CN103864926A - Method for preparing rabies human immune globulin by inactivation of double viruses - Google Patents
Method for preparing rabies human immune globulin by inactivation of double viruses Download PDFInfo
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- CN103864926A CN103864926A CN201410077239.9A CN201410077239A CN103864926A CN 103864926 A CN103864926 A CN 103864926A CN 201410077239 A CN201410077239 A CN 201410077239A CN 103864926 A CN103864926 A CN 103864926A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/06—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies from serum
- C07K16/065—Purification, fragmentation
Abstract
The invention discloses a process for preparing rabies human immune globulin by inactivation of double viruses. The method comprises the following steps: combining octanoic acid with PEG to generate a precipitate; through ion exchange after filtration, further filtrating by a nano membrane to greatly improve the rabies immune globulin yield. Compared with the conventional low pH incubation, the time is greatly shortened. The process not only can inactivate the lipid enveloped viruses, but also has a very good removal effect on non-lipid enveloped viruses.
Description
Technical field
The present invention relates to a kind of dual inactivation of virus and prepare the method for mad dog human normal immunoglobulin, belong to field of biological pharmacy.
Background technology
Mad dog human normal immunoglobulin belongs to blood products, along with widespread use clinically, how to ensure that security, prevention and the control of blood products, through the disease of blood propagation, have become the focus of world's medical and health circle and even entire society's common concern.At present, conventional blood products deactivation fado adopts S/D to process and low pH hatching method.But it is invalid to non-ester enveloped virus that S/D processes, and also can cause the sex change of partial protein; Low pH hatching method is limited in one's ability to most of non-lipid-coated virus deactivations.Aforesaid method all can not meet the safety standards and the quality standard that at present blood products are improved day by day.Also having at present utilizes Sodium octoate to remove viral report, in the time that the Sodium octoate concentration adding is higher, inactivation of viruses is had to extraordinary effect, but too high Sodium octoate concentration can cause sex change and the polymeric generation of partial immunity sphaeroprotein, and quality product is brought to very large impact.
Summary of the invention
Object of the present invention is exactly for above-mentioned defect of the prior art, provides a kind of and has reduced virus activity and ensure that albumen high reactivity, safe and reliable dual inactivation of virus prepare the method for mad dog human normal immunoglobulin.
Dual inactivation of virus is prepared a method for mad dog human normal immunoglobulin, it is characterized in that preparation technology comprises the following steps:
(1) raw blood plasma is sterilized rear 0.3 times of dilution, adjusting pH with pH4 damping fluid is 7.15 ~ 7.25, after controlling 1.5 ~ 2.5 DEG C of blood plasma temperature, spray into 95% ethanol, the final concentration of ethanol counts 8% according to volume, the speed of spraying into is less than or equal to 50L/h, again adjusts pH to 7.2, and stirs centrifugation after 2 hours and go out components I, centrifugal rotational speed is 8000 ~ 10000r/min, the components I supernatant liquor obtaining after centrifugal;
(2) it is 6.85 ~ 6.95 that the components I supernatant liquor that above-mentioned steps obtains is adjusted pH, add 95% ethanol, the final concentration of ethanol is designated as 20% according to volume, the speed of spraying into is less than or equal to 50L/h, and again adjusting pH is 6.85 ~ 6.95, and stirs after two hours and to leave standstill 2 hours, add diatomite, add-on is that every 1000ml reaction solution adds 20kg diatomite, and stirs 20 minutes, and pressure is isolated the precipitation of compositionⅱ and component III;
(3) compositionⅱ that above-mentioned steps obtains and component III precipitation are dissolved with sodium chloride solution, adjusting pH is 5.05 ~ 5.15, temperature regulating is-0.5 ~ 0 DEG C, add 95% ethanol to ethanol final concentration to be designated as 17% according to shining volume, then stir 2 hours, leave standstill 6 ~ 12 hours, obtain abundant mixed solution, the press filtration of component mixed solution is obtained to component mixed solution supernatant;
(4) the component mixed solution supernatant liquor that above-mentioned steps obtains adds sad and PEG4000, stirs 2 hours, centrifugal, collects supernatant liquor;
(5) ultrafiltration and concentration after the supernatant liquor desalination dealcoholysis that above-mentioned steps obtains, obtains component mixed concentrated liquid;
(6) the component mixed concentrated liquid that above-mentioned steps obtains carries out Chromatographic purification with gel column, obtains chromatography protein liquid;
(7) after the chromatography protein liquid that above-mentioned steps obtains is dialysed, then ultrafiltration and concentration, chromatography protein concentrated solution obtained;
(8) in the chromatography protein concentrated solution that above-mentioned steps obtains, add maltose, after tune pH 3.8 ~ 4.0, adding water to final protein mass percentage composition is 5.05% ~ 5.2%, obtains immunoglobulin (Ig) one-level goods through 0.2um degerming filter element filtering;
(9) the immunoglobulin (Ig) secondary product that above-mentioned steps obtains is again dialysed with water and ultrafiltration and concentration obtains immunoglobulin (Ig) secondary product concentrated solution;
(10) the immunoglobulin (Ig) secondary product concentrated solution that above-mentioned steps obtains adds glycine by every liter of 10 ~ 30g, and adjusts pH 4.4 ~ 4.8, obtains immunoglobulin (Ig) three tier structure product;
(11) the immunoglobulin (Ig) three tier structure product that above-mentioned steps obtains carry out nano-film filtration with 35 ~ 50nm aperture film under aseptic condition, obtain filtered solution;
(12) filtered solution that above-mentioned steps obtains regulates pH 6.4 ~ 7.4, and packing, obtains mad dog human normal immunoglobulin.
