NEWS
/
News Center
Classification

09-01

09-02

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

09-11

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
Previous page
1
2