CN107198657A - Collect sterile preparation and blow the three-in-one plastic ampoule sterile preparation technique of embedding and system - Google Patents
Collect sterile preparation and blow the three-in-one plastic ampoule sterile preparation technique of embedding and system Download PDFInfo
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- CN107198657A CN107198657A CN201610152243.6A CN201610152243A CN107198657A CN 107198657 A CN107198657 A CN 107198657A CN 201610152243 A CN201610152243 A CN 201610152243A CN 107198657 A CN107198657 A CN 107198657A
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- sterile preparation
- aseptic
- storage tank
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61J—CONTAINERS SPECIALLY ADAPTED FOR MEDICAL OR PHARMACEUTICAL PURPOSES; DEVICES OR METHODS SPECIALLY ADAPTED FOR BRINGING PHARMACEUTICAL PRODUCTS INTO PARTICULAR PHYSICAL OR ADMINISTERING FORMS; DEVICES FOR ADMINISTERING FOOD OR MEDICINES ORALLY; BABY COMFORTERS; DEVICES FOR RECEIVING SPITTLE
- A61J1/00—Containers specially adapted for medical or pharmaceutical purposes
- A61J1/05—Containers specially adapted for medical or pharmaceutical purposes for collecting, storing or administering blood, plasma or medical fluids ; Infusion or perfusion containers
- A61J1/06—Ampoules or carpules
- A61J1/067—Flexible ampoules, the contents of which are expelled by squeezing
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B67—OPENING, CLOSING OR CLEANING BOTTLES, JARS OR SIMILAR CONTAINERS; LIQUID HANDLING
- B67C—CLEANING, FILLING WITH LIQUIDS OR SEMILIQUIDS, OR EMPTYING, OF BOTTLES, JARS, CANS, CASKS, BARRELS, OR SIMILAR CONTAINERS, NOT OTHERWISE PROVIDED FOR; FUNNELS
- B67C7/00—Concurrent cleaning, filling, and closing of bottles; Processes or devices for at least two of these operations
- B67C7/0073—Sterilising, aseptic filling and closing
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61J—CONTAINERS SPECIALLY ADAPTED FOR MEDICAL OR PHARMACEUTICAL PURPOSES; DEVICES OR METHODS SPECIALLY ADAPTED FOR BRINGING PHARMACEUTICAL PRODUCTS INTO PARTICULAR PHYSICAL OR ADMINISTERING FORMS; DEVICES FOR ADMINISTERING FOOD OR MEDICINES ORALLY; BABY COMFORTERS; DEVICES FOR RECEIVING SPITTLE
- A61J2200/00—General characteristics or adaptations
- A61J2200/40—Heating or cooling means; Combinations thereof
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- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Medical Preparation Storing Or Oral Administration Devices (AREA)
Abstract
Collect sterile preparation and blow the three-in-one plastic ampoule sterile preparation technique of embedding and system, comprise the following steps：1）, preparation before preparation, 2）, weigh, 3）, feed intake, 4）, sampling detection, 5）, filtering, 6）, it is filling.The present invention collects sterile preparation and blows the three-in-one plastic ampoule sterile preparation technique of embedding, and product will not change the pH value of decoction without high-temperature sterilization, does not produce novel substance, and product inherent quality is high and reliable and stable.Because the plastic ampoule of the technique productions is without high-temperature sterilization, the production intolerant to hot product is especially suitable for.The plastic ampoule of nonterminal sterilizing is packaging material raw material using LDPE, and LDPE materials are soft, and neck can form Rule mouthful after shaping, and plastic ampoule bottle is taken out into flat without entering surrounding air when syringe is got it filled, sterile get it filled can be accomplished in product.Compared to sterilization process production, the technique can reduce substantial amounts of sterilizing energy consumption, energy-saving and emission-reduction.
Description
Technical field
Collect sterile preparation the present invention relates to a kind of plastic ampoule sterile preparation technique, more particularly to one kind and blow the conjunction of embedding three
One plastic ampoule sterile preparation technique and system, belongs to medicament manufacture field.
