CN102160897A - Method for monitoring online sterilization terminals of processing equipment and piping system during sterile manufacturing process - Google Patents
Method for monitoring online sterilization terminals of processing equipment and piping system during sterile manufacturing process Download PDFInfo
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- CN102160897A CN102160897A CN2010101267825A CN201010126782A CN102160897A CN 102160897 A CN102160897 A CN 102160897A CN 2010101267825 A CN2010101267825 A CN 2010101267825A CN 201010126782 A CN201010126782 A CN 201010126782A CN 102160897 A CN102160897 A CN 102160897A
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Abstract
The invention relates to a method for monitoring online sterilization terminals of processing equipment and a piping system during a sterile manufacturing process, and the method is mainly used for solving the problem of the prior art that a sterile production system generates microbial contamination due to incomplete sterilization when online cleaning and online sterilization are carried out on the systems in a sterile production area. The technical scheme adopted by the invention comprises the following steps: a) detecting sterilization temperature, pressure and time parameters at a condensed water discharge port in a sterilization system; b) linking the detected sterilization temperature, pressure and time parameters with a steam valve on a sterilization piping, wherein the steam valve is controlled by a time relay; and c) when the sterilization temperature, pressure and time parameters at the condensed water discharge port of the system reach the set values, considering that the sterilization terminal point arrives, and automatically cutting off the sterilization steam, therefore, the method can be preferably solving the problem in the prior art and can be used in industrial production of sterile medicaments with non-final sterilization.
Description
Technical field
The present invention relates to the monitoring method of process equipment and the online sterilization terminal point of tubing in a kind of aseptic manufacture process.
Background technology
Aseptic medicine is usually used in directly administration such as muscle, vein and spinal cord.So-called aseptic, refer to that the microorganism that does not have to live exists.Microorganism comprises various antibacterials, mycete, fungus, virus, actinomycetes, mitochondrion etc.At the occurring in nature of our life, microorganism is ubiquitous, as air, water, soil, food, animal etc.The method of microorganism of removing at present commonly used has chemical method and physical method.Chemical method comprises employing antibiotic, gasification hydrogen peroxide, ozone, oxirane etc.; Physical method comprises dry heat sterilization, wet-hot steam sterilization, radiation sterilization, filtration sterilization method etc.
Aseptic medicine according to certain technology is produced under specific environment also needs whether carry out last sterilization treatment according to characteristic, heat tolerance, the decision of its medicine, to remove the microorganism that may contain.The sterilizing methods that aseptic medicine production is adopted should effectively be removed the microorganism that may contain in the final medicine, avoids destruction and the pollution of sterilization process to the medicine effective ingredient again, also will consider to reduce production costs.The method of thermodynamics sterilization therefore commonly used is as the continuous 20 minutes sterilization of 121 ℃ flowing steam, to reach the effect of medicine sterilization.The aseptic medicine that adopts this mode to produce is called the final sterilization medicine.Corresponding, for thermal sensitivity medicine such as antibiotic and the labile medicine that is heated, then can not adopt this mode to carry out last sterilization, the production of this medicine, must carry out control of microorganisms to the overall process of producing, all reach aseptic requirement with the production link that medicine directly contacts to guarantee in the whole manufacturing process all.The medicine that adopts this mode to produce is called non-final sterilization medicine.And the process of producing this medicine just is called aseptic manufacture process.
