技术领域technical field
本发明涉及一种膜包的完整性检测方法，尤其是一种超滤膜膜包的完整性检测方法。The invention relates to a method for detecting the integrity of a membrane bag, in particular to a method for detecting the integrity of an ultrafiltration membrane bag.
背景技术Background technique
膜分离技术依据药效活性与其分子结构及分子量水平密切相关的特性，通过选用不同截留特性的膜组件构成膜分离系统对有效成分进行分离、浓缩、纯化。操作通常以压力为推动力，可在常温下完成，无需添加其它物质，具有高选择性的优点。Membrane separation technology is based on the characteristics closely related to the pharmacodynamic activity and its molecular structure and molecular weight level, and uses membrane components with different cut-off characteristics to form a membrane separation system to separate, concentrate and purify the active ingredients. The operation is usually driven by pressure and can be completed at room temperature without adding other substances, which has the advantage of high selectivity.
膜分离包括微滤，超滤与纳滤，都是以压强差为推动力的过程，其分离机理是膜孔对流体中微粒进行筛分。微滤膜是(MF)指孔径在0.1-10um间，超滤膜(UF)孔径0.01-0.1um间，纳滤膜(NF)孔径一般在0.001-0.05um间。通常病毒的粒径一般介于0.01-0.08um，菌液、病毒具有较小的相对分子量，因此使用超滤膜浓缩抗原，效果好，稳定性强，适于一定规模的生产使用。Membrane separation includes microfiltration, ultrafiltration and nanofiltration, all of which are driven by pressure difference. The separation mechanism is that the membrane pores screen the particles in the fluid. The microfiltration membrane (MF) refers to the pore size between 0.1-10um, the ultrafiltration membrane (UF) has a pore size between 0.01-0.1um, and the nanofiltration membrane (NF) generally has a pore size between 0.001-0.05um. Usually, the particle size of the virus is generally between 0.01-0.08um, and the bacterial liquid and virus have a relatively small molecular weight. Therefore, the use of ultrafiltration membranes to concentrate antigens has good effects and strong stability, and is suitable for production and use on a certain scale.
超滤膜筛分过程，以膜两侧的压力差为驱动力，以超滤膜为过滤介质，在一定的压力下，当原液流过膜表面时，超滤膜表面密布的许多细小的微孔只允许水及小分子物质通过而成为透过液，而原液中体积大于膜表面微孔径的物质则被截留在膜的进液侧，成为浓缩液，因而实现对原液的净化、分离和浓缩的目的。The ultrafiltration membrane screening process uses the pressure difference on both sides of the membrane as the driving force and the ultrafiltration membrane as the filter medium. The pores only allow water and small molecular substances to pass through and become the permeate, while the substances in the original solution that are larger than the micropore diameter of the membrane surface are trapped on the liquid inlet side of the membrane and become concentrated solution, thus realizing the purification, separation and concentration of the original solution the goal of.
在使用超滤膜膜包对抗原进行浓缩时，完整的膜包能将水分子渗透出去，富集抗原微粒达到浓缩目的。When the antigen is concentrated using the ultrafiltration membrane membrane package, the complete membrane package can permeate the water molecules and enrich the antigen particles to achieve the purpose of concentration.
超滤膜分离技术有着产品收率高、效率高、能耗低、操作简单、环境友好等优势，在传统药品生产中呈现显著的技术优势，但是由于膜特殊的高分子结构，再生、清洗、利用频率较高，会出现膜渗漏现象。事实上，由于构成膜分离系统的膜组件安装管路复杂，连接点较多，因此为膜工作过程中出现异常时，对分离系统的查漏工作比较困难。Ultrafiltration membrane separation technology has the advantages of high product yield, high efficiency, low energy consumption, simple operation, and environmental friendliness. It presents significant technical advantages in traditional pharmaceutical production. However, due to the special polymer structure of the membrane, regeneration, cleaning, If the frequency of use is high, membrane leakage will occur. In fact, due to the complex installation pipelines and many connection points of the membrane modules that make up the membrane separation system, it is difficult to check for leaks in the separation system when an abnormality occurs during the membrane operation.
