Common technical questions of injection in process research and verification (1)
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- Время публикации: 2021-02-08 09:09
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[Краткое описание]
Common technical questions of injection in process research and verification (1)
[Краткое описание]
- Категория: Центр знаний
- Автор:
- Источник:
- Время публикации: 2021-02-08 09:09
- Посещаемость:
1:According to the requirements of the EU decision-making chain, the residual probability method with F0≥8 can be selected if it cannot reach 121℃ and sterilize within 15 minutes,the question is: if the product can reach 121°C and sterilize in 12 minutes, then will not choose 121°C and 10 minutes? Similarly, if it can reach 10 minutes, then 8 minutes cannot be allowed, all of which are F0≥8?
Answer: From the mathematical model of microbial killing, under the same initial pollution, the higher the sterilization F0 value, the higher the sterility assurance level. Therefore, it is obvious that in order to reduce the risk of residual microorganisms in the product, it is logical to choose a high F0 value as much as possible.
2:Under the condition of stable product quality, it can meet 121℃, 8 minutes and 115℃, 30 minutes. Which condition should be preferred?
Answer: Regardless of the product's physical and chemical quality stability, theoretically the F0 values reached by these two conditions are almost equal, it doesn't matter which one is preferred. However, in actual production, the heat penetration in the product in the sterilizer, the difference in F0 values actually obtained by products in different parts of the sterilizer, and the difference in F0 between products in different sterilization batches must also be considered. The sterilization process with small difference in heat distribution and small difference in product F0 value should be selected.
3:The sterilization conditions in the application materials are "121℃, sterilization for 30 minutes". Is this standard?
Answer: "121°C, sterilize for 30 minutes" itself is not for terminal sterilization, because it is almost impossible to calculate the F0 value in this way. The expression of sterilization conditions can refer to the Chinese Pharmacopoeia 2005 edition appendix two sterilization method 168, 121℃ 15min or 116℃40min.
4:Is it appropriate to use the same sterilization method for 10ml and 20ml injections of the same variety?
Answer: The same type of 10ml and 20ml injections can be sterilized in the same way, but a thermal penetration test should be performed to investigate whether the thermal penetration of samples of different volumes is consistent, and the sterilization method need to ensure the sterility of large-volume products .
5:When choosing the sterilization process of highest sterility, it may conflict with product quality, such as related substances and stability., How to balance this contradiction? In addition, powder injections are marketed abroad, Is it necessary to conduct a study on the selection of sterilization process when applying for domestic applications?
Answer: In fact, in the process of selecting the sterilization process, the study of the sample quality changes under different sterilization conditions should be carried out. The process of selecting the sterilization process is also a process of balancing the sterility assurance level and (sample quality) physical and chemical indicators. In the case of products with clinical needs, the selection of sterilization process should be based on the highest level of sterility assurance that it can achieve. For powder injections marketed abroad, the use of powder injections should also be studied during domestic declaration. If the main drug is indeed unstable against heat and moisture, the same powder injection as abroad can be used; if not against heat, For water instability, a dosage form with a high level of sterility assurance should be selected according to the nature of the main drug.
6:The selection principle of the terminal sterilization process is to prefer F0≥12 instead of F0≥8; or F0≥8 is achieved?
Answer: please refer to the decision-making chain of EU sterilization processselection.
7:Does the survival probability method in the decision-making chain also prefer the temperature condition of 121℃?
Answer: Not necessarily. It is determined according to the stability of the product. If a higher temperature and shorter time can meet the survival probability method, then lower temperature, and longer sterilization are better to the product. If the product cannot withstand the high temperature of 121℃, then the temperature can be lowered and make sure the residual probability of microorganisms is less than 10-6.
8:For thermally unstable drugs (such as proteins, biological products, etc.), the aseptic production process should be directly verified.
Answer: For thermally unstable drugs (such as proteins, biological products, etc.), the aseptic process should be studied first to check whether to use sterile filtration + aseptic production process, or aseptic assembly process; Then verify the process .
9:Has the verification of the various parameters specified in the complete process specification of the product been formed before the product registration application?
Answer: The drug registration management measures stipulate that after the applicant has applied for the "drug registration application form", the applicant will be notified to apply for on-site inspection to the drug certification management center if the applicant meets the requirements after the drug evaluation center reviews. The purpose of the on-site inspection is to confirm the feasibility of the production process, a batch of samples shall be taken at the same time, and the production of the samples shall meet the requirements of GMP. Thus when applying for product registration, you should have sufficient knowledge of the process used for the production of officially marketed products. This understanding is based on the entire process of product and process development, expansion, equipment and system verification, and verification batch production. The purpose of the verification batch is to prove that the process can always produce qualified products within the specified process parameters. Therefore, before proceeding with the verification batch, you should fully understand and be able to control various key variable factors in the process.
10:When verifying the sterilization process, a calibrated probe is generally placed next to the sterilizer control probe. What are the requirements for the temperature difference between the two? Should we follow the proofing standard and only allow a deviation of ±0.5℃?
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