CN110339063B - Preparation process of sterile suspension medicament subjected to non-terminal sterilization treatment - Google Patents

Abstract

The invention discloses a preparation process of a sterile suspension medicament subjected to non-terminal sterilization treatment, which relates to the technical field of suspension medicament preparation and comprises the following process steps: s1: performing aseptic treatment on the raw material medicine; s2: pure steam is introduced into equipment and a pipeline used for preparing the suspension medicament; s3: suspending agent and adjuvant dissolved in water for regulating osmotic pressure; s4: adding the raw material medicine subjected to the sterile treatment in the step S1 into a sterile feeding device; s5: filtering the auxiliary material preparation liquid through an aseptic filter, flushing the raw material medicines in the aseptic feeding device into an aseptic mixing tank together, and dispersing and stirring uniformly; s6: filling; s7: and (5) carrying out leak detection and lamp inspection on the filled suspension medicament to obtain a finished sterile suspension medicament after the suspension medicament is qualified. The preparation method solves the problem of difficult preparation of sterile suspension medicaments such as water-insoluble and thermolabile medicaments, inhalation suspension medicaments with controlled medicament particle size, injection suspension medicaments and the like.

Description

Preparation process of sterile suspension medicament subjected to non-terminal sterilization treatment

Technical Field

The invention relates to the technical field of suspension medicaments, in particular to a preparation process of an aseptic suspension medicament subjected to non-terminal sterilization treatment.

Background

The suspension medicament is a liquid preparation formed by uniformly dispersing a solid phase and a liquid phase. The sterile suspension medicament is required to be sterilized in the preparation process. In the production process of pharmaceutical preparations, the sterilization treatment usually includes moist heat sterilization, dry heat sterilization, radiation sterilization, gas sterilization, filtration sterilization, and the like. The activity of the thermolabile drug suspension medicament is easy to change under the high temperature condition, or the particle size of the drug suspension medicament with particle size control is aggregated and increased under the high temperature condition, so that the drug effect of the suspension medicament is weakened. Therefore, the heat sterilization method cannot be adopted for thermolabile medicines and sterile suspension medicines with controlled medicine particle size.

Disclosure of Invention

Aiming at the defects in the prior art, the invention aims to provide a preparation process of a sterile suspension medicament by non-terminal sterilization treatment.

The above object of the present invention is achieved by the following technical solutions:

a preparation process of a sterile suspension medicament subjected to non-terminal sterilization treatment comprises the following process steps:

s1: performing aseptic treatment on the raw material medicine;

s2: introducing pure steam with the temperature of 135-150 ℃ into equipment and a pipeline used for preparing the suspension medicament for 20-40 min, and then cooling to 20-30 ℃;

s3: preparing auxiliary materials, namely adding water for injection and prescription auxiliary materials according to the prescription amount in sequence, and stirring and uniformly mixing for 10-20 min;

s4: adding the raw material medicine subjected to the sterile treatment in the step S1 into a sterile feeding device;

s5: filtering the auxiliary material preparation liquid through an aseptic filter, flushing the raw material medicines in the aseptic feeding device into a sterilized material mixing tank together, and dispersing and stirring uniformly;

s6: filling the suspension medicament in the dosing tank in a sterile environment through BFS (blowing, filling and sealing integrated machine) equipment;

s7: and carrying out vacuum leak detection and lamp inspection on the filled suspension medicament to obtain a finished suspension medicament after the suspension medicament is qualified.

By adopting the technical scheme, the raw material medicine after aseptic treatment is directly added into the auxiliary material liquid after aseptic filtration by using the aseptic feeding device, and then the raw material medicine is uniformly stirred in the mixing tank to obtain the required suspension medicament preparation. When the process is used for preparation, the auxiliary material and the raw material medicine are respectively subjected to aseptic treatment, and then the auxiliary material and the raw material medicine are mixed in an aseptic environment, so that the aseptic suspension medicament is obtained. And the raw material medicines of the suspension medicament can not pass through an aseptic filter for aseptic processing of the auxiliary materials, and the raw material medicines can not be intercepted by the aseptic filter, so that the added raw material medicines are all used for preparation, the use amount of the raw material medicines is saved, and the quality of the suspension medicament product is improved.

