CN102257122B - 搅拌槽反应器及方法 - Google Patents

搅拌槽反应器及方法 Download PDF

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CN102257122B
CN102257122B CN200980150670.9A CN200980150670A CN102257122B CN 102257122 B CN102257122 B CN 102257122B CN 200980150670 A CN200980150670 A CN 200980150670A CN 102257122 B CN102257122 B CN 102257122B
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W.莫亚
A.迪蓬
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Emd密理博公司
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    • C12BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
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    • C12MAPPARATUS FOR ENZYMOLOGY OR MICROBIOLOGY; APPARATUS FOR CULTURING MICROORGANISMS FOR PRODUCING BIOMASS, FOR GROWING CELLS OR FOR OBTAINING FERMENTATION OR METABOLIC PRODUCTS, i.e. BIOREACTORS OR FERMENTERS
    • C12M23/00Constructional details, e.g. recesses, hinges
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    • CCHEMISTRY; METALLURGY
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Abstract

提供了用于样本制备或处理(诸如生物体培养或处理,以及可选地样本纯化)的容器。在某些实施例中,反应器是生物反应器,其包括搅拌单元装置,其模拟切向流过滤器以减少或消除可能由产生的固体造成的阻塞。在某些实施例中,固体包括析出物或絮凝或珠,诸如包括结合所需生物分子的聚合物以及杂质。在其方法方面,本文公开的实施例包括对从细胞培养流体获得的所需的生物分子进行纯化和分离。该方法包括在容器中进行样本制备或处理,培养生物体;通过从培养液析出或絮凝所需生物分子而产生固体;通过搅拌防止固体在容器中沉降;以及诸如通过对所需生物分子洗提和过滤而进行纯化。

Description

搅拌槽反应器及方法

[0001] 本申请要求2008年12月16日提交的美国临时专利申请61/201,865的优先权,在此通过引用将其公开内容并入本文。

技术领域

[0002] 本发明涉及搅拌槽容器及相关方法。

背景技术

[0003] 制造生物分子(例如,蛋白质,特别是重组蛋白质)的大致过程通常包括两个主要步骤:(1)在宿主细胞中的蛋白质的表达,以及接着(2)蛋白质的纯化。第一步骤涉及在生物反应器中培养所需宿主细胞以进行蛋白质表达。用于该目的的细胞流水线的一些例子包括中国仓鼠卵巢(CHO)细胞、骨髓(NSO)细菌细胞(诸如e-coli细胞和昆虫细胞)。一旦以所需水平表达蛋白质,则蛋白质从宿主细胞移除并收获。悬浮的颗粒,诸如细胞、细胞片段、脂质和其它不溶物质通常通过过滤或离心而从含有蛋白质的流体中除去,得到包含所需蛋白质溶液以及其它可溶杂质的净化流体。

[0004] 第二步骤涉及所收获的蛋白质的纯化以移除在过程中所固有的杂质。杂质的例子包括宿主细胞蛋白质(HCP,所需或目标蛋白质之外的蛋白质),核酸,内毒素,病毒,蛋白质变体和蛋白质聚集体。该纯化通常包括若干层析步骤,可包括在固体基质(诸如多孔琼脂糖、聚合材料或玻璃或通过基于膜的吸附剂)上的亲和层析,离子交换,疏水作用等。

[0005] 蛋白质纯化的层析工艺流程的一个例子包括蛋白质A亲和、接着是阳离子交换,再接着是阴离子交换。蛋白质A柱通过亲和机制捕获所需蛋白质或目标蛋白质,而杂质通过该柱以便被丢弃。然后,通过洗提从该柱回收蛋白质。由于大部分所需蛋白质具有处于基本范围(8-9)的等电点(PI),因此在正常的处理条件下(低于蛋白质的PI的pH值)会带正电,因此在第二柱中它们结合到阳离子交换树脂。其它带正电的杂质也结合到该树脂。然后,在蛋白质洗提而杂质保留结合于树脂的情况下(pH值,盐浓度)通过洗提从该柱回收所需的蛋白质。阴离子交换柱通常操作于流通模式,使得任何带负电的杂质结合于树脂而带正电的所需的蛋白质回收在流通流中。该过程导致高度纯化和高浓度的蛋白质溶液。

