Method and system for sterilizing and filtering high-viscosity liquid medicine

Abstract

The invention discloses a method and a system for sterilizing and filtering high-viscosity liquid medicine, relates to the technical field of sterilizing and filtering, and solves the problems of low filtering efficiency, prolonged filtering time, increased filtering pressure in a high-resistance filtering process, low filtering cost and the like caused by high viscosity of the liquid medicine and high possibility of blocking a filtering membrane during filtering in the traditional sterile filtering method. The filter membrane is easy to damage. The method comprises the following steps: carrying out shearing dispersion treatment on a non-sterile high-viscosity liquid medicine; sequentially carrying out pre-filtering treatment and degerming filtering treatment on the liquid medicine subjected to shearing and dispersing treatment; a hydrophilic filter element is adopted in the pre-filtering treatment, and a hydrophilic degerming-grade filter element is adopted in the degerming filtering treatment; the aperture of the filter element subjected to pre-filtration treatment is larger than that of the filter element subjected to degerming filtration treatment; according to the invention, the viscosity of the high-viscosity liquid medicine is effectively reduced, the high-efficiency filtration of the high-viscosity liquid medicine is realized, the filtration efficiency is improved, the filter element is not easy to block, and the damage to the filter element is reduced.

Description

Technical Field

[0001] The invention relates to the technical field of sterilization and filtration, and in particular to a method and system for sterilization and filtration of a high-viscosity liquid medicine. Background Art

[0002] In the pharmaceutical field, for heat-unstable and high-viscosity drug liquids, existing aseptic processes usually use physical interception methods to remove microorganisms in the liquid. The industry generally uses sterilizing-grade filters with a pore size of 0.22 microns or smaller for filtration to meet the production requirements of sterile drugs.

[0003] The traditional aseptic process method mainly involves direct sterilization filtration of high-viscosity liquids. The defects of this method are: 1. Due to the high viscosity of the liquid, direct filtration is likely to block the filter membrane, resulting in low filtration efficiency and prolonged filtration time, thus affecting the filtration effect and production efficiency; 2. During the high-resistance sterilization filtration process, the filtration pressure will increase. When the filtration pressure exceeds 0.5MPa, it will damage the filter membrane, thereby increasing the risk of microbial contamination and equipment replacement costs.

[0004] Based on this, a high-viscosity liquid sterilization filtration method and system are now provided to adapt to the filtration of high-viscosity liquid medicine without causing damage to the filter membrane. Summary of the invention

[0005] The present invention aims to solve the technical problems that in traditional aseptic filtration methods, due to the high viscosity of the drug liquid, the filter membrane is easily blocked during filtration, resulting in low filtration efficiency and prolonged filtration time, and the high resistance filtration process increases the filtration pressure and easily causes damage to the filter membrane. The present invention aims to provide a high-viscosity drug liquid sterilization filtration method and system, which effectively reduces the viscosity of the high-viscosity drug liquid and realizes efficient filtration of the high-viscosity drug liquid, which has practical significance for ensuring the sterility of the drug liquid, reducing the risk of pollution and reducing product losses. At the same time, it effectively improves the filtration efficiency, is not easy to block the filter element, and reduces the damage to the filter element.

[0006] The present invention is achieved through the following technical solutions:

[0007] The first object of the present invention is to provide a method for sterilizing and filtering a high-viscosity liquid medicine, comprising the following steps:

[0008] The non-sterile high-viscosity liquid medicine is subjected to shear dispersion treatment;

[0009] The liquid medicine after shearing and dispersion treatment is sequentially subjected to pre-filtration treatment and sterilization filtration treatment;

[0010] The pre-filtration treatment uses a hydrophilic filter element, and the sterilization filtration treatment uses a hydrophilic sterilization grade filter element;

[0011] The pore size of the filter element subjected to the pre-filtration treatment is larger than the pore size of the filter element subjected to the sterilization filtration treatment.

[0012] Furthermore, during the shearing and dispersing treatment, the shearing speed is controlled at 2000-4000 rpm, the shearing time is controlled at 20-30 min, and the temperature of the drug solution is controlled at 25±5°C.

