1. In accordance with the requirements of the European Union Decision Tree, it cannot reach 121°C and sterilize within 15 minutes, and the survival probability method with F0≥8 can be selected. Excuse me, if the product can reach 121°C and sterilize in 12 minutes, can it not choose 121°C and 10 minutes? Similarly, if it can reach 10 minutes, then 8 minutes cannot be selected. It is the case that F0≥8.

Answer: From the mathematical model of microbial killing, under the same initial pollution, the higher the sterilization F0 value, the higher the level of sterility assurance. Therefore, it is clear 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℃ for 8 minutes and 115℃ for 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 the same, it doesn't matter which one is preferred. However, in actual production, the heat penetration of 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 "101℃2℃, sterilization for 30 minutes". Is this notation standard?

Answer: Not to mention whether the sterilization conditions are “101℃2℃, sterilization for 30 minutes” is standard, “101℃2℃, sterilization for 30 minutes” itself cannot be called terminal sterilization, because “101℃2 ℃, sterilization for 30 minutes" can hardly calculate the F0 value. The expression of the sterilization conditions can refer to the Chinese Pharmacopoeia 2005 edition two appendix 168 sterilization method, 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 the heat penetration test should be carried out to investigate whether the heat penetration of samples of different volumes is consistent, and the sterilization method used should be considered to ensure large-volume products The level of sterility assurance.

5. Choosing the sterilization process with the highest level of sterility assurance may conflict with the product quality, such as related substances, stability, etc. How to balance this contradiction? In addition, powder injections are marketed abroad. Is it possible for domestic applications? Still need to study the selection of sterilization process?

Answer: In fact, in the process of selecting the sterilization process, it is necessary to study the sample quality changes under different sterilization conditions. 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 can be achieved by itself. 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 the main drug is 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 as long as it reaches F0≥8?

Answer: You can refer to the decision tree of EU sterilization process selection.

7. Does the survival probability method in the decision tree also prefer the temperature condition of 121℃?

Answer: Not necessarily, it must be determined according to the stability of the product. If a higher temperature and shorter time can meet the survival probability method, it may be lower than the temperature, and longer sterilization conditions are more beneficial to the product. If the product cannot withstand the high temperature of 121°C, the temperature can be lowered and the residual probability of microorganisms can be less than 10-6.

8. For heat-labile 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 first be studied, whether to use sterile filtration + aseptic production process, or aseptic assembly process; The process is verified.

9. Has the verification of the various parameters specified in the complete process specification of the product been formed when the product registration application?

Answer: The drug registration management regulations 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 review center reviews. The purpose of the on-site inspection is to confirm the approval For the feasibility of the production process, a batch of samples shall be taken at the same time, and the production of the samples shall be in compliance with GMP requirements. It can be seen that when applying for product registration, one 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 verification batch production, you should have a full understanding and control of various key variable factors in the process.

10. When verifying the sterilization process, a calibrated probe is generally placed next to the control probe of the sterilizer. What are the requirements for the temperature difference between the two? Should it be based on the proofing standard, and only allow ±0.5℃ deviation?

Answer: Generally speaking:

A: The independent recording probe and monitoring probe that come with the sterilizer should complete sufficient verification data, and then correct the existing deviation;

B: The accuracy of the temperature measuring probe used for verification should be better than the recording probe and monitoring probe that come with the sterilizer;

C: One of the functions of the verification itself is to correct the monitoring probe and recording probe that come with the sterilizer so as to achieve a more accurate temperature value during normal use.

At present, there is no such thing as “only allow a deviation of ±0.5°C”.