[0006] 近些年还研宄了用于纯化蛋白质的其它替代性方法。一种方法包括絮凝技术。在该技术中,可溶的聚电解质添加到未净化的细胞培养液中以捕获悬浮的颗粒和一部分可溶杂质,从而形成絮凝物,随后通过过滤或离心将该絮凝物从蛋白质溶液移除。

[0007] 或者,可溶聚电解质添加到净化的细胞培养液中,以捕获所需生物分子,从而形成絮凝物,允许该絮凝物沉降,随后与溶液的其它部分分离。絮凝物通常被洗涤以松散地除去粘附的杂质。然后,溶液离子强度的提高使目标蛋白质与聚电解质分离,随后导致聚电解质的再增溶至含有蛋白质的溶液中。

[0008] 在2007年12月20日提交的共同待决的美国申请12/004314(其公开通过引用而结合于本文)中,在某些条件下(诸如温度、PH、盐、光或其组合)可溶的聚合物被用于在其可溶状态结合杂质,然后在条件(pH或温度等)改变后析出,以除去其中的杂质。然后,所需的生物分子被利用传统层析法或膜吸附剂或类似物进一步处理。

[0009] 以上所述的所有蛋白质纯化技术有一个共同点,S卩,首先在第一独立步骤中移除悬浮颗粒,然后在第二步骤中将所需的生物分子与过程中固有的可溶杂质分离。

[0010] 利用衍生磁性颗粒回收产物是蛋白质纯化技术的一个例子,其中,所需的生物分子可以直接从未净化细胞培养液纯化。在该技术中,包封磁性珠的聚合物壳以找出并结合目标蛋白质的亲和配体功能化。然后施加磁场以选择珠-蛋白质复合物,留下可溶杂质和不可溶颗粒。

[0011] 该技术的主要缺点在于其要求在设计、结构和高梯度磁性分离器的实现方面的可观的资本投资。并且,该技术还不能应用于可置换的应用中,这些可置换的应用可能成为生物过程工业中蛋白质纯化的标准。

[0012] 在2008年12月16日由Moya、Wilson等人提交的共同待决的申请(代理人卷号MCA-1046,题目为“Purificat1n of Proteins”,其公开内容通过引用而结合于本文)中,公开了一种聚合物,诸如可溶聚合物,其能够基本不可逆地结合到不可溶颗粒和一部分可溶杂质,并还能够可逆地结合到未净化的包含生物材料的流中的一个或多个所需生物分子,以及利用这种材料从该流纯化一个或多个所需生物分子而无需先期净化的方法。更具体地,该共同待决的申请公开了一种刺激响应聚合物,诸如可选择溶解的聚合物,其能够可选择地并可逆地结合到未净化的含有生物材料的流中的一个或多个所需生物分子,以及使用这种聚合物来从包括所需生物分子和各种杂质(诸如其它蛋白质(宿主细胞蛋白质)、DNA、病毒、全细胞、细胞碎片等)的材料的复合混合物中纯化一个或多个所需生物分子而无需流的先期净化的方法。

[0013] 聚合物在一定的工艺条件下(诸如pH值,盐浓度,温度,光或电场中的一个或多个)可溶,并且可与不可溶的杂质(细胞,碎片等)以及一部分可溶杂质相互作用和复合,导致在条件(温度,盐浓度,光,电场或pH值)的改变下不可溶且析出溶液,例如刺激响应聚合物。仅当析出溶液后,聚合物能够在未净化的细胞液中的流(蛋白质、多肽等)中可逆地结合到一个或多个所需生物分子。然后从流移除析出物,诸如通过从流的剩余部分滤出,并且通过诸如从析出物选择性洗提来回收所需的生物分子。