[0013] Furthermore, the pre-filtration process includes a primary pre-filtration and a secondary pre-filtration performed in sequence, and the pore size of the filter element used in the primary pre-filtration is larger than the pore size of the filter element used in the secondary pre-filtration.

[0014] Furthermore, the pore size of the filter element used in the first-stage pre-filtration is 1-10 μm, and the pore size of the filter element used in the second-stage pre-filtration is 0.45-1 μm.

[0015] Furthermore, the sterilizing filtration treatment includes primary sterilizing filtration and secondary sterilizing filtration performed in sequence, and the filter element pore sizes of the primary sterilizing filtration and the secondary sterilizing filtration are both ≤0.22 μm.

[0016] Furthermore, in the pre-filtration process and the sterilization filtration process, the filtration pressure is ≤0.4MPa and the filtration temperature is 25±5°C.

[0017] The second purpose of the present invention is to provide a high-viscosity liquid medicine sterilization filtration system, comprising a batching tank, a primary pre-filter, a secondary pre-filter, a sterilizing filter and a liquid medicine storage tank connected in sequence, a shearing device is arranged in the batching tank, and the filter element pore size of the primary pre-filter, the secondary pre-filter and the sterilizing filter gradually decreases.

[0018] Furthermore, the batching tank, the primary pre-filter, the secondary pre-filter, the sterilizing filter and the liquid medicine storage tank are connected to each other via a delivery pipeline.

[0019] Furthermore, a pressure gauge is provided on the delivery pipeline.

[0020] Furthermore, the sterilizing filter comprises a primary sterilizing filter and a secondary sterilizing filter connected in series.

[0021] Compared with the prior art, the present invention has the following advantages and beneficial effects:

[0022] 1. The present invention effectively reduces the viscosity of high-viscosity liquid medicine through shear dispersion, and realizes step-by-step filtration of high-viscosity liquid medicine by adopting a two-stage pre-filtration + two-stage sterilization filtration method with different pore size combinations, which can effectively reduce the filtration resistance and filtration pressure of the high-viscosity liquid medicine, improve the filtration efficiency, and have practical significance for ensuring the sterility of the liquid medicine, reducing the risk of contamination, and reducing product losses. Moreover, before and after the multi-stage series filtration of the present invention, the physical properties of the liquid medicine do not change significantly.

[0023] 2. The filtration system of the present invention greatly reduces the viscosity of the drug solution by using shear dispersion effect through the provision of a shear device, so as to avoid increasing the filtration resistance in the subsequent filtration process and reduce damage to the filter element. At the same time, by providing a first-level pre-filter, a second-level pre-filter and a sterilizing filter with gradually decreasing pore sizes, the drug solution is filtered step by step, which effectively improves the filtration efficiency, is not easy to clog the filter element, and reduces damage to the filter element. BRIEF DESCRIPTION OF THE DRAWINGS

[0024] In order to more clearly illustrate the technical solutions of the exemplary embodiments of the present invention, the following briefly introduces the drawings required for use in the embodiments. It should be understood that the following drawings only illustrate certain embodiments of the present invention and should not be regarded as limiting the scope. For those of ordinary skill in the art, other relevant drawings can be obtained based on these drawings without creative work. In the drawings:

[0025] Figure 1 It is a structural schematic diagram of the system of the present invention;

[0026] Marks and corresponding parts names in the attached drawings:

[0027] 1- batching tank, 2- shearing device, 3- first delivery pipeline, 4- pressure gauge, 5- primary pre-filter, 6- second delivery pipeline, 7- secondary pre-filter, 8- third delivery pipeline, 9- primary sterilizing filter, 10- fourth delivery pipeline, 11- secondary sterilizing filter, 12- fifth delivery pipeline, 13- liquid medicine storage tank. DETAILED DESCRIPTION

[0028] In order to make the objectives, technical solutions and advantages of the present invention more clearly understood, the technical solutions in the embodiments of the present invention are clearly and completely described below in combination with the embodiments and drawings. Obviously, the schematic implementation modes of the present invention and their description are only used to explain the present invention and are not intended to limit the present invention.

