CN104188916A - Amoxicillin sodium and clavulanate potassium pharmaceutical composition - Google Patents
Amoxicillin sodium and clavulanate potassium pharmaceutical composition Download PDFInfo
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- CN104188916A CN104188916A CN201410433398.8A CN201410433398A CN104188916A CN 104188916 A CN104188916 A CN 104188916A CN 201410433398 A CN201410433398 A CN 201410433398A CN 104188916 A CN104188916 A CN 104188916A
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Abstract
The invention provides an amoxicillin sodium and clavulanate potassium powder-injection for injection, a method for preparing the powder-injection as well as a method for controlling related substances in the method for preparing the powder-injection. The amoxicillin sodium and clavulanate potassium powder-injection for injection disclosed by the invention is simple in production process, safe, reliable, stable in product quality and suitable for large-scale industrial production, and the validity period of the powder-injection is 24 months.
Description
Technical field
The invention belongs to pharmaceutical field, relate to a kind of penicillin medicine compositions, particularly, relate to a kind of amoxicillin sodium for injection clavulanate potassium injectable powder, manufacture the method for this injectable powder, and the control method of related substance in this injectable powder manufacture method.
Background technology
Amoxicillin (Amoxicillin), has another name called amoxicillin or Amoxicillin, is a kind of semi-synthetic penbritin class antibiotic.The chemical name of amoxicillin is (2S, 5R, 6R)-3,3-dimethyl-6-[(R)-(-)-2-amino-2-(4-hydroxy phenyl) ether amino]-7-oxo-4-thia-1-azabicyclo [3.2.0] heptane-2-formic acid trihydrate, molecular formula is C
16h
19n
3o
5s3H
2o, molecular weight 419.46.Its chemical structural formula is as follows:
Amoxicillin (or its sodium salt) is beta-lactam antibiotic, is a kind of white powder, and the half-life is about 61.3 minutes.Amoxicillin has has a broad antifungal spectrum, in body, sterilizing ability is strong, good absorbing (75-90%), the feature of peak time short (1～2 hour), to streptococcus pneumoniae, the Streptococcus such as Hemolytic streptococcus, do not produce penicillinase staphylococcus, the aerobic gram positive coccus such as enterococcus faecalis, escherichia coli, proteus mirabilis, Salmonella, hemophilus influenza, the strain of not beta-lactamase-producing and the helicobacter pylori of the aerobic gram-negative bacteria such as Diplococcus gonorrhoeae have good antibacterial activity, since the listing sixties in 20th century, be used widely clinically always.Bactericidal action is brought into play by anti-bacteria Cell wall synthesis in amoxicillin, can make antibacterial become spheroid rapidly and dissolve, breaks.Occur more and more widely owing to producing beta-lactamase pathogenic strain, pathogenic bacterium can make the beta-lactam nucleus facile hydrolysis in the molecule of amoxicillin lose activity and produce drug resistance.
Clavulanate potassium (ClavulanatePotassium), chemical name is (Z)-(2S, 5R)-3-(2-hydroxyl ethylidene)-7-oxo-4-oxa--1-azabicyclo-[3.2.0]-heptane-2-carboxylic acid potassium, molecular formula is C
8h
8kNO
5, molecular weight 237.25.Its chemical structural formula is:
Clavulanate potassium is oxapenam compound, white or micro-yellow crystalline powder, containing a beta-lactam nucleus, only there is faint antibacterial activity, in water, very easily dissolve, heat, light, moist lability, easily decompose, but can with most beta-lactamase strong bonded, generate irreversible conjugate, there is brute force and the effect of the inhibition beta-lactamase of wide spectrum not only has effect to staphylococcic enzyme, and the enzyme that multiple gram-negative bacteria is produced also has effect, it is therefore effective beta-lactamase inhibitor.
