CN101327323A - Lyophilization technique for preparing lyophilized hepatitis A attenuated live vaccine - Google Patents
Lyophilization technique for preparing lyophilized hepatitis A attenuated live vaccine Download PDFInfo
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- CN101327323A CN101327323A CNA2008100587301A CN200810058730A CN101327323A CN 101327323 A CN101327323 A CN 101327323A CN A2008100587301 A CNA2008100587301 A CN A2008100587301A CN 200810058730 A CN200810058730 A CN 200810058730A CN 101327323 A CN101327323 A CN 101327323A
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Abstract
The invention provides a freeze-drying technics for preparing freeze-dry hepatitis A attenuated live vaccine. The freeze-dry hepatitis A attenuated live vaccine is made by the technical process of sublimation and dry of the vaccine, removal of the contraction and sublimation at the bottom of the vaccine, invisible sublimation of the vaccine, and resolve and dry of the vaccine. The freeze-drying technics provided by the invention avoids the continuous temperature rise and temperature rise mutation of the vaccine during sublimation period, and reduces and removes the greater loss of vaccine infection titer, thus ensuring the residual moisture content of the vaccine to reach the mark and the vaccine is refined and satiety in shape, the freeze-dry production period of the single batch of the vaccine is reduced by 50 percent, and the energy consumption of the vaccine in a single batch during freeze-dry production period is reduced by 40 percent to 50 percent; in this way, the sustainable development characterized by energy saving, energy reduction, pollution reduction, and effect increment is realized. The freeze-drying technics is suitable for virulence attenuated live vaccine and live extract preparation in laboratory development process, particular for large-scale production of the products.
Description
Technical field
The present invention relates to a kind of preparation method of freeze-dired attenuated live vaccine for hepatitis A, especially be suitable for the freeze-dry process of extensive freeze-dired attenuated live vaccine for hepatitis A, belong to biological product technical field.
Background technology
In the large-scale production process of attenuated hepatitis A live vaccine, freeze-dry process is one of requisite critical process of rebuild vaccine infection titre stability.Because existing freeze-dry process is a foundation with the experience that accumulates from laboratory development to the large-scale production process development process mainly, have following several respects deficiency: one, lyophilization cycle is long, makes that actual lyophilizing production capacity is lower, energy consumption is excessive.The modern vaccination production scale often requires every freeze dryer to produce millions of even up to ten million person-portion vaccines per year; compare with the research and development of laboratory small lot; this production capacity that is based upon on the flourishing GMP infrastructure; at first must rely on powerful energy resource supply scale basis; single batch of vaccine freeze-drying cycle is consuming time long more; then energy consumption is big more relatively, and annual capacity is also just low more.Two, freeze-dry process is not mature enough, in the practical large-scale freeze-drying process, has the big phenomenon of vaccine infection titre loss, and production cost is produced material impact; Three, there are defectives such as the different depression of degree, atrophy in the presentation quality of goods after the lyophilizing.
Summary of the invention
Purpose of the present invention is just for solving a kind of freeze-dry process for preparing freeze-dired attenuated live vaccine for hepatitis A that the prior art above shortcomings provide.
Purpose of the present invention realizes by following technical proposal: a kind of freeze-dry process for preparing freeze-dired attenuated live vaccine for hepatitis A is characterized in that through following process steps:
A, vaccine pre-freeze: in temperature is under 5～15 ℃ of conditions, and attenuated hepatitis A live vaccine is incubated 20～60 minutes, and the speed with 0.5～1.67 ℃ of per minute cools the temperature to-40 ℃ afterwards, is incubated 60～90 minutes; With the speed of 0.4～0.6 ℃ of per minute temperature is gone back up to-27.4～-24.9 ℃ from-40 ℃ again, with the speed of 0.1～1.67 ℃ of per minute temperature is reduced to T afterwards
1, i.e. T
1=-27.5～-25.0 ℃;
B, vaccine sublimation drying:
1) be T, in temperature
1=-27.5～-25.0 ℃, vacuum is P
1Under the condition of=150～400 μ bar, begin to carry out the sublimation drying of vaccine.With the speed of 0.0000～0.0056 ℃ of per minute with temperature from T
1Drop to T
2, T
2=[T
1-(0～0.5 ℃)]～T
1
2) be T, in temperature
2=[T
1-(0～0.5 ℃)]～T
1, vacuum is P
2=P
1Under the condition of-(5～50 μ bar), with the speed of 0.0000～0.0056 ℃ of per minute with temperature from T
2Drop to T
3, T
3=[T
2-(0～0.5 ℃)]～T
2
3) be T, in temperature
3=[T
2-(0～0.5 ℃)]～T
2, vacuum is P
3=P
1Under-2 * (5～50 μ bar) the condition, with the speed of 0.0000～0.0056 ℃ of per minute with temperature from T
3Drop to T
4, T
4=[T
3-(0～0.5 ℃)]～T
3
......