膜包的完整性是保证分离效果的前提，而膜包纤维的完整性检测大都依赖于膜包厂家的检测方法，而实际应用中发现厂家检测方法检测合格的膜包，对病毒分离效果仍然不好。事实上用于病毒分离，对膜包的要求较高，膜纤维细微的破损会造成病毒泄露，从而造成抗原损失和对环境的污染。The integrity of the membrane package is the premise to ensure the separation effect, and the integrity detection of the membrane package fiber mostly depends on the detection method of the membrane package manufacturer, but in actual application, it is found that the membrane package that is qualified by the manufacturer’s detection method is still not effective for virus separation. good. In fact, when used for virus isolation, the requirements for the membrane package are relatively high, and slight damage to the membrane fibers will cause virus leakage, resulting in antigen loss and environmental pollution.
目前膜完整性检测，一般按照设备厂家提供的方法进行泡点试验法检测。打开完整性测试装置的气源，对系统加压。在系统加压过程中，完整性测试装置上显示的空气流速首先将提高，然后下降至一个稳定的流速。测量到的这个稳定的流速就是空气前进流(扩散流)，如果这个稳定的流速，降低到了可接受规范之下，并且与先前的量值一致，那么说明通过了膜完整性测试。At present, the integrity of the membrane is generally detected by the bubble point test method according to the method provided by the equipment manufacturer. Turn on the air supply to the integrity test device to pressurize the system. During system pressurization, the air flow rate displayed on the integrity test device will initially increase and then decrease to a steady flow rate. This measured steady flow rate is the air forward flow (diffuse flow). If this steady flow rate drops below the acceptable specification and is consistent with the previous value, then the membrane integrity test is passed.
设备厂家提供的具体检测方法如下：The specific detection methods provided by the equipment manufacturer are as follows:
在对膜堆进行完整性检测之前，系统应该经过充分的清洗和冲洗，残留的清洁剂会对结果有很大的影响。确定系统清洗好，膜已经完全湿透后，将系统内的水排空，将压力可调的气源接在膜堆的进口或回流口，将没有接气源的进口或回流口封闭，透过液口是开放的。慢慢加压到指定气压，然后稳定5分钟让残留水排出。测量并记录气压、温度和从透过口出来的气体流量，气体流量可用气体流量剂测量，比较检测的流量和规定的指标，如果超滤膜不完整，其所测得空气流量将大大超过表中流速指标的上限。The system should be thoroughly cleaned and flushed before performing an integrity test on the membrane stack, as residual cleaning agents can have a significant impact on the results. After confirming that the system is cleaned well and the membrane is completely wetted, drain the water in the system, connect the pressure-adjustable air source to the inlet or return port of the membrane stack, and close the inlet or return port that is not connected to the air source. The liquid outlet is open. Slowly pressurize to the specified air pressure, then stabilize for 5 minutes to allow residual water to drain. Measure and record the air pressure, temperature and the gas flow from the permeation port. The gas flow can be measured with a gas flow agent. Compare the detected flow with the specified index. If the ultrafiltration membrane is not complete, the measured air flow will greatly exceed the table. The upper limit of the medium flow rate index.
也有的报道用噪音检测法，但由于切向流过滤的压力和流速较大，噪音检测的方法不可取。Some reports use the noise detection method, but due to the high pressure and flow rate of tangential flow filtration, the noise detection method is not advisable.
发明内容Contents of the invention
本发明所要解决的技术问题是，提供一种在线检测方法，能检测膜包是否破损的超滤膜膜包的完整性检测方法。The technical problem to be solved by the present invention is to provide an online detection method, which can detect whether the membrane bag is damaged or not.