The invention is further configured to: the specific operation steps of the sterile treatment of the bulk drug in the step S1 are as follows:

a 1: introducing pure steam with the temperature of 135-150 ℃ into equipment and pipelines in the raw material medicine sterile treatment step for 20-40 min, then cooling to 20-30 ℃, and introducing sterile filtered hot compressed air to remove residual water in the equipment and the pipelines;

a 2: adding a solvent for dissolving the raw material medicines into a dissolving tank, adding the raw material medicines, heating to 60-65 ℃, and then stirring for 15-20 min;

a 3: after the dissolved bulk drug solution is filtered in two stages of pre-filtration and sterilization filtration, transferring the sterilized nitrogen into a crystallization tank, continuously adding a bulk drug solvent into the dissolution tank for washing, and transferring the washed bulk drug solvent into the crystallization tank.

a 4: adding water for injection into a dissolving tank, pressing the water for injection into a crystallizing tank by using sterilized nitrogen for constant volume, then cooling to 20-30 ℃, and stirring for 60-100 min to obtain a solid-liquid mixed solution;

a 4: introducing the solid-liquid mixed solution into a solid-liquid separator in an aseptic isolator for separation to obtain solid raw material medicine;

a 5: sending the separated solid bulk drug into a drying oven in an aseptic isolator for drying;

a 6: feeding the dried raw material medicine into airflow crushing equipment in an aseptic isolator for crushing;

a 7: packaging the pulverized raw materials in batches.

By adopting the technical scheme, the raw material medicine is subjected to aseptic processing before the suspension medicine is added, the raw material medicine is subjected to aseptic processing through an aseptic filter after being dissolved, then the bacteria-carrying raw material medicine is converted into the aseptic raw material medicine through recrystallization and solid-liquid separation, and then the raw material medicine according with the particle size is obtained through drying and crushing, so that the raw material medicine powder can be directly added into the auxiliary material liquid for dispersion, and the aseptic suspension medicine preparation is obtained.

The invention is further configured to: in the step a3, the pre-filtering filter element is 5 inches, is made of polyether sulfone and has the filter diameter of 0.45 mu m; the sterilizing filter element is 5 inches, is made of polyether sulfone and has the filter diameter of 0.22 mu m.

The invention is further configured to: the sterilization process for equipment and tubing includes the steps of: introducing 135-150 ℃ pure steam into the equipment and the pipeline to keep the temperature of the coldest point above 121 ℃ for not less than 20min, and then cooling to 20-30 ℃.

The invention is further configured to: the sterile feeding device in the step S4 comprises a sterile pipeline, a sterile filter is installed in the sterile pipeline, a sterile isolation box is installed on one side of the sterile pipeline, the sterile isolation box is arranged on one side of the sterile filter along the flowing direction of an auxiliary agent in the sterile pipeline, a feeding device is installed in the sterile isolation box and comprises a connecting pipe which penetrates through the side wall of the sterile isolation box and is communicated with the sterile pipeline, and one end, far away from the connecting pipe, of the connecting pipe, which is connected with the sterile pipeline is connected with a feeding pipe; a first connecting piece is arranged between the charging pipe and the connecting pipe, the first connecting piece comprises a first connecting disc connected with the end wall of the charging pipe and a second connecting disc connected with the end wall of the connecting pipe, the first connecting disc and the second connecting disc are connected in an abutting mode, and clamping hoops for locking the first connecting disc and the second connecting disc are arranged on the side walls of the first connecting disc and the second connecting disc; the side wall of the feeding pipe is connected with an air pressure balance pipe, one end of the air pressure balance pipe is communicated with the side wall of the feeding pipe, the other end of the air pressure balance pipe penetrates through the side wall of the sterile isolation box to be communicated with the external atmosphere, and a sterile filter is arranged at one end of the air pressure balance pipeline communicated with the external atmosphere; install transmission assembly in the connecting pipe, the connecting pipe includes the link that links to each other with the filling tube and the transmission section that links to each other with the link, install driving motor on the lateral wall of link, driving motor's output shaft passes the lateral wall key connection of link and has the rolling disc, fixedly connected with follows the flight that connecting pipe length direction set up on the rolling disc.