N), temperature is reduced to T
n=[T
N-1-(0～0.5 ℃)]～T
N-1, vacuum is P
n=P
1-(n-1) * (5～50 μ bar), and sublimation drying time when proceeding to 240～270 minutes, the temperature rise China that edges down that finishes vaccine;
C, be T in temperature
n=[T
N-1-(0～0.5 ℃)]～T
N-1, vacuum is P
n=P
1Under-(n-1) * (5～50 μ bar) the condition, with the speed cooling of 0.0056～0.017 ℃ of per minute, fall 0.5 ℃ at every turn, lower the temperature continuously 5 times, each corresponding decompression 5～50 μ bar successively eliminate the distillation that shrink the vaccine bottom to finish;
D, maintenance temperature are (T
n-2.5 ℃), be P from vacuum
n-4 * (5～50 μ bar) beginnings are evenly reduced pressure 5 times successively, and vacuum is dropped to 60 μ bar, and each decompression kept 15～120 minutes, to finish the invisible ice face distillation to vaccine;
E, to keep vacuum be 60 μ bar, with the speed of 0.017～0.05 ℃ of per minute with temperature by (T
n-2.5 ℃) be upgraded to (T
n-2.0 ℃), kept 10～30 minutes; With the speed of 0.1～0.2 ℃ of per minute with temperature from (T
n-2.0 ℃) be upgraded to-25.0 ℃, kept 10～20 minutes, with 0.2～1.0 ℃ speed temperature is upgraded to-20.0 ℃ from-25.0 ℃, kept 5～25 minutes; With 0.33～1.0 ℃ speed temperature is upgraded to-15.0 ℃ from-20.0 ℃, kept 5～15 minutes, with the phase same rate temperature is upgraded to-10.0 ℃ from-15.0 ℃ afterwards, kept 5～15 minutes, with the speed of 0.2～0.5 ℃ of per minute temperature is upgraded to-5.0 ℃ from-10.0 ℃, kept 10～25 minutes; With the phase same rate temperature is upgraded to 0.0 ℃ from-5.0 ℃ again, kept 10～25 minutes; With the speed of 0.5～1.0 ℃ of per minute temperature is upgraded to 5.0 ℃ from 0.0 ℃ again, kept 5～20 minutes, temperature is upgraded to 10.0 ℃ from 5.0 ℃, kept 5～20 minutes with same speed; At last temperature is upgraded to 25～27 ℃ from 10.0 ℃, kept 60～150 minutes, the process that is rapidly heated when finishing the vaccine parsing-desiccation with the speed of 1.0～1.7 ℃ of per minutes;
F, lyophilizing vacuum is reduced to 5 μ bar, under 25.0～27.0 ℃ of temperature, kept 120～240 minutes;
G, when per 5 minutes pressure liters＜20～60 μ bar, the remaining water content of goods is qualified, freeze-dired attenuated live vaccine for hepatitis A.
Described attenuated hepatitis A live vaccine is commercial product.
Difficult point of the present invention is:
(1) freeze-drying process is a harmless process of preserving and making it to obtain maximum stable of the infection titer that is had during with the vaccine packing; therefore, to still taking place under classical protective agent effect, the freeze-drying process that infection titer loses in various degree carried out deeply probing into.On in conjunction with classical lyophilizing theoretical basis, the lyophilizing thermodynamics basic model that to have set up with viral attenuated live vaccine infection titer change procedure be core.
(2) explored around the unfolded internal relation problem that makes between lyophilizing mechanism, lyophilizing kinetic model and the freeze-drying time that infection titer preserved of above-mentioned thermodynamics basic model.
(3) set up the thermodynamics approach of above-mentioned model and the freeze-dry process step of process of according with provided by the invention.