为了解决上述技术问题，本发明采用的技术方案是：一种超滤膜膜包的完整性检测方法，包括以下步骤：In order to solve the above-mentioned technical problems, the technical solution adopted in the present invention is: a method for detecting the integrity of an ultrafiltration membrane membrane bag, comprising the following steps:
(1)首先对新膜包按照厂家标准操作方法正确安装，开启机器，待运转稳定后，进行检测；(1) First, install the new film bag correctly according to the manufacturer's standard operation method, turn on the machine, and perform inspection after the operation is stable;
(2)进行检测时，将含有作为标示抗原的新城疫病毒和需要分离的抗原的抗原液经过超滤膜膜包，取膜包渗出液，对取出的渗透液做HA检测(红细胞凝集试验)，测血凝价HA，如果HA＞3log2，说明超滤膜膜包不完整，检测结束；如果HA≤3log2，继续进行下面步骤(3)检测；(2) When testing, the antigen solution containing the Newcastle disease virus as the labeled antigen and the antigen to be separated is passed through the ultrafiltration membrane membrane bag, the membrane bag exudate is taken, and the HA detection (erythrocyte agglutination test) is performed on the infiltrate taken out ), measure the blood coagulation value HA, if HA>3log2, it means that the ultrafiltration membrane membrane package is incomplete, and the detection is over; if HA≤3log2, proceed to the following step (3) detection;
(3)取十日龄无特定抗体的鸡胚10个，其中8个胚每胚尿囊内接种膜包渗出液0.2ml，留2枚作对照，接种后37℃培养120小时，每日照鸡胚，观察2次，如果胚非特异性死亡不超过1个，期间发现死亡的胚立刻置于2-8℃保存，120小时后进行下面步骤(4)检测；(3) Take 10 chicken embryos without specific antibodies at the age of ten days, among which 8 embryos were inoculated with 0.2ml of membrane-packed exudate in the allantois of each embryo, and 2 embryos were reserved as controls. Chicken embryos, observed twice, if no more than one embryo died non-specifically, the dead embryos were found to be stored at 2-8°C immediately, and the following step (4) was tested after 120 hours;
(4)对所有鸡胚取胚液测定血凝价HA，如果HA≤3log2，说明超滤膜膜包的完整，如果HA＞3log2，说明超滤膜膜包的不完整。(4) Measure the hemagglutination value HA for all chicken embryos. If HA≤3log2, it indicates that the ultrafiltration membrane capsule is complete, and if HA>3log2, it indicates that the ultrafiltration membrane capsule is incomplete.
所述抗原液中新城疫病毒抗原液按体积比计占0.5-1％。The Newcastle disease virus antigen solution accounts for 0.5-1% by volume in the antigen solution.
所述需要分离的抗原为禽流感病毒或鸡新城疫病毒。The antigen to be isolated is avian influenza virus or chicken Newcastle disease virus.
本发明的有益效果是：利用病毒的敏感性，以及病毒对红细胞的凝集作用，通过检测凝集价，判定膜包的完整性，方法简单易行，相比厂家的方法更精确，可用于单个膜包的检测，多个膜包以及系统的检测。用病毒的效价检测膜的完整性，检测方法简便易行，并且不用停止生产。The beneficial effects of the present invention are: the sensitivity of the virus and the agglutination of the virus to red blood cells are used to determine the integrity of the membrane package by detecting the agglutination value. Detection of packs, detection of multiple membrane packs and systems. The integrity of the membrane is detected by the titer of the virus, and the detection method is simple and easy, and there is no need to stop production.
具体实施方式Detailed ways
下面结合具体实施方式对本发明作进一步详细说明：Below in conjunction with specific embodiment the present invention is described in further detail:
本发明的超滤膜膜包的完整性检测方法，包括以下步骤：The integrity detection method of the ultrafiltration membrane membrane bag of the present invention comprises the following steps:
(1)首先对新膜包按照厂家标准操作方法正确安装，开启机器，待运转稳定后，进行检测；(1) First, install the new film bag correctly according to the manufacturer's standard operation method, turn on the machine, and perform inspection after the operation is stable;
(2)进行检测时，将含有作为标示抗原的新城疫病毒和需要分离的抗原的抗原液经过超滤膜膜包，取膜包渗出液，对取出的渗透液做HA检测(红细胞凝集试验)，测血凝价HA，如果HA＞3log2，说明超滤膜膜包不完整，检测结束；如果HA≤3log2，继续进行下面步骤(3)检测；(2) When testing, the antigen solution containing the Newcastle disease virus as the labeled antigen and the antigen to be separated is passed through the ultrafiltration membrane membrane bag, the membrane bag exudate is taken, and the HA detection (erythrocyte agglutination test) is performed on the infiltrate taken out ), measure the blood coagulation value HA, if HA>3log2, it means that the ultrafiltration membrane membrane package is incomplete, and the detection is over; if HA≤3log2, proceed to the following step (3) detection;
(3)取十日龄无特定抗体的鸡胚10个，其中8个胚每胚尿囊内接种膜包渗出液0.2ml，留2枚作对照，接种后37℃培养120小时，每日照鸡胚，观察2次，如果胚非特异性死亡不超过1个，期间发现死亡的胚立刻置于2-8℃保存，120小时后进行下面步骤(4)检测；(3) Take 10 chicken embryos without specific antibodies at the age of ten days, among which 8 embryos were inoculated with 0.2ml of membrane-packed exudate in the allantois of each embryo, and 2 embryos were reserved as controls. Chicken embryos, observed twice, if no more than one embryo died non-specifically, the dead embryos were found to be stored at 2-8°C immediately, and the following step (4) was tested after 120 hours;
(4)对所有鸡胚取胚液测定血凝价HA，如果HA≤3log2，说明超滤膜膜包的完整，如果HA＞3log2，说明超滤膜膜包的不完整。(4) Measure the hemagglutination value HA for all chicken embryos. If HA≤3log2, it indicates that the ultrafiltration membrane capsule is complete, and if HA>3log2, it indicates that the ultrafiltration membrane capsule is incomplete.