Background technology
Ampoule bottle is mainly used as the Packaging Bottle of medical injection, and traditional ampoule bottle is made up of glass, and its is frangible, be not easy to fortune
Defeated and recycling, and need to break the bottleneck portion of bottle into pieces using apparatuses such as emery wheels when in use to open, easily scratch behaviour
The hand or gloves of author, injury is brought to operator, and glass chip is also also easy to produce in the moment of corkage, pollutes operating desk face ring
Border, glass chip are it is also possible into causing liquid medicine contamination in ampoule bottle.Meanwhile, the glass chip and glass dust produced during unlatching
Dirt can be entered in patient's body by decoction, trigger phlebitis, Granuloma in lung, blood vessel embolism, tumour, allergy and the reaction of pyrogen sample etc.
Adverse reaction.Regenerated with the continuous renewal of medical package apparatus, increasing transfusion package starts to be plastics (with PE and PP
Based on) substitute, ampoule bottle also develops plastic ampoule, and plastic ampoule is just progressively being substituted existing with the high advantage of its security
Glass ampoule bottles and the development trend for having formed industry.
Patent 2014106067575 discloses a kind of three-in-one production technology of continous way plastic ampoule, it is characterised in that bag
Include following steps：(1) pan feeding；(2) material is heated, material is become fluid state；(3) by fluid foods be injected into pipe embryo into
In pattern head (5), pipe embryo (6) is obtained；(4) plastic ampoule is continuously shaped：All moulds (8) carry out circulatory motion, wherein
A set of that bottle processed is carried out to pipe embryo (6), pipe embryo (6) pours into decoction molded body in in-mold molding after forming body, with
It close to rear one set of die above molded body will be sealed.The beneficial effect of the patent is：Relative to batch (-type)
Production technology, the technique eliminates transhipment and takes the processes such as pipe embryo, the cut-out of pipe embryo, simplifies flow, substantially reduces every mold
Each product output time, improve production efficiency；The apparatus structure rationally, reduces the floor space of existing equipment, and
Production cost is reduced, the continous way production that is set to of mould provides necessary technical support, improves production efficiency,
Reduce labor intensity.
The 2013.05.24 US of United States Patent (USP) 13/902,385 are a kind of to be used for the product channels to blowing-filling-sealer
The technique carried out disinfection, it includes step：Tank will be kept to isolate with the product channels；, will when the holding tank is isolated
Disinfectant is supplied to the product channels；When a threshold is reached, the disinfectant is stopped to the supply of the product channels；Work as institute
When the supply for stating disinfectant stops, the compressed air of filtering is supplied to the product channels, wherein the product channels are productions
Product from it is described holding tank outlet march to the blowing-filling-sealer filling nozzle path, the technique it is each
Individual step passes through processor control.
Patent 201510818859.8 discloses a kind of liquid drugs injection injection medicament and blows embedding full-automatic sterile production technology, and it is given birth to
Production. art comprises the following steps：Raw material sterilizes：PP GRANULES is poured into raw material hopper, PP GRANULES is automatically into pulsation
Vacuum sterilization kettle, under 116 DEG C of high temperature, pulse vacuum autoclaving, sterilization time 15-21 minutes are carried out to material；（2）It is former
Expect removal of impurities：PP GRANULES is brought into sterilizing and stoving room by 60-70 DEG C of filtrated air hot blast, the blowout of sterilizing and stoving room bottom
116 DEG C of filtrated air hot blasts, suspend heat drying and removal of impurities are carried out to PP GRANULES；（3）Material molten：Polypropylene after heating
Particle enters in extruder, in extruder barrel, and heating and temperature control surpasses at 180-220 DEG C while carrying out 60 DEG C to screw rod
Temperature cooling, screw rod is shifted molten material at the bin stock of barrel head onto, and material enters extruder head after screen pack and extruded, extrusion
The heating collar that head exit is set enables the outflow of fused materials at the uniform velocity, forms tubulose, while the coaxial valve of extruder head is to pipe
