Injectables change sterilization process application is a more common supplementary application. There are several common changes in the current application materials: change from sterilization filtration process to terminal sterilization process; change residual residual sterilization process to excessive Killing sterilization process; changing from the steam sterilization process to the residual probability method or the overkill sterilization process. According to the “Technical Guidelines for Listed Chemicals Change Research”, the above changes may have a significant impact on the safety, effectiveness and quality controllability of the drug. It is a Class III change and requires comprehensive research and verification.
This paper analyzes some of the most common problems in the recent application for sterilization process change, and proposes corresponding recommendations for researchers' reference.
Question 1: The physicochemical properties of unbound drugs are a comprehensive study of the sterilization process
For example, for some varieties with good stability and ability to withstand excessive sterilization, the applicant still uses the residual probability sterilization process. In some varieties that are sensitive to temperature, some of the application materials only provide process verification data according to the changed sterilization conditions, but do not provide screening information for sterilization conditions (including the control range for determining the F0 value and the control of degradation impurities). ). In addition, in the process screening, the effect of hot spot temperature on the sample was not investigated in combination with the verification of the sterilizer; in the sterilization process of some heat sensitive drugs, only the final selected sterilization temperature was investigated, but not Investigate the effects of other temperature conditions on the product.
Recommendation: Applicants should apply for a sterilization process change for injections in accordance with the “Notice on the Release of Basic Technical Requirements for Chemical Injections and Multi-Component Biochemical Injections” (National Food and Drug Administration [2008] No. 7).
Applicants can refer to the EU liquid product sterilization decision tree and design the sterilization conditions according to the characteristics of the product. The choice of sterilization process should first depend on the level of sterility assurance of the sterilized product and the thermal stability of the drug, rather than other factors such as packaging materials. As long as the conditions permit, the overkill sterilization process should be preferred because the sterility of the process is very safe and the control requirements for the whole process are relatively low, as long as the drug is organized in strict accordance with the requirements of the drug GMP. This ensures a sterility assurance value of ≤10-6 without worrying about the bioburden and heat resistance of the load. The residual probability sterilization process starts from the two aspects of microbial contamination control and sterilization process control before sterilization, so that the sterilized assurance level specified by the pharmacopoeia can be ensured even when the sterilization F0 value is low.
In general, when the product's thermal stability cannot tolerate the overkill process, the residual probabilization process can be selected and optimized by the formulation process (including the sterilization process) (some products can be added with antioxidants, In the process of nitrogen filling, etc., to maximize the product sterilization F0 value, to ensure the level of sterility assurance, while also minimizing the thermal degradation of the drug. In addition, the actual effects of the selected sterilization procedure on the quality of the drug should be examined and evaluated in conjunction with the specifics of the drug.
In addition, it should be noted that the temperature in different positions in the sterilizer is not completely the same, but there are some differences. When verifying the sterilizer, it is necessary to control the temperature difference of the cold hot spot, such as: control the average temperature and cold of the chamber. The point temperature does not exceed 2.5 ° C or the maximum temperature and cold point temperature does not exceed 2.5 ° C. Therefore, the F0 value at different positions in the sterilizer has a fluctuation range. For example, if the sterilization condition is selected to be 121 ° C for 8 minutes, the difference between the maximum chamber temperature and the cold spot temperature is 2.5 ° C. When the F0 value is 8 for the cold spot, the maximum temperature difference is calculated, and the hot spot temperature is 123.5 ° C. The F0 value will go far beyond 8. Under the premise that the sterility guarantee meets the requirements, the above temperature difference has little effect on the heat stable product, but it may have a significant impact on the heat sensitive variety. Therefore, in the process research, it is necessary to pay attention to the degree of influence of hot spot sterilization conditions on the drug, and study and select the F0 value adaptation range (ie, design space) of the product; when performing the heat distribution and heat penetration and other sterilization process verification It should be noted that the F0 value of the hot spot should be within the above adaptation range. At the same time, in the process verification or sampling inspection, for the heat sensitive products, attention should also be paid to sampling and testing the hot spot samples. The above research actually reflects the concept of quality from design (QBD).
