40. Does the container tightness test have to be completed in all injection forms such as ampoules and vials?

Answer: The container tightness test must be carried out in all injection forms such as ampoules and vials. However, the methods used are not the same. Ampoules generally use physical testing methods, and vials use physical and microbiological testing methods.

41. What is the current level of sterile filtration verification that domestic manufacturers can achieve? Which level is recognized by the country?

Answer: According to the "Basic Technical Requirements for Chemical Injections (Trial)" issued by the Drug Registration Department of the State Administration on January 10, 2008 (2) the requirements for freeze-dried powder injections in point 4 of the preparation process, the sterilization filtration system is adapted to The performance verification test includes the compatibility test of the filtration system, the integrity test of the filtration membrane before and after filtration, and the microbial retention test of the filtration membrane when necessary.

The verification of the sterilization process is currently in the process of advancement. The above are the phased requirements based on the current understanding, and will continue to be improved with the understanding of this issue.

42. Does the microbiological challenge test of the filter membrane need to be carried out for each specific product? Since this part of the test is carried out by the manufacturer, is there any requirement for the qualification of the manufacturer? That is, how to determine whether the test report provided to me by the supplier is Effective?

Answer: If different products have different effects on the permeability of the filter, resulting in different retention efficiency, the microbiological challenge test should be carried out separately, otherwise it is not necessary.

At present, there are no legal requirements for the qualification of filter manufacturers. It is recommended to choose manufacturers that have passed industry certification and whose products are widely used in international and domestic, with guaranteed quality and high creditworthiness. Whether the selected filter supplier is credible is based on the pharmaceutical manufacturer's knowledge of the products to be produced and the understanding of the filtering process. Whether the filter manufacturer is legally qualified is not the most important thing. The most important thing is whether the pharmaceutical manufacturer knows that the filter of its choice is suitable for the product it produces, whether the material of the filter meets the safety requirements and meets the requirements of pharmaceuticals. Does the pharmaceutical manufacturer know whether the filtration process developed by itself is effective? In other words, only if you truly understand the professional knowledge of filtering, and understand the product and process, can you determine the validity of the supplier's inspection report.

In addition, you can also go to the filter supplier to see the inspection process with your own eyes and conduct quality audits on the supplier, which also helps to enhance the accuracy of judgment.

43. Two filter elements are used in series for sterilization filtration. Is the pore size the same? If it affects the ingredients of the main medicine, how to solve it?

Answer: The pore size of the two sterile filters connected in series should be the same. It is better if the two sterile filter cartridges in series are of different production batch numbers.

If the filter membrane has an impact on the main ingredients, filter membranes of other materials should be selected according to the results of the compatibility test of the filter system so that it has no effect on the main drug ingredients.

44. Please introduce the test method of filter integrity test in detail, such as "diffusion flow test".

Answer: The test method of filter integrity test should refer to the method provided by the supplier's manual. If the diffusion flow method is adopted, please use the specified medium to wet the filter according to the supplier's instructions, and then connect it to the special instrument and pressure gas (compressed air or nitrogen) of the diffusion flow method, and provide the filter with the pressure determined by the supplier's instructions , The dedicated instrument will automatically print out the test results, indicating that the test passed or failed.

45. Which filter verification must be carried out by the manufacturer? Which is provided by the supplier?

Some teachers mentioned in the lecture that the "microbial challenge test is done by the supplier to avoid contamination of the product", and some teachers mentioned in the lecture that the sterile filter microbial challenge test should be verified under actual production parameters. And the microbial retention test must be carried out in the drug solution, which seems to be done only by the drug manufacturer. How to understand? How to conduct this experiment to better ensure the scientific value of the verification?

Answer: The two are not contradictory. Filter manufacturers should have their own laboratories, such as Pall and Millipore, which can use the liquid medicine provided by pharmaceutical manufacturers to select the appropriate filter and determine the filtration parameters in actual production, and carry out microbial challenges within these parameters. test.

46. In the bubble point test before and after the filter is used, should it be tested after washing with water for injection after use, or should it be tested directly?

Answer: The bubble point test needs to keep the filter fully wet, and the wetted medium should be determined when the filter is selected and verified)

47. In the filter integrity test, the bubble point test and the forward flow test, do you only need to choose one, or do you have to do both?

Answer: Just choose one, but it should be carried out according to the test conditions and standards of the integrity test determined in the filter verification)

48. How to remedy Tween to increase the pore size of the filter membrane to ensure the safety of the drug?

Answer: The company should provide the filter manufacturer with information on the composition and characteristics of the product, and the filter manufacturer selects the appropriate filter material according to the product characteristics and conducts sterile filtration verification)

49. How should sterile drugs monitor the microbial and bacterial endotoxin contamination of intermediate products? Non-terminal sterilization? Terminal sterilization? Generally, microbiological testing takes 4-5 days, and intermediate products must be completed on the same day to determine whether they can enter the next channel. Process.

Answer: In the production process of sterile drugs, whether it is a non-terminal sterilization or terminal sterilization process, although the microbiological test of the intermediate product takes a few days, usually it is not necessary to wait for the results of the microbiological test, and the next step of production can be directly carried out. . After the microbiological test result of the intermediate product comes out, corresponding measures can be taken according to the test result. If the test result of the intermediate product is qualified, the product can continue to be produced until the final product, if the test result of the intermediate product is unqualified, the product cannot be released .

50. Control of the production environment: (1) During the production process, should the placement of the sinker on the aseptic filling line be completed before the operation starts? (2) How long should the sinker be exposed? (3) In the lecture notes In the production environment monitoring frequency of the aseptic filling area mentioned on page 60, what kind of test item does the test item "surface microorganism" refer to, what are its content and standards, and whether the monitoring frequency is once per batch? (4) Dynamic sedimentation bacteria During the test, it has been 2-3 days after the results come out. How to make a judgment based on the results? (5) How is the microbiological test of compressed air performed well?

Answer: (1) Yes, so you can monitor the entire operation process. (2) The EU and FDA require no more than 4 hours. The current requirement in China is 30 minutes. When the new GMP is revised, the internationally accepted requirements may be considered. (3) Surface microbiological testing is to investigate the microbial status of surfaces such as walls, floors, operating tables, equipment, etc., generally using the method of contacting dishes or cotton swabs. For related standards, please refer to EU GMP Annex 1 and FDA related aseptic production Craft guide. (4) Due to the characteristics of microbial culture, the results of environmental microbial monitoring performed during batch production need to wait at least 2-3 days. Once the standard exceeds the standard, a comprehensive analysis and investigation are required to find out the cause of the deviation, and Assess the risk of contamination of the product. (5) Because the compressed gas is under pressure, it is difficult to directly measure the air planktonic bacteria sampler, and it needs to be decompressed first. There are commercial compressed gas planktonic bacteria samplers.