所述抗原液中新城疫病毒抗原液按体积比计占0.5-1％。The Newcastle disease virus antigen solution accounts for 0.5-1% by volume in the antigen solution.
所述需要分离的抗原为禽流感病毒或鸡新城疫病毒。The antigen to be isolated is avian influenza virus or chicken Newcastle disease virus.
鸡新城疫病毒病毒(NDV)属于副粘病毒科，副粘病毒属，核酸为单链RNA。成熟的病毒粒子呈球形，直径为120-300nm。由螺旋形对称盘绕的核衣壳和囊膜组成。囊膜表面有放射状排列的纤突，其中含有神经氨酸酶，因此病毒能吸附在禽类的红血球表面，引起红血球的凝集。新城疫病毒的半数感染量EID50：每0.1ml病毒含量≥108EID50。鸡新城疫病毒的粒径较小，据有凝血性，稀释较高滴度时仍有灵敏的凝血现象，同时由于检测方法简单易行，可作为灵敏的指示剂。Newcastle disease virus (NDV) belongs to the family Paramyxoviridae, the genus Paramyxovirus, and its nucleic acid is single-stranded RNA. Mature virions are spherical with a diameter of 120-300nm. It consists of a helical and symmetrically coiled nucleocapsid and an envelope. There are radially arranged fibrils on the surface of the capsule, which contain neuraminidase, so the virus can be adsorbed on the surface of red blood cells of poultry, causing agglutination of red blood cells. Half infectious dose of Newcastle disease virus EID50 : every 0.1ml virus content ≥ 108 EID50 . The particle size of chicken Newcastle disease virus is small, it is said to have coagulation, and it still has sensitive coagulation phenomenon when it is diluted to a higher titer. At the same time, because the detection method is simple and easy, it can be used as a sensitive indicator.
而对抗原含量测定时以通过红细胞凝集试验，检测HA效价为主。并且测定简便、快捷、易行，在生产中便于实行。The determination of the antigen content is mainly through the hemagglutination test to detect the titer of HA. And the determination is simple, quick and easy, and it is easy to implement in production.
下面具体进行说明：The following is a detailed description:
测定血凝价HA的方法，又称红细胞凝集试验法，详见《中华人民共和国兽用生物制品规程》2000年版红细胞凝集试验。The method for determining the hemagglutination value of HA, also known as the red blood cell agglutination test, is detailed in the "Regulations of the People's Republic of China for Veterinary Biological Products" 2000 edition of the red blood cell agglutination test.
所采用膜包购于颇尔公司，膜包的截留分子量100kd，本超滤膜堆，截留分子量10万分子量，有效过滤面积为0.5m2，压力0.6MPa。The membrane package used was purchased from Pall Company. The molecular weight cut-off of the membrane package is 100kd. The ultrafiltration membrane stack has a molecular weight cut-off of 100,000 molecular weight, an effective filtration area of 0.5m2 , and a pressure of 0.6MPa.