[0014] 然而,析出物的移除是个问题,因为其通常是大块污物的形式。

[0015] 希望提供一种装置和方法,来有效率地纯化样本,特别是包含生物分子的样本,优选在单一的一体的设备中,其减少或消除可能导致污染或材料损失的一个或多个工艺步骤。

发明内容

[0016] 通过本文公开的实施例来克服现有技术的问题,其包括用于样本制备或处理(诸如生物体培养或处理以及可选地样本的纯化)的容器或壳体。在某些实施例中,容器或壳体是混合器。在某些实施例中,容器或壳体是反应器。在某些实施例中,反应器是可置换或可重用的生物反应器,其包括搅拌单元装置,该搅拌单元装置可模拟切向流过滤器以减少或消除可能由产生的固体造成的阻塞。在某些实施例中,固体包括析出物或浮物,诸如包括结合所需生物分子的聚合物的固体,以及诸如细胞和细胞成分的杂质。在某些实施例中,搅拌单元组件包括例如在所需的生物分子的回收(例如,通过洗提)过程中用于纯化的一个或多个膜。在某些实施例中,生物分子是蛋白质、多肽或抗体。在某些实施例中,容器具有两个部分。在某些实施例中,容器具有两个部分,每一部分在其内具有膜。在某些实施例中,容器具有两个部分,第一部分具有膜,第二部分与第一部分出口下游的过滤器装置流体连通。

[0017] 在其方法方面,本文公开的实施例包括对从细胞培养流体中获得的所需生物分子的纯化和分离。在某些实施例中,方法包括在容器或壳体中实施样本制备或处理,诸如培养生物体;通过诸如从培养液析出或絮凝所需生物分子来产生固体;通过搅拌防止固体在容器内沉降;以及诸如通过结合所需生物分子并洗提以及过滤而进行纯化。在某些实施例中,样本处理包括对所需蛋白质的表达。在某些实施例中,固体包括析出物,该析出物包括结合到所需蛋白质的聚合物,并且纯化包括结合和洗提以及一个或多个过滤步骤。在某些实施例中,固体包括析出物,该析出物包括结合到所需蛋白质的聚电解质,纯化包括结合和洗提以及一个或多个过滤步骤。在某些实施例中,聚合物结合到杂质(细胞,细胞碎片等),并且生物分子保留在上清液中。析出步骤可代替传统的层析分离,可以用作直接捕获步骤以使所需蛋白质与细胞培养液分离,或仅仅是中间纯化步骤。在某些实施例中,可以使用亲和或离子交换珠或具有能够纯化生物分子的配体或功能的珠代替聚合物来结合所需生物分子。在某些实施例中,在与样本处理相同的装置中实施一个或多个过滤步骤。在某些实施例中,洗提的蛋白质受到进一步的纯化,诸如通过亲和和/或离子交换层析。

附图说明

[0018] 图1是根据某些实施例的生物反应器的透视图;

[0019] 图2是图1的生物反应器的一部分的横截面图;

[0020] 图3是根据某些实施例的生物反应器底部的透视图;

[0021] 图4是图3的底部的透视图,包括密封于其上的膜;

[0022] 图5是生物反应器组件的透视图,包括壳体、生物反应器底部和过滤底部;

[0023] 图6是根据某些实施例的过滤底部的透视图;

[0024] 图7是根据某些实施例的搅拌器的透视图。

具体实施方式

[0025] 可用于本文的合适的容器或壳体不被具体地限制。为了说明的目的,将详细讨论反应器,特别是生物反应器,其包括可置换的以及可重用的生物反应器。例如,可以使用具有硼硅玻璃筒和PTFE成分的抗溶剂的生物反应器,诸如可从Millipore公司商业购买到的。类似地,可使用利用袋或由半刚性或刚性模制塑料形成的可置换的生物反应器。这种可置换的生物反应器通常是预先消毒的。在生物反应器中搅拌的方法也不具体限制,并且包括基于叶轮的搅拌、磁性搅拌器以及波引起的搅拌和由气泡引起的搅拌。对于防止固体沉降以及堵塞用于纯化的一个或多个膜来说,搅拌是重要的。