By adopting the technical scheme, the interception of the bulk drugs by the sterile filter is reduced, the utilization rate of the bulk drugs is improved, and the quality of the product is improved. The transmission assembly enables the transportation of the bulk drugs to be smoother and not easy to remain in the connecting pipe.

The invention is further configured to: the end, far away from the connecting pipe, of the feeding pipe is hinged with a sealing cover, the side wall, close to the inner cavity of the feeding pipe, of the sealing cover is connected with a rubber block, and the diameter, far away from the end connected with the sealing cover, of the rubber block is smaller than that of the end connected with the sealing cover; the utility model discloses a flexible feed pipe, including closing cap, filling tube, telescopic slot, turning block, rotating groove, telescopic spring's one end and the fixed linking to each other of telescopic slot tank bottom, telescopic spring's the other end is connected with flexible piece, be connected with the turning block on the lateral wall of filling tube, the rotating groove has been seted up on the turning block, the turning block rotates with the rotating groove to be connected, set up on the lateral wall of closing cap and stir the hole with flexible groove intercommunication, be connected with on the flexible piece and stir the piece, stir the piece and stir hole sliding connection.

Through adopting above-mentioned technical scheme, the closing cap is closed at the mouth of pipe of filling tube when filling tube and connecting pipe need disinfect the sterilization process, and the rubber piece makes the connection between closing cap and the filling tube inseparabler, and the rubber piece plays certain locking effect to the closing cap for the closing cap chucking is at the mouth of pipe of filling tube.

The invention is further configured to: the side wall of the sterile isolation box is connected with a fixing frame, the fixing frame is connected with a storage pipe, one end of the storage pipe, which is connected with the feeding pipe, is provided with a control part, and the side wall of the storage pipe is marked with scales; the control piece comprises a control frame, one end of the control frame is clamped with the opening of the feeding pipe, the other end of the control frame is connected with the storage pipe through a hoop, a first through hole is formed in the side wall of the control frame, a first lug is slidably mounted in the first through hole, one end, penetrating through the side wall of the control frame, of the first lug is hinged with a second lug which is symmetrical to the axis of the first lug, one end, far away from the end connected with the first lug, of the second lug is hinged with a third lug, the third lug is hinged with the side wall of the control frame, and a rubber sealing layer is connected between the side wall of the control frame and the second lug as well as between the side wall of the control frame and the third lug; the second lug is far away from the one end that links to each other with first lug and is connected with the stopper, the locating piece is connected to the control frame in, the limiting groove has been seted up along the length direction of locating piece on the locating piece, stopper and limiting groove sliding connection.

Through adopting above-mentioned technical scheme, the memotron can store partial bulk drug powder for when adding the bulk drug in aseptic pipeline, only need put in through control spare, do not need the people to manually feed in raw materials, it is more convenient to throw the material mode. The scales on the storage pipe are convenient for the staff to determine the feeding amount.

Compared with the prior art, the invention has the beneficial effects that:

1. the method comprises the steps of performing sterile treatment on water-insoluble bulk drugs, adding the sterile-treated bulk drugs into a sterilized auxiliary material preparation solution, and preparing the suspension medicament in a dosing tank with a high-shear dispersion emulsifying machine, so that the problem that thermolabile drugs and drugs with particle size control are difficult to prepare into the sterile suspension medicament is solved;

2. the raw material medicines are added into the sterile pipeline filtered by the sterile filter in a sterile environment by arranging the sterile isolation box, so that the raw material medicines are fed in a pollution-free manner and are an important part in the preparation process of sterile suspension medicaments;

3. the storage tube with the control part is arranged on the feeding tube, so that the bulk drug is added into the storage box firstly, and then the material is fed through the control part, and the feeding is more convenient and faster.

Drawings

FIG. 1 is a perspective view of an aseptic feeding device;

FIG. 2 is an exploded view of the transmission assembly and connecting tube;

FIG. 3 is an exploded view of the fill tube and attachment end;

FIG. 4 is an exploded view of the closure cap and filler tube;

fig. 5 is a perspective view of the control member.