In addition, a kind of freeze-dry process for preparing freeze-dired attenuated live vaccine for hepatitis A provided by the invention divides three Main Stage, that is: the phase I is the pre-freeze phase, and second stage is the sublimation drying phase, and the phase III is the parsing-desiccation phase.Wherein:
The acquisition of sublimation drying phase vaccine constant temperature or accurate constant temperature effect: omnidistance constant temperature level pressure distillation of the sublimation drying phase mode that adopts with existing freeze-dry process is different, the present invention has carried out three segment process to the sublimation drying phase and has divided, and is followed successively by: 1. as seen the ice face distillation phase, 2. elimination phase and 3. invisible ice face distillation phase are shunk in the bottom.Each segment process process is carried out the time period respectively segment, each segmentation period is a sublimation step.Specifically:
1. as seen the ice face distils the phase (comprise the bottom and shrink the elimination phase): sublimation step is carried out the linear cooling of shelf and freeze drying box pressure decline is operated by successively each being segmented again, make the vaccine distillation be in " accurate constant temperature sublimation condition ", when certain segmentation sublimation step proceeds to vaccine distillation and can not continue to keep " accurate constant temperature sublimation condition ", carry out the linear cooling of shelf of next step, the freeze drying box of successively decreasing simultaneously pressure makes vaccine produce next step interior " accurate constant temperature sublimation process "; Recursion successively is till finishing to visible ice face distillation.
2. the elimination phase is shunk in the bottom: be the visible interim special process of ice face distillation, propelling along with the sublimation drying process, as seen ice face and move down a minimizing and a close bottle end gradually, as keep " the linear cooling+freeze drying box pressure of shelf " combination of current step always, a certain moment before visible ice face complete obiteration then, temperature rise sudden change flex point will appear in vaccine, and the bottom is shunk rapidly and formed, and contraction will last till the complete obiteration of visible ice face.From shrinking certain period before taking place, adopt faster " the linear rate of temperature fall of shelf " and the freeze drying box pressure that successively decreases continuously, the bottom shrinkage phenomenon of vaccine will be eliminated fully, after the whole disappearances of visible ice face, continue linear fast cooling of recursion shelf and freeze drying box pressure decline operation, as seen ice face and all disappear to guarantee the FCL vaccine.
3. the invisible ice face distillation phase: as seen the ice face moves down and objectively is not equal to the parallel of distillation face and moves down, and when visible ice face disappeared, the sightless ice-nucleus of residual fraction was gone back in vaccine inside.Because the steam that the ice-nucleus distillation produces will transmit in the more and more longer porous channel of the dried cake of vaccine, channel resistance is also increasing.The technique processing method that effectively discharges this part steam is: keep the rapid shelf temperature of previous step constant, adopt freeze drying box pressure (vacuum) decrement operations successively in a plurality of segmentation period, when the vaccine temperature rose to shelf temperature gradually, invisible ice face disappeared, and sublimation process is finished.This final step in period sublimation drying time of proper extension, all disappear to guarantee the invisible ice face of FCL vaccine.
4. whole sublimation drying phase freeze drying box pressure (vacuum) scope is 50 μ bar～400 μ bar, (example 1 distillation initial shelf temperature-25.5 ℃ after having determined suitable distillation phase freeze drying box initial pressure (vacuum) and initial shelf temperature, distillation initial depression 350 μ bar), in phase, omnidistance freeze drying box pressure (vacuum) is the continuous gradient downward trend at whole sublimation drying; Before visible ice face disappeared, the freeze dryer shelf temperature was continuous non-linear downward trend, and the vaccine sublimation temperature is " accurate constant temperature distillation " state and the interior downward trend of continuous time in the segmentation period; After visible ice face disappeared, shelf temperature linearly constant temperature kept trend, and the vaccine sublimation temperature is falls the back trend that rises earlier.
Parsing-desiccation phase technology characteristics: keeping under the distillation phase final vacuum permanence condition, with speed between 0.1 ℃～freeze dryer of the per minute design maximum heating rate, shelf temperature is promoted/keeps operation continuously by certain gradient, shelf temperature is promoted rapidly and remain on the highest permission baking temperature of vaccine, when treating that product heats up near shelf temperature, freeze drying box vacuum is reduced to final vacuum, when being dried to pressure with qualified moisture equivalence and rising in the test passes value scope, tamponade, parsing-desiccation finishes.
The present invention compared with prior art has following advantage and effect: the present invention with the constant temperature sublimation process setting up and obtain vaccine as the core process in the viral attenuated live vaccine freeze-dry process, heat up continuously and temperature rise jumping phenomenon (as shown in Figure 1) with the vaccine of avoiding existing freeze-dry process in the distillation phase, to be caused, reduce to greatest extent and eliminates the loss of vaccine infection titre than problem greatly.Make the lyophilizing production cycle of existing single batch of vaccine shorten about 1/2 time, enterprise is implemented under the newly-built of GMP Factory Building and matched facilities or the reorganization and expansion condition need not, can realize the production capacity upgrading economically.The infection titer loss of vaccine in freeze-drying process reduced, can produce favourable influence the saving of upstream pure culture production capacity and the saving of whole production cost.Design lyophilization cycle 20～36 hours, owing to significantly reduced cold consumption of freeze-drying process and facilities and equipment self energy consumption in time, single batch of cycle can save energy about 40～50%; Have the manufacturing enterprise that lyophilization cycle is produced 1000 ten thousand person-portion freeze-dired attenuated live vaccine for hepatitis A per year now for an employing, yearly productive capacity can improve 70～100%, but about year production saves energy 200～3,000,000 degree.Freeze-dry process provided by the invention, preparation freeze-dired attenuated live vaccine for hepatitis A quality of item meet that " the Chinese pharmacopoeia requirement has realized industry energy conservation, lowers consumption, subtracts dirt, synergic sustainable development purpose.
