1) In the process of verification and production, the temperature probe used for monitoring or recording and the temperature probe used for control shall be set separately, and the setting position shall be determined through verification. The time temperature curve of the sterilization process should be recorded for each sterilization. The use of automatic control and monitoring systems shall be verified to ensure that they meet the requirements of key processes. The automatic control and monitoring system should be able to record system and process failures and be monitored by the operator. The readings from a stand-alone temperature display should be regularly compared with the maps recorded during the sterilization process.
2) Chemical or biological indicators can be used to monitor the sterilization process, but not as a substitute for physical testing.
3) The heating time required by each loading mode shall be monitored, and the sterilization time shall be calculated from the time when all the sterilized products or items reach the set sterilization temperature.
4) Measures shall be taken to prevent the sterilized products or items from being contaminated during cooling. Any cooling medium (liquid or gas) in contact with the product or item should be sterilized unless it can be demonstrated that any leaked products or items can be removed during production.
2.wet heat sterilization shall meet the following requirements:
1) The parameters of wet heat sterilization process monitoring should include sterilization time, temperature or pressure. A sterilization cabinet with a drain at the bottom of the chamber, if necessary, measure and record the temperature data at this point during the whole process of sterilization. If vacuum operation is included in the sterilization process, the chamber shall be tested regularly for leak detection.
2) Except the sealed product, the sterilized item should be properly wrapped with appropriate materials, and the materials and wrapping method should be conducive to air emission, steam penetration and prevent pollution after sterilization. All parts of the sterilized item should be in full contact with the sterilizing medium at the specified temperature and time.
3.Dry heat sterilization meets the following requirements:
1) During dry heat sterilization, the air in the chamber of the sterilization cabinet should be circulated and maintained positive pressure to prevent the entry of non-sterile air. Air entering the chamber shall be filtered through a HEPA filter and the HEPA filter shall be integrity tested.
2) When dry heat sterilization is used to remove pyrogen, validation should include bacterial endotoxin challenge test.
3) The temperature, time and pressure difference inside and outside the chamber in the process of dry heat sterilization should be recorded.
4.Radiation sterilization shall meet the following requirements:
1) Radiation sterilization can be used only if it has been proved to have no adverse effect on product quality. Radiation sterilization shall comply with the《Pharmacopoeia of the People’s Republic of China》and the relevant requirements for registration and approval.
2) The radiation sterilization process should be verified. The verification scheme should include radiation dose, radiation time, packaging material and loading method, and investigate the influence of packaging density change on sterilization effect.
3) In the process of radiation sterilization, dose indicator should be used to measure the radiation dose.
4) Biological indicators can be used as an additional means of monitoring.
5) Measures shall be taken to prevent the mixing of irradiated and non-irradiated items. A radiation indicator which can produce a color change after radiation shall be attached to each package.
6) The total radiation dose standard should be reached within the specified time.
7) Radiation sterilization shall be recorded.
5.Ethylene oxide sterilization shall meet the following requirements:
1) Ethylene oxide sterilization shall comply with the《Pharmacopoeia of the People’s Republic of China》and relevant requirements for registration and approval.
2) The sterilization process verification shall be able to prove that ethylene oxide will not cause destructive effects on the product, and the exhaust conditions and time set for different products or materials can ensure that all residual gases and reaction products are reduced to the set qualified limits.
3)Measures should be taken to prevent microorganisms from being encased in crystals or dry proteins and to ensure direct contact between the sterilization gas and microorganisms. The effect of the nature and quantity of packaging material for the sterilized item on the sterilization effect should be identified.
4)After the sterilized items reach the temperature and humidity conditions specified in the sterilization process, sterilizing gas should be injected as soon as possible to ensure the sterilization effect.
5)In each sterilization, appropriate and certain number of biological indicators should be placed in different parts of the sterilized items to monitor the sterilization effect, and the monitoring results should be included in the corresponding batch records.
6)The content of each sterilization record shall include the time to complete the whole sterilization process; the pressure, temperature and humidity of the chamber during the sterilization process, the concentration of ethylene oxide and the total consumption. The pressure and temperature throughout the sterilization process should be recorded and the sterilization curve should be included in the appropriate batch record.
7)Sterilized items should be stored in a controlled ventilated environment to reduce residual gases and reaction products to the prescribed limits.
6.Filtering and sterilization of non-final sterilized products shall meet the following requirements:
1) The final sterilization process shall not be replaced by the filtration and sterilization process for the products that can be finally sterilized. If the drug product cannot be sterilized in its final packaging container, strain the solution into the pre-sterilized container with a 0.22μm sterilizing filter (smaller or the same filtration power). Because the virus or mycoplasma can not be completely filtered by sterilizing filter, heat treatment method can be used to make up for the deficiency of sterilizing filter.
2) Measures should be taken to reduce the risk of filtration and sterilization. A second sterilized sterilized filter should be installed to filter the solution again and the final sterilized filter should be as close to the filling point as possible.
3) Upon use of the sterilizing filter, its integrity must be checked and recorded in an appropriate way immediately. Commonly used methods include the bubbling point test, diffusion flow test or pressure holding test.
4) Filtration and sterilization process shall be verified, and the time required to filter a certain amount of liquid medicine and the pressure on the two sides of the filter shall be determined in the verification. Any significant deviation from normal time or pressure should be documented and investigated, and the findings should be classified as batch records.
5) The use time limit of the sterilizing filter of the same specification and model should be verified, generally not more than one working day.