id="literaturereference" style="display:none"> <div class="similarity "> <h3 class="all_title" id="enpatent111">引文网络</h3> <div class="referencetab clearfix"> <ul id="referencedaohang"> <li dataid="referenceul">参考文献</li> <li dataid="citationul">引证文献</li> <li dataid="commonreferenceul">共引文献</li> <li dataid="commoncitationul">同被引文献</li> <li dataid="tworeferenceul">二级参考文献</li> <li dataid="twocitationul">二级引证文献</li> </ul> </div> <div class="reference_details" id="referenceList"> <ul id="referenceul"></ul> <ul id="citationul"></ul> <ul id="commonreferenceul"></ul> <ul id="commoncitationul"></ul> <ul id="tworeferenceul"></ul> <ul id="twocitationul"></ul> </div> </div> </div> <div class="literature cardcommon"> <div class="similarity "> <h3 class="all_title" 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href="/search.html?doctypes=4_5_6_1-0_4-0_1_2_3_7_9&sertext=李云&option=202" target="_blank" rel="nofollow" class="tuijian_auth tuijian_authcolor">,李云</a> <a href="/search.html?doctypes=4_5_6_1-0_4-0_1_2_3_7_9&sertext=戴勇超&option=202" target="_blank" rel="nofollow" class="tuijian_auth tuijian_authcolor">,戴勇超</a> <span> <a href="/journal-cn-57009/" target="_blank" rel="nofollow" class="tuijian_authcolor"> . 中国消毒学杂志 </a> </span> <span> . 2007</span><span>,第6期</span> </span> </div> </li> <li> <div> <b>5. </b><a class="enjiyixqcontent" href="/academic-journal-cn_chinese-journal-histochemistry-cytochemistry_thesis/0201285483392.html">丙肝病毒抗原在肝细胞癌组织中的定位——共聚焦激光扫描显微镜观察</a> <b>[J]</b> <span> <a href="/search.html?doctypes=4_5_6_1-0_4-0_1_2_3_7_9&sertext=张王海&option=202" target="_blank" rel="nofollow" class="tuijian_auth tuijian_authcolor"> . 张王海</a> <a href="/search.html?doctypes=4_5_6_1-0_4-0_1_2_3_7_9&sertext=朱世能&option=202" target="_blank" rel="nofollow" class="tuijian_auth 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tuijian_authcolor">,邱珊</a> <span> <a href="/conference-cn-9048/" target="_blank" rel="nofollow" class="tuijian_authcolor"> . 2011年环境污染与大众健康学术会议 </a> <span> <span> . 2011</span> </span> </div> </li> <li> <div> <b>7. </b><a class="enjiyixqcontent" href="/academic-degree-domestic_mphd_thesis/020312388947.html">热处理和化学处理对梨离体植株中病毒的影响</a> <b>[A] </b> <span> <a href="/search.html?doctypes=4_5_6_1-0_4-0_1_2_3_7_9&sertext=王利平&option=202" target="_blank" rel="nofollow" class="tuijian_auth tuijian_authcolor"> . 王利平</a> <span> . 2006</span> </span> </div> </li> </ul> <ul style="display: none;"> <li> <div> <b>1. </b><a class="enjiyixqcontent" href="/patent-detail/06120106846467.html">液体处理用筒状过滤器、捕获并去除液体中的油分的方法、制备饮料液体的方法和测量筒状过滤器的油克数持续时间的方法</a> <b>[P]</b> . <span> 中国专利： CN102665848A </span> <span> . 2012-09-12</span> </div> </li> <li> <div> <b>2. </b><a class="enjiyixqcontent" href="/patent-detail/061201274620.html">使用最优定向线性轴线去除由基于车辆的相机捕获的图像中的阴影</a> <b>[P]</b> . <span> 中国专利： CN102314602B </span> <span> . 2013.10.30</span> </div> </li> <li> <div> <b>3. </b><a class="enjiyixqcontent" href="/patent-detail/06130403983258.html">virus or virus like particle, plurality of isolated viruses or isolated virus-like particles, recombinant nucleic acid, isolated suspension-adapted cell, membrane-bound portion of the cell, isolated suspension-adapted cell, plurality of isolated suspension-adapted cells, and method of identifying a t cell epitope</a> <b>[P]</b> . <span> 外国专利：  BR112016016937A8 </span> <span> . 2018-12-18</span> </div> <p class="zwjiyix translation" style="max-width: initial;height: auto;word-break: break-all;white-space: initial;text-overflow: initial;overflow: initial;"> <span>机译：病毒或病毒样颗粒，多个分离的病毒或分离的病毒样颗粒，重组核酸，分离的悬浮液适应细胞，细胞膜结合部分，分离的悬浮液适应细胞，多个分离的悬浮液适应细胞以及在细胞表位鉴定的方法 </span> </p> </li> <li> <div> <b>4. </b><a class="enjiyixqcontent" href="/patent-detail/06130454413524.html">Papilloma virus capsid protein isolated and purified capsids virus-like particles process of producing the purified protein recombinant papillone virus vaccine pharmaceutical compositions treatment or prevention process against papillary virus infection kit for the detection of papilloma virus or antibodies papillomavirus processes for the production of a recombinant papillone virus capsid protein to induce an immune response in an animalvertebrate synthetic system</a> <b>[P]</b> . <span> 外国专利：  BR9510520A </span> <span> . 1998-07-14</span> </div> <p class="zwjiyix translation" style="max-width: initial;height: auto;word-break: break-all;white-space: initial;text-overflow: initial;overflow: initial;"> <span>机译：乳头瘤病毒衣壳蛋白分离纯化的衣壳病毒样颗粒的制备方法病毒衣壳蛋白诱导动物脊椎动物合成系统中的免疫反应 </span> </p> </li> <li> <div> <b>5. </b><a class="enjiyixqcontent" href="/patent-detail/06130417738813.html">Hantavirus non-replicative particles consisting of Lipid membranes including GN/GC HANTA virus; pharmacological components including the particles; for the treatment, prevention and/or diagnosis of Hantavirus infection; particle generation procedures.</a> <b>[P]</b> . <span> 外国专利：  CL2011001085A1 </span> <span> . 2014-05-02</span> </div> <p class="zwjiyix translation" style="max-width: initial;height: auto;word-break: break-all;white-space: initial;text-overflow: initial;overflow: initial;"> <span>机译：由脂膜组成的汉坦病毒非复制性颗粒，包括GN / GC HANTA病毒;包括颗粒的药理成分;用于治疗，预防和/或诊断汉坦病毒感染;粒子生成程序。 </span> </p> </li> </ul> </div> </div> </div> <div class="theme cardcommon" style="overflow: auto;display:none"> <h3 class="all_title" id="enpatent55">相关主题</h3> <ul id="subject"> </ul> </div> </div> </div> </div> <div class="right rightcon"> <div class="details_img cardcommon clearfix" style="margin-bottom: 10px;display:none;" > </div> </div> </div> <div id="thesis_get_original1" class="downloadBth" style="bottom: 19px;z-index: 999;" onclick="ywcd('0704021880250','4',7,2,1,'',this,24)" class="delivery" prompt="010401" title="通过人工服务将文献原文发送至邮箱" >获取原文</div> <div class="journalsub-pop-up" style="display: none"> <div class="journal-sub"> 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