Description of drawings
Fig. 1 is existing freeze-dry process production instance;
Fig. 2 is that the constant temperature sublimation process with vaccine provided by the invention (or accurate constant temperature sublimation process) is the viral attenuated live vaccine freeze-dry process production instance of core process.
The specific embodiment
Below in conjunction with embodiment the present invention is described further.
Embodiment 1
The present invention adopts the following step that the semi-finished product liquid attenuated hepatitis A live vaccine (commercial product) of packing is carried out lyophilization, 54358 bottles of vanning amounts, and 26 hours 40 minutes lyophilization cycle time:
(1). control freeze dryer freeze drying box shelf temperature is 5 ℃, and successively fully loaded liquid attenuated hepatitis A live vaccine through semi-finished product packing and false add plug till each layer shelf is all fully loaded, is closed the lyophilizing chamber door, and freeze-drying process begins;
(2). control freeze drying box shelf temperature is 5 ℃, keeps 60 minutes;
(3). with 1.5 ℃ of speed of per minute the freeze drying box shelf temperature is reduced to-40 ℃, when shelf temperature reaches-40 ℃, kept-40 ℃ of temperature 90 minutes;
(4). with 0.5 ℃ of left and right sides speed of per minute shelf temperature is gone back up to-24.9 ℃, 25 minutes heating-up times from-40 ℃;
(5). with 0.2 ℃ of speed of per minute shelf temperature is reduced to-25.0 ℃, temperature fall time 1 minute from-24.9 ℃;
(6). when freeze-drying process begins, the cold-trap coil temperature is reduced to-60 ℃, kept 1 minute, finish vaccine pre-freeze with 3.0 ℃ of speed of per minute;
(7). keeping shelf temperature is-25.0 ℃, starts vacuum pump, opens the vacuum line isolating valve, to the freeze drying box evacuation, is 350 μ bar up to freeze drying box vacuum;
(8). keep freeze drying box vacuum 350 μ bar, shelf temperature is dropped to-25.5 ℃, temperature fall time 90 minutes from-25.0 ℃ with 0.022 ℃ of speed of per minute;
(9). freeze drying box vacuum is reduced to 300 μ bar, shelf temperature is dropped to-26.0 ℃, temperature fall time 90 minutes from-25.5 ℃ with 0.0056 ℃ of speed of per minute;
(10). freeze drying box vacuum is reduced to 250 μ bar, shelf temperature is reduced to-26.5 ℃, temperature fall time 90 minutes, the temperature rise China that edges down that finishes vaccine from-26.0 ℃ with 0.0056 ℃ of speed of per minute;
(11). freeze drying box vacuum is reduced to 200 μ bar, shelf temperature is reduced to-27.0 ℃, temperature fall time 30 minutes from-26.5 ℃ with 0.017 ℃ of speed of per minute;
(12). freeze drying box vacuum is reduced to 150 μ bar, with 0.017 ℃ of speed of per minute shelf temperature is reduced to-27.5 ℃ from-27.0 ℃, temperature fall time 30 minutes is finished and is successively eliminated the distillation that shrink the vaccine bottom;
(13). freeze drying box vacuum is reduced to 110 μ bar, and keeping shelf temperature is-27.5 ℃, 60 minutes time;
(14). freeze drying box vacuum is reduced to 90 μ bar, and keeping shelf temperature is-27.5 ℃, 60 minutes time;
(15). freeze drying box vacuum is reduced to 70 μ bar, and keeping shelf temperature is-27.5 ℃, 60 minutes time;
