CN113518655B - 使用径迹蚀刻膜过滤生物流体的方法 - Google Patents

使用径迹蚀刻膜过滤生物流体的方法 Download PDF

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CN113518655B
CN113518655B CN202080018189.0A CN202080018189A CN113518655B CN 113518655 B CN113518655 B CN 113518655B CN 202080018189 A CN202080018189 A CN 202080018189A CN 113518655 B CN113518655 B CN 113518655B
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filtrate
cartridge
membrane
cassette
feed
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CN113518655A (zh
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克雷格·罗宾逊
普里蒂·本加尼卢茨
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Ripley Gold
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Abstract

本发明提供了用于过滤的径迹蚀刻膜。还提供了使用这种膜的过滤方法和细胞培养方法。

Description

使用径迹蚀刻膜过滤生物流体的方法
技术领域
本公开内容涉及径迹蚀刻膜在切向流过滤系统中的用途。
背景技术
过滤被用于分离、澄清、改性和/或浓缩流体溶液、混合物或悬浮液。它通常是生物技术、制药和医疗行业在药物、诊断和化学品的生产、加工和分析阶段的必要步骤。例如，过滤可被用于从溶液中去除所需化合物，或去除副产物，留下更浓缩的介质。可以通过选择各种过滤材料、孔径和/或其他过滤器变量来适当地调整这些过程。
切向流过滤(TFF)，也称为错流过滤(CFF)，在整个行业中用于根据材料流体悬浮液或溶液的尺寸或电荷差异来对其分离或纯化。在TFF系统中，包含各种分子或颗粒物质的流体进料沿平行于半透膜表面的方向流入过滤容器。在过滤容器中，进料被分成两个组分流：渗透物流(也称为滤液)，其通过膜并包括进料中的某些物质；以及截留物流，其不通过膜并包括未进入渗透物的任何物质。
与TFF相比，流体垂直于膜表面流动的常规直流过滤系统(或死端过滤系统)中，保留物质在膜表面上的积累发生得快得多，这可能导致膜结垢。TFF系统与死端系统相比有多个优点，例如过滤器表面上材料的堆积较慢，并且由于进料被切向流冲走，结垢率较低。这使得它们特别适用于各种应用(包括生物加工和制药应用)的高固体含量和高粘度进料流。
TFF系统通常使用板框或盒设计来实现。这些设计通常包括布置在外部平板和歧管之间的多个平板膜。在使用中，流体进料通过歧管的入口进入盒中，并与膜的第一(上)表面相切。渗透物流通过膜，然后通过盒进入歧管的专用渗透通道，而截留物不穿过膜并进入歧管的单独的截留物通道。
传统上，通过将多层膜与压敏粘合剂(PSA)和筛网交织，并可选地将一些或所有层固定在一起，例如通过使用硅树脂或聚氨酯聚合物进行封装来制造盒。TFF盒通常包括用于与歧管接口的孔或其他特征。当层彼此错位或与歧管接口错位时，盒设计可能容易泄漏。因此，在使用中，盒经常夹在平板或垫圈之间以密封盒子以防止这种泄漏。