Reference numerals: 3. a sterile conduit; 4. a sterile isolation box; 41. a connecting pipe; 411. a transmission section; 412. a connecting end; 42. a transmission assembly; 421. a drive motor; 422. rotating the disc; 423. a spiral sheet; 43. a feed tube; 431. a first connecting member; 432. a first splice tray; 433. a second connecting disc; 434. clamping a hoop; 435. a closure cap; 436. a rubber block; 44. a pressure balance tube; 45. a fixed mount; 451. a storage tube; 46. a control member; 461. a control frame; 462. a first through hole; 463. a first bump; 464. a second bump; 465. a limiting block; 466. positioning blocks; 467. a limiting groove; 468. a third bump; 469. a sealing layer; 47. a telescopic groove; 471. a tension spring; 472. a telescopic block; 473. rotating the block; 474. a rotating groove; 475. a toggle hole; 476. and a poking block.

Detailed Description

The invention is described in detail below with reference to the figures and examples.

Example 1:

the invention discloses a preparation process of a sterile suspension medicament subjected to non-terminal sterilization treatment, which comprises the following process steps:

s1: the aseptic treatment of the bulk drug comprises the following steps:

a 1: introducing 135 deg.C pure steam into the equipment and pipeline in the aseptic treatment step to maintain the coldest point at 121 deg.C for 30min, cooling to 25 deg.C, and introducing sterile filtered hot compressed air to remove residual water in the equipment and pipeline;

a 2: adding the raw material medicine solvent into a dissolving tank, adding the raw material medicine solvent, heating to 60 ℃, and then stirring for 15 min;

a 3: after the dissolved bulk drug solution is filtered in two stages of pre-filtration and sterilization filtration, transferring the sterilized nitrogen into a crystallization tank, continuously adding a bulk drug solvent into the dissolution tank for washing, and transferring the washed bulk drug solvent into the crystallization tank;

a 4: adding water for injection into a dissolving tank, pressing the water for injection into a crystallizing tank by using sterilized nitrogen for constant volume, then cooling to 20 ℃, and stirring for 90min to obtain a solid-liquid mixed solution;

a 4: introducing the solid-liquid mixed solution into a solid-liquid separator in an aseptic isolator for separation to obtain solid raw material medicine;

a 5: sending the separated solid raw material medicine into an oven in a sterile isolator for drying, wherein the drying temperature is set to be 60 ℃, the vacuum degree is-90 Pa, and the drying time is controlled to be 8 hours;

a 6: feeding the dried raw material medicine into airflow crushing equipment in an aseptic isolator to crush the raw material medicine to a specified particle size;

a 7: quantitatively packaging the crushed raw material medicines.

S2: introducing pure steam of 135 deg.C into the equipment and pipeline for preparing suspension agent, keeping the coldest point temperature at 121 deg.C for 30min, and cooling to 20 deg.C;

s3: preparing auxiliary materials, namely adding water for injection and prescription auxiliary materials according to the prescription amount in sequence, and stirring and uniformly mixing for 20 min;

s4: adding the raw material medicine subjected to the sterile treatment in the step S1 into a sterile feeding device;

s5: filtering the auxiliary material preparation solution through a sterile filter, flushing the raw material medicines in the sterile feeding device into a sterilized mixing tank with a high-shear dispersing emulsifying machine, starting the high-shear dispersing emulsifying machine and a stirring device, and uniformly dispersing and suspending;

s6: filling the suspension medicament in the dosing tank in a sterile environment through BFS (blowing, filling and sealing integrated machine) equipment;

s7: and (4) carrying out vacuum leakage detection and lamp detection on the filled suspension medicament, and obtaining a finished suspension medicament after the suspension medicament is qualified.

The aseptic feeding device in the step S4 includes an aseptic pipeline 3 through which the liquid auxiliary flows, and an aseptic filter is installed in the aseptic pipeline 3. And a sterile isolation box 4 is arranged on one side of the sterile pipeline 3, and the sterile isolation box 4 is arranged on one side of the liquid auxiliary agent outflow surface of the sterile filter. The sterile isolation box 4 is internally provided with a connecting pipe 41 which passes through the side wall of the sterile isolation box 4 and is communicated with the sterile pipeline 3.