[0029] The following is a detailed description of an embodiment of a high-viscosity liquid sterilization filtration method and system of the present invention with reference to the accompanying drawings as appropriate. However, there may be cases where unnecessary detailed descriptions are omitted. For example, there may be cases where detailed descriptions of well-known matters and repeated descriptions are omitted. This is to avoid the following description from becoming unnecessarily lengthy and to facilitate the understanding of those skilled in the art.

[0030] The "range" disclosed in this application is defined in the form of a lower limit and an upper limit, and a given range is defined by selecting a lower limit and an upper limit, and the selected lower limit and upper limit define the boundaries of the particular range. The range defined in this way can be inclusive or exclusive of the end values, and can be arbitrarily combined, that is, any lower limit can be combined with any upper limit to form a range.

[0031] Unless otherwise specified, all embodiments and optional embodiments of the present application can be combined with each other to form a new technical solution.

[0032] Unless otherwise specified, all technical features and optional technical features of this application can be combined with each other to form a new technical solution.

[0033] Unless otherwise specified, the terms "include" and "comprising" mentioned in this application may be open-ended or closed-ended. For example, the terms "include" and "comprising" may mean that other substances not listed may also be included or only the listed substances may be included.

[0034] If there is no special explanation, all the steps of the present application can be performed sequentially or randomly, preferably sequentially.

[0035] The technical solution of the present invention is to provide a high-viscosity liquid sterilization and filtration method, comprising the following steps:

[0036] (1) Shearing and dispersing the non-sterile high-viscosity liquid medicine: After the raw materials are mixed, they are sheared by a shearing device; the purpose of shearing and dispersing is to reduce the viscosity of the liquid medicine and improve the uniformity and stability of the active pharmaceutical ingredients in the liquid medicine, thereby changing the rheological properties of the drug. The shearing speed is controlled at 2000-4000 rpm, the shearing time is controlled at 20-30 min, and the liquid medicine temperature is controlled at 25±5°C. After shearing, the suspended particles in the liquid medicine reach a relatively uniform and stable state.

[0037] (2) Primary pre-filtration: After shearing and dispersion, the drug solution is transported to the primary pre-filter (using a hydrophilic filter element with a pore size of 1-10 μm) through a closed pipeline for primary pre-filtration. The purpose of this step is to remove exogenous foreign matter introduced during the process or impurities introduced by the raw materials themselves. The filtration pressure of this step is ≤0.4 MPa, the filtration time is ≤30 h (30 L), and the filtration temperature is 25±5°C.

[0038] (3) Secondary pre-filtration: After the primary pre-filtration, the liquid medicine is further transported to the secondary pre-filter (using a hydrophilic filter element with a pore size of 0.45-1μm). The purpose of this step is to reduce the microbial load and remove finer particles. The filtration pressure of this step is ≤0.4MPa, the filtration time is ≤1h (30L), and the filtration temperature is 25±5℃.

[0039] (4) Primary sterilization filtration: After two-stage pre-filtration treatment, the drug solution is transported to the primary sterilization filter (using a hydrophilic sterilization grade filter element with a pore size of 0.22 μm) for filtration. The filtration pressure of this step is ≤0.3 MPa, the filtration time is ≤30 min (30 L), and the filtration temperature is 25±5°C.

[0040] (5) Secondary sterilization filtration: After two-stage pre-filtration, the drug solution is transported to a secondary sterilization filter (using a hydrophilic sterilization grade filter element with a pore size of ≤0.22 μm) for filtration to finally prepare a sterile drug solution. The filtration pressure of this step is ≤0.3 MPa, the filtration time is ≤30 min (30 L), and the filtration temperature is 25±5°C.

[0041] Among them, the microbial contamination level of the drug solution needs to be tested before entering the first-level sterilization filtration and after the filtration is completed. At the same time, after the production is completed, the sterilization-grade filter element needs to be tested for integrity to confirm that the test complies with regulations.

[0042] The present invention effectively reduces the viscosity of high-viscosity liquid medicine through shear dispersion treatment, and realizes step-by-step filtration of high-viscosity liquid medicine by adopting a two-stage pre-filtration + two-stage sterilization filtration method with different pore size combinations, which can effectively reduce the filtration resistance and filtration pressure of the high-viscosity liquid medicine and improve the filtration efficiency. It has practical significance for ensuring the sterility of the liquid medicine, reducing the risk of contamination, and reducing product losses. Moreover, before and after the multi-stage series filtration of the present invention, the physical properties of the liquid medicine do not change significantly.