Described a kind of dual inactivation of virus is prepared the method for mad dog human normal immunoglobulin, it is characterized in that in above-mentioned steps (3), the usage quantity of sodium chloride solution is that the precipitation of every kg of component II and component III is dissolved with 9L 0.01mol/L sodium chloride solution, and adjusting pH solution used is the acetum of pH 4.
Described a kind of dual inactivation of virus is prepared the method for mad dog human normal immunoglobulin, it is characterized in that add-on sad in step (4) is 10 ~ 20mmol, and the add-on of PEG4000 is 1% ~ 2%, and centrifugal rotational speed is 8000 ~ 10000r/min.
Described a kind of dual inactivation of virus is prepared the method for mad dog human normal immunoglobulin, it is characterized in that the concrete grammar of desalination dealcoholysis ultrafiltration and concentration in step (5) is, with the water for injection dialysis of 2 ~ 8 DEG C of 5 times of volumes.
Described a kind of dual inactivation of virus is prepared the method for mad dog human normal immunoglobulin, it is characterized in that in step (6), gel column used is DEAE-Sepharose-FF gel column.
Described a kind of dual inactivation of virus is prepared the method for mad dog human normal immunoglobulin, it is characterized in that in step (11), nanometer film except virus actual conditions be: goods pH is 4.4 ~ 4.8, glycine content is 10 ~ 30g/L, protein concentration is 110 ~ 150g/L, filtration temperature is 18 ~ 20 DEG C, and filtration yield is 230L/1.63 m
2, filtration velocity is less than or equal to 5L/min, nanometer film integrity mensuration', and before and after filter membrane, bubble point pressure is>=4.5bar/cm
2.
Effective result of the present invention is: current mad dog people immunity ball all adopts a kind of mode of inactivation of virus to remove residual virus in vain in process of production, there is the potential risk of propagating through blood, mad dog human normal immunoglobulin prepared by dual inactivation of virus provided by the invention reduces the disease of propagating through blood greatly, quality of item meets " in and name republic pharmacopeia " requirement completely, through verifying by Pseudorabies virus, HIV virus, really can make 5 of its virus titers more than Log, ensure that goods are more safe and reliable completely.Utilize the mad dog people immunity ball of this explained hereafter to compare in vain general method at present and have higher yield, and in this product, Content of polymer is relatively on the low side, can ensure higher quality product.
Embodiment
Embodiment 1.
This strain is by the human normal plasma component of the Rabies virus antibody containing high-titer, through the separation and purification of cold ethanol albumen sepn method, and adopt sad combination PEG generation precipitation and nanometer film except viral dual inactivation of virus production technique, be mainly used in prevention and treatment rabies, be particularly useful for mad dog toxinicide allergy sufferers.
1, the above acceptable material blood plasma of 100 person-portion is led out in blood plasma merging, after cleaning-sterilizing, melts, and the blood plasma after thawing is incorporated in retort, and blood plasma in retort is measured, in retort, blood plasma samples after uniform stirring, for surveying total protein content, albumin purity and Rabies virus antibody.
2, the making of component (I+II+III) F I+II+III.