(16). freeze drying box vacuum is reduced to 60 μ bar, and keeping shelf temperature is-27.5 ℃, 60 minutes time, finishes the invisible ice face distillation of vaccine;
(17). keeping freeze drying box vacuum is 60 μ bar, with 0.017 ℃ of speed of per minute shelf temperature is upgraded to-27.0 ℃, 30 minutes heating-up times by-27.5 ℃;
(18). at shelf temperature is under-27.0 ℃, keeps 10 minutes, and keeping freeze drying box vacuum simultaneously is 60 μ bar;
(19). keeping freeze drying box vacuum is 60 μ bar, with 0.1 ℃ of speed of per minute shelf temperature is upgraded to-25.0 ℃, 20 minutes heating-up times by-27.0 ℃;
(20). at shelf temperature is-25.0 ℃, and freeze drying box vacuum is under the 60 μ bar conditions, keeps 20 minutes;
(21). keeping freeze drying box vacuum is 60 μ bar; With 0.125 ℃ of speed of per minute shelf temperature is upgraded to-20.0 ℃, 40 minutes heating-up times by-25.0 ℃;
(22). at shelf temperature is-20.0 ℃, and freeze drying box vacuum is under the 60 μ bar, keeps 40 minutes;
(23). keeping freeze drying box vacuum is 60 μ bar, with 0.33 ℃ of speed of per minute shelf temperature is upgraded to-15.0 ℃, 15 minutes heating-up times by-20.0 ℃;
(24) be-15.0 ℃ at shelf temperature, freeze drying box vacuum is under the 60 μ bar, keeps 15 minutes;
(25). keeping freeze drying box vacuum is 60 μ bar, with 0.33 ℃ of speed of per minute shelf temperature is upgraded to-10.0 ℃, 15 minutes heating-up times by-15.0 ℃;
(26). in shelf control temperature is-10.0 ℃, and freeze drying box vacuum is under the 60 μ bar, keeps 15 minutes;
(27). keeping freeze drying box vacuum is 60 μ bar, with 0.33 ℃ of speed of per minute shelf is controlled temperature and is upgraded to-5.0 ℃, 15 minutes heating-up times by-10.0 ℃;
(28). in shelf control temperature is-5.0 ℃, and freeze drying box vacuum is under the 60 μ bar, keeps 15 minutes;
(29). keeping freeze drying box vacuum is 60 μ bar, with 0.33 ℃ of speed of per minute shelf is controlled temperature and is upgraded to 0.0 ℃ by-5.0 ℃, 15 minutes heating-up times;
(30). at shelf temperature is 0.0 ℃, and freeze drying box vacuum is under the 60 μ bar conditions, keeps 15 minutes;
(31). keeping freeze drying box vacuum is 60 μ bar, with 1.0 ℃ of speed of per minute shelf is controlled temperature and is upgraded to 5.0 ℃ by 0.0 ℃, 5 minutes heating-up times;
(32). at shelf temperature is 5.0 ℃, and freeze drying box vacuum is under the 60 μ bar conditions, keeps 5 minutes;
(33). keeping freeze drying box vacuum is 60 μ bar; With 1.0 ℃ of speed of per minute shelf is controlled temperature and be upgraded to 10.0 ℃ by 5.0 ℃, 5 minutes heating-up times;
(34). at shelf temperature is 10.0 ℃, and freeze drying box vacuum is under the 60 μ bar, keeps 5 minutes;
(35). keeping freeze drying box vacuum is 60 μ bar; With 1.07 ℃ of speed of per minute shelf is controlled temperature and be upgraded to 26.0 ℃ by 10.0 ℃, 15 minutes heating-up times;
(36). in shelf control temperature is 26 ℃, and freeze drying box vacuum is under the 60 μ bar, keeps 150 minutes;
(37). freeze drying box vacuum is reduced to 5 μ bar, and keeping shelf temperature is 26 ℃, 240 minutes;
(38). detect 5 minutes pressure liters of freeze drying box every 30 minutes Automatic Cycle, the remaining water content of goods is qualified when pressure liter＜55 μ bar, starts tamponade, qualified freeze-dired attenuated live vaccine for hepatitis A.