Question 2: Sterilization process verification is inconsistent with process research information
For example, the modified sterilization process parameters (such as the F0 value range or the F0 value of the thermal penetration test cold spot) exceed the maximum F0 value of the sterilization process screening study, and the process shows that the maximum F0 value is stable to the product. The impact is significant and cannot be adopted. Some of the application materials show that the residual probability sterilization process is used, but the F0 value of the thermal penetration test can sometimes be greater than 18, 19, while the stability test sample sampling does not indicate the F0 value of the sampling point. The information provided does not reflect the sterilization process. The rationality of the change.
Recommendation: F0 values accumulate over time and temperature, and drug degradation also accumulates over time and temperature, which means that changes in temperature and cooling procedures can affect kill time, affect product stability, improper warming and / or cooling may have a significant impact on the F0 value. Therefore, for some heat sensitive products, the temperature rise and temperature drop rate should be controlled as important parameters, so that the sterilization process always meets the design standards.
Question 3: The submitted sterilization process verification data is not comprehensive
For example, the test data and results of the no-load heat distribution are not provided, or the verification data and results of the minimum loading conditions are only provided, and the test data and results under full load conditions are not provided; only one batch of samples is provided, and three verifications are not provided. The data and map; only the pre-test verification results of the thermocouple used in the verification test are provided, and the comparison results after the test are not provided; the information of the sample for the full-load heat distribution test is not provided, and the verification of the multi-species variety is not comprehensive, only Test data and results for individual specifications; the number of times the biological indicator challenge test was run, whether the biological indicator was placed at a cold spot, etc.
Recommendation: The no-load heat distribution test is the basic test for the verification of sterilization equipment. It mainly investigates the performance parameters of the equipment, the temperature difference at different positions of the sterilization cabinet during the sterilization process, the maximum fluctuation data of the highest temperature and the lowest temperature, cold spot, The location of the secondary cold spot and the hot spot and the secondary hot spot provide data support for the next full load heat test. The same sterilization process should be run at least three times in total to demonstrate uniformity and reproducibility of the sterilization equipment.
The load heat distribution test plan shall be formulated according to the results of the no-load heat distribution test, and the uniformity of the temperature distribution in the sterilization chamber under the loading condition shall be investigated and determined, that is, whether the load has a special influence on the heat distribution of the chamber, resulting in the occurrence of cold spots and hot spot. At least the heat distribution test under full load conditions should be performed. The main reason for the influence on the heat distribution is the quantity and physical shape of the product. It is acceptable from the risk management perspective to use pure water instead of some real aqueous products, but the packaging form should be the same as the verification type packaging, multiple specifications. Varieties can be tested by brackets to reasonably reduce the number of test runs, ie, products with minimum and maximum specifications. The complete sterilization procedure should be run at least three times in succession. The cold spot or hot spot found in this test is the location that the heat penetration test needs to focus on.
Question 4: Thermal penetration test is not well thought out
For example, the heat penetration test does not consider the variety, specification, loading method and quantity, or replaces the declared variety with other varieties, specifications and packaging forms, and does not provide data that supports the thermal penetration of the substitute sample and the declared variety; The temperature probe placement position of the test was not satisfactory, and the cold spot of the container was not determined.
Recommendation: A thermal penetration test protocol should be developed based on the results of the full load heat distribution test. The purpose of the thermal penetration test is to obtain the temperature and F0 value actually obtained during the sterilization process of the samples in different positions in the sterilization cabinet, thereby obtaining the temperature and F0 value data between the samples at different positions, and grasping the temperature inside the sample. And the difference between the F0 value and the temperature and F0 value recorded by the sterilization equipment during daily production runs.
Due to the differences in the thermal penetration of different varieties and packaging containers, the heat penetration test should generally be carried out using the varieties to be declared, and the batch number, batch size and loading method of the samples should be clarified. If there is a cold spot or hot spot found in the full load heat distribution test, it is usually important to collect the heat penetration data at that location.