Clavulanate potassium is combined use with beta-lactam antibiotic; can protect in varying degrees amoxicillin not by TEN-1; SHV-1; PSE-4; these 5 kinds of wide spectrum beta-lactam enzyme-deactivatings of KI and K-CAZ; thereby the effect of fastbacteria is killed in raising amoxicillin, the aerobic and anaerobe of gram positive bacteria and negative bacterium is had to the effect of broad-spectrum antiseptic, improves clinical efficacy.
Amoxicillin and clavulanate potassium is researched and developed by GlaxoSmithKline PLC company, obtains FDA approval listing in 1984.Clavulanate potassium is combined with amoxicillin, the destruction of the beta-lactamase that can suppress the microorganisms such as staphylococcus, hemophilus influenza, micrococcus catarrhalis, escherichia coli, klebsiella bacillus, proteus mirabilis, proteus vulgaris, gonococcus, legionella, bacteroides fragilis to amoxicillin, therefore the product enzyme to above-mentioned pathogen or not produce enzyme strain effective.Also streptococcus pneumoniae, micrococcus scarlatinae, viridans streptococci, clostruidium, dyspepsiacoccus, peptostreptococcus of not producing β-Nei phthalein amine enzyme etc. are also had to antibacterial action.
Existing amoxicillin and clavulanate potassium mostly is the solid dosage formss such as tablet, capsule, dispersant, but draws moistly because clavulanate potassium has, and easily causes Moisture high UCL, causes poor stability.In addition, oral formulations onset is slow, has first pass effect, and tablet, capsule preparation technology's complexity, poorly water-soluble etc. have all produced obstruction to its extensive use; Injection is rapid-action, but product stability is bad, and easily variable color is rotten, needs low temperature storage and transport, gives drug flow, uses and brought great inconvenience.
Amoxicillin sodium for injection clavulanate potassium injectable powder mostly is and adopts solid phase mixing legal system standby at present.The preparation method of the disclosed amoxicillin sodium and clavulanate potassium injection of such as CN102600081A be by aseptic raw materials such as a certain proportion of Amoxicillin Sodium, clavulanate potassium, pH adjusting agents respectively after comminution by gas stream, the screening particle diameter that sieves is the powder of 75～100 μ m, fully mixes.For another example the disclosed Amoxicillin potassium clavulanate powder injection of CN102406614A is first with glucose for injection dilution clavulanate potassium monomer, make clavulanate potassium content of monomer be reduced to 40%, and then be mixed and made into amoxicillin sodium for injection clavulanate potassium with Amoxicillin Sodium.The standby shortcoming of solid phase mixing legal system is to be difficult to really Amoxicillin Sodium and clavulanate potassium be mixed, and causes subpackage inhomogeneous, and quality standard is difficult to unified.Solid phase mixing is high to raw material and environmental requirement in addition, and the organic solvent residual that raw material exists in the process of preparation is also difficult to remove.CN100464750C discloses a kind of method of preparing containing the medicinal mixture of Amoxicillin Sodium and clavulanate potassium, the method adopts supercritical fluid technology to prepare micropowder, it need be using water or methanol as solvent in preparation process, because having, clavulanate potassium draws moist and poor stability, in preparation process, can there is certain moisture entrapment or organic solvent residual, in addition supercritical methanol technology due to exist fluid physical property occur sharply change, thereby affect its stability and safety.Lyophilization is the method for preparing injectable powder of commonly using, but it is generally acknowledged and adopt amoxicillin sodium and clavulanate potassium to be difficult to effectively remove moisture, poor stability, easily to produce particulate matter and its related substances exceeds standard.
Therefore, need a kind of steady quality, technique simple, safe and reliable, be suitable for clinical use amoxicillin sodium for injection clavulanate potassium preparation that can mass industrialized production.
Summary of the invention
The object of this invention is to provide a kind of amoxicillin sodium for injection clavulanate potassium injectable powder, overcome the defect of prior art by the special inner packing of medicine and the optimization of production technology.
A first aspect of the present invention provides a kind of amoxicillin sodium for injection clavulanate potassium injectable powder, it is characterized in that Amoxicillin Sodium and the mixing of clavulanate potassium sterilized powder are placed in soda-lime glass molding injection agent bottle, pack with halogenated butyl rubber plug, bottleneck rolls antibiotic bottle aluminium-plastic combined cover.