[0043] Based on the above filtering method, the present invention provides a high viscosity liquid sterilization filtering system, such as Figure 1 As shown, it includes a batching tank 1, a primary pre-filter 5, a secondary pre-filter 7, a sterilizing filter and a liquid medicine storage tank 13 connected in sequence, a shearing device 2 is arranged in the batching tank 1, and the filter element pore sizes of the primary pre-filter 5, the secondary pre-filter 7 and the sterilizing filter are gradually reduced.

[0044] When the system of the present invention is in use, the raw materials are first put into the batching tank 1, and the non-sterile high-viscosity medicinal liquid is pre-sheared and dispersed by the shearing device 2 arranged in the batching tank 1. The viscosity of the medicinal liquid is reduced by the shearing and dispersion effect to avoid increasing the filtration resistance in the subsequent filtration process, reduce the damage to the filter element, and help improve the filtration efficiency. Then the medicinal liquid enters the primary pre-filter 5 and the secondary pre-filter 7. The primary pre-filter 5 removes exogenous foreign matter introduced in the process or impurities introduced by the raw materials themselves. The secondary pre-filter 7 reduces the microbial load and removes finer particles at the same time. The medicinal liquid is initially filtered step by step by two-stage pre-filters with different filter element pore sizes, which can not only ensure the filtration effect of the medicinal liquid, but also improve the filtration efficiency. Finally, the sterilizing filter with a smaller pore size is further filtered to obtain a sterile medicinal liquid.

[0045] The batching tank 1, the primary pre-filter 5, the secondary pre-filter 7, the sterilizing filter and the liquid medicine storage tank 13 are connected to each other via a delivery pipeline; the sterilizing filter includes a primary sterilizing filter 9 and a secondary sterilizing filter 11 connected in series.

[0046] Specifically, the batching tank 1 and the primary pre-filter 5 are connected via a first delivery pipeline 3, the primary pre-filter 5 and the secondary pre-filter 7 are connected via a second delivery pipeline 6, the secondary pre-filter 7 and the primary sterilizing filter 9 are connected via a third delivery pipeline 8, and the primary sterilizing filter 9 and the secondary sterilizing filter 11 are connected via a fourth delivery pipeline 10. The circulation of the liquid medicine in the system is achieved through the delivery pipelines.

[0047] The delivery pipeline is provided with a pressure gauge 4, through which the system pressure can be monitored in real time.

[0048] The primary pre-filter 5 and the secondary pre-filter 7 both use hydrophilic filter elements. Specifically, the filter element pore size used in the primary pre-filter 5 is 1-10 μm, and the filter element pore size used in the secondary pre-filter 7 is 0.45-1 μm. The primary pre-filter 5 is intended to remove exogenous foreign matter introduced by the process or impurities introduced by the raw materials themselves, and the secondary pre-filter 7 is intended to reduce the microbial load and remove finer particles.

[0049] The sterilizing filter adopts a hydrophilic sterilizing grade filter element. The filter element pore size of the primary sterilizing filter 9 and the secondary sterilizing filter 11 is the same. Specifically, the filter element pore size of the primary sterilizing filter 9 and the secondary sterilizing filter 11 is ≤0.22μm. In this embodiment, the primary sterilizing filter 9 and the secondary sterilizing filter 11 adopt a filter element with a pore size of 0.22μm. By filtering through two-stage sterilizing filters, a sterile liquid medicine can be obtained.

[0050] The technical solution of the present invention is further described in detail below in conjunction with specific embodiments.

[0051] It should be noted that the experimental methods used in the examples are conventional methods unless otherwise specified. The materials, reagents, methods and instruments used are conventional materials, reagents, methods and instruments in the art unless otherwise specified, and can be obtained by those skilled in the art through commercial channels.

[0052] Example 1

[0053] Raw materials used: sodium carboxymethylcellulose (CMCNa), manufacturer: ASHLAND SPECIALTY INGREDIENTSG.P.