Base is blown into 180 DEG C of filtrated air streams, and filtrated air stream makes pipe keep mobility and plumpness after guide plate is oriented to；(4)
Filling and shaping：Pipe enters the mould chain relatively rotated, and multi-functional filling pin is surrounded, and mould chain carries multistage mould
Tool, pipe is with the movement of mould, the leading extrusion tube blank of subordinate's mould, pipe bottom lock, while higher level's mould is gradually to pipe
Base is drawn close, and mould is closed by 110bar pressure, closed bottle edge, forms bottle, while positioned at higher level's die region
Multi-functional filling pin bottom stomata start blow out 5-30 DEG C of filtrated air, formed cold air curtain, while multi-functional filling pin
The spray hole of bottom is to sterile liquid medicine of spraying is molded in pipe, and as chain is moved, pipe moves down disengaging with higher level's mould
Multi-functional filling pin, the mould upstream of correspondence bottleneck blows out 170 DEG C of filtrated air, it is ensured that prefabricated neck part position heat-sealing temperature
Do not reduce, the mould at bottleneck position is closed, bottle base head is closed；（5）Die sinking：The bottle of sealing is allowed, with mould
Chain is transported, and is sent out from mould；（6）Punching, cutting：First deliver to bicker by conveyer belt to be punched out, then deliver to cutting machine
Row cutting, removes unnecessary base side；（7）Check：Whether examine the wall thickness of plastic ampoule bottle, seal, resistance to temperature.The patent
Beneficial effect is：The invention has that production efficiency is high, saves resource, it is sterile environmentally friendly the features such as.The present invention can allow local in bottle
Rapid drop in temperature is to minimum 7 °C, to guarantee the filling decoction required to low temperature；And special technique can guarantee that now
Bottle top is still in molten condition；In addition, flow velocity, wall thickness and the degree of eccentricity of extrusion pipe can be by advanced high-accuracy machine drivings
To adjust.Because pipe is continuous product bar, to ensure that bottle wall thickness is uniform, the present invention can also adjust pipe support air pressure
Power.Heating, melting material step in the present invention carry out sterilization to material, reduce the application risk of material.It is filling with into
In type, by extrusion-bottle blowing-Local cooling-filling-sealing-die sinking, it is three-in-one to blow embedding, short into the bottle time, sealed
The pollution of microbes in air and particulate to decoction, the especially customer service of ultralow temperature Canning Technique traditional mode are avoided in environment
Disadvantage.Whole process uses filtrated air simultaneously, efficiently avoid the pollution of microbes in air, greatly ensure that medicine matter
Amount.
From above-mentioned patent it is seen that, at present, domestic and international research and production are concentrated mainly on plastic ampoule
Embedding this technical field is blown, is not taken much count of for compounding system, but BFS（Blow embedding）Machine can only be accomplished in sterile shape
Completion blows/filling/and seals process, it is ensured that product is not contaminated, do not possess sterilizing function under state（Sterilizing filter is relied primarily on to remove
Microorganism in decoction）.Because sterilizing filter can not all filter out virus or mycoplasma, to micro- in whole technical process
Biological control is extremely important.Sterile preparation system and supplies aseptic process for preparation, occupy in whole BFS technical process and weigh very much
The position wanted.So be badly in need of now it is a kind of can collect sterile preparation and blow the three-in-one plastic ampoule sterile preparation technique of embedding,
So as to realize the production for the plastic ampoule that nonterminal sterilizes.
The content of the invention
The purpose of the present invention is to overcome the deficiencies in the prior art there is provided a kind of collection sterile preparation and blow the three-in-one modeling of embedding
Expect ampoule of sterile preparation process and system, effectively by sterile cooperation and embedding can be blown fully combined by the present invention, it is ensured that
The product of production is without terminal sterilization.