In a preferred embodiment, every bottle contains Amoxicillin Sodium 0.5g (with C
16h
19n
3o
5s meter) and clavulanate potassium 0.1g (with C
8h
9nO
5meter).
In another preferred embodiment, every bottle contains Amoxicillin Sodium 1.0g (with C
16h
19n
3o
5s meter) and clavulanate potassium 0.2g (with C
8h
9nO
5meter).
A second aspect of the present invention provides a kind of manufacturing process of amoxicillin sodium for injection clavulanate potassium injectable powder, and this manufacturing process mainly comprises the following steps:
(1) preparation of aseptic Amoxicillin Sodium and clavulanate potassium crude drug;
(2) washing and sterilizing of soda-lime glass molding injection agent bottle;
(3) halogenated butyl rubber plug washing and sterilizing;
(4) antibiotic bottle aluminium-plastic combined cover washing and sterilizing;
(5) directly contact the preparation of point component of raw material medicated powder;
(6) aseptic subpackaged;
(7) roll lid;
(8) packaging.
Preferably, manufacture according to flow process shown in Fig. 1.
In a specific embodiment, aseptic amoxicillin sodium and clavulanate potassium crude drug in above-mentioned steps (1) transmits from general production area and enters A level clean area and carries out needing aseptic subpackaged process successively through C level clean area and the sterilizing step by step of B level clean area, and its concrete steps comprise: in general production area with clear rear with 0.2% bromo geramine or 2% lysol spray disinfectant drinking water outside; At C stage material pass-through box self-cleaning 10min; At C level 1% peracetic acid (PAA) spray disinfectant for clean area; At B stage material pass-through box self-cleaning 10min; Temporary at B level clean area material temporary room.The most preferred embodiment of raw material transmission is carried out according to flow process shown in Fig. 2.
Above-mentioned steps (2) comprises cleaning and two steps of sterilizing of soda-lime glass molding injection agent bottle.
In a specific embodiment, soda-lime glass molding injection agent bottle sterilization steps comprises two sections of hot air circulation sterilizings, more than temperature is respectively 310 DEG C and more than 320 DEG C.
Soda-lime glass molding injection agent bottle cleans and the most preferred embodiment of sterilizing is carried out according to flow process shown in Fig. 3 and Fig. 4 respectively.
In a specific embodiment, in above-mentioned steps (3) and (4), plug and aluminium lid adopt moist heat sterilization, and sterilising conditions is 121 DEG C, 15min; After sterilizing, vacuum drying 30min, then hot air drying 30min, is finally cooled to below 60 DEG C.The most preferred embodiment of plug and aluminium lid washing and sterilizing is carried out according to flow process shown in Fig. 5 and Fig. 6 respectively.
In a specific embodiment, in above-mentioned steps (5), directly a point component for contact raw material medicated powder is sent into the clean utensil of C level purge chamber after dismantling and checking, purified water previous cleaning, water for injection rinsing, dry, airtight under laminar flow protection after water for injection rinses; An airtight good point component is put into sterilizing cabinet and is carried out sterilizing; After sterilizing, object storing effect duration is 3 days.In the most preferred embodiment, a point component sterilizing is carried out according to flow process shown in Fig. 7.
Above-mentioned steps (6) operates in A level clean area, and the most preferred embodiment is carried out according to flow process shown in Fig. 8.
The most preferred embodiment of above-mentioned steps (7) is carried out according to flow process shown in Fig. 9.
The most preferred embodiment of above-mentioned steps (8) is carried out according to flow process shown in Figure 10.
A third aspect of the present invention provides the control method of related substance in above-mentioned amoxicillin sodium for injection clavulanate potassium injectable powder manufacturing process.