在生产细胞培养物时，通常需要过滤正在生长的培养物中的废物。生物制造工艺的进步现在允许大规模生产细胞培养物，从而能够生产重组蛋白、病毒样颗粒(VLP)、基因治疗颗粒和疫苗，其通常使用过程容器装置。去除代谢废物并用额外的营养物更新培养物的细胞保留装置广泛可用。通常，这种保留用利用切向流过滤或交替切向流(ATF)过滤的膜使用过程容器培养物的灌注来进行。。
膜通常用于细胞培养物澄清，但它们在应用中的使用可能因带有细胞碎片使膜结垢的可能性而变得复杂。反过来，结垢可能导致膜保留预期产品而不是使其通过。这些是通常在超滤(UF)和微滤(MF)范围内在750kDμm至0.65μm之间的大尺寸孔隙。然而，膜需要一直改进，使其在允许过滤具有高固体含量的溶液的同时抗结垢。此外，传统膜的另一个问题是孔隙堵塞。由于孔隙的形成方法，孔隙通常在它们的尺寸或分布上不是线性的或不特别均一。当滤液试图移动通过孔隙时，这导致堵塞，其阻碍溶液的进一步过滤。值得注意的是，孔隙的产生是不可预测的，并且通常导致孔隙具有蜿蜒的路径、可变的长度和大小以及各种形状。
膜也被用于单克隆抗体浓缩、蛋白质纯化和其他超滤/渗滤应用。极化和膜结垢都可能对这些应用造成影响。由于其均一的孔径和窄的孔径分布，TE膜在这些应用中也可以有很大用处。
一种适合过滤的潜在材料是径迹蚀刻(TE)膜。通常，TE膜太薄而不适用于TFF组装或加工。这种薄度已导致膜无法承受这些类型的分离所需的操作压力。无论如何，TE膜的光滑表面、均一的孔径和路径长度以及一致的孔隙率提供了寻找其用途的解决方案的动力。进一步的动力来自对孔径和形状的可控水平。
过去TE膜的另一个潜在限制是低孔隙率和因此的低渗透性。但是，可以使用添加剂对膜表面进行改性，使其更具亲水性。这些添加剂可以包括聚乙烯吡咯烷酮、胺基团或其他亲水基团。
膜盒的化学稳定性可以是盒稳定性的一个重要因素。氢氧化钠通常用作防腐/储存溶液(通常用于一次性应用)以及清洁溶液(通常用于可重复使用的盒)。凭借更厚的膜和改善的化学稳定性，TE膜可用于一次性和可重复使用的应用两者。
发明内容
本公开内容提供一次性和可重复使用的TFF盒以及制造和使用它们的方法，其提供降低的失效风险和减少的用户组装。本公开内容的一个方面涉及一种切向流过滤盒，其包括柔性隔离板，垫圈和过滤板中的至少一个，以及布置在柔性隔离板和垫圈或过滤板之间的多个交错层，这些层限定至少一层膜、至少一个进料通道和至少一个滤液通道。多个交错层可以包括：滤液通道间隔件，其限定由内周界界定的开放内部容积并且包括一个或多个流体端口；非柔性进料通道间隔件，其也限定由内周界界定的开放内部容积并且也包括一个或多个流体端口；以及设置在进料通道间隔件和滤液通道间隔件之间的膜。这些层还任选地包括将膜与滤液通道间隔件和进料通道间隔件之一粘合在一起的压敏粘合剂，所述压敏粘合剂薄膜的厚度小于相邻通道高度的50％。柔性隔离板可以包括柔性聚合物或热塑性弹性体并且结合到交错叠层的第一表面。膜可以包括多个径迹蚀刻(TE)膜，其中膜可以包括多个孔隙，并且孔隙的尺寸和形状可以是均一的。在各种实施方案中，多个孔隙的直径、深度和/或路径长度可以是均一的。平均孔径为约100kD至约30微米。TE膜可具有高达60微米的厚度。TE膜可以包括多个聚碳酸酯、聚酰亚胺、聚偏二氟乙烯或聚酯平板。多个孔隙可以具有以下结构中的一种或多种：圆柱状、圆锥状、雪茄状、漏斗状和沙漏状。TE膜可以具有光滑的表面。该盒可用于交替切向流过滤。