Embodiment 2
Semi-finished product liquid attenuated hepatitis A live vaccine (commercial product) after adopting the following step to packing carries out lyophilization, 55000 bottles of vanning amounts, and 21.5～22.5 hours lyophilization cycle time:
(1). control freeze dryer freeze drying box temperature is 10 ℃, and the successively fully loaded bottle that divides the liquid attenuated hepatitis A live vaccine that semi-finished product and false add plug are housed till each layer shelf is all fully loaded, is closed the lyophilizing chamber door, and freeze-drying process begins;
(2). control freeze drying box shelf temperature is 10 ℃, keeps 30 minutes;
(3). with 1.5 ℃ of speed of per minute the freeze drying box shelf temperature is reduced to-40 ℃, keep shelf temperature-40 ℃, 90 minutes;
(4). with 0.60 ℃ of speed of per minute shelf temperature is gone back up to-24.9 ℃, 30 minutes heating-up times from-40 ℃;
(5). shelf temperature is reduced to-25.0 ℃ with 0.1 ℃ of speed of per minute again, temperature fall time 1 minute;
(6). when freeze-drying process begins, the cold-trap coil temperature is reduced to-60 ℃ synchronously with 2.5 ℃ of speed of per minute;
(7). keeping shelf temperature is-25.0 ℃, starts vacuum pump, opens the vacuum line isolating valve, to the freeze drying box evacuation, is 350 μ bar up to freeze drying box vacuum;
(8). under shelf temperature is-25.0 ℃, freeze drying box vacuum 350 μ bar conditions, kept 30 minutes;
(9). keeping shelf temperature is-25.0 ℃, and freeze drying box vacuum is reduced to 335 μ bar, keeps 30 minutes;
(10). keeping shelf temperature is-25.0 ℃, and freeze drying box vacuum is reduced to 320 μ bar, keeps 30 minutes;
(11). keeping shelf temperature is-25.0 ℃, and freeze drying box vacuum is reduced to 305 μ bar, keeps 30 minutes;
(12). keeping shelf temperature is-25.0 ℃, and freeze drying box vacuum is reduced to 290 μ bar, keeps 30 minutes;
(13). keeping shelf temperature is-25.0 ℃, and freeze drying box vacuum is reduced to 275 μ bar, keeps 30 minutes;
(14). keeping shelf temperature is-25.0 ℃, and freeze drying box vacuum is reduced to 260 μ bar, keeps 30 minutes;
(15). keeping shelf temperature is-25.0 ℃, and freeze drying box vacuum is reduced to 245 μ bar, keeps 30 minutes;
(16). keeping shelf temperature is-25.0 ℃, and freeze drying box vacuum is reduced to 230 μ bar, keeps 30 minutes, finishes the temperature rise China that edges down of vaccine;
(17). with 0.017 ℃ of speed of per minute shelf temperature is reduced to-25.5 ℃ by-25.0 ℃, freeze drying box vacuum is reduced to 215 μ bar, temperature fall time 30 minutes;
(18). with 0.017 ℃ of speed of per minute shelf temperature is reduced to-26.0 ℃ by-25.5 ℃, freeze drying box vacuum is reduced to 200 μ bar, temperature fall time 30 minutes;
(19). with 0.017 ℃ of speed of per minute shelf is controlled temperature and reduce to-26.5 ℃, freeze drying box vacuum is reduced to 185 μ bar, temperature fall time 30 minutes by-26.0 ℃;
(20). with 0.017 ℃ of speed of per minute shelf is controlled temperature and reduce to-27.0 ℃, freeze drying box vacuum is reduced to 170 μ bar, temperature fall time 30 minutes by-26.5 ℃;
(21). with 0.017 ℃ of speed of per minute shelf is controlled temperature and reduce to-27.5 ℃ by-27.0 ℃, freeze drying box vacuum is reduced to 155 μ bar, temperature fall time 30 minutes is finished and is successively eliminated the distillation that shrink the vaccine bottom;
(22). keeping shelf temperature is-27.5 ℃, and freeze drying box vacuum is reduced to 140 μ bar; Kept 15 minutes;
(23). keeping shelf temperature is-27.5 ℃, and freeze drying box vacuum is reduced to 120 μ bar; Kept 15 minutes;
(24). keeping shelf temperature is-27.5 ℃, and freeze drying box vacuum is reduced to 100 μ bar; Kept 15 minutes;
(25). keeping shelf temperature is-27.5 ℃, and freeze drying box vacuum is reduced to 80 μ bar; Kept 15 minutes;
(26). keeping shelf temperature is-27.5 ℃, and freeze drying box vacuum is reduced to 60 μ bar; Kept 15 minutes, and finished the invisible ice face distillation of vaccine;
(27). keeping freeze drying box vacuum is 60 μ bar, with 0.033 ℃ of speed of per minute shelf is controlled temperature and is upgraded to-27.0 ℃, 15 minutes heating-up times by-27.5 ℃.
(28). at shelf temperature is-27.0 ℃, and freeze drying box vacuum is under the condition of 60 μ bar, keeps 15 minutes;
(29). keeping freeze drying box vacuum is 60 μ bar, with 0.133 ℃ of speed of per minute shelf is controlled temperature and is upgraded to-25.0 ℃, 15 minutes heating-up times by-27.0 ℃.
(30). at shelf temperature is-25.0 ℃, and freeze drying box vacuum is under the condition of 60 μ bar, keeps 15 minutes;
(31). keeping freeze drying box vacuum is 60 μ bar, with 0.333 ℃ of speed of per minute shelf temperature is upgraded to-20.0 ℃, 15 minutes heating-up times by-25.0 ℃.