The technical solution adopted for the present invention to solve the technical problems is：
Collect sterile preparation and blow the three-in-one plastic ampoule sterile preparation technique of embedding, it is characterised in that comprise the following steps：
1）, preparation before preparation, specifically include：
A, the supply pressure for confirming compressed air are that 2-4bar, the supply pressure of pure steam are that more than 2bar, water for injection have been supplied
Should,
B, on-line cleaning and sterilizing are carried out to blending tank, aseptic storage tank,
C, in blending tank collection process amount water for injection, open magnetic stirring apparatus, speed setpoint frequency be 35-45Hz；
2）, weigh, specifically include：
Operation laminar flow hood at least 20 minutes before A, weighing,
B, the scale that selection range of weighing and supplementary material weighing value are close in negative pressure weighing storehouse,
C, the base of regulation scale make bubble be in the center of monitor, correct and be zeroed, according to specified containers or vinyon
Bag is weighed, after record data after numerical stability；
3）, feed intake, specifically include：
A, according to processing step by several times supplementary material is put into after blending tank, stirring and dissolving, add to the full amount of water for injection；
If necessary with the acid or alkali regulating liquid medicine pH value of technique concentration to prescribed limit, remixing makes solution uniform for 60 minutes and remembers
Record pH value；
4）, sampling detection, specifically include：
A, take blending tank inner liquid medicine 100ml-150ml decoctions send laboratory detect corresponding index；
5）, filtering, specifically include：
A, closing storage tank compressed air inlet valve door, confirm tank bottom material and vent valves Close All,
B, open air filtering core lower drain valves by storage tank pressure release to 0.4-0.6bar,
C, pressure of storage tank are discharged to after specified value, close air filtering core lower discharge valve, tank weights are reset；
D, mixing pressure tank is set to rise to 1.0-1.5bar, initiation pressure keeps test after filtering 5-10Kg solution, tests 5 points
Clock, pressure drop should be 0bar, and filter operation is carried out after being successfully tested,
E, material, which are prepared, to be met through 1 micron of clarification filtration, 0.45 micron, 0.22 micron of aseptic filtration after standard,
In filter process, air cleaner lower drain valves are somewhat opened, excess pressure in storage tank is discharged, filter process is controlled
Middle control pressure of storage tank is not less than 0.5bar,
After F, filtering terminate, aseptic storage tank pressure is risen into 1.2-1.5 bar pressurizes immediately and 0.2um solution strainers are carried out
Integrity test,
Pre- fill operations are carried out after the completion of G, integrity test；
6）, it is filling, specifically include：
A, on-line cleaning and online sterilizing are carried out to BFS aseptic fillers,
B, the sterile fillings of BFS that the preparation prepared is transported to by on-line cleaning by aseptic filtration compressed air and sterilized online
Installation carries out filling.
Preferably, the step 5）Also include 0.2um solution strainer integrity tests after filtering.
Preferably, the pressure keeps the method for test to close the inlet valve of aseptic storage tank and entering for blending tank
Air valve, when the pressure gauge values constant of blending tank, it was demonstrated that blending tank and the first pipeline are intact.
Preferably, the on-line cleaning comprises the following steps：100kg, 70~80 DEG C of injections are added into jar
With water, mixing speed F is set as 30Hz, is opened magnetic stirrer and is closed magnetic stirring apparatus after 5 minutes；Treat pressure in jar
When reaching 1.5bar, the water for injection and flushing line in main line and bypass, emptying jar are successively opened.
Preferably, the online sterilizing is included into vapour exhaust → sterilizing → air inlet steam discharge → cool drying → pressurize
It is standby/to use immediately.
Collect sterile preparation and blow the three-in-one plastic ampoule sterile preparation system of embedding, it is characterised in that including：Dispensing
Tank, aseptic storage tank, the material-compound tank bottom are connected by the first pipeline and aseptic storage tank upper end, and the aseptic storage tank bottom passes through
Second pipe and the connection of BFS bottle placers.
Preferably, be disposed with first pipeline 1 micron of clarification filtration, 0.45 micron and 0.22 micron
Aseptic filtration.
Preferably, the material-compound tank, be also equipped with air cleaner on aseptic storage tank.
Beneficial effects of the present invention：
1st, a kind of to collect sterile preparation and blow the three-in-one plastic ampoule sterile preparation technique of embedding, present invention process system is closed
Direct draught is manufactured, and product will not change the pH value of decoction without high-temperature sterilization, does not produce novel substance, and product inherent quality is high, and
It is reliable and stable.
2nd, because the plastic ampoule of the technique productions is without high-temperature sterilization, it is especially suitable for the production intolerant to hot product.
3rd, the plastic ampoule of nonterminal sterilizing is packaging material raw material using LDPE, and LDPE materials are soft, and neck can shape after shaping
Into Rule mouthful, plastic ampoule bottle is taken out flat without entering surrounding air when syringe is got it filled, can accomplish sterile in product
Get it filled.
4th, produced compared to sterilization process, the technique can reduce substantial amounts of sterilizing energy consumption, energy-saving and emission-reduction.
Brief description of the drawings
Fig. 1 is system structure diagram of the invention；
Wherein, 1, blending tank, 2, aseptic storage tank, 3, BFS bottle placers, the 4, first pipeline, 5, second pipe, 6,1 micron it is clarified
Filter, 7,0.45 micron, 8,0.22 micron of aseptic filtration, 9, air cleaner.
