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09-01 

【Qianhui Sharing】Common technical problems in the research and verification of injection sterility assurance technology (5)

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

09-02 

【Qianhui Sharing】Common technical problems in the research and verification of injection sterility assurance technology (4)

30. In the medium filling test, after the medium is sterilized and before filling, it is sterilized and filtered through a filter membrane to observe the aseptic effect of the filter during the sterilization and installation process. Is it feasible? Answer: The culture medium filling test is an investigation of the degree of sterility assurance in all steps including aseptic filtration. It is recommended to use the culture medium directly in the aseptic filtration and subsequent filling process after preparation. Pay attention to the actual operation Prevent insoluble particles from clogging the filter. 31. The medium filling test year is re-verified twice a year, how many batches each time? Answer: For the annual re-verification of a certain product, the usual practice is to conduct two medium filling tests every year, one batch each time. 32. The aseptic culture time of the 2005 edition of the Chinese Pharmacopoeia has changed to 14 days. Does the culture test at two temperatures after the simulated filling of the medium need to be extended? Answer: The total cultivation time should not be less than 14 days. It can be divided into two temperatures (22.5 degrees and 32.5 degrees) for at least 7 days each, or it can be cultured directly at one temperature (22.5 degrees). 33. The confidence limit of the qualification standard for the medium filling test is 95%, and the probability of infection is 0.1%. Please explain in detail which statistical method is used and how to calculate it by looking up the table. Answer: For a detailed description of the calculation formula, please refer to page 258 of the "Guidelines for Drug Production Verification (2003)" (Chemical Industry Press) compiled by the Drug Safety Supervision Department of the State Food and Drug Administration and the Drug Certification Management Center. There are two calculation methods. One is to use the approximate value calculation formula of the Poisson distribution, namely P(X>0)=1-e-Np>0.95 Among them, P is the confidence limit, N is the number of simulated bottles or batches, p=0.1% (probability of contamination) Another calculation method is the more accurate binomial calculation formula, namely P(X>0)=1-(1-X)N where P is the confidence limit, N is the number of simulated bottles or batches, X = 0.1% (probability of contamination) On page 259 of the book, there is a table of the relationship between simulated dispensing quantity, pollution quantity and pollution probability in one simulated dispensing when the credibility limit is 95%. The simulated dispensing quantity and pollution quantity can be found from this table. The corresponding value of. 34. In the film 59 on page 72 of the lecture notes, what are the differences in the process verification of powder injections, freeze-dried powder injections, and small-volume injections? , Where does it start and where does it end? Answer: For sterile powder injections, the form of medium filling has some special characteristics. For example, if you want to prepare a simulated sterile powder, use a syringe to add the liquid medium to the bottle after dispensing; or divide the sterile medium powder into the bottle. After finishing, add sterile water for injection with a syringe. But the purpose is still to investigate the degree of sterility assurance of the entire aseptic packaging process. 35. How to verify the tightness of the container? Answer: Physical and microbiological testing methods are often used to verify the tightness of containers. Physical detection has many advantages, such as high sensitivity, convenient use, rapid detection and low cost. During the validity period of the product, physical testing methods can be used to determine whether the integrity of the package meets the specified requirements. An important reason for packaging integrity testing is to ensure that sterile products are always sterile. Therefore, in the development stage of product packaging, microbial penetration tests should be considered, or physical test methods that have been verified and more effective than microbial detection should be considered to detect the integrity of product packaging. However, for the stability test of the product within the validity period, it is more difficult to carry out the microbial invasion test, so physical testing methods are recommended. The microbial invasion test is a challenging test for the integrity of the terminally sterilized container/sealing system. In the verification test, take an infusion bottle or a vial (vial), fill it with a culture medium, stopper and cap sterilize on a normal production line. Then, the sealing surface of the container is immersed in the high-concentration motility bacterial liquid, taken out, cultivated, and checked for microbial invasion to confirm the integrity of the container sealing system. At the same time, a positive control test is required to confirm the growth-promoting ability of the medium. 36. When using

09-03 

【Qianhui Sharing】Common technical problems in the research and verification of injection sterility assurance technology (3)