According to the requirement of Good Manufacturing Practice and Quality Control of Drug (GMP), aseptic manufacture process must be produced according to the special process of pharmacopeia defined in the production environment of certain air purity of having of requirement up to specification and microbial limit.The all constituents that production process is related, comprise that supplementary material, immediate packaging materials, process water, production Work tool, surrounding air etc. all will carry out certain sterilization/degerming and handle, the operative employee must replace with aseptic working clothing according to certain procedure, the pollution of the necessary strict controlling microbial of whole process of production.According to the GMP of European Union standard, medicine directly is exposed to the core production area (being also referred to as the sterile production district) of environment in the aseptic manufacture process, must carry out under cleanliness factor is A level way flow protection under the B level background.And above-mentioned cleaniliness classs and corresponding microbial limit thereof require to see the following form (select from the GMP of European Union appendix one: sterile production):
Toilet's air purity rank table
Microbial contamination limit parameter list
| Rank | Air sample cfu/m 3 | Sedimentation dish (Φ 90mm) cfu/4 hour (b) | Contact dish (Φ 55mm) cfu/ dish | 5 finger gloves cfu/ glove |
| A | ＜1 | ＜1 | ＜1 | ＜1 |
| B | 10 | 5 | 5 | 5 |
| C | 100 | 50 | 25 | - |
| D | 200 | 100 | 50 | - |
This shows, the aseptic manufacture process that non-final sterilization aseptic medicine is adopted, be that specification requirement is the highest in the pharmaceutical production, the process that control of microorganisms is the strictest, whole process must be to may effectively controlling each link that product, environment pollute.
Process equipment in the sterile production district and material conveying pipe, after every batch of pharmaceutical production finishes, all will be according to the program of empirical tests, carry out repeatedly cleaning with water for injection, the residual liquor that thorough flush away last consignment of is produced, carry out moist heat sterilization with pure steam then, remove the microorganism of deactivation, make system reach aseptic condition.The feed proportioning system of sterile production adopts the method for moist heat sterilization usually, and the effect of sterilization can be represented with the sterilization constant.The constant relevant with moist heat sterilization comprises:
The D value: the heat-resistance coefficient of microorganism, even the microbe quantity of living reduces by a needed time of the order of magnitude.
Z value: sterilising temp coefficient.Mean the log unit of D value decline that makes a certain microorganism, the number of degrees that sterilising temp should raise are got 10 ℃ usually.
F
0Value: the standard sterilization time means the equivalent sterilization time of sterilizing article under 121 ℃.
SAL: aseptic guarantee value, the negative logarithm of the microorganism survival probability of product after sterilization.Be used to represent that article are by the aseptic condition after sterilizing.Usually get 6, promptly the contamination by micro probability of sterilization back product must not be greater than 10
-6
According to the regulation of Chinese Pharmacopoeia appendix XVII sterilization, the moist heat sterilization condition is generally 121 ℃ of * 15min, 121 ℃ of * 30min, or 116 ℃ of * 40min, or adopt other temperature-time parameters, but must guarantee SAL＜=10
-6To the heat stability product, can adopt and excessively kill method, its SAL should SAL＜=10
-12, the standard sterilization time F of the product that heat stability is relatively poor
0Generally be not less than 8min.
Hence one can see that, and the effect of moist heat sterilization depends on sterilising temp and persistent period.When sterile working's process finishes must be to equipment, utensil, when conveyance conduit carries out moist heat sterilization, must monitor this two parameters at any time, must guarantee that in whole sterilization process, the temperature of disinfection system each several part can not be lower than the sterilising temp of setting simultaneously.Therefore the necessary appropriate design of disinfection system must be found out the minimum point of system temperature and also be monitored, to guarantee sterilization effect.
Sterile production district equipment and material conveying pipe system commonly used at present, as document CN97193796.6, generally after cleaning, adopt pure steam to carry out system's sterilization, but the temperature of system, pressure etc. are all monitored on material-compound tank, can not reflect the situation of the cold spot of whole system.Though can take increase pressure, promote temperature, the method that prolongs sterilization time is remedied, but can not guarantee that system's each point all can satisfy basic sterilising conditions requirement, does not promptly reach the F0 value of regulation yet.Like this system might sterilize not thorough, thereby the aseptic degree of assurance of aseptic medicine is affected, and medication person's healthy and life security is caused serious threat.
Summary of the invention
Technical problem to be solved by this invention is when existence is carried out on-line cleaning, online sterilization to the sterile production sound zone system in the prior art, thereby because of sterilization thoroughly the sterile production system produce the problem of microbial contamination, the monitoring method of process equipment and the online sterilization terminal point of tubing in a kind of new aseptic manufacture process is provided.This method has the characteristics completely of sterilizing.