The making of 2.1 components Is: 0.14mol/L NaCl diluent for blood plasma, after dilution mixes.Adjust blood plasma pH7.2 ± 0.05 with pH4.0 acetate buffer solution, be cooled to 0 DEG C and start to spray into-15 DEG C of following 95% ethanol, make final alcohol concn reach 8%, spray into ethanol speed≤50L/h.Spray in ethanol process must not be higher than 0 DEG C, but the freezing point that also must not mix with goods lower than ethanol.Goods outlet temperature is controlled at-2.5 ± 0.5 DEG C, repetition measurement pH is also adjusted to pH 7.2 ± 0.05. with acetate buffer solution and continues to stir after 2 hours, separate F I or proceed precipitation and the separation of F II+III, F I supernatant is for separating of F II+III, and F I precipitation is used for researching and developing product innovation or autoclaving is destroyed;
0.14mol/LNaCl dosage (L)=(0.25 ± 0.05) × V blood plasma (L)
95% amount of alcohol added (L)=0.095 ± 0.003 × (V blood plasma+V
naCl+ V damping fluid) L
Acetate buffer solution add-on is (L)=(2.6 ± 0.5) × V blood plasma (L)/1000
Goods pH measures: be under 20 DEG C, normal saline dilution to 8% ethanol content condition, and combined electrode measuring point result.Following blood plasma classification step pH pH-value determination pH is identical therewith.
The making of 2.2 compositionⅱs+III: F I supernatant is adjusted pH to 6.90 ± 0.05 with pH4.0 acetate buffer solution, spray into-15 DEG C of following 95% ethanol, make final alcohol concn reach 20%(v/v), spray into ethanol speed≤50L/h, spray into products temperature in ethanol process all the time must not be higher than-1 DEG C, goods outlet temperature is controlled at-0.5 DEG C ± 0.5 DEG C, repetition measurement pH is also adjusted to pH6.9 ± 0.05 with acetate buffer solution, continue to stir 2 hours, leave standstill after 2 hours, add diatomite, continue to stir 30 minutes, F II+III precipitation and supernatant are isolated in press filtration, fluid goes out liquid temp and is controlled at-4.5 ± 1 DEG C, press filtration pressure-controlling is at≤0.1MPa, F II+III supernatant is for separating of F IV-1, F II+III precipitation is for the production of human normal immunoglobulin or-30 DEG C of following preservations,
95% amount of alcohol added (liter)=0.165 ± 0.005 × V reaction solution (L)+0.27 ± 0.01 × V damping fluid (L)
Acetate buffer solution add-on (L)=(1.0 ± 0.4) × V reaction solution (L)/1000
Diatomite dosage (Kg)=25 × V reaction solution (L)/1000.
3, the separation of component III (F III): every Kg F I+II+III precipitates with 9L 0.01mol/L NaCl(0 ~ 0.5 DEG C) dissolve after, metering volume, add pH4.0 sodium acetate soln, adjust pH5.10 ± 0.05, adjust 0 ~ 0.5 DEG C of reacting liquid temperature, ethanol to the ethanol ultimate densities that add in advance below being chilled to-15 DEG C are 17%, note adding ethanol speed by gradually fast slowly, and controlling end reaction liquid temp is-4.5 DEG C ~-5.5 DEG C.Ethanol dropwises, stir 2 hours, leave standstill 6 hours above or spend the night, reaction solution is carried out to press filtration separation, note controlling feed liquor speed, first be circulated to out liquid temp at-4.5 ± 1.0 DEG C, collect filtered liquid, require filtrate limpid, after having filtered, dry up, to 17% alcohol flushing liquid filtration, merging filtrate is collected in filtered liquid, after having filtered, dries up precipitation.In precipitation collection, the postposition-30 DEG C freezer of weighing, after preservation or autoclaving, destroy; Reaction solution after collection press filtration, suction retort in time, cooling postposition-3 ~-5 DEG C, make compositionⅱ;
0.01mol/L sodium chloride solution dosage (L)=compositionⅱ+III (Kg) × 9
PH4.0 acetate buffer solution (L)=(1.1 ± 0.3) × load responsive fluid/1000
95% ethanol dosage (L)=(0.218 ± 0.005) × load responsive fluid
17% ethanol washing lotion configuration amount (L)=F II+III (Kg) × 3.
4, component mixed solution supernatant liquor adds sad and PEG4000, and sad add-on is 10 ~ 20mmol, and the add-on of PEG4000 is 1% ~ 2%, and centrifugal rotational speed is 8000 ~ 10000r/min, adds and stirs 2 hours, centrifugal, collects supernatant liquor.
5, desalination dealcoholysis is concentrated: the supernatant liquor of collecting is stirred and slowly adds 0.5mol/L hydrochloric acid solution, regulate pH to 3.8 ~ 4.0, with 2 ~ 8 DEG C of water for injection dialysis of 5 times of volumes, dialyse to ethanol content < 1%, protein liquid is concentrated into 3% above concentration, suction Stainless Steel Products bucket.Sampling detects protein content.
6, DEAE-Sepharose-FF gel filtration chromatography is purified.