Embodiment
All examples below is only easy to explain basic condition of the present invention, to constitute preferred embodiment in rotating speed,
The extension of frequency, temperature and time etc. will have been described, the related change category after reading and understanding situation of the invention
In industry technical ability.In addition, after reading and understanding the situation of the present invention, coordinating specified weight, pressure and similar desired ratio
Change also fall within industry technical ability.
Same or like component is indicated with identical label in different figures；In addition it is understood that such as " first " in text,
" second ", " the 3rd ", " on ", " under ", "front", "rear", " interior ", " outer ", " end ", " portion ", " section ", " width ", " thickness ", " area "
Etc. and similar term be only easy to observer to describe the present invention with reference to help is constructed and be only used in figure, be not to this
The restriction of invention.For example, the first pipeline of the present invention, second pipe can design identical size, primarily to being easy to observation
Person watches clear.
Embodiment 1：
Collect sterile preparation and blow the three-in-one plastic ampoule sterile preparation technique of embedding, it is characterised in that comprise the following steps：
1）, preparation before preparation, specifically include：
A, the supply pressure for confirming compressed air are that 4bar, the supply pressure of pure steam are that more than 3bar, water for injection have been supplied,
B, to blending tank, aseptic storage tank carry out on-line cleaning, sterilizing,
C, closing mixing bottom valve, the water for injection of collection process amount in blending tank open magnetic stirring apparatus, speed setting frequency
Rate is 45Hz,
Operation laminar flow hood 30 minutes before D, weighing；By extracting the air in room, through filtering, then the top from negative pressure weighing storehouse
Laminar flow hood is excluded, and constantly purification negative pressure weighs the air in storehouse, just can guarantee that within 20 minutes that negative pressure weighs the self-cleaning requirement in storehouse；
2）, weigh, specifically include：
A, the scale that selection range of weighing and supplementary material weighing value are close in negative pressure weighing storehouse,
Used negative pressure weighs storehouse and provides vertical one-way gas flow, and part pure air is circulated in workspace, and part is discharged,
Workspace is produced negative pressure, prevent cross pollution, and raising up for dust reagent can be controlled excessive, prevent dust reagent to human body
Inhalation hazard.
B, the base of regulation scale make bubble be in the center of monitor, correct and be zeroed, according to specified containers or polyethylene
Polybag is weighed, after record data after numerical stability；
3）, feed intake, specifically include：
A, according to processing step by several times supplementary material is put into after blending tank, stirring and dissolving, add to the full amount of water for injection；
If necessary with the acid or alkali regulating liquid medicine pH value of technique concentration to prescribed limit, remixing makes solution uniform for 60 minutes and remembers
Record pH value；
4）, sampling detection, specifically include：
A, take blending tank inner liquid medicine 150ml decoctions send laboratory detect corresponding index；
5）, filtering, specifically include：
A, closing storage tank compressed air inlet valve door, confirm tank bottom material and vent valves Close All,
B, air filtering core lower drain valves are opened by storage tank pressure release to 0.6bar（Gone out the storage tank after bacterium can only from tank deck pressure release,
Prevent pollution）,
C, pressure of storage tank are discharged to after specified value, air filtering core lower discharge valve (being opened again during filtering) are closed, by storage tank weight
Amount is reset；
D, mixing pressure tank is set to rise to 1.5bar, initiation pressure keeps test after filtering 10Kg solution, tests 5 minutes, pressure drop
0bar is should be, filter operation is carried out after being successfully tested,
E, material, which are prepared, to be met after standard through 1 micron of clarification filtration, 0.45 micron, 0.22 micron of aseptic filtration, sterile preparation system
Sterilizing filter in system carries the degerming task of whole materials, the greatest risk of aseptic filtration in all sterilization process.
Using sterilizing filter as boundary in sterile preparation system, the material into aseptic storage tank must reach sterility requirements, and can be close
The long period can be preserved under envelope state；The present invention is operated by three filter progress and dependence test, is solved from preparation
To the problem of filling closed aseptic preparation.
In filter process, air cleaner lower drain valves are somewhat opened, excess pressure in storage tank, control filtering is discharged
During control pressure of storage tank be not less than 0.5bar,
After F, filtering terminate, aseptic storage tank pressure is risen into 1.5 bar pressurizes immediately and 0.2um solution strainers carried out complete
Property test,
Pre- fill operations are carried out after the completion of G, integrity test；
6）, it is filling, specifically include：
A, on-line cleaning and online sterilizing are carried out to BFS aseptic fillers,
B, the sterile fillings of BFS that the preparation prepared is transported to by on-line cleaning by aseptic filtration compressed air and sterilized online
Installation carries out filling.