另外，可以对新膜包按照标准操作方法正确安装，开启机器，待运转稳定后，取下流渗出液，分别测血凝价HA，作为完整性的参照值。下述实施例中的百分比为体积百分比。In addition, the new membrane package can be installed correctly according to the standard operation method, turn on the machine, and after the operation is stable, remove the outflow exudate, and measure the blood coagulation value HA separately, as a reference value for integrity. The percentages in the following examples are volume percentages.
实施例1Example 1
(1)首先对新膜包按照厂家标准操作方法正确安装，开启机器，待运转稳定后，进行检测；(1) First, install the new film bag correctly according to the manufacturer's standard operation method, turn on the machine, and perform inspection after the operation is stable;
(2)进行检测时，将含有0.5％作为标示抗原的新城疫病毒和99.5％需要分离的禽流感病毒的抗原液经过超滤膜膜包，取膜包渗出液10ml，对取出的渗透液做HA检测(红细胞凝集试验)，测血凝价HA，如果HA＞3log2，说明超滤膜膜包不完整，检测结束；如果HA≤3log2，继续进行下面步骤(3)检测；(2) When testing, the antigen solution containing 0.5% of Newcastle disease virus and 99.5% of the avian influenza virus that needs to be separated is passed through the ultrafiltration membrane membrane bag, and 10 ml of the membrane bag exudate is taken, and the permeate that is taken out Do HA detection (erythrocyte agglutination test), measure blood coagulation value HA, if HA>3log2, it means that the ultrafiltration membrane membrane package is incomplete, and the detection is over; if HA≤3log2, continue to the following step (3) detection;
(3)取十日龄无特定抗体的鸡胚10个，其中8个胚每胚尿囊内接种膜包渗出液0.2ml，留2枚作对照，接种后37℃培养120小时，每日照鸡胚，观察2次，如果胚非特异性死亡不超过1个，期间发现死亡的胚立刻置于2-8℃保存，120小时后进行下面步骤(4)检测；(3) Take 10 chicken embryos without specific antibodies at the age of ten days, among which 8 embryos were inoculated with 0.2ml of membrane-packed exudate in the allantois of each embryo, and 2 embryos were reserved as controls. Chicken embryos, observed twice, if no more than one embryo died non-specifically, the dead embryos were found to be stored at 2-8°C immediately, and the following step (4) was tested after 120 hours;
(4)对所有鸡胚取胚液(尿囊液和羊水)测定血凝价HA，如果HA≤3log2，说明超滤膜膜包的完整，如果HA＞3log2，说明超滤膜膜包的不完整。(4) Determination of hemagglutination value HA for all chicken embryos with embryo fluid (allantoic fluid and amniotic fluid). If HA≤3log2, it indicates that the ultrafiltration membrane package is complete. If HA>3log2, it indicates that the ultrafiltration membrane package is not good. whole.
实施例2Example 2
(1)首先对新膜包按照厂家标准操作方法正确安装，开启机器，待运转稳定后，进行检测；(1) First, install the new film bag correctly according to the manufacturer's standard operation method, turn on the machine, and perform inspection after the operation is stable;
(2)进行检测时，将含有1％作为标示抗原的新城疫病毒和99％需要分离的禽流感病毒的抗原液经过超滤膜膜包，取膜包渗出液10ml，对取出的渗透液做HA检测(红细胞凝集试验)，测血凝价HA，如果HA＞3log2，说明超滤膜膜包不完整，检测结束；如果HA≤3log2，继续进行下面步骤(3)检测；(2) When testing, the antigen solution containing 1% of the Newcastle disease virus and 99% of the avian influenza virus that needs to be separated is passed through the ultrafiltration membrane membrane bag, and the membrane bag exudate 10ml is taken out, and the permeate that is taken out Do HA detection (erythrocyte agglutination test), measure blood coagulation value HA, if HA>3log2, it means that the ultrafiltration membrane membrane package is incomplete, and the detection is over; if HA≤3log2, continue to the following step (3) detection;
(3)取十日龄无特定抗体的鸡胚10个，其中8个胚每胚尿囊内接种膜包渗出液0.2ml，留2枚作对照，接种后37℃培养120小时，每日照鸡胚，观察2次，如果胚非特异性死亡不超过1个，期间发现死亡的胚立刻置于2-8℃保存，120小时后进行下面步骤(4)检测；(3) Take 10 chicken embryos without specific antibodies at the age of ten days, among which 8 embryos were inoculated with 0.2ml of membrane-packed exudate in the allantois of each embryo, and 2 embryos were reserved as controls. Chicken embryos, observed twice, if no more than one embryo died non-specifically, the dead embryos were found to be stored at 2-8°C immediately, and the following step (4) was tested after 120 hours;
(4)对所有鸡胚取胚液(尿囊液和羊水)测定血凝价HA，如果HA≤3log2，说明超滤膜膜包的完整，如果HA＞3log2，说明超滤膜膜包的不完整。(4) Determination of hemagglutination value HA for all chicken embryos with embryo fluid (allantoic fluid and amniotic fluid). If HA≤3log2, it indicates that the ultrafiltration membrane package is complete. If HA>3log2, it indicates that the ultrafiltration membrane package is not good. whole.