21. What is the test method of microbial contamination level and heat resistance (D value) before sterilization? Answer: The level of microbial contamination usually uses membrane filtration to retain microorganisms, and then transfer the membrane to the surface of a solid medium, cultivate and count the microorganisms. Attention should be paid to the volume of filtration and the number of retained microorganisms to ensure a sufficient detection rate (a sufficient amount of filtration) and countability (too many retained microorganisms cannot be counted). The heat resistance test performed on each batch of products is not a D value test, but a so-called boiling test-a qualitative test. Put the filter membrane that trapped microorganisms into a test tube containing the same product liquid, boil it in a water bath for 15 minutes or more, and perform a sterility test on the liquid. If it is a heat-resistant bacteria, the D value needs to be further measured. More than 99% of the inspected products are non-heat-resistant bacteria. The measurement of D value is quite complicated, please refer to the "Guidelines for Pharmaceutical Production Verification" (Blue Book, edited by the State Drug Administration), Chapter 3, Section 1, for a detailed introduction. 22. How to calculate the amount of inoculation based on the D value? Answer: Calculation of spore inoculation amount: Ni=10Do(lgNo+6)/Di where Ni is the number of heat-resistant spores inoculated as a biological indicator No is the limit of contaminating microorganisms in the intended product before sterilization Do is the maximum allowable value of D for contaminating microorganisms Di is the D value of the biological indicator heat-resistant spores in the product 23. For products that are terminally sterilized by the survival probability method, if the microbial limit is tested for each batch before sterilization, and the microbial limit detection time is 72 hours, and the actual production cycle of continuous production is much shorter than 72 hours, the test result is only Is it a reference to the sterility assurance level of the product after sterilization? Answer: Obviously, the result of the microbiological content inspection before sterilization lags far behind the production process, and its purpose is not to be used for intermediate control of the current batch of products. The inspection has two main meanings: first, it is used to evaluate the sterility assurance level of the batch of products; second, after long-term accumulation of multiple batches of pre-sterilization microbial content data, it can be The microbial contamination status of each process step is evaluated as a whole, so as to indicate whether the production system is effectively controlling the microbial contamination at a good level, whether it needs to be improved, and so on. 24. What is the method of microbial species and quantity research? What equipment is needed? If the residual probability method is adopted, is it necessary to measure the microbial level during the production process? If it is introduced, how much cost will it increase? As a large infusion manufacturer, use the residual probability Method, is it necessary to establish a special microbiology laboratory to test the microbial contamination level of the liquid medicine before sterilization? Answer: The degree of microbial contamination-that is, the quantity inspection can be carried out in accordance with the microbial limit inspection method included in the Pharmacopoeia; the type of microorganisms can be identified from the following aspects: 1) Observe the colony morphology by naked eyes; 2) Microscopically inspect the morphology and Mobility; 3) General biochemical test: Gram stain or 3% KOH test; 4) Biochemical identification (ie API test) to identify species. When the residual probability method is used, the level of microbial contamination before the product sterilization should be tested, including the boiling test of the contaminated bacteria (such as 100°C, 15 minutes) and the microbial count. Microbiology laboratory is essential for injection manufacturers. Its basic functions should include microbial limit inspection of raw materials, microbial contamination inspection before product sterilization, product sterility inspection, bacterial endotoxin inspection, and production environment dynamic inspection (air Particles, planktonic bacteria and sedimentation bacteria count). Conditional laboratories can also carry out the following tasks: microbiological identification test (it is recommended that the central laboratory of the enterprise group carry out API identification), the calibration of biological indicators (that is, the determination of the D value, it is recommended that the central laboratory of the enterprise group carry out this work) . 25. Is sterilization process verification necessary for the overkill method? What is the difference between the product development proc

09-04 

【Qianhui Sharing】Common technical problems in the research and verification of injection sterility assurance technology (2)

11. In the same large-volume injection production line, if there is a sterilization cabinet, multiple specifications of products (such as 250ml, 100ml) and products with different sterilization parameters (such as different sterilization temperature and time) need to be sterilized, then In the process of verification and re-verification, how to verify the design of heat distribution and heat penetration? Do various specifications and various sterilization conditions need to be verified separately? Answer: Generally speaking, various specifications and various sterilization conditions need to be verified separately. Sterilization of mixed loading of different specifications is not recommended unless a lot of relevant content can be confirmed. 12. During the verification or re-verification of the humid 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 spot found is 3 times The 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, etc. For thermal penetration, the cold spot of the large volume injection (LVP, >100ml) is located at the geometric center of the product and at the bottom of the product along the longitudinal axis, but verification is required. The location of the cold spot is not typical in small volume injections, because the rate of heating of the solution is almost the same as that of the sterilizer. Also, the orientation of the container will also affect the location of the cold spot. When the container is rotated or turned over, there may be no discernible cold spot. If the load remains the same, the capacity is the same, there is no barrier to steam penetration, and the cold spot still cannot be reproduced, the equipment, process, pressure, steam quality, etc. should be checked for possible uncertainties. 13. What is the difference between the full-load heat distribution and the no-load heat distribution for the sterilization effect? Answer: Both tests measure the temperature distribution of the sterilization chamber, and do not reflect the temperature and thermal benefits in the product, nor can it directly reflect the sterilization effect of the product. But the chamber condition obviously affects the situation inside the product. During the verification, the no-load heat distribution, full-load heat distribution, and product heat penetration tests are carried out in sequence. The main purpose of using this kind of test is to reveal the objective situation as much as possible with as few tests as possible. The results of the previous test provide information for the latter test. 14. Is the full load heat distribution test performed with an empty bottle or an infusion bottle with water for injection? Answer: The full load heat distribution test is carried out with simulated samples. 15. If the loading method during verification is half-load or full-load, is it necessary to verify if it is between full-load and half-load in future production? Answer: For the loading method between full load and half load, it is recommended to use simulated product filling to achieve full load, so as to ensure that the loading method during production is consistent with that during verification. 16. How to do the thermal 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 this point obtains a sufficient sterility 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°C. For changes in operating conditions that may affect the sterilization effect, corresponding verifications should be made to confirm the operating methods. For example: when a stainless steel cover is added to each sterilization tray, the heating time inside the actual product (solution) will be 2 minutes slower than that without the cover, so it is necessary to add 2 minutes when setting the sterilization program. The placement of the thermocouple is consistent with the full-load heat distribution test procedure, and the standard thermocouple is placed in the center of the sterilization solution. 17. What is the concept of simulated samples in the heat penetration test? Does it refer to small batch samples in the laboratory? Answer: The simulated sample in the thermal penetration test refers to the sample with the same thermal penetration performance as the real sample, not a small batch of laboratory samples. 18. Does the type of biological indicator for the microbial challenge test need to be selected according t