[0026] 下文的描述参考生物反应器。本领域技术人员将认识到,其仅用于说明目的,本文所公开的实施例可应用于包含液体样本的任何容器,其具有或最终形成具有相对高固体含量的样本。

[0027] 现在参考图1和图2,示出了生物反应器2被保持在支架4中,该支架4由若干腿6 (在该实施例中是3个腿,但也可以使用一个连续的腿或2个较大腿或多于3个腿)和支撑边缘8组成。如图所示,腿6可在底部或底部附近具有可选的支撑件10,以便当生物反应器2填充在支架4中时保持腿6不外扩。

[0028] 取决于使用的循环或搅拌系统的类型,支架4还可以支撑用于循环机构的驱动机构12 (如图所示),该驱动机构12典型地是搅拌器或叶片组件14。在该特定实施例中,驱动机构12是马达并且通过若干臂18 (尽管示出了 3个臂18,但可以使用其它数目)安装到生物反应器2的顶部16以上的顶部中央。诸如安装块(未示出)等的其它特征可以形成在顶部16或支撑边缘8上,以支撑驱动机构12。如图所示,驱动机构12具有可连接到搅拌器的轴20,如本文以下所述。也可以使用其它支架代替以上所述的设计,并也将同样良好地工作。

[0029] 生物反应器本体22 (在图1中仅部分示出)具有内部空间,流体、细胞、探针和生物反应器的其它装置至少部分地包含在该内部空间中。本体22密封地连接到顶部16。这可以通过机械密封,诸如橡胶垫圈和夹片24 (如图所示)或通过夹具,诸如带环夹或Ladish或TriClover夹具,顶部16和本体22上的配合的螺纹等。或者,它们可以通过顶部16和本体22的粘合剂或热密封而密封或以一件式形成在一起,诸如在滚塑模制设备中。

[0030] 本体22具有从顶部16向下延伸的一个或多个侧壁26。如图所示,一个侧壁26是圆形或圆柱体设计。或者,如果需要,可以是3,4或更多个侧壁(未示出)。

[0031] 优选地,本体22由一件式模制塑料或玻璃制成。或者,其可由通过热、胶或垫圈(未示出)密封在一起的两件或多件塑料或玻璃制成。可用于形成顶部和本体的合适的聚合物包括但不限于聚碳酸酯、聚酯、尼龙、PTFE树脂和其它含氟聚合物、丙烯酸和异丁烯酸树脂和共聚物、聚醚醚酮、聚醚砜、聚芳砜、聚苯乙烯、聚醚酰亚胺、尼龙、聚酯、聚对苯二甲酸乙二酯(PET)、聚氯乙烯、氯化聚氯乙烯、ABS及其合金及混合物、聚烯烃、优选是聚乙烯,诸如线性低密度的聚乙烯、低密度聚乙烯、高密度聚乙烯和超高分子量聚乙烯及其共聚物、聚丙烯及其共聚物和金属茂生成的聚烯烃。优选的聚合物是聚烯烃,特别是聚乙烯及其共聚物,聚苯乙烯和聚碳酸酯。顶部和本体可以按照需要由相同的聚合物或不同的聚合物制成。在可重用的实施例中,本体可由玻璃、丙烯酸树脂或无害于工艺的其它材料制成。如本领域已知的,本体22还可以是可置换的塑料袋。

[0032] 形成于本实施例的生物反应器2中的还有一个或多个端口 30 (在该实施例中,对于总共5个端口,有三种类型30a-c)形成在顶部16,以及一个或多个端口 32形成在本体22中(在该实施例中,对于总共7个端口,至少有两种不同类型的32a-b)。顶部16和本体22可具有多个相似和/或不同类型的端口以在生物反应器2的所需位置上提供所需类型的多个端口。这些端口 30、32或它们的至少一部分形成为顶部16和/或本体22的一部分。它们可以形成有螺纹,该螺纹与可密封的盖配合,该盖例如是封闭的帽、在衬垫内具有通孔的衬垫帽、或各种鲁尔接头。或者,可以通过钻或烧制孔在塑料顶部16和/或本体22上产生一个或多个端口,然后通过或围绕该孔将端口安装(注入通过热结合或粘合剂)在位置上。可以适应很多不同的端口类型和尺寸。