In above-mentioned amoxicillin sodium for injection clavulanate potassium injectable powder manufacturing process, the clean rank of plug sterile chamber, point component sterile chamber, aluminium lid sterile chamber, wash bottle chamber is C level, and subpackage chamber, to roll the clean rank of covering chamber be A+B level.
In above-mentioned steps (2), the glass bottle after every batch of sterilizing is carried out to the monitoring of antibacterial, bacterial endotoxin, moisture, visible foreign matters and particulate matter.
In a specific embodiment, Standard of Monitoring is as follows: detecting through aseptic experiment should be aseptic; Bacterial endotoxin is less than 0.25EU/ml; Moisture≤1.2mg/ bottle; Must not detect become mildewed, black patch, metal fillings, chips of glass, length or maximum particle diameter exceed the obviously visible foreign matters such as fiber and block of 2mm, and must not detect when rotated smoke-like microparticle column, if any detecting, should≤3; In each test sample container, 500 must not be exceeded containing 10 μ m and microgranules more than 10 μ m, 50 must not be exceeded containing 25 μ m and microgranules more than 25 μ m.
In above-mentioned steps (3), the plug after every batch processing is carried out to the monitoring of antibacterial, bacterial endotoxin, moisture, visible foreign matters and particulate matter.
In a specific embodiment, Standard of Monitoring is as follows: detecting through aseptic experiment should be aseptic; Bacterial endotoxin is less than 0.25EU/; Moisture≤0.2%; Must not detect metal fillings, chips of glass, length or maximum particle diameter and exceed the obviously external visible foreign matters such as 2mm cilium and block, and must not detect when rotated smoke-like microparticle column, other visible foreign matters≤10; In each test sample container, 2000 must not be exceeded containing 10 μ m and microgranules more than 10 μ m, 100 must not be exceeded containing 25 μ m and microgranules more than 25 μ m.
In above-mentioned steps (4), the aluminium-plastic combined cover after every batch processing is carried out to the monitoring of antibacterial and outward appearance.
In a specific embodiment, Standard of Monitoring is as follows: detecting through aseptic experiment should be aseptic; Range estimation is dry, nothing distortion.
In above-mentioned steps (6), carry out subpackage monitoring, the monitoring of A level clean area and the monitoring of B level clean area.Wherein, A level clean area monitoring project is suspended particles, sedimentation bacterium, the bacterium that swims, humiture, and Standard of Monitoring is: suspended particles≤3520 more than 0.5 μ m, suspended particles≤20 more than 5.0 μ m; Bacterium ﹤ 1cfu/m swims
3; 18 DEG C～24 DEG C of temperature; Humidity≤65%.B level clean area monitoring project is sedimentation bacterium, suspended particles, finger bacterium colony, article and implement bacterium colony, and Standard of Monitoring is: sedimentation bacterium ﹤ 5cfu/4h; Suspended particles≤352000 more than 0.5 μ m, suspended particles≤2900 more than 5.0 μ m; Finger bacterium colony ﹤ 5cfu/5 finger gloves; Article and implement bacterium colony ﹤ 5cfu/ dish.
In above-mentioned steps (7), roll the monitoring of covering quality, sedimentation bacterium and finger bacterium colony.
In a specific embodiment, Standard of Monitoring is as follows: get continuously 8 bottles, should accomplish to roll that to cover bound edge smooth, smooth, there is no scollop, scallop and straight flange, bound edge is more than 1mm, and three fingering are twisted aluminium-plastic combined cover must not be had loosening; Sedimentation bacterium ﹤ 5cfu/4h; Finger bacterium colony ﹤ 5cfu/5 finger gloves.
In above-mentioned steps (8), carry out lamp inspection and packaging monitoring.Wherein, the Standard of Monitoring of lamp inspection is: check its outward appearance, answer intact lid, lack plug, roll and cover abnormal phenomena; Without broken bottle, dirty bottle; Foreign in bottle; Without the phenomenon such as empty bottle, obvious many powder.
Amoxicillin sodium for injection clavulanate potassium injectable powder production technology of the present invention is simple, safe and reliable, and constant product quality, is valid up to 24 months, is applicable to mass industrialized production.