(32). at shelf temperature is-20.0 ℃, and freeze drying box vacuum is under the condition of 60 μ bar, keeps 15 minutes;
(33). keeping freeze drying box vacuum is 60 μ bar, with 0.333 ℃ of speed of per minute shelf is controlled temperature and is upgraded to-15.0 ℃, 15 minutes heating-up times by-20.0 ℃.
(34). at shelf temperature is-15.0 ℃, and freeze drying box vacuum is under the 60 μ bar, keeps 15 minutes;
(35). keeping freeze drying box vacuum is 60 μ bar, with 0.333 ℃ of speed of per minute shelf is controlled temperature and is upgraded to-10.0 ℃, 15 minutes heating-up times by-15.0 ℃.
(36). at shelf temperature is-10.0 ℃, and freeze drying box vacuum is under the 60 μ bar, keeps 15 minutes;
(37). keeping freeze drying box vacuum is 60 μ bar, with 0.333 ℃ of speed of per minute shelf is controlled temperature and is upgraded to-5.0 ℃, 15 minutes heating-up times by-10.0 ℃.
(38). at shelf temperature is-5.0 ℃, and freeze drying box vacuum is under the 60 μ bar, keeps 15 minutes;
(39). keeping freeze drying box vacuum is 60 μ bar, with 0.333 ℃ of speed of per minute shelf is controlled temperature and is upgraded to 0.0 ℃ by-5.0 ℃, 15 minutes heating-up times.
(40). at shelf temperature is 0.0 ℃, and freeze drying box vacuum is under the 60 μ bar, keeps 15 minutes;
(41). keeping freeze drying box vacuum is 60 μ bar, with 1.0 ℃ of speed of per minute shelf is controlled temperature and is upgraded to 5.0 ℃ by 0.0 ℃, 5 minutes heating-up times.
(42). at shelf temperature is 5.0 ℃, and freeze drying box vacuum is under the 60 μ bar, keeps 5 minutes;
(43). keeping freeze drying box vacuum is 60 μ bar, with 1.0 ℃ of speed of per minute shelf is controlled temperature and is upgraded to 10.0 ℃ by 5.0 ℃, 5 minutes heating-up times.
(44). at shelf temperature is 10.0 ℃, and freeze drying box vacuum is under the 60 μ bar, keeps 5 minutes;
(45). keeping freeze drying box vacuum is 60 μ bar, with 1.07 ℃ of speed of per minute shelf is controlled temperature and is upgraded to 26.0 ℃ by 10.0 ℃, 15 minutes heating-up times.
(46). in shelf control temperature is 26.0 ℃, and freeze drying box vacuum is under the 60 μ bar, keeps 150 minutes;
(47). keeping shelf temperature is 26.0 ℃, and freeze drying box vacuum is reduced to 5 μ bar; Kept 180 minutes;
(48). detect 5 minutes pressure liters of freeze drying box every 30 minutes Automatic Cycle, the remaining water content of goods is qualified when 5 minutes pressure liters＜55 μ bar, starts tamponade, qualified freeze-dired attenuated live vaccine for hepatitis A.
Claims (1)
1. freeze-dry process for preparing freeze-dired attenuated live vaccine for hepatitis A is characterized in that through following process steps:
A, vaccine pre-freeze: in temperature is under 5～15 ℃ of conditions, and attenuated hepatitis A live vaccine is incubated 20～60 minutes, and the speed with 0.5～1.67 ℃ of per minute cools the temperature to-40 ℃ afterwards, is incubated 60～90 minutes; With the speed of 0.4～0.6 ℃ of per minute temperature is gone back up to-27.4～-24.9 ℃ from-40 ℃ again, with the speed of 0.1～1.67 ℃ of per minute temperature is reduced to T afterwards
1, i.e. T
1=-27.5～-25.0 ℃;
B, vaccine sublimation drying:
1) be T, in temperature
1=-27.5～-25.0 ℃, vacuum is P
1Under the condition of=150～400 μ bar, begin to carry out the sublimation drying of vaccine.With the speed of 0.0000～0.0056 ℃ of per minute with temperature from T
1Drop to T
2, T
2=[T
1-(0～0.5 ℃)]～T
1
2) be T, in temperature
2=[T
1-(0～0.5 ℃)]～T
1, vacuum is P
2=P
1Under the condition of-(5～50 μ bar), with the speed of 0.0000～0.0056 ℃ of per minute with temperature from T
2Drop to T
3, T
3=[T
2-(0～0.5 ℃)]～T
2
3) be T, in temperature
3=[T
2-(0～0.5 ℃)]～T
2, vacuum is P
3=P
1Under-2 * (5～50 μ bar) the condition, with the speed of 0.0000～0.0056 ℃ of per minute with temperature from T
3Drop to T
4, T
4=[T
3-(0～0.5 ℃)]～T