09-11 

【Qianhui Sharing】Common technical problems in the research and verification of injection sterility assurance technology (1)

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 ver

09-14 

【Qianhui Sharing】Answers to common problems of chemical medicine and biological products-pharmacology and toxicology

Question 1: Issues related to special safety tests Special safety test, or "irritation, allergy, hemolytic test", "preparation safety test" or "No. 21 data"; involving a variety of dosage forms, such as injections, patches, sprays, inhalants, drops Eye drops, ointments, etc. The following common issues only apply to chemical drugs. 1, irritation test ①Route of administration: only the proposed clinical route can be used ②The number of doses: should include single and multiple doses ③Dosing volume for vascular irritation test: Whether using intravenous drip or bolus injection, the volume should not be too small. It is common to convert the amount of drug used in the human body based on the equivalent dose, and the resulting dose volume may be too small to reflect the actual situation of clinical drug use. At this time, attention should be paid to the local exposure volume of vascular administration, not just the dose. ④Drug concentration: If a drug includes multiple strengths (concentrations), at least the highest concentration planned for clinical use should be used for testing; If the formulation is different, it should be done under normal circumstances. ⑤Skin irritation test: Generally, it should include intact skin and broken skin. 2, allergy test Chemical drug injection, usually only active systemic allergy test is performed. Certain antibiotics, macromolecules or injections containing special excipients, depending on the specific circumstances, consider whether to add other allergy tests. 3. Is it necessary to set up original research/marketed reference products for imitation products? If a result that is significantly different from the original research/marketed product is found, it is necessary to set up a comparison between the original research/marketed product to analyze the cause of the resulting product. 4, GLP requirements For situations where only special safety tests are required, the country has no regulations requiring tests in GLP laboratories. However, judging from the actual situation of the current review, some tests conducted under non-GLP conditions cannot guarantee the quality of the test, and supplementary information is often caused because of this. It is recommended to conduct the test in the certified GLP test. 5. Requirements for imported products For imported products, if standardized animal specific safety tests and/or standardized clinical trials have been conducted to study the local safety of imported products when they are marketed overseas, the above-mentioned animal data or clinical data can be provided as a substitute. 6. Which products do not require special safety tests? Water for injection, glucose injection, sodium chloride injection, glucose sodium chloride injection, mannitol injection do not need to provide special safety test data. Question 2: Are biological products necessarily conducted in GLP trials? According to national regulations, all safety tests of biological products need to be carried out in GLP laboratories. Question 3: Requirements for submitting relevant supporting documents for non-clinical trials completed overseas At present, there is an increasing number of cases in which pharmacological and toxicological research data conducted abroad support domestic applicants for drug registration and application. The following consensus has been reached after the meeting between the Drug Registration Department of the National Administration of China and the Center for Drug Evaluation: Using pharmacological and toxicological research materials that have been completed overseas to support the chemical drug application of domestic applicants, it should: 1. Provide evidence of the consistency of the material basis between the test substance used for overseas research and the domestic application. 2. Provide certification materials of overseas research institutions, such as institution licenses, business scope, etc. 3. Safety research should be carried out in a research institution that complies with GLP specifications, and a GLP Compliance Statement must be provided, as well as the recent GLP inspection records and conclusions of the institution by overseas regulatory authorities. The above-mentioned supporting documents such as 2 and 3 need to be notarized. The above requirements do not apply to imported products/international multi-center clinical trial products, but the applicant may be required to provide relevant information based on the needs of the review. Question 4: Carcinogenicity test According to the relevant provisions of the "Administrative Measures for Drug Registration", carcinogenicity trials or literature should be provided for drugs that are clinically expected to be used continuously for more than 6 months (including 6 months) or that require frequent intermittent use for the treatment of chronic recurrent diseases. According to the general rules of new drug development, the applicant can complete the anim