The step 5）Also include 0.2um solution strainer integrity tests after filtering, the 0.2um solution strainers are complete
The test of whole property be specially 0.2 micron diameter bacterium dam efficiency reach 10 7 powers.
The on-line cleaning comprises the following steps：100kg, 80 DEG C of waters for injection, setting stirring are put into aseptic filler
Speed F is 30Hz, opens magnetic stirrer and closes magnetic stirring apparatus after 5 minutes；Treat that pressure is reached in aseptic filler
During 1.5bar, water for injection in emptying aseptic filler.
The online sterilizing includes immediately making into vapour exhaust → sterilizing → air inlet steam discharge → cool drying → pressurize is standby/
With.
Embodiment 2：
Collect sterile preparation and blow the three-in-one plastic ampoule sterile preparation technique of embedding, it is characterised in that comprise the following steps：
1）, preparation before preparation, specifically include：
A, the supply pressure for confirming compressed air are that 2bar, the supply pressure of pure steam are that 2bar, water for injection have been supplied,
B, to blending tank, aseptic storage tank carry out on-line cleaning, sterilizing,
C, closing mixing bottom valve, the water for injection of collection process amount in blending tank open magnetic stirring apparatus, speed setting frequency
Rate is 35Hz,
Operation laminar flow hood 20 minutes before D, weighing；
2）, weigh, specifically include：
A, the scale that selection range of weighing and supplementary material weighing value are close in negative pressure weighing storehouse,
B, the base of regulation scale make bubble be in the center of monitor, correct and be zeroed, according to specified containers or vinyon
Bag is weighed, after record data after numerical stability；Calciumlevofolinate 6180g, sodium chloride 4000g, sodium hydroxide 5g are weighed,
3）, feed intake, specifically include：
A, according to processing step supplementary material is put into after blending tank, stirring and dissolving by several times, plus water for injection 451kg is to full dose；
If necessary with the acid or alkali regulating liquid medicine pH value of technique concentration to prescribed limit, remixing makes solution uniform for 60 minutes and remembers
It is 8.47 to record pH value；
4）, sampling detection, specifically include：
A, take blending tank inner liquid medicine 100ml decoctions send laboratory detection level, pH value be 8.4（6.5-8.5 is regime values）；
5）, filtering, specifically include：
A, closing storage tank compressed air inlet valve door, confirm tank bottom material and vent valves Close All,
B, open air filtering core lower drain valves by storage tank pressure release to 0.4bar,
C, pressure of storage tank are discharged to after specified value, close air filtering core lower discharge valve, tank weights are reset；
D, mixing pressure tank is set to rise to 1.0bar, initiation pressure keeps test after filtering 5Kg solution, tests 5 minutes, and pressure drop should
For 0bar, filter operation is carried out after being successfully tested,
E, material, which are prepared, to be met through 1 micron of clarification filtration, 0.45 micron, 0.22 micron of aseptic filtration after standard,
In filter process, air cleaner lower drain valves are somewhat opened, excess pressure in storage tank is discharged, filter process is controlled
Middle control pressure of storage tank is not less than 0.5bar,
After F, filtering terminate, aseptic storage tank pressure is risen into 1.2 bar pressurizes immediately and 0.2um solution strainers carried out complete
Property test,
Pre- fill operations are carried out after the completion of G, integrity test；
6）, it is filling, specifically include：
A, on-line cleaning and online sterilizing are carried out to BFS aseptic fillers,
B, the sterile fillings of BFS that the preparation prepared is transported to by on-line cleaning by aseptic filtration compressed air and sterilized online
Installation carries out filling.
Reference《Chinese Pharmacopoeia（Version two in 2010）》Using containing for the high effective liquid chromatography for measuring relevant material of the present invention
Amount, the results are shown in Table 1.
Using the content in high effective liquid chromatography for measuring embodiment 2 about material.
Instrument：Agilent 1260 .
Chromatographic condition：It is filler, wavelength 280nm, sample size 1mL, flow velocity with octadecylsilane chemically bonded silica
1.0mL/min, 40 DEG C of column temperature.