Referring to fig. 1 and 2, a driving assembly 42 is installed in the connection pipe 41, and the connection pipe 41 includes a driving section 411 connected to the aseptic isolation box 4 and a connection end 412 vertically connected to the driving section 411. A driving motor 421 is installed on the side wall of the transmission section 411 connected to the connection end 412, an output shaft of the driving motor 421 penetrates through the side wall key of the transmission section 411 to be connected to a rotation disc 422, and a spiral piece 423 arranged along the length direction of the connection pipe 41 is fixedly connected to the rotation disc 422.

Referring to fig. 1 and 3, a first connection member 431 is provided at the connection end 412, and the first connection member 431 is connected to the filling pipe 43. The first connecting member 431 includes a first connecting plate 432 connected to the end wall of the charging pipe 43 and a second connecting plate 433 connected to the end wall of the connecting pipe 41, the first connecting plate 432 and the second connecting plate 433 are abutted, and a clamp 434 locking the first connecting plate 432 and the second connecting plate 433 is provided on the side walls of the first connecting plate 432 and the second connecting plate 433.

Referring to fig. 3 and 4, a closing cover 435 is hinged to an end of the feeding tube 43 away from the connecting tube 41, a rubber block 436 is fixedly connected to a side wall of the closing cover 435 close to the inner cavity of the feeding tube 43, and a diameter of an end of the rubber block 436 away from the end connected with the closing cover 435 is smaller than a diameter of an end of the rubber block 436 connected with the closing cover 435. Telescopic groove 47 has been seted up to the one end that closing cap 435 and filling tube are connected, telescopic spring 471 is installed in the telescopic groove 47, telescopic spring 471's one end and telescopic groove 47 tank bottom are fixed to be connected to each other, telescopic spring 471's the other end is connected with flexible piece 472, be connected with turning block 473 on the lateral wall of filling tube, turning block 473 has been seted up on turning block 473 and has been rotated groove 474, turning block 473 rotates with rotating groove 474 and is connected, set up the stirring hole 475 that is linked together with telescopic groove 47 on the lateral wall of closing cap 435, be connected with stirring block 476 on the flexible piece 472, stir block 476 and stir hole 475 sliding connection.

Referring to fig. 1, an air pressure balance tube 44 is fixedly connected to the sidewall of the feeding tube 43, one end of the air pressure balance tube 44 is communicated with the feeding tube 43, the other end of the air pressure balance tube 44 passes through the sidewall of the aseptic isolation box 4 to be communicated with the outside atmosphere, and a sterile filter is arranged at one end of the air pressure balance tube 44 which is communicated with the outside atmosphere.

Referring to fig. 1 and 5, a fixing frame 45 is connected to a side wall of the aseptic isolation container 4, and a transparent storage tube 451 is installed on the fixing frame 45. The side wall of the reservoir tube 451 is marked with a scale. The transparent storage tube 451 is provided with a control member 46 at an end thereof adjacent to the feeding tube 43, the control member 46 includes a control frame 461, and the control frame 461 is connected to the storage tube 451 through a clamp 434. First through-hole 462 has been seted up on the lateral wall of control frame 461, slidable mounting has first lug 463 in first through-hole 462, first lug 463 passes the articulated second lug 464 that has the first lug 463 axis of symmetry of one end of control frame 461 lateral wall, the one end that second lug 464 keeps away from to link to each other with first lug 463 is connected with stopper 465, the control frame 461 in-connection has locating piece 466, spacing groove 467 has been seted up along the length direction of locating piece 466 on the locating piece 466, stopper 465 and spacing groove 467 sliding connection. The end of the second bump 464 far away from the end connected with the first bump 463 is hinged with a third bump 468, the third bump 468 is hinged with the side wall of the control frame 461, and a rubber sealing layer 469 is connected between the side wall of the control frame 461 and the second bump 464 and the third bump 468. The end of the control frame 461 remote from the end connected to the storage tube 451 is engaged with the inlet of the feeding tube 43.