[0033] 端口 30a可以用于液体或气体的入口或出口或用于探针(诸如pH探针)、温度表或热电偶等。端口 30b可用于类似目的。端口 30c用于将在以下更详细描述的搅拌器轴。或者,如果生物反应器是气升式设计并且不使用搅拌器杆,那么端口 30c可用于容纳至本体的底部或接近底部的喷洒器的空气管路,或用于其它所需目的。端口 32a可用于对液体采样,或用于探针采样诸如pH、温度、溶解的氧、乳糖水平等在这种生物反应器上常见的变量。端口 32a尽管在图中示出为形成在侧壁26上,但如果需要也可形成在底部,如图2所示。端口 32b是一种阀端口,其可用于将气体供应到本体22和/或作为从本体的排放口或出口。通过将三位置阀或Y形管与Y形的各臂上的阀(诸如夹阀)相连接来控制流(未示出),则端口可具有这两项功能。用于端口 32b的阀的一种合适的系统是LYNX®连接器,其可从 Millipore Corporat1n of Billerica, Massachusetts 公司获得,在美国专利出版N0.2005/0016620 中示出。

[0034] 优选地,本体的一个或多个端口 32形成在低于生物反应器的正常液体/气体界面水平的位置。

[0035] 如果需要,图1中的一个或多个端口 32a或32b可用于将气体提供到本体内部。塑料过滤器板,诸如P0REX®多孔材料、微孔膜或陶瓷石或烧结的金属过滤器可在本体内连接到端口的内部以提供所需尺寸的气泡。或者,顶部16中的端口 30a可用于保持向下延伸进入本体的管,以提供气体供应。另外,它可使用过滤器板或陶瓷石或烧结的金属过滤器或膜以提供所需的气泡尺寸。或者,气体可以通过搅拌单元组件内的多孔过滤器/膜110被提供到本体的内部,气体的供应可以通过端口 32b提供。

[0036] 图2示出了生物反应器2,顶部16和本体22彼此密封,并且合适的搅拌机构14处于合适位置。示出的搅拌机构由轴40和一个或多个叶片、圆形盘、叶轮、桨叶或类似物42形成。轴40延伸通过端口 30c并连接到驱动机构12的轴20 (未示出)。优选地,端口 30c中的一个或多个O形环允许轴40的移动而不破坏本体22内的密封的完整性。或者,可以通过超声波或在膜或过滤器表面上进行的振动来防止固体聚集在表面上而实现“搅拌”以避免堵塞。防止堵塞过滤器/膜的另一种方法是通过引入粘附于固体的气泡而使固体浮在液相的顶部。

[0037] 根据某些实施例,生物反应器22是圆柱形的管,可移除并密封地附接于底部,用于提供搅拌单元组件。例如,在所示的实施例中,轴40在叶片42以下延伸,通过短轴部分40’,附加了另外的叶片或类似物42’(图7)。叶片42’优选地位于底部中的膜110 (以下讨论)之上,以便避免与可能损坏它的膜的接触。这样定位,其可以搅拌膜之上的流体并防止固体(例如,亲和珠、析出物或浮物)沉降在膜上,这种沉降可能阻塞或堵塞膜的孔。优选地,叶片足够地宽,使得其基本对应于膜的有效直径的宽度,或稍小于该宽度,以便在膜的有效过滤面积上提供均匀的流体搅拌。在某些实施例中,叶片42’可以由适当的材料构成,诸如橡胶或类似海绵的材料,使得在搅拌期间与膜的表面的接触不会损伤膜,并且是可接受的,以便进一步确保固体不沉降在膜表面上。本领域技术人员将认识到,除了叶片之外的合适的装置,诸如充分地搅拌本体22的内部空间中的流体的圆形盘或波搅拌器也在本文公开的实施例的范围内。