垫圈可以结合到交错叠层的第二表面，该垫圈包括用于进料通道和滤液通道的单独的流体端口，并且包括流体歧管的过滤板任选地结合到垫圈，使得过滤板的进料端口与垫圈的进料端口对齐，并且过滤板的滤液端口与垫圈的滤液端口对齐。在一些实施方案中，TFF盒可包括位于盒侧壁上的标签或雕刻，以通过库存单位(SKU)编号、批号、序列号、容量、进料通道和/或滤液通道的数量以及膜的数量中的一个或多个来标识TFF盒。标签或雕刻可包括条形码。在某些情况下，TFF盒可以是一次性的。TFF盒可以重复使用。它可以包括密封边缘。在一些情况下，进料通道和/或滤液通道可包括设置在由通道间隔件限定的空间内的筛网。筛网可包括编织网、非编织网或聚合物网。至少一个滤液通道可包括设置在由滤液通道间隔件限定的空间内的滤液筛网。滤液筛网可包括编织网、非编织网或挤出的聚合物网。
在一些方面，本公开内容描述过滤细胞培养物的方法，包括使用盒。盒可包括柔性隔离板、垫圈和过滤板中的至少一个、以及设置在柔性隔离板和垫圈或过滤板之间的多个交错层，该多个交错层限定至少一个进料通道和至少一个滤液通道，其中多个交错层可包括由内周界界定的开放内部容积并且包括一个或多个流体端口的滤液通道间隔件，由内周界界定的开放内部容积并且包括一个或多个流体端口的非柔性进料通道间隔件，设置在滤液通道间隔件和进料通道间隔件之间的膜，以及任选地将膜与滤液通道间隔件和进料通道间隔件之一粘合在一起的压敏粘合剂，所述压敏粘合剂薄膜的厚度小于相邻通道高度的50％，其中(a)柔性隔离板包括柔性聚合物或热塑性弹性体并结合到交错叠层的第一表面，以及(b)膜包括多个径迹蚀刻(TE)膜，其中膜包括多个孔隙，并且其中孔隙的大小和形状是均一的。将盒外壳连接到过程容器，将盒外壳连接到分离系统，通过径迹蚀刻膜过滤器和分离系统循环细胞培养物，通过膜过滤器过滤细胞培养物，收集所得滤液，和将细胞培养物返回至过程容器。在一些实施方案中，细胞培养物可以是哺乳动物细胞培养物。细胞培养物的循环可以通过交替切向流进行。细胞培养物的循环可以通过切向流过滤进行。
由于TE膜表面光滑、孔径均一、孔隙率一致以及具有多种孔径的特性，因此发现TE膜适用于这些盒中的过滤。生产厚达60微米的TE膜可允许它们用于过滤器，因为它们足够坚固以承受系统压力。TE膜(例如由it4ip制造的膜)可结合过程容器和传统分离系统在盒内使用。当通过交替切向流或切向流过滤使用系统时，TE膜导致更有效地过滤滤液，从而导致更大的截留物浓度。此外，由于TE膜的孔隙比传统膜材料大得多(最大30微米)，因此这些过滤方法可能适用于生物加工以外的领域。产生一致的圆柱形(或类似形状)孔隙的能力允许确定的滤液更大程度地移动通过孔，防止孔隙堵塞。与分布不均匀且尺寸、路径长度和形状可变的传统膜孔隙不同，TE膜允许可控地、人为地构建具有确定的尺寸、形状和路径长度的孔。
附图说明
图1描绘了一种通过相转化制成的膜和另一种通过径迹蚀刻工艺制成的膜的扫描电子显微镜(SEM)图像；
图2描绘了TE膜与通过相转化制成的聚醚砜膜的容量的比较的示例性数据；
图3示出了根据本公开内容的实施方案的TE盒的水通量对径迹蚀刻膜的跨膜压力值；
图4显示了用氢氧化钠冲洗前后TE盒的水通量。
具体实施方式
综述
本文已经发现了TE膜适用于细胞培养物的过滤和其他生物分离。不希望受任何理论束缚，据信这些膜的性能归因于它们的抗结垢性以及控制孔隙形状和尺寸的能力，从而导致高效和有效的分离。这些特性可以利于许多生物加工应用。