Brief description of the drawings
Fig. 1 amoxicillin sodium for injection clavulanate potassium manufacturing process flow diagram and environmental area explanation.
Fig. 2 sterile bulk drug conveying flow figure.
Fig. 3 soda-lime glass molding injection agent bottle cleaning process flow figure.
Fig. 4 soda-lime glass molding injection agent bottle sterilization process flow chart.
Fig. 5 halogenated butyl rubber plug washing and sterilizing process chart.
Aluminium-plastic combined cover washing and sterilizing process chart for Fig. 6 antibiotic bottle.
Fig. 7 directly contacts point component sterilization process flow chart of raw material medicated powder.
The aseptic subpackaged process chart of Fig. 8.
Fig. 9 rolls cover process flow chart.
Figure 10 packaging process flow figure.
Detailed description of the invention
Further illustrate the present invention below by embodiment, but the present invention is not limited.The experimental technique of unreceipted actual conditions in the following example, conventionally according to normal condition, or the condition of advising according to manufacturer.As nothing specializes, the percent hereinafter occurring is mass percent.
BOM used (1.2g specification) is in table 1.
Table 1
Between each process operations and capital equipment in table 2.
Table 2
1. raw material is prepared:
(1) check the raw material name of an article, lot number, quantity.
(2) carry out raw material transmission according to the technological process shown in Fig. 2.
2. the washing and sterilizing of soda-lime glass molding injection agent bottle:
(1) the de-bag of soda-lime glass molding injection agent bottle checks outward appearance, confirms upwards to push bottle washer without bottleneck after damaged broken bottle.
(2) clean according to the technological process shown in Fig. 3.
(3) carry out sterilizing according to the technological process shown in Fig. 4.
To the operation supervise and control standard of glass bottle washing and sterilizing in table 3.
Table 3
To the middle Standard of Monitoring of glass bottle after washing and sterilizing in table 4.
Table 4
3. rubber plug cleaning sterilizing:
Carry out the washing and sterilizing of plug according to the technological process shown in Fig. 5.
To the operation supervise and control standard of rubber plug cleaning sterilizing in table 5.
Table 5
To the middle Standard of Monitoring of plug after washing and sterilizing in table 6.
Table 6
4. aluminium lid washing and sterilizing:
Carry out the washing and sterilizing of aluminium lid according to the technological process shown in Fig. 6.
To the operation supervise and control standard of aluminium lid washing and sterilizing in table 7.
Table 7
To the Standard of Monitoring of aluminium lid after washing and sterilizing in table 8.
Table 8
5. the directly preparation of point component of the former powder of contact:
(1) point component that directly contacts raw material medicated powder is sent into the clean utensil of C level purge chamber according to desired order in " BKFG-300 aseptic powder injection racking machine clean operation code " after dismantling and checking; purified water previous cleaning; water for injection rinsing, dry, airtight under laminar flow protection after water for injection rinses.
(2) an airtight good point of component put into sterilizing cabinet and carried out sterilizing according to technological process shown in Fig. 7 by " XG1.GMH-0.8 pulsation vacuum sterilizer rule of operation "; After sterilizing, object storing effect duration is 3 days.
To the operation supervise and control standard of subpackage cleaning parts sterilizing in table 9.
Table 9
6. aseptic subpackaged
(1) install racking machine according to the requirement of installation order in " BKFG-300 aseptic powder injection racking machine rule of operation ".
(2) confirm lot number and the total quantity of the raw material of receiving according to production ordering.Check humidity in A level system, need reach technological requirement.
(3) loading amount is set: debug loading amount scope when all subpackage head loading amounts and think, 5 bottles of each subpackage head continuous drawings carry out loading amount selective examination, can formally produce after qualified.
(4) carry out aseptic subpackaged according to technological process shown in Fig. 8.
(5) loading amount selective examination: each subpackage head weighed once at least every 15 minutes, and content should conform with the regulations, and Standard of Monitoring is in table 10.