[0054] A high-viscosity liquid sterilization filtration method adopts shear dispersion + primary prefiltration (1.2 μm) + secondary prefiltration (0.45 μm) + primary sterilization filtration (0.2 μm) + secondary sterilization filtration (0.2 μm).

[0055] The specific steps include:

[0056] (1) Shear dispersion treatment: 10-15 kg of water for injection was injected into the batching tank online, 150-200 g of CMCNa was added into the batching tank through the feeding port, and the feeding port was closed. The shearing device was turned on, the shearing speed was 500-1000 rpm, the shearing time was 20 min, and a non-sterile sodium carboxymethylcellulose solution was prepared, and the initial viscosity of the solution was 10.86 mPa.s / cP.

[0057] (2) Primary pre-filtration: Compressed air (pressure 0.02-0.20 MPa) is introduced into the batching tank, and the above solution enters the primary pre-filter (filter element pore size: 1.2 μm). The filtration pressure is 0.20-0.40 MPa, the filtration time is 15 min, and the filtration temperature is 20-25°C. After pre-filtration by a 1.2 μm pore filter element, the solution viscosity is 10.79 mPa.s / cP.

[0058] (3) Secondary pre-filtration: The solution enters the secondary pre-filter (filter element pore size: 0.45 μm), the filtration pressure is 0.20-0.40 MPa, the filtration time is 15 min, the filtration temperature is 20-25 °C, and the solution viscosity after pre-filtration by the 0.45 μm pore size filter element is 10.78 mPa.s / cP.

[0059] (4) Primary sterilization filtration: The solution enters the primary sterilization filter (filter element pore size: 0.22 μm), the filtration pressure is 0.10-0.30 MPa, the filtration time is 10 min, the filtration temperature is 20-25 °C, and the solution viscosity after primary sterilization filtration is 10.78 mPa.s / cP.

[0060] (5) Secondary sterilization filtration: The solution enters the secondary sterilization filter (filter element pore size: 0.22 μm), the filtration pressure is 0.10-0.30 MPa, the filtration time is 10 min, the filtration temperature is 20-25 °C, and the solution viscosity after secondary sterilization filtration is 10.78 mPa.s / cP.

[0061] (6) Testing the sterility and other quality indicators of the sterile drug solution obtained by filtration.

[0062] Comparative Example 1

[0063] The difference between this comparative example and Example 1 is that the pharmaceutical solution is prepared without shearing and dispersing, but is prepared by ordinary stirring, with a stirring parameter of 300 rpm and a stirring time of 90 min.

[0064] The preparation time and viscosity of the drug solution were tested, and the data are shown in Table 1.

[0065] Table 1. Comparative data of preparation time and viscosity of Example 1 and Comparative Example 1

[0066] project Example 1 Comparative Example 1 Liquid viscosity, mPa.s / cP 10.86 20.35 Preparation time, min 20 120

[0067] It can be seen from the data in Table 1 that when the same pharmaceutical raw materials are used to prepare the pharmaceutical solution, the shear dispersion method used in Example 1 can effectively reduce the viscosity of the pharmaceutical solution in a shorter time to obtain a low-viscosity pharmaceutical solution.

[0068] Comparative Example 2

[0069] The difference between this comparative example and Example 1 is that the drug solution is directly subjected to two-stage sterilization filtration (0.22 μm).

[0070] Comparative Example 3

[0071] The difference between this comparative example and Example 1 is that the drug solution is subjected to one-stage pre-filtration (1.2 μm) + two-stage sterilization filtration (0.22 μm).

[0072] The filtration time of the drug solution was tested, and the data are shown in Table 2.

[0073] Table 2. Comparative data of total filtration time of Example 1 and Comparative Examples 2-3

[0074]

[0075] From the data in Table 2, it can be seen that for the same viscosity of the liquid medicine, Example 1 adopts the method of two-stage pre-filtration + two-stage sterilizing filtration, and the filtration time is less than 1 hour. Comparative Example 2 directly performs two-stage sterilizing filtration, and the filtration time is greater than 5 hours, and even the situation that filtration cannot be performed occurs. Comparative Example 3 adopts the method of one-stage pre-filtration + two-stage sterilizing filtration, and the filtration time is also long. It can be seen from the comparative data in Table 2 that the present invention adopts the method of two-stage pre-filtration + two-stage sterilizing filtration with different pore size combinations to achieve step-by-step filtration of high-viscosity liquid medicine, which can effectively reduce the filtration resistance and filtration pressure of high-viscosity liquid medicine, improve the filtration efficiency, and have practical significance for ensuring the sterility of the liquid medicine, reducing the risk of pollution, and reducing product losses. Moreover, before and after the multi-stage series filtration of the present invention, the physical properties of the liquid medicine do not change significantly.