本公开内容关注于切向流过滤。在为这些应用设计的示例性系统中，切向流TE膜设置在过滤盒内以限定进料/截留物流体通道和渗透物(也称为滤液)流体通道，所述通道通过过滤器元件彼此分开。在该系统中，进料/截留物通道通过过程容器和过滤器外壳的进料通道(对应于流体进料)之间的流体耦合，并且任选地，通过过滤器外壳的出口(对应于截留物)和过程容器之间的回流耦合与生物反应器或其他过程容器流体连通。根据本公开内容的在其过滤器中使用TE膜的过滤培养系统可使得滤液过滤更有效，同时减少结垢，导致更大的截留物浓度。
本公开内容的TE膜可由聚碳酸酯、聚酰亚胺、聚偏二氟乙烯和/或聚酯制成。不希望受任何理论束缚，这些材料为膜构建了光滑的表面，这可以防止表面结垢。这些膜可以具有至高60微米的厚度并且具有100kD至30微米范围内的孔径。不希望受任何理论束缚，膜的厚度可允许膜承受系统的高操作压力。膜内的孔隙可以是多种形状中的任何一种，包括圆柱状、圆锥状、雪茄状、漏斗状和沙漏状。不希望受任何理论束缚，控制孔隙形状的能力可以允许溶液的更大和更特定的分离。孔隙的开口直径、路径长度、形状和密度也可以是均一的。不希望受任何理论束缚，开口直径、路径长度、形状和孔密度的均一性可以产生比传统膜更特定的分离和更少的结垢。径迹蚀刻膜片包含多个尺寸形状一致的孔，其中孔的尺寸和形状均一。孔可以大于1微米。不希望受任何理论束缚，较大的孔径可以实现宏观水平的过滤。
图1举例说明了PES膜和TE膜之间孔径和形状的差异。顶行显示了通过传统相转化方法制成的2种不同PES膜表面的扫描电子显微镜(SEM)图像(放大倍数分别为20000倍和5000倍)。底行显示了两种不同TE膜表面的SEM图像(放大倍数分别为25000倍和500倍)。
滤液通道间隔件限定由内周界界定的开放内部容积并且包括一个或多个流体端口。非柔性进料通道间隔件也限定了由内周界界定的开放内部容积并且也包括一个或多个流体端口。
本公开内容的过滤盒可用于需要错流过滤的各种小型和大型应用，并且可以特别适用于小型和大型制药和生物制药过滤过程，包括但不限于疫苗、单克隆抗体的生产和患者特异性治疗。
本公开内容的盒通常包括柔性隔离板以及垫圈和过滤板中的一个或两个。在柔性隔离板和垫圈和/或过滤板之间为多个交错层，其形成至少一个进料通道和至少一个滤液通道。多个交错层包括滤液通道间隔件、非柔性进料通道间隔件、滤液通道间隔件和进料通道间隔件之间的膜，以及潜在地将膜与滤液通道间隔件和/或进料通道间隔件粘合在一起的压敏粘合剂。压敏粘合剂的厚度小于相邻通道高度的50％。柔性隔离板由柔性聚合物或热塑性弹性体制成并粘合到交错叠层的第一表面。
在盒中，垫圈可以结合到交错叠层的第二表面并且可以构成用于进料通道和滤液通道的单独的流体端口。当过滤板与垫圈粘合时，过滤板是流体歧管，其中过滤板的进料端口与垫圈的进料端口对齐，并且过滤板的滤液端口与垫圈的滤液端口对齐。
盒可以在盒的侧壁上具有标签或雕刻，以通过库存单位(SKU)号、批号、序列号、容量、进料通道和/或滤液通道的数量以及膜的数量来标识盒。该标签或雕刻可以是条形码。
盒在使用后可以是一次性的并且还可以具有密封边缘。
盒的进料通道可以在由进料通道间隔件限定的空间内具有进料筛。该进料筛可以是编织的或挤出的聚合物网。滤液通道可以是在由滤液通道间隔件限定的空间内的滤液筛。该滤液筛可以是编织的或挤出的聚合物网。
根据本公开内容的过滤系统可包括径迹蚀刻膜、盒外壳、导管和其他耐用且可消毒(例如，通过高压灭菌、蒸汽清洁、伽马辐射、化学消毒等)的元件，这些元件可用常用化学试剂(如氢氧化钠)清洁，并多次重复使用；或者，一个或多个元件可以是一次性的并且可以在使用后丢弃。