Table 10
7. roll lid:
(1) carry out the trial run work of Cover-rolling machine according to " PZL8 rolls aluminium lid machine operation code ".First low speed debugging, when roll continuously cover 24 bottles all qualified after formally production run.
(2) roll lid according to the technological process of Fig. 9.
(3) roll selective examination at least every 30 minutes in the process of lid and once, get at least continuously 8 bottles at every turn, Standard of Monitoring is in table 11.
Table 11
8. packaging:
(1) lamp inspection personnel carry out lamp inspection by bottle, will roll defective works such as covering substandard products, foreign body, multiple dose, few dosage, broken bottle and detect.
(2) receive packaging material by batch production ordering.Before production, check name of product, specification, quantity and various packaging material printing quality.Pack according to the technological process shown in Figure 10.
(3) debug associated production information in label sticking machine, ink jet numbering machine, after QA confirmation is qualified, started to carry out labeling, coding.
(4) work certificate and case label should require to print the contents such as lot number according to batch packaging directive under the confirmation of QA.
(5) packing specification: 12 bottles, every box is put into a description, and every case 60 boxes are put into a work certificate.
(6) in packaging process, product in the middle of underproof labeling (tiltedly sign, rake angle, lot number is imperfect etc.) are removed after label to labeling again, discarded label is placed on to assigned address, after end to be produced, count destruction.
(7) other discarded printing packaging materials (carton, the quality certification, description) that occur in packaging process, all should collect in assigned address, after end to be produced, count destruction.
The operation supervise and control standard of packaging process is in table 12.
Table 12
Middle product Standard of Monitoring in packaging process is in table 13.
Table 13
9. material balance is calculated:
Yield rate: product actual production ÷ theoretical yield × 100%
Glass bottle utilization rate: actual production ÷ (actual production+each operation number of rejects) × 100%
Plug utilization rate: actual production ÷ (actual production+each operation number of rejects) × 100%
Aluminium-plastic combined cover utilization rate: actual production ÷ (actual production+each operation number of rejects) × 100%
Crude drug powder material balance: (actual production × average loading amount+each operation rejection number) the actual neck of ÷ material amount
Adopt technological process of the present invention, yield rate is 96%～104%, and glass bottle utilization rate is more than 98%, and plug utilization rate is more than 97%, and aluminium-plastic combined cover utilization rate is more than 98%, and crude drug powder material balance reaches 100%.
Claims (12)
1. an amoxicillin sodium for injection clavulanate potassium injectable powder, it is characterized in that Amoxicillin Sodium and the mixing of clavulanate potassium sterilized powder are placed in soda-lime glass molding injection agent bottle, pack with halogenated butyl rubber plug, bottleneck rolls antibiotic bottle aluminium-plastic combined cover.
2. injectable powder according to claim 1, is characterized in that with C
16h
19n
3o
5s meter, every bottle contains Amoxicillin Sodium Amoxicillin Sodium 0.5g, with C
8h
9nO
5meter, every bottle contains clavulanate potassium 0.1g.
3. injectable powder according to claim 1, is characterized in that with C
16h
19n
3o
5s meter, every bottle contains Amoxicillin Sodium Amoxicillin Sodium 1.0g, with C
8h
9nO
5meter, every bottle contains clavulanate potassium 0.2g.
4. a method of manufacturing injectable powder described in claim 1-3 any one, is characterized in that comprising the following steps:
(1) preparation of aseptic Amoxicillin Sodium and clavulanate potassium crude drug;
(2) washing and sterilizing of soda-lime glass molding injection agent bottle;
(3) halogenated butyl rubber plug washing and sterilizing;
(4) antibiotic bottle aluminium-plastic combined cover washing and sterilizing;
(5) directly contact the preparation of point component of raw material medicated powder;
(6) aseptic subpackaged;
(7) roll lid;
(8) packaging.
5. method according to claim 4, is characterized in that operating according to flow process shown in Fig. 1.