3
N), temperature is reduced to T
n=[T
N-1-(0～0.5 ℃)]～T
N-1, vacuum is P
n=P
1-(n-1) * (5～50 μ bar), and sublimation drying time when proceeding to 240～270 minutes, the temperature rise China that edges down that finishes vaccine;
C, be T in temperature
n=[T
N-1-(0～0.5 ℃)]～T
N-1, vacuum is P
n=P
1Under-(n-1) * (5～50 μ bar) the condition, with the speed cooling of 0.0056～0.017 ℃ of per minute, fall 0.5 ℃ at every turn, lower the temperature continuously 0～5 time, each corresponding decompression 5～50 μ bar successively eliminate the distillation that shrink the vaccine bottom to finish;
D, maintenance temperature are (T
n-2.5 ℃), be P from vacuum
n-4 * (5～50 μ bar) beginnings are evenly reduced pressure 0～5 time successively, and vacuum is dropped to 60 μ bar, and each decompression kept 15～120 minutes, to finish the invisible ice face distillation to vaccine;
E, to keep vacuum be 60 μ bar, with the speed of 0.017～0.05 ℃ of per minute with temperature by (T
n-2.5 ℃) be upgraded to (T
n-2.0 ℃), kept 10～30 minutes; With the speed of 0.1～0.2 ℃ of per minute with temperature from (T
n-2.0 ℃) be upgraded to-25.0 ℃, kept 10～20 minutes, with 0.2～1.0 ℃ speed temperature is upgraded to-20.0 ℃ from-25.0 ℃, kept 5～25 minutes; With 0.33～1.0 ℃ speed temperature is upgraded to-15.0 ℃ from-20.0 ℃, kept 5～15 minutes, with the phase same rate temperature is upgraded to-10.0 ℃ from-15.0 ℃ afterwards, kept 5～15 minutes, with the speed of 0.2～0.5 ℃ of per minute temperature is upgraded to-5.0 ℃ from-10.0 ℃, kept 10～25 minutes; With the phase same rate temperature is upgraded to 0.0 ℃ from-5.0 ℃ again, kept 10～25 minutes; With the speed of 0.5～1.0 ℃ of per minute temperature is upgraded to 5.0 ℃ from 0.0 ℃ again, kept 5～20 minutes, temperature is upgraded to 10.0 ℃ from 5.0 ℃, kept 5～20 minutes with same speed; At last temperature is upgraded to 25～27 ℃ from 10.0 ℃, kept 60～150 minutes, the process that is rapidly heated when finishing the vaccine parsing-desiccation with the speed of 1.0～1.7 ℃ of per minutes;
F, lyophilizing vacuum is reduced to 5 μ bar, under 25.0～27.0 ℃ of temperature, kept 120～240 minutes;
G, when per 5 minutes pressure liters＜20～60 μ bar, the remaining water content of goods is qualified, freeze-dired attenuated live vaccine for hepatitis A.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNA2008100587301A CN101327323A (en) | 2008-07-25 | 2008-07-25 | Lyophilization technique for preparing lyophilized hepatitis A attenuated live vaccine |
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|---|---|---|---|
| CNA2008100587301A CN101327323A (en) | 2008-07-25 | 2008-07-25 | Lyophilization technique for preparing lyophilized hepatitis A attenuated live vaccine |
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|---|---|---|---|
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101904540A (en) * | 2010-08-24 | 2010-12-08 | 中国热带农业科学院香料饮料研究所 | Method for processing green peppers |
| CN112791177A (en) * | 2019-10-28 | 2021-05-14 | 深圳翰宇药业股份有限公司 | Somatostatin freeze-dried composition for injection and preparation method thereof |
| CN113679832A (en) * | 2021-05-24 | 2021-11-23 | 苏州大学 | Method for preparing baculovirus carp herpesvirus II type DNA vaccine by utilizing freeze drying |
-
2008
- 2008-07-25 CN CNA2008100587301A patent/CN101327323A/en active Pending
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101904540A (en) * | 2010-08-24 | 2010-12-08 | 中国热带农业科学院香料饮料研究所 | Method for processing green peppers |
| CN112791177A (en) * | 2019-10-28 | 2021-05-14 | 深圳翰宇药业股份有限公司 | Somatostatin freeze-dried composition for injection and preparation method thereof |
| CN113679832A (en) * | 2021-05-24 | 2021-11-23 | 苏州大学 | Method for preparing baculovirus carp herpesvirus II type DNA vaccine by utilizing freeze drying |
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Application publication date: 20081224 |