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℃?

Answer: Generally speaking:

①The independent recording probe and monitoring probe that come with the sterilizer should complete sufficient verification data, and then correct the existing deviation;

②The accuracy of the temperature measuring probe used for verification should be better than the recording probe and monitoring probe that come with the sterilizer;

③One of the functions of the verification itself is to correct the monitoring probe and recording probe that come with the sterilizer to achieve a more accurate temperature value during normal use. At present, there is no such saying that "only allow a deviation of ±0.5℃".

11:In the same production line of large volume injection, if there is a sterilizer 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 how to design the verification of heat distribution and heat penetration during the process of validation and revalidation? Are specifications and sterilization conditions individually validated?

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 many of the relevant information can be identified.

12:In the process of verifying or reverifying the wet heat sterilizer, when verifying the heat distribution and heat penetration, if 12 or 16 thermocouples are set in the cabinet for temperature testing, the cold point found may be different in the three verifications, what should be done if this situation occurs?

Answer:Generally speaking, the cold point 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 thermal penetration, the cold point of the large volume injection (LVP, >100ml) is located in the geometric center of the product and along the vertical axis at the bottom of the product, but validation is required.The location of the cold point is not typical for small volume injections because the solution heats at almost the same rate as the sterilizer.

Also, the orientation of the container also affects the location of the cold point, and when the container is rotated or flipped, there may be no discernible cold point.If the loading is constant, the capacity is the same, there is no barrier of steam penetration, etc., and the cold point still cannot be reappeared, the possible uncertainty in equipment, process, pressure, steam quality, etc., should be checked.

13:What is the difference between full load heat distribution and no-load heat distribution in terms of the effect of sterilization?

Answer:Both tests measured the temperature distribution in the sterilization chamber, but they did not reflect the temperature and thermal benefit in the product, so they could not directly reflect the sterilization effect of the product.But what's going on in the chamber obviously affects what's going on inside the product.In the verification process, heat distribution tests of no-load, full-load and product heat penetration were carried out successively.The main purpose of such tests is to reveal as much objective information as possible with as few tests as possible.The results of the previous experiment provide information for the later experiment.

14:Is the full load heat distribution test carried out with an empty bottle or with an infusion bottle containing WFI?

Answer:Full load heat distribution tests are performed with simulated samples.

15:If the loading mode in the verification is half load or full load, does it need to be verified if it is between full load and half load in the future production?

Answer:For loads between full load and half load, it is recommended to use simulated product filling to reach full load to ensure that the loading mode at production is consistent with that at validation.

16:How to do the heat penetration test?

Answer:The purpose of the heat penetration test is to determine the "coldest point" in the sterilization chamber loading, and to confirm that the point has obtained sufficient asepsis guarantee value in the predetermined sterilization procedure, that is, the residual amount of bacteria ≤10-6 and the difference between the temperature of each detection point and the average temperature in the sterilization chamber ≤2.5℃.Verification should be done for changes in operation that may affect the sterilization effect and confirm the operation method.For example, when a stainless steel cover is added to each sterilization tray, the heating time inside the actual product (solution) is 2 minutes later than that without a cover, so add 2 minutes to the sterilization procedure setting.The placement of the thermocouple is consistent with the full load heat distribution test protocol and the standard thermocouple is placed in the center of the sterilization solution.

17:What is the concept of a simulated sample in a heat penetration test, referring to a small batch sample in the laboratory?

Answer:The simulated samples in the thermal penetration test refer to the samples with the same thermal penetration performance as the real samples, not the laboratory small batch samples.

18:Does the type of biological indicator for microbial challenge test need to be selected according to the variety? How to choose?

Answer:The type and selection of bioindicator for microbial challenge test can refer to the Chinese Pharmacopoeia 2005 edition of the second part of appendix 169 sterilization method.

19:Method for determination of microbial contamination level before sterilization?

Answer:Membrane filtration is the most common method. It should be verified before use.

20:The microbial limit test result of the product is 0CFU, and no heat-resistant microorganisms were found. Therefore, can bacillus subtilis with a slightly lower D value be used as a biological indicator for verification in the verification process?

Answer:1）、There was no causal relationship between the results of the microbial limit test and the choice of Bacillus subtilis with a slightly lower D value as a biological indicator.

2）、According to the questioner's question, it can be considered that the method of survival probability sterilization is used.For survival probability method of sterilization process to test the survival probability can choose biological indicator, and simply because of the product or packaging itself cannot bear too much killing, and choose to compare the strict process control, and the initial bacteria amount control products, or combined with aseptic filtration process, and so on, and then select the biological indicator sensitivity test, measure the average content of bacteria N0, for not less than 4 gradient bacteria quantity, batch, quantity of the product enough before and after sterilization of microbial limit test (if necessary, also want to test with different sterilization time), to find and get greater than the decline in six logarithmic grades of state parameter, Under the condition that the value of F0 is between 8 to 12, the value of D can be calculated.

Précédent: Design points of freeze-dried powder injection workshop

Suivant: Common technical questions of injection in process research and verification (2)

Précédent: Design points of freeze-dried powder injection workshop

Suivant: Common technical questions of injection in process research and verification (2)