本公开内容还描述了使用TE膜过滤器过滤溶液的系统的使用方法。在一组实施方案中，TE膜过滤器可与盒外壳一起使用。外壳可以通过第一导管连接到过程容器并且通过第二导管连接到滤液容器。泵可以连接到系统。泵的启动可将液体抽拉通过TE膜过滤器盒，去除滤液并保留截留物。在一些实施方案中，溶液是生物溶液，而在其他实施方案中，溶液是细胞培养物。细胞培养物可以是哺乳动物的并且可以通过交替切向流或切向流过滤进行循环。
实施例
本公开内容的某些原理通过以下实施例进一步说明：
实施例1
将平板TE膜制成100cm2的盒，其带有“E屏”间隔件(即来自RepligenCorporation,Waltham MA的粗进料间隔件)。用去离子水冲洗盒，排空通道，并进行空气完整性测试，以测试盒是否完整并适合使用。在3psi(MF膜的典型测试条件范围内)下，空气流量小于1.2ml/min，表明盒是完整的。
实施例2
将孔径为0.2微米的平板TE膜制成100cm2的带有“E-屏”(即来自Repligen的粗进料间隔件)的盒(TE02)。使用两种不同的中国仓鼠卵巢(CHO)细胞培养进料流，将其性能与使用0.2微米聚醚砜(PES)转相膜制成的面朝上(PES02SU)和面朝下(PES02SD)的盒进行了比较。这导致图2所示的阳性结果。与具有相似孔径的PES膜相比，TE膜显示出较高的渗透性(LMH/psi)、较高的容量(L/m2)和较高的筛分率。TE02膜的蛋白质筛分率明显更高，并保持恒定在78％。PES02SU显示出筛分率从开始时的68％急剧下降到结束时的34％，即不到使用TE02盒的筛分率的一半。
与相转化膜(PES02SU和PES02SD)相比，TE02的压降最低，表明其抗结垢性更高。3种膜在开始时的压降都相似，为0.22-0.24psi。最后，TE02膜的压降仅为0.88psi，而PES02SU的压降为1.6psi(即两倍高)，表明PES02SU结垢程度更大。
实施例3
为了测试由TE膜制成的盒承受TFF应用所需压力的能力，将水通过100cm2的TE盒，并在多种跨膜压力(TMP)下测量通量。测试通过将TMP值从低到高(即1到8.5psi)逐渐增加，并测量每个TMP下的水通量来进行。为了确保在高压下测试后膜不被损坏，通过将TMP从高值降低到低值从8.5psi降低到2.2和1.2psi来进行测试。如图3所示，在任一方向上测得的水通量没有显著差异，表明压力稳定性强。
实施例4
为了测试用TE膜制成的盒的化学稳定性，用0.2N氢氧化钠溶液冲洗100cm2盒，每平方米膜面积使用2升。将盒冲洗30分钟，并在3psi的TMP下测量前后的水通量。化学清洁前后的水通量几乎相同，如图4所示，表明其对常用于清洁和储存盒的试剂具有良好的化学稳定性，并具有制造可重复使用盒的潜力。

Claims (25)

1.一种切向流过滤(TFF)盒，其包括：
柔性隔离板；
垫圈和过滤板中的至少一个；和
设置在柔性隔离板和垫圈或过滤板之间的多个交错层，所述多个交错层限定至少一个膜、至少一个进料通道和至少一个滤液通道，所述多个交错层包括：
滤液通道间隔件，其限定了由内周界界定的开放内部容积并且包括一个或多个流体端口；
非柔性进料通道间隔件，其限定了由内周界界定的开放内部容积并且包括一个或多个流体端口；以及
设置在滤液通道间隔件和进料通道间隔件之间的膜；
其中柔性隔离板包括柔性聚合物或热塑性弹性体并结合到交错叠层的第一表面，并且膜包括多个径迹蚀刻(TE)膜，其中膜包括多个孔隙，并且其中孔隙的尺寸和形状是均一的。
2.根据权利要求1所述的盒，其中所述多个交错层还包括将膜与滤液通道间隔件和进料通道间隔件之一粘合在一起的压敏粘合剂，所述压敏粘合剂的薄膜的厚度小于相邻通道高度的50％。