[0038] 参考图3,示出了生物反应器底部100,其包括支撑表面101,该表面形成有用于流或流体的槽102或类似物。不具体限制槽102的构造,但优选的构造是所示的同心圆。槽102与孔口 103流体连通,该孔口与端口 32b流体连通,用于从底部100排出流体。

[0039] 底部100的表面101支撑一个或多个膜110 (图4)。优选地,一个或多个膜中的一个是相对粗糙的过滤器或膜,特别是当液的固体含量高(诸如固体体积含量大约20-35%)时。使用粗糙的过滤器或膜作为初始过滤步骤可帮助保护并延长接下来通过更密的通常更昂贵的膜进行的下游过滤的寿命,该更昂贵的膜例如是0.2微米消毒级别的膜(以下更详细论述)。合适的膜包括但不限于,聚合物,包括但不限于烯烃,诸如聚乙烯,包括超高分子量的聚乙烯、聚丙烯、EVA共聚物和α烯烃,金属茂烯烃聚合物,PFA,MFA,PTFE,聚碳酸酯,乙烯共聚物,诸如PVC,聚酰胺,诸如尼龙,聚酯,纤维素,醋酸纤维素,再生纤维素,纤维素合成物,聚砜、聚醚砜、聚芳砜、聚苯砜、聚丙烯腈,聚偏氟乙烯(PVDF)及其混合物。所选的膜依赖于应用、所需的过滤特性、所过滤的颗粒类型和尺寸以及所需的流。优选的基于过滤器的膜包括可从 Millipore Corporat1n of Billerica Massachusetts 购买的 DURAPORE®PVDF 膜,可从 Millipore Corporat1n of Billerica Massachusetts 购买的 MILLIPOREEXPRESS®和MILLIPORE EXPRESS® PLUS或SH PES膜。在这些实施例中也可以使用预过滤器、深度过滤器及类似物,诸如可从Millipore Corporat1n of Billerica Massachusetts购买的Polygard®预过滤器(Polygard CE预过滤器)和深度过滤器(Polygard CR深度过滤器)。

[0040] 取决于混合物、聚合物和生物分子的性质,过滤器可以是亲水的或疏水的。优选的过滤器是亲水的并且在蛋白质结合方面较低。

[0041] 过滤器,是膜或其它,在其深度上孔的尺寸可以是对称的,诸如可以从MilliporeCorporat1n of Billerica Massachusetts购买的DURAPORE® PVDF膜,或在其厚度上孔的尺寸可以是非对称的,例如可从Millipore Corporat1n of Billerica Massachusetts购买的 MILLIPORE EXPRESS® 和 MILLIPORE EXPRESS® PLUS 或 SH PES 膜。如果需要的话,其可包含预过滤器层,作为单独的上游层或作为膜本身的一体的上游部分。

[0042] 依赖于产生的颗粒的尺寸,膜可以是超过滤膜。例如,在颗粒尺寸与微孔膜的孔尺寸相比较小时,带有较小孔(在UF范围内)的膜将是更合适的,以避免堵塞。适当的超过滤膜包括再生纤维素和聚醚砜膜,包括孔尺寸大于0.2微米的膜,例如,孔尺寸为0.45,0.65、1.0,2.0微米或更大的膜。可选地,带孔的支撑体(未示出)可以放置在底部的表面101和膜110之间。膜(以及支撑体,如果有的话)利用O形环106密封在底部上,该O形环106通过支撑环107 (诸如丙烯酸树脂环)保持在位置上。在使用多于一个膜110的情况下,这些膜可以堆叠的关系组装。在使用多于一个膜的情况下,每个膜不需要是相同的性能特性(例如,孔尺寸,通量,容量,表面化学性质等)。例如,靠着叶片42’的上膜可以是比下膜有更大的孔尺寸,和/或可与下膜具有不同的材料。

