USP_EP、中国药典干热灭菌除热原条件对照表

EU,USP及 ChP对干热灭菌/除热原条件对照表 1 / 7 EU,USP及 ChP对干热灭菌/除热原条件对照表 EP 6.0 USP32-NF27 中国药典 2010 Dry heat sterilisation. （附件 1-2） 2.6.14. BACTERIAL ENDOTOXINS （附件1-2） 1211 STERILIZATION AND STERILITY ASSURANCE OF COMPENDIAL ARTICLES 附件2-1 85 BACTERIAL ENDOTOXINS TEST 附件 2-2 灭菌方法 内毒素检测方 法 For this method of terminal sterilisation the reference conditions are a minimum of 160 °C for at least 2 h. Other combinations of time and temperature may be used provided that it has been satisfactorily demonstrated that the process chosen delivers an adequate and reproducible level of lethality when operated routinely within the established tolerances. The Apparatus Depyrogenate all glassware and other heat-stable apparatus in a hot-air oven using a validated process. A commonly used minimum time and temperature is 30 minutes at 250 °C. If employing plastic apparatus, such as microtitre plates and pipette tips for automatic pipetters, use A typical acceptable range in temperature in the empty chamber is ±15 when the unit is operating at not less than 250 . A microbial survival probability of 10–12 is considered achievable for heat-stable articles or components. An example of a biological indicator for validating and monitoring dry-heat sterilization is a preparation of Bacillus APPARATUS AND GLASSWARE Commonly used minimum time and temperature settings are 30 minutes at 250 . 干热灭菌条件 一般为 160～ 170℃×120min 以上、170～ 180℃×60min 以上或 250℃ ×45min以上， 也可采用其它 温度和时间参 数。 检测用玻璃器 皿去热原温度 在 250℃，30 分钟以上。 总之，应 保证灭菌后的 产品其 SAL≤10-6。干 热过度杀灭后 产品的SAL应 ≤10-12， EU,USP及 ChP对干热灭菌/除热原条件对照表 2 / 7 procedures and precautions employed are such as to give an SAL of 10− 6 or better. Dry heat at temperatures greater than 220 °C is frequently used for sterilisation and depyrogenation of glassware. In this case demonstration of a 3-log reduction in heat resistant endotoxin can be used as a replacement for biological indicators (5.1.2). apparatus shown to be free of detectable endotoxin and of interfering effects for the test. NOTE: In this chapter, the term ‘tube’ includes all types of receptacles, for example microtitre plate wells. subtilis spores. Since dry heat is frequently employed to render glassware or containers free from pyrogens as well as viable microbes, a pyrogen challenge, where necessary, should be an integral part of the validation program, e.g., by inoculating one or more of the articles to be treated with 1000 or more USP Units of bacterial endotoxin. The test with Limulus lysate could be used to demonstrate that the endotoxic substance has been inactivated to not more than 1/1000 of the original amount (3 log cycle reduction). 250℃ 45min 的干热灭菌也 可除去无菌产 品包装容器及 有关生产灌装 用具中的热原 物质。 细菌内毒 素灭活验证试 验是证明除热 原过程有效性 的试验。一般将 不小于 1000单 位的细菌内毒 素加入待去热 原的物品中，证 明该去热原工 艺能使内毒素 至少下降 3个 对数单位。细菌 内毒素灭活验 证试验所用的 细菌内毒素一 般为大肠杆菌 内毒素 EU,USP及 ChP对干热灭菌/除热原条件对照表 3 / 7 （ Escherichia coli endoxin ）。 结论 对去热原温度和时间组合没有明 确要求，对温度下限有要求。 对温度和时间有要求，同 USP，ChP. 对去热原温度和时间组合没有明 确要求，对温度下限有要求 对温度和时间有 要求，同EP，ChP. 对去热原温度 和时间组合有 建议要求，没 有强制要求。 对温度和时间 有 要 求 ， 同 EP，USP. EU,USP 及 ChP 对 干 热 灭 菌 / 除 热 原 条 件 对 照 表 4 / 7 附件 1 -1 EP6.0 5.1.1. METHODS OF PREPARATION OF STERILE PRODUCTS) Dry heat sterilisation. For this method of terminal sterilisation the reference conditions are a minimum of 160 °C for at least 2 h. Other combinations of time and temperature may be used provided that it has been satisfactorily demonstrated that the process chosen delivers an adequate and reproducible level of lethality when operated routinely within the established tolerances. The procedures and precautions employed are such as to give an SAL of 10− 6 or better. Dry heat sterilisation is carried out in an oven equipped with forced air circulation or other equipment specially designed for the purpose. The steriliser is loaded in such a way that a uniform temperature is achieved throughout the load. Knowledge of the temperature within the steriliser during the sterilisation procedure is usually obtained by means of temperature-sensing elements inserted into representative containers together with additional elements at the previously established coolest part of the loaded steriliser. The temperature throughout each cycle is suitably recorded. Where