The implementation principle of the embodiment is as follows: before using the device, the closing cap 435 is closed and then the high temperature pure steam is introduced into the tube for sterilization. After the sterilization is finished, the liquid auxiliary agent in the sterile pipeline 3 starts to flow, and bacteria in the liquid are killed after the liquid auxiliary agent passes through the sterile filter. The storage tube 451 is then mounted to the mounting bracket 45, and one side of the control frame 461 is fixed to the storage tube 451 by the clamp 434, and the other side of the control frame 461 is fixed to the feed scraper. Sterile bulk drug powder is then added to the internal storage tube 451 in the sterile isolation container 4. After the addition is finished, when the raw material medicine is required to be added into the liquid auxiliary agent, the first bump 463 is pressed, the first bump 463 slides in the first through hole 462, the first bump 463 drives the second bump 464 to slide along the positioning block 466, the limiting block 465 slides in the limiting groove 467, one end, hinged to the second bump 464 and the third bump 468, is away from each other, the rubber sealing layer 469 is supported by the second bump 464 and the third bump 468, so that the raw material medicine in the storage tube 451 enters the feeding tube 43 and then enters the connecting tube 41 along the feeding tube 43. Then the driving motor 421 is started, the output shaft of the driving motor 421 drives the rotating disc 422 to rotate, and the rotating disc 422 rotates to drive the spiral piece 423 to rotate, so that the bulk drug powder entering the connecting pipe 41 is conveyed to the sterile pipeline 3.

The difference between examples 2-5 and example 1 is that the aseptic processing conditions of the equipment and the pipeline during the bulk drug preparation and suspension drug preparation are shown in the following table.

Examples 6 to 9 differ from example 1 in that the stirring time of the auxiliary materials is as follows.

Examples	Time of stirring of auxiliary materials
		Example 6	12.5
Example 7	10
		Example 8	17.5
Example 9	20

Examples 10 to 13 are different from example 1 in that the temperature rise and the stirring time for temperature rise during the preparation of the drug substance are shown in the following table.

Examples	Temperature rise	Time of stirring
			Example 10	61.25	16.25
Example 11	62.5	17.5
			Example 12	63.75	18.75
Example 13	65	20

Examples 14 to 17 are different from example 1 in that the cooling temperature and the cooling stirring time are shown in the following table during the preparation of the raw material drug.

Comparative example

Comparative example 1 differs from example 1 in that: adding the raw materials into the auxiliary materials, uniformly stirring, and then performing aseptic filtration through an aseptic filter;

comparative example 2 differs from example 1 in that: the raw material medicine and the auxiliary material are not subjected to aseptic processing, and are mixed and stirred uniformly to obtain a suspension medicament.

Detection method

Bacteria content test

2ml of the sample was placed in a test tube, and 2ml of TCA solution was added, followed by shaking extraction for 3 min. Putting 1ml of extracting solution into a 50ml volumetric flask, and then fixing the volume by using Tris-acetate buffer solution with the pH value of 7.8; and storing the diluted extracting solution at 4 ℃ to be tested. A standard curve was then prepared using standard ATP reagents. Then the relative luminescence value of the sample is measured. And (4) comparing the luminous value of the measured sample with a standard curve to obtain the ATP content in the sample, wherein the ATP content can be converted into the bacterial concentration according to the standard curve. (each microorganism contains 5X 10^-16gATP)

The test results are given in the following table:

examples	ATP(g)	Bacterial concentration (one/ml)
			Example 1	0	0
Comparative example 1	0	0
			Comparative example 2	2×10-14	430

The raw material medicine adopts budesonide powder, the auxiliary materials comprise polysorbate 80, edetate disodium, citric acid monohydrate, sodium citrate dihydrate and sodium chloride, and the preparation solvent adopts water for injection.

The budesonide content in example 1, comparative example 1 and comparative example 2 was measured as follows:

examples	Budesonide concentration
		Example 1	0.496mg/ml
Comparative example 1	0.093mg/ml
		Comparative example 2	0.506mg/ml

And (4) conclusion: the comparison of the experimental data shows that bacteria in the embodiment 1 and the comparative example 1 after the aseptic treatment are basically removed completely, and the effect of non-terminal sterilization treatment of the liquid medicine can be achieved, but the comparison of the concentrations of the raw material medicines in the embodiment 1 and the comparative example 1 shows that the content of the raw material medicine in the product is obviously reduced in the comparative example 1 when the same raw material medicine is added, which indicates that the aseptic treatment by adopting the process of the invention can well ensure that the water-insoluble medicine is prepared into the aseptic suspension medicine.