For solving the problems of the technologies described above, the technical solution used in the present invention is as follows: the monitoring method of process equipment and the online sterilization terminal point of tubing in a kind of aseptic manufacture process may further comprise the steps:
A) detect sterilising temp, pressure and the time parameter that coagulates the water outlet place in the disinfection system;
B) with the interlock of the steam valve on detected sterilising temp, pressure and time parameter and the sterilization pipeline, described steam valve is controlled by the time relay;
When c) sterilising temp, pressure and the time parameter that coagulates the water outlet place when system reaches setting value, think that the sterilization terminal point arrives, and cuts off sterilization steam automatically.
In the technique scheme, 100～154 ℃ of sterilising temps, sterilization pressure 101.3～506.5kPa, sterilization time 15～80 minutes.The sterilising conditions preferable range is: 110～143 ℃ of sterilising temps, sterilization pressure 147.8～405.2kPa, sterilization time 20～60 minutes.Sterilising conditions more preferably scope is: 115～133 ℃ of sterilising temps, sterilization pressure 202.5～303.9kPa, sterilization time 30～45 minutes.
Among the present invention, described pressure is absolute pressure.
The inventive method is at first rationally determined the cold spot position of the online sterilization of system.Be connected to the anti-pollution water discharge system that coagulates by steam condensation water that system is sterilized, make sterilization process extend to this and coagulate the water emission point.Because internal system material-compound tank, conveyance conduit are simple in structure, steam evenly is full of whole system during sterilization, so the temperature minimum point position is located in and should coagulates the water emission point away from the steam inlet in the sterilization process.Secondly, control this sterilising temp that coagulates the water outlet place, pressure and time parameter, and link, control by the time relay with the sterilization steam valve.In sterilization process, judge by temperature, the pressure of monitoring this temperature minimum point whether whole system reaches the sterilizing parameter of regulation everywhere, and after parameter arrives setting, keep the regular hour, to reach the thoroughly effect of sterilization of system, guarantee sterilization process F up to specification
0The value requirement has obtained better technical effect.
The present invention is further elaborated below by embodiment.
The specific embodiment
[embodiment 1]
The online sterilization of aseptic filtration liquid basin during freeze-dried powder is produced.
Detect the sterilising temp, pressure and the time parameter that coagulate the water outlet place in the disinfection system; With the interlock of the steam valve on detected sterilising temp, pressure and time parameter and the sterilization pipeline, described steam valve is controlled by the time relay; When sterilising temp, pressure and the time parameter that coagulates the water outlet place when system reaches setting value, think that the sterilization terminal point arrives, and cuts off sterilization steam automatically.The control sterilising temp is 121～123 ℃, and pressure is 208.5～219.6kPa, after 17 minutes, and F
0Value is for＞8.
[embodiment 2～3]
Step according to [embodiment 1].Sterilising temp, pressure and the time of concrete control, and the F that finally reaches
0Value sees Table 1.
[embodiment 4～6]
The online sterilization of material pipe during aseptic liquid drugs injection is produced.
Step according to [embodiment 1].Sterilising temp, pressure and the time of concrete control, and the F that finally reaches
0Value sees Table 1.
Table 1
| Embodiment | Sterilising temp, ℃ | Sterilization pressure, kPa | Sterilization time, min | F 0Value |
| 2 | 116～118 | 182.5～194.1 | ?42 | ＞8 |
| 3 | 121～123 | 208.5～219.6 | ?31 | ＞8 |
| 4 | 116～118 | 182.5～194.1 | ?42 | ＞8 |
| 5 | 121～123 | 208.5～219.6 | ?17 | ＞8 |
| 6 | 126～128 | 238.9～252.1 | ?21 | ＞8 |
Claims (4)
1. the monitoring method of process equipment and the online sterilization terminal point of tubing in the aseptic manufacture process may further comprise the steps:
A) detect sterilising temp, pressure and the time parameter that coagulates the water outlet place in the disinfection system;
B) with the interlock of the steam valve on detected sterilising temp, pressure and time parameter and the sterilization pipeline, described steam valve is controlled by the time relay;
When c) sterilising temp, pressure and the time parameter that coagulates the water outlet place when system reaches setting value, think that the sterilization terminal point arrives, and cuts off sterilization steam automatically.