6.1 use 0.5mol/L NaOH solution, adjust protein liquid pH=6.4 ~ 6.8, with 1mol/L PB solution, adjust protein liquid electricity to lead 2.1 ± 0.2 × 10
3us/cm.
6.2 use phosphate buffered saline buffer balanced gel posts.
6.3 loading protein liquids, treat that IgG protein peak has just occurred that collection penetrates protein liquid.
After 6.4 completion of the sample, rinse with phosphate buffered saline buffer, treat that IgG peak drops to approximately 2/3 place at climax, rinse chromatography column with acetate buffer.
7, dialysis desalting, concentrated: to collect chromatography protein liquid, slowly add while stirring 0.5mol/L hydrochloric acid solution, regulate pH to 3.8 ~ 4.0, with 2 ~ 8 DEG C of water for injection dialysis of 5 times of volumes, dialyse to ethanol content <0.025%, protein liquid is concentrated into 6% above concentration, suction Stainless Steel Products bucket.Sampling detects protein content.
8, make immunoglobulin (Ig) one-level goods: the protein liquid after ultrafiltration and concentration is added to maltose, adjusts pH, adds water and make end article protein content 5.05% ~ 5.2%, maltose 10 ± 1%, pH is 3.8 ~ 4.0.Then obtain immunoglobulin (Ig) one-level goods through 0.2um degerming filter element filtering.
9, make immunoglobulin (Ig) secondary product: immunoglobulin (Ig) one-level goods are dialysed and ultrafiltration and concentration with 2 ~ 8 DEG C of waters for injection of 5 times of volumes again.
10, make immunoglobulin (Ig) three tier structure product: the immunoglobulin (Ig) secondary product concentrated solution obtaining adds glycine by every liter of 10 ~ 30g, and adjusts pH 4.4 ~ 4.8.
11,35 ~ 50nm nano-film filtration: the goods that preparation is finished, be transferred between hundred grades of degerming, carry out nano-film filtration.Filtration temperature is 18 ~ 20 DEG C, and filtration yield is 230L/1.63 m
2, filtration velocity is less than or equal to 5L/min, nanometer film integrity mensuration', and before and after filter membrane, bubble point pressure is>=4.5bar/cm
2.
12, regulate pH 6.4 ~ 7.4, then packing.
Embodiment 2: inactivation of virus effect comparison.
Can find by carrying out process certification with Pseudorabies virus, HIV virus, Sindbis virus, canine parvovirus shown in following table: virus removal effect of the present invention is higher than conventional S/D+DV50 nanometer film and incubated at low pH+DV50 nanometer film production technique.
Embodiment 3: single Homodimer size distribution and protein recovery comparison.
Relatively can find by different process list Homodimer size distribution and protein recovery in following table: the product quality indicator that technique of the present invention is produced will be higher than other two kinds of products that method is prepared.
Claims (6)
1. dual inactivation of virus is prepared a method for mad dog human normal immunoglobulin, it is characterized in that preparation technology comprises the following steps:
(1) raw blood plasma is sterilized rear 0.3 times of dilution, adjusting pH with pH4 damping fluid is 7.15 ~ 7.25, after controlling 1.5 ~ 2.5 DEG C of blood plasma temperature, spray into 95% ethanol, the final concentration of ethanol counts 8% according to volume, the speed of spraying into is less than or equal to 50L/h, again adjusts pH to 7.2, and stirs centrifugation after 2 hours and go out components I, centrifugal rotational speed is 8000 ~ 10000r/min, the components I supernatant liquor obtaining after centrifugal;
(2) it is 6.85 ~ 6.95 that the components I supernatant liquor that above-mentioned steps obtains is adjusted pH, add 95% ethanol, the final concentration of ethanol is designated as 20% according to volume, the speed of spraying into is less than or equal to 50L/h, and again adjusting pH is 6.85 ~ 6.95, and stirs after two hours and to leave standstill 2 hours, add diatomite, add-on is that every 1000ml reaction solution adds 20kg diatomite, and stirs 20 minutes, and pressure is isolated the precipitation of compositionⅱ and component III;
(3) compositionⅱ that above-mentioned steps obtains and component III precipitation are dissolved with sodium chloride solution, adjusting pH is 5.05 ~ 5.15, temperature regulating is-0.5 ~ 0 DEG C, add 95% ethanol to ethanol final concentration to be designated as 17% according to shining volume, then stir 2 hours, leave standstill 6 ~ 12 hours, obtain abundant mixed solution, the press filtration of component mixed solution is obtained to component mixed solution supernatant;