The above description is only a preferred embodiment of the present invention, and the protection scope of the present invention is not limited to the above embodiments, and all technical solutions belonging to the idea of the present invention belong to the protection scope of the present invention. It should be noted that modifications and embellishments within the scope of the invention may occur to those skilled in the art without departing from the principle of the invention, and are considered to be within the scope of the invention.

Claims (6)

1. A preparation process of a sterile suspension medicament subjected to non-terminal sterilization treatment is characterized by comprising the following steps: the method comprises the following process steps:

s1: performing aseptic treatment on the raw material medicine;

s2: sterilizing equipment and pipelines used for preparing the suspension medicament;

s3: preparing auxiliary materials, namely adding water for injection and prescription auxiliary materials according to the prescription amount in sequence, and stirring and uniformly mixing for 10-20 min;

s4: adding the raw material medicine subjected to the sterile treatment in the step S1 into a sterile feeding device;

s5: filtering the adjuvant preparation solution through an aseptic filter, flushing the aseptic raw materials in the aseptic feeding device into a sterilized mixing tank, and uniformly dispersing and stirring;

s6: filling the suspension medicament in the dosing tank in a sterile environment through BFS blowing, filling and sealing integrated machine equipment;

s7: carrying out vacuum leak detection and lamp inspection on the filled suspension medicament to obtain a finished suspension medicament after the suspension medicament is qualified;

the sterile feeding device in the step S2 comprises a sterile pipeline (3), a sterile filter is installed in the sterile pipeline (3), a sterile isolation box (4) is installed on one side of the sterile pipeline (3), the sterile isolation box (4) is arranged on one side of the sterile filter along the flowing direction of an auxiliary agent in the sterile pipeline (3), a feeding device is installed in the sterile isolation box (4), the feeding device comprises a connecting pipe (41) which penetrates through the side wall of the sterile isolation box (4) and is communicated with the sterile pipeline (3), and one end, far away from the connecting pipe (41), of the connecting pipe (41) and connected with the sterile pipeline (3) is connected with a feeding pipe (43);

a first connecting piece (431) is arranged between the feeding pipe (43) and the connecting pipe (41), the first connecting piece (431) comprises a first connecting disc (432) connected with the end wall of the feeding pipe (43) and a second connecting disc (433) connected with the end wall of the connecting pipe (41), the first connecting disc (432) is abutted to the second connecting disc (433), and clamping bands (434) for locking the first connecting disc (432) and the second connecting disc (433) are arranged on the side walls of the first connecting disc (432) and the second connecting disc (433);

the side wall of the feeding pipe (43) is connected with an air pressure balance pipe (44), one end of the air pressure balance pipe (44) is communicated with the side wall of the feeding pipe (43), the other end of the air pressure balance pipe (44) penetrates through the side wall of the sterile isolation box (4) to be communicated with the external atmosphere, and one end of the air pressure balance pipe (44) communicated with the external atmosphere is provided with a sterile filter;

install drive assembly (42) in connecting pipe (41), connecting pipe (41) include link (412) that link to each other with filling tube (43) and transmission section (411) that link to each other with link (412), install driving motor (421) on the lateral wall of link (412), the lateral wall key connection that the output shaft of driving motor (421) passed link (412) has rolling disc (422), fixedly connected with along connecting pipe (41) length direction spiral piece (423) set up on rolling disc (422).

2. The process according to claim 1, wherein the sterile suspension is prepared by a non-terminal sterilization method, comprising the following steps: the specific operation steps of the sterile treatment of the bulk drug in the step S1 are as follows:

a 1: sterilizing equipment and pipelines in the raw material medicine sterile treatment step, cooling to 20-30 ℃, and then introducing sterilized and filtered hot compressed air to remove residual water in the equipment and the pipelines;

a 2: adding a solvent for dissolving the raw material medicines into a dissolving tank, adding the raw material medicines, heating to 60-65 ℃, and then stirring for 15-20 min;

a 3: after the dissolved bulk drug solution is subjected to two-stage filtration of pre-filtration and sterilization filtration, the sterilized nitrogen is pressed into a crystallization tank, the bulk drug solvent is continuously added into the dissolution tank for washing, and the washed bulk drug solvent is transferred into the crystallization tank;