[0043] 生物反应器本体22,诸如圆柱形管,放置成与底部100成密封关系,如图5所示。可以提供多个腿6’,这些腿6’从底部100向下延伸,以支撑底部100。

[0044] 在某些实施例中,如果需要附加的纯化,则可以将另外的过滤器底部加到组件中,如图5和图6所示。因此,提供底部100’,类似于底部100,其也带有具有适当槽的支撑表面,一个或多个膜密封地支撑于其上,诸如通过适当的O形环和支撑环。例如,可以使用消毒膜,诸如0.2微米膜(可选地带有适当的有孔支撑体)。密封到过滤器底部100’的是壳体22’,其提供了生物反应器底部100和过滤器底部100’之间的腔或内部空间。壳体22’可以是圆柱形的管,优选具有与生物反应器壳体22相同的直径,并由相同材料制成。它应该具有足以容纳至少一部分体积的直接从生物反应器接收到的将要纯化的流体的高度。壳体22’的顶部边缘优选径向向内突出,并优选包括O形环106’,使得壳体22’和底部100能够以密封的关系附接。可以提供多个腿6’’,从底部100’向下延伸,以支撑组件。尽管优选过滤器底部100’与生物反应器组件一体以形成一件式反应器组件用于样本处理和直接纯化,但在某些实施例中,该接下来的纯化步骤可以利用与生物反应器本体22物理分离的过滤器(尽管该过滤器可选地与生物反应器本体22流体连通)实现。

[0045] 壳体22’包括入口端口 50,该端口 50可以放置为(诸如通过合适的管5’)与底部100的出口 32b流体连通。过滤器底部100’包括出口端口 32b’,该端口 32b’与底部中的排放口(未示出)流体连通,用于将所需的生物分子引导到适当的使用点,诸如进一步的纯化步骤(例如,层析工艺流程)。

[0046] 替代性实施例具有与底部100的出口 32流体连通的第二壳体22’的出口,但具有不含有过滤器或膜的第二壳体。相反,出口端口 32’通过管或其它管道(未示出)与自包含的过滤器装置(未示出,诸如Millex®过滤器,或Optiscale®或Opticap®过滤器)流体连通,这些过滤器然后对所需的生物分子消毒过滤。然后,该过滤器装置的出口连接到适当的使用点,诸如进一步纯化的步骤(例如,层析工艺流程)。

[0047] 适当地或期望地,适当的阀和检测装置可以与各种入口和出口中的一个或多个连接,以检测或测量和控制流或任何其它性质,诸如生物分子的存在或杂质的存在。例如,在细胞培养阶段,底部100的出口 32b关闭,使得当气体通过端口 32a或30a施加的时候,流体保持在本体22中。

[0048] 在聚合物添加到细胞培养液以选择性地和可释放地结合所需生物分子的某些实施例中,适当的聚合物包括聚(N乙烯基己内酰胺)、聚(N丙烯酰基哌啶)、聚(N乙烯基异丁酰胺)、聚(N取代丙烯酰胺),包括聚(N异丙基丙烯酰胺)、聚(N,N’ 二甲基丙烯酰胺)和聚(N丙烯酰N烷基哌嗪)、羟烷基纤维素、丙烯酸和甲基丙烯酸的共聚物、2或4乙烯基吡啶和壳聚糖的聚合物和共聚物,带有配体或功能团附接于其上。

[0049] 适当的所需生物分子包括蛋白质和抗体。适当的抗体包括从重组抗体、重组单克隆抗体、多克隆抗体、人源化抗体和抗体片段组成的组中选择的抗体。

[0050] 操作中,消毒装置放置在支架中,并且用于空气、液体、探针、采样等的各种连接件在适当的端口连接到该装置。该装置填充有期望水平的介质,形成液体/空气界面,在该界面之下顶部16连接到本体22以留出气体的头部空间,这在该装置中是常见的。至少一个端口 32位于界面水平以下。

[0051] 然后用要培养的有机体来种植介质,其可以是植物、动物细胞(例如CHO或NSO细胞)、病毒、酵母、霉或细菌(诸如E.coli),循环或搅拌液体,空气/气体和液体以在内部有效地培养培养物的方式进入装置或从装置移出。