[0076] Finally, it should be noted that the above specific embodiments are only used to explain in detail the purpose, technical solutions and beneficial effects of the present invention. It should be understood that the above description is only a specific implementation method of the present invention and is not used to limit the protection scope of the present invention. Although the present invention is described in detail with reference to the above specific embodiments, ordinary technicians in this field should understand that it is still possible to modify the technical solutions recorded in the above embodiments, or to replace or improve some or all of the technical features therein. These modifications, equivalent replacements and improvements do not make the essence of the corresponding technical solutions deviate from the scope of the technical solutions of the embodiments of the present invention, and they should all be included in the scope of the claims and description of the present invention.

Claims

1. A method for sterilizing and filtering a high-viscosity liquid medicine, characterized in that: The following steps are involved: The non-sterile high-viscosity liquid medicine is subjected to shear dispersion treatment; The liquid medicine after shearing and dispersion treatment is sequentially subjected to pre-filtration treatment and sterilization filtration treatment; The pre-filtration treatment uses a hydrophilic filter element, and the sterilization filtration treatment uses a hydrophilic sterilization grade filter element; The pore size of the filter element subjected to the pre-filtration treatment is larger than the pore size of the filter element subjected to the sterilization filtration treatment.

2. A high viscosity liquid sterilization filtration method according to claim 1, characterized in that: During the shearing and dispersing treatment, the shearing speed is controlled at 2000-4000 rpm, the shearing time is controlled at 20-30 min, and the temperature of the drug solution is controlled at 25±5°C.

3. A high viscosity liquid sterilization filtration method according to claim 1, characterized in that: The pre-filtration process includes a primary pre-filtration and a secondary pre-filtration performed in sequence, and the filter element pore size used in the primary pre-filtration is larger than the filter element pore size of the secondary pre-filtration.

4. A high viscosity liquid sterilization and filtration method according to claim 3, characterized in that: The pore size of the filter element used in the first-stage pre-filtration is 1-10 μm, and the pore size of the filter element used in the second-stage pre-filtration is 0.45-1 μm.

5. The method for sterilizing and filtering a high-viscosity liquid medicine according to claim 1, characterized in that: The sterilizing filtration treatment includes primary sterilizing filtration and secondary sterilizing filtration performed in sequence, and the filter core pore sizes of the primary sterilizing filtration and the secondary sterilizing filtration are both ≤0.22 μm.

6. A high viscosity liquid sterilization and filtration method according to claim 1, characterized in that: In the pre-filtration process and sterilization filtration process, the filtration pressure is ≤0.4MPa and the filtration temperature is 25±5℃.

7. A high viscosity liquid sterilization filtration system, characterized in that: The invention comprises a batching tank (1), a primary pre-filter (5), a secondary pre-filter (7), a sterilizing filter and a liquid medicine storage tank (13) which are connected in sequence. A shearing device (2) is arranged in the batching tank (1). The pore sizes of the filter elements of the primary pre-filter (5), the secondary pre-filter (7) and the sterilizing filter gradually decrease.

8. A high viscosity liquid sterilization filtration system according to claim 1, characterized in that: The batching tank (1), the primary pre-filter (5), the secondary pre-filter (7), the sterilizing filter and the liquid medicine storage tank (13) are connected to each other via a delivery pipeline.

9. A high viscosity liquid sterilization filtration system according to claim 8, characterized in that: A pressure gauge (4) is provided on the delivery pipeline.

10. A high viscosity liquid sterilization filtration system according to claim 7, characterized in that: The sterilizing filter comprises a primary sterilizing filter (9) and a secondary sterilizing filter (11) connected in series.

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