a biological assessment is carried out, this is obtained using a suitable biological indicator (5.1.2). Dry heat at temperatures greater than 220 °C is frequently used for sterilisation and depyrogenation of glassware. In this case demonstration of a 3-log reduction in heat resistant endotoxin can be used as a replacement for biological indicators (5.1.2) 附件 1-2 2.6.14. BACTERIAL ENDOTOXINS The test for bacterial endotoxins is used to detect or quantify endotoxins of gram-negative bacterial origin using amoebocyte lysate from horseshoe crab (Limulus polyphemus or Tachypleus tridentatus). There are 3 techniques for this test : the gel-clot technique, which is based on gel formation ; the turbidimetric technique, based on the development of turbidity after cleavage of an endogenous substrate ; and the chromogenic technique, based on the development of colour after cleavage of a synthetic peptide-chromogen complex. The following 6 methods are described in the present EU,USP 及 ChP 对 干 热 灭 菌 / 除 热 原 条 件 对 照 表 5 / 7 chapter : Method A. Gel-clot method: limit test Method B. Gel-clot method: semi-quantitative test Method C. Turbidimetric kinetic method 182 See the information section on general monographs (cover pages) EUROPEAN PHARMACOPOEIA 6.0 2.6.14. Bacterial endotoxins Method D. Chromogenic kinetic method Method E. Chromogenic end-point method Method F. Turbidimetric end-point method Proceed by any of the 6 methods for the test. In the event of doubt or dispute, the final decision is made based upon method A unless otherwise indicated in the monograph. The test is carried out in a manner that avoids endotoxin contamination. Apparatus Depyrogenate all glassware and other heat-stable apparatus in a hot-air oven using a validated process. A commonly used minimum time and temperature is 30 minutes at 250 °C. If employing plastic apparatus, such as microtitre plates and pipette tips for automatic pipetters, use apparatus shown to be free of detectable endotoxin and of interfering effects for the test. NOTE: In this chapter, the term ‘tube’ includes all types of receptacles, for example microtitre plate wells. indicators (5.1.2). 附件 2-1 1211 STERILIZATION AND STERILITY ASSURANCE OF COMPENDIAL ARTICLES This informational chapter provides a general description of the concepts and principles involved in the quality control of articles that must be sterile. Any modifications of or variations in sterility test procedures from those described under Sterility Tests 71 should be validated in the context of the entire sterility assurance program and are not intended to be methods alternative to those described in that chapter. Within the strictest definition of sterility, a specimen would be deemed sterile only when there is complete absence of viable microorganisms from it. However, this absolute definition cannot currently be applied to an entire lot of finished compendial articles because of limitations in testing. Absolute sterility cannot be practically demonstrated without complete destruction of every finished article. The sterility of a lot purported to be sterile is therefore defined EU,USP 及 ChP 对 干 热 灭 菌 / 除 热 原 条 件 对 照 表 6 / 7 in probabilistic terms, where the likelihood of a contaminated unit or article is acceptably remote. Such a state of sterility assurance can be established only through the use of adequate sterilization cycles and subsequent aseptic processing, if any, under appropriate current good manufacturing practice, and not by reliance solely on sterility testing. The basic principles for validation and certification of a sterilizing process are enumerated as follows: 1. Establish that the process equipment has capability of operating within the required parameters. 2. Demonstrate that the critical control equipment and instrumentation are capable of operating within the prescribed parameters for the process equipment. 3. Perform replicate cycles representing the required operational range of the equipment and employing actual or simulated product. Demonstrate that the processes have been carried out within the prescribed protocol limits and finally that the probability of microbial survival in the replicate processes completed is not greater than the prescribed limits. 