In the heat penetration test, the temperature probe should be inserted into the product to be sterilized, and the sample placed with the temperature probe should be placed at the cold spot and hot spot determined by the heat distribution test. The heat penetration test also needs to pay attention to the way the temperature probe is placed, the maximum F0 value, the minimum F0 value, and the average F0 value of the sterilization process.
The cold spot of the container is the lowest F0 portion of the liquid container in the sterilization process. The method of establishing a sterilization procedure using cold spots is a relatively conservative method because it assumes that all microorganisms in the container are concentrated at a cold spot and sterilized at a cold spot temperature. Prior to the heat penetration test, the mapping of the container is first required in order to determine the coldest spot in the container filled with liquid. For large volume injections, the cold spot is at the bottom of the product's geometric center and longitudinal axis. This cold spot needs to be confirmed. In the case of small volume injections, the positioning of the cold spots is not typical because the rate of temperature rise of the solution is almost the same as that of the sterilizer. The location of the cold spot is also affected by the orientation of the container, and when the container is rotated or swayed, there may be no discernible cold spots.
As a small-volume injection, if there is a sufficient basis, its heat distribution and heat penetration can be carried out simultaneously.
Question 5: Microbial limit control for pre-sterilization liquid is not strict
For example, when the residual probability sterilization process is used, the microbial limit control is not performed on the pre-sterilization liquid, and the heat resistance of the contaminated microorganisms is not examined. Or microbial limit control standards have been established, but the method of inspection is not standardized, or the standard has not been tested as a worst-case microbial challenge.
Recommendation: For the residual probability sterilization process, the amount of contaminated microorganisms before sterilization and the heat resistance of contaminated microorganisms are the key factors in determining whether the sterilization process reaches the sterility assurance level. Microbiological intermediate control standards should be established, including the amount of microbial contamination prior to sterilization and the heat tolerance standards of contaminated bacteria. Sampling of samples prior to sterilization shall cover the entire production filling process, including the beginning, middle and end stages of filling, and it should be noted that the samples taken should be stored under the same conditions as the samples to be sterilized.
According to the current technical requirements, for products using the terminal sterilization process, such as the overkill sterilization method, in the verification work, attention should be paid to the investigation of heat distribution and heat penetration, such as the use of residual probability sterilization method, except for inspection. In addition to heat distribution and heat penetration, attention should also be paid to microbial challenge testing and control of microbial load prior to sterilization.
Question 6: Microbial challenge test is not comprehensive
For example, the antibiotics and bacteriostatic-containing varieties are directly inoculated into the varieties without considering the bacteriostasis of the varieties for microbial challenge tests.
Recommendation: The microbiological challenge test is usually in the form of quantifying a biological indicator into a product, preparing a test product with a defined number of microbial spores, placing the product in a specific location within the sterilization device, and sterilizing as low as possible. The parameters (close to the lower limit of the proposed sterilization parameters) run the sterilization procedure, perform sterility inspection on the tested products, and determine the residual probability of the microorganisms after sterilization by a certain degree of microbial contamination. In order to confirm the liquid-loaded biological indicator, a suitable biological indicator (BI) is to be inoculated on the sealed and potted liquid container and seal. The liquid medium can be a product or a suitable substitute. If the liquid product contains preservatives or other antibiotic ingredients (which inhibit microbial growth), it may be necessary to use a liquid substitute as a suspending agent. The use of which product as a suspending agent requires the support of experimental data to demonstrate that they do not inhibit the growth of microorganisms.
The source, type, and specification (D value and number of bacteria) used in the microbial challenge test should be clarified. The test results should indicate whether the heat resistance and quantity of the biological indicator used in the test constitute a sterilization process. The necessary challenges. The heat resistance of the biological indicator should be greater than the heat resistance of the common contaminating bacteria in the production environment and products. The test protocol should be designed based on the results of the thermal penetration test. If the thermal penetration test proves that there is a significant difference in heat penetration characteristics between products at different locations, between different loadings, and between different loading specifications, at least the position, loading capacity and capacity specification with the lowest sterilizing F0 value should be selected (ie the most Poor condition) for microbial challenge test