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01 According to the requirements of the EU decision tree, if it cannot be sterilized at 121°C for 15 minutes, the residual probability method with F0≥8 can be selected. Excuse me, if the product can be sterilized at 121°C for 12 minutes, can you not choose 121°C for 10 minutes? Similarly, if it can reach 10 minutes, you can’t choose 8 minutes. It’s all F0≥8.
Answer: From the mathematical model of microbial killing, it can be known that in the case of the same initial contamination, the greater the sterilization F0 value, the higher the level of sterility assurance. Therefore, 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.
02 Under the condition of stable product quality, both 121°C, 8 minutes and 115°C, 30 minutes can be satisfied, which condition should be preferred?
Answer: Regardless of the stability of the physical and chemical quality of the product, theoretically the F0 values achieved by the two conditions are almost equal, and it does not matter which one is preferred. However, in actual production, it is also necessary to consider the heat penetration of the product in the sterilizer, the difference in the F0 value actually obtained by the product in different parts of the sterilizer, and the difference in the F0 of the product between different sterilization batches. The sterilization process with small difference in heat distribution and small difference in product F0 value should be selected.
03 The sterilization condition in the application materials is “101°C, 2°C, sterilization for 30 minutes”. Is this notation standardized?
Answer: Let’s not say whether the sterilization condition is “101°C, 2°C, sterilize for 30 minutes”. Bacteria for 30 minutes” can hardly calculate the F0 value. The expression of the sterilization conditions can refer to the sterilization method in Appendix 168 of the Second Part of the Chinese Pharmacopoeia in 2005, 121°C for 15 minutes or 116°C for 40 minutes.
04 Is it appropriate to adopt the same sterilization method for 10ml and 20ml injections of the same variety?
Answer: The 10ml and 20ml injections of the same variety can be sterilized in the same way, but a heat penetration test should be carried out to investigate whether the heat penetration of samples of different volumes is consistent, and the sterilization method should be able to ensure that large-volume products sterility assurance level.
05 Choosing the sterilization process with the highest level of sterility assurance may conflict with product quality, such as related substances, stability, etc. How to balance this contradiction? In addition, since powder injections are marketed abroad, is it necessary to conduct research on the selection of sterilization processes when applying domestically?
Answer: In fact, during the research process of sterilization process selection, the research on the quality change of samples under different sterilization conditions should be carried out. The process of selecting a sterilization process is also a process of balancing the sterility assurance level and (sample quality) physical and chemical indicators. When the product has clinical needs, the selection of the sterilization process should be based on the principle of the highest sterility assurance level that can be achieved by itself. For powder injections marketed abroad, research should also be carried out on the use of powder injections in the domestic application. If the main drug is indeed unstable to heat and water, the same powder injection as foreign can be used; if the main drug is not sensitive to heat, If it is unstable to water, a dosage form with a high level of sterility assurance should be selected according to the nature of the main drug.
06 The selection principle of the terminal sterilization process is to choose F0≥12 instead of F0≥8; or only need to achieve F0≥8?
Answer: You can refer to the decision tree for EU sterilization process selection.
07 Does the residual probability method in the decision tree also give priority to the temperature condition of 121°C?
Answer: Not necessarily, it should be determined according to the stability of the product. If higher temperature and shorter time can satisfy the survival probability method, it may be more beneficial to the product than lower temperature and longer time sterilization conditions. If the product cannot withstand the high temperature of 121°C, the temperature can be lowered to ensure that the survival probability of microorganisms is less than 10-6.
08 For thermally unstable drugs (such as proteins, biological products, etc.), the verification of the aseptic production process should be carried out directly.
Answer: For thermally unstable drugs (such as proteins, biological products, etc.), the aseptic process should be studied first, whether to use sterile filtration + aseptic production process, or aseptic assembly process; and then aseptic The process is verified.
09 Has the verification of various parameters specified in the complete process specification of this product been formed at the time of product registration declaration?
Answer: The drug registration management method stipulates that after the applicant declares the “drug registration application form”, if it meets the requirements after being reviewed by the Drug Evaluation Center, the applicant will be notified to apply for a production site inspection to the Drug Certification Management Center. The purpose of the on-site inspection is to confirm the approval. To check the feasibility of the production process, take a batch of samples at the same time, and stipulate that the production of the samples should meet the requirements of GMP. It can be seen that when applying for product registration, one should have a sufficient understanding of the process used for the production of officially launched products. This understanding is based on the entire process of product and process development, scale-up, validation of equipment and systems, and production of validation batches. The purpose of the verification batch is to demonstrate that within the range of specified process parameters, the process can consistently produce qualified products. Therefore, the key variables in the process should be well understood and controlled prior to conducting a validation batch.
10 When verifying the sterilization process, a calibration probe is generally placed next to the control probe of the sterilizer. What are the requirements for the temperature difference between the two? Should the proof standard only allow a deviation of ±0.5°C?
Answer: Generally speaking:
①: The independent recording probe and monitoring probe that comes with the sterilizer should complete enough verification data, and then correct the existing deviation;
②: The accuracy of the temperature measuring probe used for verification should be better than the recording probe and monitoring probe that comes with the sterilizer;
③: One of the functions of the verification itself is to correct the monitoring probe and recording probe that comes with the sterilizer, so as to achieve a more accurate temperature value during normal use.
At present, there is no statement that “only ±0.5°C deviation is allowed”.
11 In the same large-capacity injection production line, if there is a sterilization cabinet that needs to sterilize products of multiple specifications (such as 250ml, 100ml) and products with different sterilization parameters (such as different sterilization temperature and time), then in In the process of verification and re-validation, how to carry out the verification design of heat distribution and heat penetration? Do all specifications and sterilization conditions need to be verified separately?
Answer: Generally speaking, various specifications and various sterilization conditions need to be verified separately.
Sterilization of mixed loads of different specifications is not recommended unless a lot of relevant content can be confirmed.
12 During the verification or re-verification of the moist heat sterilizer, when verifying the heat distribution and heat penetration, if 12 or 16 thermocouples are installed in the cabinet for temperature testing, the cold spots found in the third verification may be different, what should I do if this happens?
Answer: Generally speaking, the cold spot of no-load heat distribution should be around a certain location, otherwise it may be caused by equipment, pressure, incomplete air replacement, steam quality and other reasons.
For loading heat penetration, the cold spot for large volume injectables (LVP, >100ml) is located at the geometric center of the product and along the longitudinal axis at the bottom of the product, but verification is required. The location of the cold spot is not typical in small volume parenterals because the solution is heated at nearly the same rate as the sterilizer.
Also, the orientation of the container can also affect the location of the cold spot, and when the container is rotated or turned over, there may not be a discernible cold spot.
If the loading is the same, the capacity is the same, there is no barrier to steam penetration, etc., and the cold spot is still not reproducible, the possible uncertainties in equipment, process, pressure, steam quality, etc. should be checked.