实施例3Example 3
(1)首先对新膜包按照厂家标准操作方法正确安装，开启机器，待运转稳定后，进行检测；(1) First, install the new film bag correctly according to the manufacturer's standard operation method, turn on the machine, and perform inspection after the operation is stable;
(2)进行检测时，将新城疫病毒的抗原液经过超滤膜膜包，取膜包渗出液10ml，对取出的渗透液做HA检测(红细胞凝集试验)，测血凝价HA，如果HA＞3log2，说明超滤膜膜包不完整，检测结束；如果HA≤3log2，继续进行下面步骤(3)检测；(2) When testing, put the antigen solution of Newcastle disease virus through the ultrafiltration membrane membrane bag, take 10ml of membrane bag exudate, do HA detection (erythrocyte agglutination test) on the taken out infiltration fluid, measure the hemagglutination value HA, if HA>3log2, indicating that the ultrafiltration membrane membrane package is incomplete, and the detection is over; if HA≤3log2, continue to the following step (3) detection;
(3)取十日龄无特定抗体的鸡胚10个，其中8个胚每胚尿囊内接种膜包渗出液0.2ml，留2枚作对照，接种后37℃培养120小时，每日照鸡胚，观察2次，如果胚非特异性死亡不超过1个，期间发现死亡的胚立刻置于2-8℃保存，120小时后进行下面步骤(4)检测；(3) Take 10 chicken embryos without specific antibodies at the age of ten days, among which 8 embryos were inoculated with 0.2ml of membrane-packed exudate in the allantois of each embryo, and 2 embryos were reserved as controls. Chicken embryos, observed twice, if no more than one embryo died non-specifically, the dead embryos were found to be stored at 2-8°C immediately, and the following step (4) was tested after 120 hours;
(4)对所有鸡胚取胚液(尿囊液和羊水)测定血凝价HA，如果HA≤3log2，说明超滤膜膜包的完整，如果HA＞3log2，说明超滤膜膜包的不完整。(4) Determination of hemagglutination value HA for all chicken embryos with embryo fluid (allantoic fluid and amniotic fluid). If HA≤3log2, it indicates that the ultrafiltration membrane package is complete. If HA>3log2, it indicates that the ultrafiltration membrane package is not good. whole.
综上所述，本发明的内容并不局限在上述的实施例中，相同领域内的有识之士可以在本发明的技术指导思想之内可以轻易提出其他的实施例，但这种实施例都包括在本发明的范围之内。In summary, the content of the present invention is not limited to the above-mentioned embodiments, people of insight in the same field can easily propose other embodiments within the technical guidance of the present invention, but this embodiment All are included within the scope of the present invention.
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 201110360538CN102430340B (en) | 2011-11-15 | 2011-11-15 | Method for testing integrity of ultra-filtration membrane envelope |
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 201110360538CN102430340B (en) | 2011-11-15 | 2011-11-15 | Method for testing integrity of ultra-filtration membrane envelope |
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| CN102430340Btrue CN102430340B (en) | 2013-09-18 |
| Application Number | Title | Priority Date | Filing Date |
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| CN 201110360538ActiveCN102430340B (en) | 2011-11-15 | 2011-11-15 | Method for testing integrity of ultra-filtration membrane envelope |
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