a 4: adding water for injection into a dissolving tank, pressing the water for injection into a crystallizing tank by using sterilized nitrogen for constant volume, then cooling to 20-30 ℃, and stirring for 60-100 min to obtain a solid-liquid mixed solution; introducing the solid-liquid mixed solution into a solid-liquid separator in an aseptic isolator for separation to obtain solid raw material medicine;

a 5: sending the separated solid bulk drug into a drying oven in an aseptic isolator for drying;

a 6: feeding the dried raw material medicine into airflow crushing equipment in an aseptic isolator for crushing;

a 7: packaging the pulverized raw materials in a sterile isolator in a fixed amount.

3. The process according to claim 2, wherein the sterile suspension is prepared by a non-terminal sterilization method, comprising the following steps: in the step a3, the pre-filtering filter element is 5 inches, is made of polyether sulfone and has the filter diameter of 0.45 mu m; the sterilizing filter element is 5 inches, is made of polyether sulfone and has the filter diameter of 0.22 mu m.

4. The process according to claim 1, wherein the sterile suspension is prepared by a non-terminal sterilization method, comprising the following steps: the sterilization process for equipment and tubing includes the steps of: introducing 135-150 ℃ pure steam into the equipment and the pipeline to keep the temperature of the coldest point above 121 ℃ for not less than 20min, and then cooling to 20-30 ℃.

5. The process according to claim 1, wherein the sterile suspension is prepared by a non-terminal sterilization method, comprising the following steps: one end, far away from the connecting pipe (41), of the feeding pipe (43) is hinged with a sealing cover (435), the side wall, close to the inner cavity of the feeding pipe (43), of the sealing cover (435) is connected with a rubber block (436), and the diameter of one end, far away from the end connected with the sealing cover (435), of the rubber block (436) is smaller than that of the end, far away from the end connected with the sealing cover (435), of the rubber block (436);

telescopic groove (47) have been seted up to the one end that closing cap (435) and filling tube (43) are connected, telescopic spring (471) have been installed in telescopic groove (47), the one end and the telescopic groove (47) tank bottom of telescopic spring (471) are fixed to be connected with, telescopic spring's (471) other end is connected with flexible piece (472), be connected with turning block (473) on the lateral wall of filling tube (43), turning block (473) have been seted up and have been rotated groove (474), turning block (473) rotate with rotation groove (474) and be connected, set up on the lateral wall of closing cap (435) and stir hole (475) that are linked together with telescopic groove (47), be connected with on flexible piece (472) and stir piece (476), stir piece (476) and stir hole (475) sliding connection.

6. The process according to claim 1, wherein the sterile suspension is prepared by a non-terminal sterilization method, comprising the following steps: a fixing frame (45) is connected to the side wall of the sterile isolation box (4), a storage pipe (451) is connected to the fixing frame (45), a control part (46) is arranged at one end, connected with the feeding pipe (43), of the storage pipe (451), and scales are marked on the side wall of the storage pipe (451);

the control part (46) comprises a control frame (461), one end of the control frame (461) is clamped with the orifice of the feeding pipe (43), the other end of the control frame (461) is connected with the storage pipe (451) through a clamp (434), a first through hole (462) is arranged on the side wall of the control frame (461), a first lug (463) is arranged in the first through hole (462) in a sliding way, one end of the first lug (463) passing through the side wall of the control frame (461) is hinged with a second lug (464) symmetrical with the axis of the first lug (463), the end of the second lug (464) far away from the end connected with the first lug (463) is hinged with a third lug (468), the third bump (468) is hinged with the side wall of the control frame (461), and a rubber sealing layer (469) is connected between the side wall of the control frame (461) and the second bump (464) as well as between the side wall of the control frame (461) and the third bump (468);

one end, far away from the end connected with the first lug (463), of the second lug (464) is connected with a limiting block (465), a positioning block (466) is connected in the control frame (461), a limiting groove (467) is formed in the positioning block (466) along the length direction of the positioning block (466), and the limiting block (465) is connected with the limiting groove (467) in a sliding mode.

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