[0052] 加入在一定的工艺条件下可溶的聚合物,导致在条件(例如,温度,盐浓度,光,电场或PH值)改变下不可溶并析出溶液。或者,可以添加亲和或离子交换珠或具有能够纯化生物分子的配体或功能的珠,以结合到所需生物分子或结合到可溶杂质。继续搅拌,以防止固体沉降,并且固体(在该实施例中包括包含聚合物、杂质的析出物,诸如细胞和细胞碎片、宿主细胞蛋白质、DNA及相似物和所需生物分子)可以被洗涤一次或多次(诸如在适当的缓冲液中)以确保在液体中的或俘获在聚合物中的任何杂质都被移除。洗涤步骤可以由通过底部100中的一个或多个膜进行的过滤来实现,上清液通过端口 32b发送至废品。

[0053] 然后可以回收所需的生物分子,诸如通过改变离子强度和/或溶液的pH条件选择性地使目标生物分子从析出物(或珠)洗提出来,而杂质(包括可溶和不可溶的材料)以析出的聚合物保持复合。优选地,诸如通过将底部100的出口连接到本体22’的入口 50而使过滤底部100’与底部100流体连通,回收与消毒过滤步骤一起进行。相应地,来自底部100的出口的渗透物进入本体22’,使膜110’变湿,通过膜110’进行过滤。然后通过底部100’的出口端口 32b’在洗提池中回收纯化的所需生物分子。析出的聚合物-杂质复合物(或亲和珠)可以被丢弃。过滤的驱动力可以是压力或真空。

Claims (9)

1.用于培养或处理流体样本的组件,包括: 具有内部空间的第一容器,适于密封地连接到所述第一容器并支撑至少一个第一膜的第一底部,所述至少一个第一膜密封到所述第一底部以过滤所述流体样本,所述至少一个第一膜具有第一孔尺寸; 在所述第一底部中的用于所述过滤后的流体样本的出口; 适于与所述第一底部的出口流体连通的第二容器,适于密封地连接到所述第二容器的第二底部,所述第二底部包括第二膜,其具有小于所述第一孔尺寸的第二孔尺寸,包括用于流体流动的槽的支撑表面,以及设置在所述内部空间中以搅拌所述流体样本的搅拌器,其中,所述搅拌器刚好位于所述膜之上,并且防止固体沉降在所述膜上, 所述支撑表面是平的支撑表面, 所述槽在所述支撑表面中并且从所述支撑表面凹入。
2.如权利要求1所述的组件,其中,所述第二容器支撑至少一个膜。
3.如权利要求1所述的组件,其中,所述第一容器是生物反应器。
4.如权利要求1所述的组件,还包括在所述第一容器的本体内的搅拌器,以搅拌所述样本。
5.一种利用权利要求1所述的组件从包含杂质的混合物中纯化生物分子的方法,包括: a.提供在一定条件下的混合物, b.加入一种或多种聚合物,所述聚合物在所述一定条件下可溶于所述混合物,并能够可逆地并有选择地结合到生物分子, c.在所述混合物中混合所述一种或多种溶解的聚合物, d.通过改变所述混合物中的条件,使所述一种或多种聚合物以及结合的生物分子从溶液析出, e.通过使用洗涤溶液接触所述析出物而洗涤所述析出物并通过第一底部的膜过滤上清液, f.从所述聚合物回收结合的生物分子并且通过第二底部的膜过滤所述生物分子。
6.如权利要求5所述的方法,其中,对所述上清液的所述过滤和对所述生物分子的所述过滤在相同的装置中实施。
7.如权利要求5所述的方法,其中,所述生物分子是从重组抗体、多克隆抗体、人源化抗体和抗体片段组成的组中选择的抗体。
8.如权利要求5所述的方法,其中,所述生物分子是蛋白质。
9.如权利要求7所述的方法,其中,所述重组抗体是重组单克隆抗体。
CN200980150670.9A 2008-12-16 2009-12-08 搅拌槽反应器及方法 CN102257122B (zh)

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