3.根据权利要求1所述的盒，其中所述多个孔隙在直径、深度和/或路径长度上是均一的。
4.根据权利要求1所述的盒，其中平均孔径为100千道尔顿至30微米。
5.根据权利要求1所述的盒，其中所述TE膜具有至多60微米的厚度。
6.根据权利要求1所述的盒，其中所述径迹蚀刻膜包括多个聚碳酸酯、聚酰亚胺、聚偏二氟乙烯或聚酯平板。
7.根据权利要求1所述的盒，其中所述多个孔隙可以具有以下结构中的一种或多种：圆柱状、圆锥状、雪茄状、漏斗状和沙漏状。
8.根据权利要求1所述的盒，其中所述径迹蚀刻膜具有光滑的表面。
9.根据权利要求1所述的盒，其中所述盒用于交替切向流过滤中。
10.根据权利要求1所述的盒，其中垫圈结合到所述交错叠层的第二表面，所述垫圈包括用于所述进料通道和滤液通道的单独的流体端口。
11.根据权利要求1所述的盒，其中过滤板结合到所述垫圈，所述过滤板包括流体歧管，其中所述过滤板的进料端口与所述垫圈的进料端口对齐，并且所述过滤板的滤液端口与垫圈的滤液端口对齐。
12.根据权利要求1所述的盒，还包括在所述盒的侧壁上的标签或雕刻，以通过库存单位(SKU)号、批号、序列号、容量、进料通道和/或滤液通道的数量以及膜的数量中的一个或多个来标识所述TFF盒。
13.根据权利要求12所述的盒，其中所述标签或雕刻包括条形码。
14.根据权利要求1所述的盒，其中所述TFF盒在使用后是一次性的。
15.根据权利要求1所述的盒，其中所述TFF盒是可重复使用的。
16.根据权利要求1所述的盒，其中所述TFF盒包括密封边缘。
17.根据权利要求1所述的盒，其中所述至少一个进料通道包括设置在由所述进料通道间隔件限定的空间内的进料筛。
18.根据权利要求17所述的盒，其中所述进料筛包括编织网、非编织网或挤出的聚合物网。
19.根据权利要求17所述的盒，其中所述至少一个滤液通道包括设置在由所述滤液通道间隔件限定的空间内的滤液筛。
20.根据权利要求19所述的盒，其中所述滤液筛包括编织网、非编织网或挤出的聚合物网。
21.一种过滤细胞培养物的方法，其包括：
使用盒，其中所述盒包括：
柔性隔离板；
垫圈和过滤板中的至少一个；和
设置在柔性隔离板和垫圈或过滤板之间的多个交错层，所述多个交错层限定至少一个进料通道和至少一个滤液通道，所述多个交错层包括：
滤液通道间隔件，其限定了由内周界界定的开放内部容积并且包括一个或多个流体端口；
非柔性进料通道间隔件，其限定了由内周界界定的开放内部容积并且包括一个或多个流体端口；以及
设置在滤液通道间隔件和进料通道间隔件之间的膜；
其中柔性隔离板包括柔性聚合物或热塑性弹性体并结合到交错叠层的第一表面，并且膜包括多个径迹蚀刻(TE)膜，其中膜包括多个孔隙，并且其中孔隙的尺寸和形状是均一的；
将盒外壳连接到过程容器；
将盒外壳连接到分离系统；
通过径迹蚀刻膜过滤器和分离系统循环细胞培养物；
通过膜过滤器过滤细胞培养物；
收集所得滤液；和
将细胞培养物返回至过程容器。
22.根据权利要求21所述的盒，其中所述多个交错层还包括将膜与滤液通道间隔件和进料通道间隔件之一粘合在一起的压敏粘合剂，所述压敏粘合剂的薄膜的厚度小于相邻通道高度的50％。
23.根据权利要求21所述的方法，其中所述细胞培养物是哺乳动物细胞培养物。
24.根据权利要求21所述的方法，其中所述细胞培养物的循环通过交替切向流进行。
25.根据权利要求21所述的方法，其中所述细胞培养物的循环通过切向流过滤进行。
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