(4) the component mixed solution supernatant liquor that above-mentioned steps obtains adds sad and PEG4000, stirs 2 hours, centrifugal, collects supernatant liquor;
(5) ultrafiltration and concentration after the supernatant liquor desalination dealcoholysis obtaining, obtains component mixed solution contracting liquid;
(6) the component mixed solution contracting liquid that above-mentioned steps obtains carries out Chromatographic purification with gel column, obtains chromatography protein liquid;
(7) after the chromatography protein liquid that above-mentioned steps obtains is dialysed, then ultrafiltration and concentration, chromatography protein concentrated solution obtained;
(8) in the chromatography protein concentrated solution that above-mentioned steps obtains, add maltose, after tune pH 3.8 ~ 4.0, adding water to final protein mass percentage composition is 5.05% ~ 5.2%, obtains immunoglobulin (Ig) one-level goods through 0.2um degerming filter element filtering;
(9) the immunoglobulin (Ig) secondary product that above-mentioned steps obtains is again dialysed with water and ultrafiltration and concentration obtains immunoglobulin (Ig) secondary product concentrated solution;
(10) the immunoglobulin (Ig) secondary product concentrated solution that above-mentioned steps obtains adds glycine by every liter of 10 ~ 30g, and adjusts pH 4.4 ~ 4.8, obtains immunoglobulin (Ig) three tier structure product;
(11) the immunoglobulin (Ig) three tier structure product that above-mentioned steps obtains carry out nano-film filtration with 35 ~ 50nm aperture film under aseptic condition, obtain filtered solution;
(12) filtered solution that above-mentioned steps obtains regulates pH 6.4 ~ 7.4, and packing, obtains mad dog human normal immunoglobulin.
2. a kind of dual inactivation of virus as claimed in claim 1 is prepared the method for mad dog human normal immunoglobulin, it is characterized in that in above-mentioned steps (3), the usage quantity of sodium chloride solution is that the precipitation of every kg of component II and component III is dissolved with 9L 0.01mol/L sodium chloride solution, and adjusting pH solution used is that pH is 4 acetum.
3. a kind of dual inactivation of virus as claimed in claim 1 is prepared the method for mad dog human normal immunoglobulin, it is characterized in that add-on sad in step (4) is 10 ~ 20mmol, and the add-on of PEG4000 is 1% ~ 2%, and centrifugal rotational speed is 8000 ~ 10000r/min.
4. a kind of dual inactivation of virus as claimed in claim 1 is prepared the method for mad dog human normal immunoglobulin, it is characterized in that the concrete grammar of desalination dealcoholysis ultrafiltration and concentration in step (5) is, with the water for injection dialysis of 2 ~ 8 DEG C of 5 times of volumes.
5. a kind of dual inactivation of virus as claimed in claim 1 is prepared the method for mad dog human normal immunoglobulin, it is characterized in that in step (6), gel column used is DEAE-Sepharose-FF gel column.
6. a kind of dual inactivation of virus as claimed in claim 1 is prepared the method for mad dog human normal immunoglobulin, it is characterized in that in step (11), nanometer film except virus actual conditions be: goods pH is 4.4 ~ 4.8, glycine content is 10 ~ 30g/L, protein concentration is 110 ~ 150g/L, filtration temperature is 18 ~ 20 DEG C, and filtration yield is 230L/1.63 m
2, filtration velocity is less than or equal to 5L/min, nanometer film integrity mensuration', and before and after filter membrane, bubble point pressure is>=4.5bar/cm
2.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107880116A (en) * | 2016-09-30 | 2018-04-06 | 盖立复集团公司 | method for preparing immunoglobulin |
| CN116355085A (en) * | 2023-03-31 | 2023-06-30 | 西安麦博泰克生物科技有限公司 | Tetanus antitoxin production method |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101450967A (en) * | 2007-11-29 | 2009-06-10 | 山东泰邦生物制品有限公司 | High-purity rabies human immunoglobulin and raw material production method thereof |
-
2014
- 2014-03-05 CN CN201410077239.9A patent/CN103864926B/en active Active
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101450967A (en) * | 2007-11-29 | 2009-06-10 | 山东泰邦生物制品有限公司 | High-purity rabies human immunoglobulin and raw material production method thereof |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107880116A (en) * | 2016-09-30 | 2018-04-06 | 盖立复集团公司 | method for preparing immunoglobulin |
| CN107880116B (en) * | 2016-09-30 | 2023-02-03 | 盖立复集团公司 | Method for producing immunoglobulins |
| CN116355085A (en) * | 2023-03-31 | 2023-06-30 | 西安麦博泰克生物科技有限公司 | Tetanus antitoxin production method |
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