6. a control method for related substance in the method described in claim 4 or 5, wherein, the clean rank of plug sterile chamber, point component sterile chamber, aluminium lid sterile chamber, wash bottle chamber is C level, subpackage chamber, to roll the clean rank of covering chamber be A+B level.
7. control method according to claim 6, wherein, in described step (2), the glass bottle after every batch of sterilizing is carried out to the monitoring of antibacterial, bacterial endotoxin, moisture, visible foreign matters and particulate matter, Standard of Monitoring is as follows: detecting through aseptic experiment should be aseptic; Bacterial endotoxin is less than 0.25EU/ml; Moisture≤1.2mg/ bottle; Must not detect become mildewed, black patch, metal fillings, chips of glass, length or maximum particle diameter exceed the obviously visible foreign matters such as fiber and block of 2mm, and must not detect when rotated smoke-like microparticle column, if any detecting, should≤3; In each test sample container, 500 must not be exceeded containing 10 μ m and microgranules more than 10 μ m, 50 must not be exceeded containing 25 μ m and microgranules more than 25 μ m.
8. control method according to claim 6, wherein, in described step (3), the plug after every batch processing is carried out to the monitoring of antibacterial, bacterial endotoxin, moisture, visible foreign matters and particulate matter, Standard of Monitoring is as follows: detecting through aseptic experiment should be aseptic; Bacterial endotoxin is less than 0.25EU/; Moisture≤0.2%; Must not detect metal fillings, chips of glass, length or maximum particle diameter and exceed the obviously external visible foreign matters such as 2mm cilium and block, and must not detect when rotated smoke-like microparticle column, other visible foreign matters≤10; In each test sample container, 2000 must not be exceeded containing 10 μ m and microgranules more than 10 μ m, 100 must not be exceeded containing 25 μ m and microgranules more than 25 μ m.
9. control method according to claim 6 wherein, is carried out the monitoring of antibacterial and outward appearance to the aluminium-plastic combined cover after every batch processing in described step (4), and Standard of Monitoring is as follows: detecting through aseptic experiment should be aseptic; Range estimation is dry, nothing distortion.
10. control method according to claim 6 wherein, is carried out subpackage monitoring, the monitoring of A level clean area and the monitoring of B level clean area in described step (6); A level clean area monitoring project is suspended particles, sedimentation bacterium, the bacterium that swims, humiture, and Standard of Monitoring is: suspended particles≤3520 more than 0.5 μ m, suspended particles≤20 more than 5.0 μ m, the bacterium ﹤ 1cfu/m3 that swims, 18 DEG C～24 DEG C of temperature, humidity≤65%; B level clean area monitoring project is sedimentation bacterium, suspended particles, finger bacterium colony, article and implement bacterium colony, Standard of Monitoring is: sedimentation bacterium ﹤ 5cfu/4h, suspended particles≤352000 more than 0.5 μ m, suspended particles≤2900 more than 5.0 μ m, finger bacterium colony ﹤ 5cfu/5 finger gloves, article and implement bacterium colony ﹤ 5cfu/ dish.
11. control methods according to claim 6, wherein, in described step (7), roll the monitoring of covering quality, sedimentation bacterium and finger bacterium colony, Standard of Monitoring is as follows: get continuously 8 bottles, should accomplish to roll that to cover bound edge smooth, smooth, there is no scollop, scallop and straight flange, bound edge is more than 1mm, and three fingering are twisted aluminium-plastic combined cover must not be had loosening; Sedimentation bacterium ﹤ 5cfu/4h; Finger bacterium colony ﹤ 5cfu/5 finger gloves.
12. control methods according to claim 6 wherein, are carried out lamp inspection and packaging monitoring in described step (8); The Standard of Monitoring of lamp inspection is: check its outward appearance, answer intact lid, lack plug, roll and cover abnormal phenomena, without broken bottle, dirty bottle, foreign in bottle, without the phenomenon such as empty bottle, obvious many powder.
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| CN104188916B (en) | 2015-11-11 |
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