2. according to the monitoring method of process equipment and the online sterilization terminal point of tubing in the described aseptic manufacture process of claim 1,100～154 ℃ of sterilising temps, sterilization pressure 101.3～506.5kPa, sterilization time 15～80 minutes.
3. according to the monitoring method of process equipment and the online sterilization terminal point of tubing in the described aseptic manufacture process of claim 2,110～143 ℃ of sterilising temps, sterilization pressure 147.8～405.2kPa, sterilization time 20～60 minutes.
4. according to the monitoring method of process equipment and the online sterilization terminal point of tubing in the described aseptic manufacture process of claim 3,115～133 ℃ of sterilising temps, sterilization pressure 202.6～303.9kPa, sterilization time 30～45 minutes.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2010101267825A CN102160897A (en) | 2010-02-20 | 2010-02-20 | Method for monitoring online sterilization terminals of processing equipment and piping system during sterile manufacturing process |
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|---|---|---|---|
| CN2010101267825A CN102160897A (en) | 2010-02-20 | 2010-02-20 | Method for monitoring online sterilization terminals of processing equipment and piping system during sterile manufacturing process |
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Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN85100602A (en) * | 1985-04-01 | 1986-07-09 | 北京林学院 | Self-acting controlled high pressure steam sterilizer |
| CN1215997A (en) * | 1996-02-16 | 1999-05-05 | 斯特里斯公司 | System and method for real-time monitoring and control of load sterilization and parametric release |
| US20030235511A1 (en) * | 1998-12-30 | 2003-12-25 | Jacobs Paul T. | Sterilization system and method and inlet control apparatus therefor |
| EP1493449A1 (en) * | 2003-06-30 | 2005-01-05 | Ethicon | Test Device for Sterilization Indicators |
| CN1833729A (en) * | 2006-02-15 | 2006-09-20 | 周宝国 | Monitor of vacuum sterilizer |
| CN101028526A (en) * | 2007-04-04 | 2007-09-05 | 菱花集团有限公司 | Method for sterilizing fermenter |
| CN101227931A (en) * | 2005-07-28 | 2008-07-23 | 拜奥奎尔英国有限公司 | Detection of sterilisation vapour condensation point |
-
2010
- 2010-02-20 CN CN2010101267825A patent/CN102160897A/en active Pending
Patent Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN85100602A (en) * | 1985-04-01 | 1986-07-09 | 北京林学院 | Self-acting controlled high pressure steam sterilizer |
| CN1215997A (en) * | 1996-02-16 | 1999-05-05 | 斯特里斯公司 | System and method for real-time monitoring and control of load sterilization and parametric release |
| US20030235511A1 (en) * | 1998-12-30 | 2003-12-25 | Jacobs Paul T. | Sterilization system and method and inlet control apparatus therefor |
| EP1493449A1 (en) * | 2003-06-30 | 2005-01-05 | Ethicon | Test Device for Sterilization Indicators |
| CN101227931A (en) * | 2005-07-28 | 2008-07-23 | 拜奥奎尔英国有限公司 | Detection of sterilisation vapour condensation point |
| CN1833729A (en) * | 2006-02-15 | 2006-09-20 | 周宝国 | Monitor of vacuum sterilizer |
| CN101028526A (en) * | 2007-04-04 | 2007-09-05 | 菱花集团有限公司 | Method for sterilizing fermenter |
Non-Patent Citations (1)
| Title |
|---|
| 白慧良，李武臣: "《药品生产验证指南2003》", 31 December 2003, article "热力灭菌动力学基础与无菌保证", pages: 233 * |
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Address after: 100728 Beijing, Chaoyangmen, North Street, No. 22, No. Applicant after: China Petrochemical Group Corp. Applicant after: SINOPEC Shanghai Engineering Company Limited Address before: 100728 Beijing, Chaoyangmen, North Street, No. 22, No. Applicant before: China Petrochemical Group Corp. Applicant before: Sinopec Shanghai Engineering Co., Ltd. |
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Application publication date: 20110824 |