Heat sterilisation process

Validation and Foutine Monitoring of Moist Heat Sterilisation Processes, ISO 11134, International Standards Organization, Geneva, Switzerland. 

A pilot study on the heat sterilisation process of the sediment material was performed to evaluate the losses of CBs. From the results it was concluded that the heat treatment has to be carried out at ca. 120°C over a period of 2 h in order to have the least effect on the CB content. Immediately after sampling, the sediment was air-dried at 40°C over a period of several weeks with continuous churning up and removal of larger objects. The dried sediment was then sieved (pore size 2 mm) and jet-milled for a particle size of less than 125 pm and heat sterilised at 120 C for 2 h, homogenised in a 250 L multi-purpose mixer during semi-automatic filling of bottles. The material was finally packed in 4400 bottles, each one containing 40 g. 

Notes (1) Where the heat sterilisation process is fully monitored using sensors, recorders and microbiological indicators, Section C2 of Appendix C permits a reduced number of containers to be sampled for sterility testing. 

To verify the continuing effectiveness of dry heat sterilising cycles, suitable microbiological indicators of known high resistance to the dry heat sterilisation process should be included in sterilising cycles and placed at representative locations in typical loads. The indicators should be located in the most difficult-to-sterilise site within the steriliser and, where appropriate, within the product... 

Geobacillus stearothermophilus is a thermophile and grows at temperatures between 50 °C and 65 °C. It is used as a test organism (biological indicator) to verify the efficacy of moist heat sterilisation processes. 

According to the decision trees, where it is not possible to carry out terminal sterilisation by heating due to formulation instability, a decision should be made to utilise an alternative method of terminal sterilisation, filtration and/or aseptic processing. If this alternative route is taken, then a clear scientific justification for not using terminal heat sterilisation will be required in the NDA/MAA dossier. Commercial reasons will not be acceptable because terminal sterilisation offers the highest possible level of sterility assurance. 

It was demonstrated that the drug in the formulation could not withstand terminal heat sterilisation. Furthermore, the product was poured into LDPE bottles fitted with an LDPE dropper plug and polypropylene cap, which could not withstand heat sterilisation either. It was therefore necessary to develop a process to sterilise the solution by aseptic filtration followed by aseptic filling into pre-sterilised packaging components. This process was accomplished by exposure of the drug, the LDPE bottles, the dropper plug and the polypropylene cap to ethylene oxide. 

Process development studies showed that terminal sterilisation of the gel was not possible. Heat sterilisation and gamma irradiation methods both caused unacceptable physical degradation of the gel and also caused chlorbutol hydrolysis. Aseptic filtration was not possible because the drug was suspended in the gel vehicle and viscosity would also have been a problem. The process described below was therefore developed with consideration of the sterilisation of the product components and the maintenance of asepsis throughout manufacture. 

Resistance to sterilisation process (dry heat, moist heat, irradiation, UV, etc.). 

Non-thermoplastic Tolerates most heat sterilising and other processes ... 

All sterilisation processes should be validated. Particular attention should be given when the adopted sterilisation method is not described in the current edition of the European Pharmacopoeia, or when it is used for a product which is not a simple aqueous or oily solution. Where possible, heat sterilisation is the method of choice. In any case, the sterilisation process must be in accordance with the marketing and manufacturing authorizations. 

Moist heat sterilisation is achieved by exposure to saturated steam under pressure in a suitably designed chamber. Under these conditions there is an exact relationship between steam temperature and pressure, but the pressure is used solely to obtain the temperature required and otherwise contributes nothing to the sterilisation process. The temperature and not the pressure must be used to control and monitor the process. 

Chemical indicators are available for heat, ethylene oxide and radiation sterilisation, usually in the form of adhesive tapes or patches, colour spot cards, small tubes or sachets. They change colour as a result of chemical reaction brought about by the sterilisation process, but it is possible for the change to take place before the sterilising time has been completed, and hence, with the exception of plastic dosimeters used in radiation sterilisation, they are unsuitable as proof of sterilisation. 

Thermally stable material such as glassware or metal instruments may be sterilised by heating them in an oven at 185°C for two hours. The material is wrapped in autoclave paper prior to heating, and after removal remains sterile until the wrapping paper is removed. Steam treatment in an autoclave is normally used for the sterilisation of aqueous material. The autoclave uses steam at a pressure greater than atmospheric and laboratory systems normally operate at 15 lbs in which corresponds to a temperature of 121 °C. This makes the assumption that the atmosphere inside the autoclave is composed only of steam and therefore it is necessary to expel all the air before the sterilisation process commences. 

Dry heat is generally used at 180°C for a period of two hours for the sterilisation of glassware, metal instruments and thermostable products. Spore strips of Bacillus stearothermophilus may be placed in the oven as a biological sensor, and removed for culturing at the end of the heating period. Growth indicates that the sterilisation process was inadequate, whilst no growth shows a suitable temperature was maintained for the requisite time. 

Sterilisation was made using the dry heat hig tmperatuie method. Dry and wet sanqrles were subjected at 12S t3 during 3 hours to attain their complete sterilisation. The sterilisation process can induce some kind of annealing, melting and reoystallisation mo fying their fine structure. 

Temperature measurements are readily made using commercially available instrumentation. Thermocouples of the copper-constantan (T) type are usually chosen as the measurement probes. These can be made sufficiently small to ensure point measurements can be taken. Thermocouple hot junctions less than 1 mm wide can be used to measure temperatures in small containers and crevices, regions likely to retain air in sterilisation processes or into which heat conduction or convection is inefficient. Kemper gives full details of the theory and applications of thermocouple devices. 

Classical sterilisation techniques using an autoclave and saturated steam under pressure, hot water or dry heat are practical and reliable. Other reliable sterilisation methods include membrane filtration, ionising radiatirm sterilisation (gamma and electron-beam radiation) and gas sterilisation (ethylene oxide, formaldehyde). Sterilisation equipment (autoclaves, membrane filters, and other sterilisers) is often used in industrial manufacturing, in preparation in pharmacies, and in other healthcare establishments. Standard sterilisation processes are described in the Ph. Eur., in other current Pharmacopoeias, in ISO standards and National guidelines. 

For both the calculation of the lethality during the heating and cooling phase and the comparison of sterilisation processes at various temperatures, the F-value has been introduced. The F-value of a sterilisation process at a certain specified temperature (not the reference temperature) is the number of minutes that a sterilisation process would need to last at a reference temperature (usually 121 °Q to obtain the same degree of elimination. This is expressed by the equation ... 

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