Mobile phase：Disodium hydrogen phosphate buffer solution containing 0.1% TBAH：Methanol（78:22）.
Diluent：Add water 99ml.
Contrast solution：Middle inspection institute, lot number：100252-201204, content：55.6%.
About the content of material in the lercovorin calcium injection of table 1
The lercovorin calcium injection bacterial endotoxin that this technique is prepared as can be seen from Table 1 is relatively low, illustrates this technique
Calciumlevofolinate stability is high, is not easily decomposed；Single miscellaneous content control 0.04-0.06%, total miscellaneous content control 0.08% with
Under, impurity content is considerably less.The medicament manufactured by present invention process meets relevant criterion.
The present invention can adapt to non-final sterilization process requirement, because without using final sterilization technique, the present invention can also
Reduce the risk in production process, the various accidents that may occur of reply, such as BFS machines break down, in production process suddenly
Power failure, air-conditioning water manufacturing system failure etc..
Can carry out most long storage time checking by testing sterile preparation system of the present invention, supported with checking data be
The most long pot life limit of system, verifies pressure 1.5kg, challenges 15 days time.
Concrete operating principle and process of the present invention：
Described sterile preparation system, mainly include negative pressure weigh between, material-compound tank, aseptic storage tank, filter, valve, process duct
Road, temperature, pressure monitoring system etc. are constituted.Described negative pressure weighs the sterile weighing and distribution that storehouse is used to complete supplementary material, in it
Portion's lustration class is A grades.Load weighted supplementary material is stored in sealed container until being transported to material-compound tank.Described material-compound tank
With coil pipe chuck, chuck interior energy is passed through industrial steam or cooling water, meets temperature requirement of the different product to preparing process.
Preparation environment, which meets working condition, compounding system, have been completed to carry out the preparation in full of material on the premise of CIP/SIP in material-compound tank,
Material, which is prepared, to be met through 1 micron of clarification filtration after standard, and 0.45 micron, 0.22 micron of aseptic filtration are degerming into aseptic storage tank
Integrity detection is carried out to 0.45 and 0.22 micron of sterilizing filter immediately after filtering, after filter is by integrity detection,
Aseptic storage tank just can convey solution to BFS machines（Now BFS machines have completed CIP/SIP）Carry out sterile filling.
Described sterile preparation system, the conveying of its decoction is used as power source, each compressed air using compressed air
Point of use be respectively mounted sterilizing filter, it is ensured that the compressed air contacted with decoction is all sterile, clean.Compared to more general
Logical compounding system uses pump as power, and each jar must install respirator, to ensure pressure during decoction conveying inside jar
Dynamic balance, if system blow-by, outside air is highly likely to enter system and brings pollution.The sterile preparation system is empty using compression
Gas is used as power source, it is ensured that whole system is constantly in the state of malleation, improves sterility barrier ability.
The basic teaching of the present invention has been illustrated, for the people with the usual technical ability in this area, many extensions and change
Change will be aobvious and the valve operation of the person of being apparent from, such as blending tank and aseptic storage tank are those skilled in the art's general knowledge, and the present invention exists
This does not elaborate.Because the present invention that specification is disclosed can be without departing from the other specific of spiritual or general characteristics of the invention
Form is implemented, and some forms of these particular forms have been noted, so, specification embodiments of the disclosure should be regarded as lifting
Example is illustrative and not limiting.The scope of the present invention is defined by appended claim, rather than is defined by described above,
All changes of impartial meaning and scope for falling into claim still will be contained within the scope of it.
To sum up, the present invention produces a desired effect.