4. Monitor the validated process during routine operation. Periodically as needed, requalify and recertify the equipment. 5. Complete the protocols, and document steps (1) through (4) above. METHODS OF STERILIZATION In this informational chapter, five methods of terminal sterilization, including removal of microorganisms by filtration and guidelines for aseptic processing, are described. Modern technological developments, however, have led to the use of additional procedures. These include blow-molding (at high temperatures), forms of moist heat other than saturated steam and UV irradiation, as well as on-line continuous filling in aseptic processing. The choice of the appropriate process for a given dosage form or component requires a high level of knowledge of sterilization techniques and information concerning any effects of the process on the material being sterilized.1 Dry-Heat Sterilization The process of thermal sterilization of Pharmacopeial articles by dry heat is usually carried out by a batch process in an oven designed expressly for that purpose. A modern oven is supplied with heated, filtered air, distributed uniformly throughout the chamber by convection or radiation and employing a blower system with devices for sensing, monitoring, and controlling the critical parameters. The validation of a dry-heat sterilization facility is carried out in a manner similar to that for a steam sterilizer described earlier. Where the unit is employed for sterilizing components such as containers intended for intravenous solutions, care should be taken to avoid accumulation of EU,USP 及 ChP 对 干 热 灭 菌 / 除 热 原 条 件 对 照 表 7 / 7 particulate matter in the chamber. A typical acceptable range in temperature in the empty chamber is ±15 when the unit is operating at not less than 250 . In addition to the batch process described above, a continuous process is frequently employed to sterilize and depyrogenate glassware as part of an integrated continuous aseptic filling and sealing system. Heat distribution may be by convection or by direct transfer of heat from an open flame. The continuous system usually requires a much higher temperature than cited above for the batch process because of a much shorter dwell time. However, the total temperature input during the passage of the product should be equivalent to that achieved during the chamber process. The continuous process also usually necessitates a rapid cooling stage prior to the aseptic filling operation. In the qualification and validation program, in view of the short dwell time, parameters for uniformity of the temperature, and particularly the dwell time, should be established. A microbial survival probability of 10–12 is considered achievable for heat-stable articles or components. An example of a biological indicator for validating and monitoring dry-heat sterilization is a preparation of Bacillus subtilis spores. Since dry heat is frequently employed to render glassware or containers free from pyrogens as well as viable microbes, a pyrogen challenge, where necessary, should be an integral part of the validation program, e.g., by inoculating one or more of the articles to be treated with 1000 or more USP Units of bacterial endotoxin. The test with Limulus lysate could be used to demonstrate that the endotoxic substance has been inactivated to not more than 1/1000 of the original amount (3 log cycle reduction). For the test to be valid, both the original amount and, after acceptable inactivation, the remaining amount of endotoxin should be measured. For additional information on the endotoxin assay, see Bacterial Endotoxins Test 85 . 附件 2-2 85 BACTERIAL ENDOTOXINS TEST APPARATUS AND GLASSWARE Depyrogenate all glassware and other heat-stable materials in a hot-air oven using a validated process. 2 Commonly used minimum time and temperature settings are 30 minutes at 250 . If employing plastic apparatus, such as microplates and pipet tips for automatic pipetters, use only that which has been shown to be free of detectable endotoxin and not to interfere with the test. [note—In this chapter, the term “tube” includes any other receptacle such as a micro-titer well.]