Claims (8)
1. collect sterile preparation and blow the three-in-one plastic ampoule sterile preparation technique of embedding, it is characterised in that comprise the following steps：
1）, preparation before preparation, specifically include：
A, the supply pressure for confirming compressed air are that 2-4bar, the supply pressure of pure steam are that more than 2bar, water for injection have been supplied
Should,
B, on-line cleaning and sterilizing are carried out to blending tank, aseptic storage tank,
C, in blending tank collection process amount water for injection, open magnetic stirring apparatus, speed setpoint frequency be 35-45Hz；
2）, weigh, specifically include：
Operation laminar flow hood at least 20 minutes before A, weighing,
B, the scale that selection range of weighing and supplementary material weighing value are close in negative pressure weighing storehouse,
C, the base of regulation scale make bubble be in the center of monitor, correct and be zeroed, according to specified containers or vinyon
Bag is weighed, after record data after numerical stability；
3）, feed intake, specifically include：
A, according to processing step by several times supplementary material is put into after blending tank, stirring and dissolving, add to the full amount of water for injection；
4）, sampling detection, specifically include：
A, 100mL-150mL decoctions are taken in blending tank to send laboratory to detect corresponding index；
5）, filtering, specifically include：
A, closing aseptic storage tank compressed air inlet valve door, confirm aseptic storage tank bottoms material and vent valves Close All,
B, open air filtering core lower drain valves by aseptic storage tank pressure release to 0.4-0.6bar,
C, aseptic storage tank pressure are discharged to after specified value, close air filtering core lower discharge valve, aseptic storage tank weight is reset；
D, mixing pressure tank is set to rise to 1.0-1.5bar, initiation pressure keeps test after filtering 5-10Kg solution, tests 5 minutes,
Pressure drop should be 0bar, and filter operation is carried out after being successfully tested,
Through 1 micron of clarification filtration, 0.45 micron, 0.22 micron of aseptic filtration after E, material preparation,
After F, filtering terminate, aseptic storage tank pressure is risen into 1.2-1.5 bar pressurizes immediately and 0.2um solution strainers are carried out
Integrity test,
Pre- fill operations are carried out after the completion of G, integrity test；
6）, it is filling, specifically include：
A, on-line cleaning and online sterilizing are carried out to BFS aseptic fillers,
B, the sterile fillings of BFS that the preparation prepared is transported to by on-line cleaning by aseptic filtration compressed air and sterilized online
Installation carries out filling.
2. according to claim 1 collect sterile preparation and blow the three-in-one plastic ampoule sterile preparation technique of embedding, its feature
It is：The step 5）Also include 0.2um solution strainer integrity tests after filtering.
3. according to claim 1 collect sterile preparation and blow the three-in-one plastic ampoule sterile preparation technique of embedding, its feature
It is：The pressure keeps the method for test to close the inlet valve of aseptic storage tank and the intake valve of blending tank, when blending tank
Pressure gauge values constant, it was demonstrated that blending tank and the first pipeline are intact.
4. according to claim 1 collect sterile preparation and blow the three-in-one plastic ampoule sterile preparation technique of embedding, its feature
It is：The on-line cleaning comprises the following steps：100kg, 70~80 DEG C of waters for injection, setting stirring are put into aseptic filler
Speed F is 30Hz, opens magnetic stirrer and closes magnetic stirring apparatus after 5 minutes；Treat that pressure is reached in aseptic filler
During 1.5bar, water for injection in emptying aseptic filler.
5. according to claim 1 collect sterile preparation and blow the three-in-one plastic ampoule sterile preparation technique of embedding, its feature
It is：The online sterilizing includes using immediately into vapour exhaust → sterilizing → air inlet steam discharge → cool drying → pressurize is standby/.
6. collect sterile preparation and blow the three-in-one plastic ampoule sterile preparation system of embedding, it is characterised in that including：Material-compound tank, nothing
Bacterium storage tank, the material-compound tank bottom is connected by the first pipeline and aseptic storage tank upper end, and the aseptic storage tank bottom passes through second
Pipeline and the connection of BFS bottle placers.
7. according to claim 7 collect sterile preparation and blow the three-in-one plastic ampoule sterile preparation system of embedding, its feature
It is：1 micron of clarification filtration, 0.45 micron and 0.22 micron of aseptic filtration are disposed with first pipeline.
8. according to claim 7 collect sterile preparation and blow the three-in-one plastic ampoule sterile preparation system of embedding, its feature
It is：Air cleaner is also equipped with the material-compound tank, aseptic storage tank.
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| CN108144373A (en) * | 2017-12-19 | 2018-06-12 | 新乡华青药业有限公司 | The aseptic delivery system of sterile ophthalmic ointment agent material |
| CN109381917A (en) * | 2018-11-23 | 2019-02-26 | 楚天科技股份有限公司 | The filling preceding sterilization filter device of medical fluid, aseptic filtration method, bulking system and packaging process |
| CN109395113A (en) * | 2018-12-27 | 2019-03-01 | 中国大冢制药有限公司 | A kind of preparation method and preparation system of the infusion preparation of plastic ampoule |
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Application publication date: 20170926 |