Summary: This article describes the acceptable criteria for determining the feasibility of the analytical methods used in the material inspection.
key words: the relevant substance inspection analysis method verification can receive standards
Since the presence of these substances can affect the purity of the drug, which in turn may produce toxic side effects, the control of the substance is an important aspect of drug research and development, and is one of the key points that we have been focusing on in the drug review.
to carry out strict control of the substances concerned, we can not be separated from the analysis methods with strong attributes and high sensitivity, which involves the screening and verification of the analytical methods. From the available reporting data, drug research and development units have basically realized the importance of analytical method verification, but there is no clear acceptable criteria for the feasibility of the specific indicators at the time of verification, making it difficult to judge the results of verification.
In order to solve this problem, this paper, combined with the requirements of some large foreign drug research and development enterprises in this regard, put forward acceptable standards for the verification of the relevant substance inspection methods, for domestic drug research and development units in the study of reference.
1. The accuracy
this indicator is mainly reflected by the recovery rate. Verification generally requires the preparation of three parts of the test solution of three concentrations of the impurity according to the quantitative limit of the substance in question and the limit of the impurity in the quality standard (e.g. the limit of an impurity is 0.2%, the impurity concentration may be separately rationed) 0.1%, 0.2% and 0.3% of impurity solutions, respectively, to determine its content, compare the measured values with theoretical values, calculate the recovery rate, and calculate the relative standard deviation (RSD) of the nine recovery rate data.
2. Linear
in the quantitative limit to a certain concentration range of 6 different concentrations of test fluid, respectively, to determine the area of the impurity peak, calculate the corresponding content. Linear regression analysis is performed with the content as horizontal coordinates (X) and the peak area as the ordinate coordinates (Y).
5. The intensity ratio
6. The ratio of
intensity ratio between impurity peak and noise peak signal should not be less than 10. In addition, the preparation of 6 solutions with minimum quantitative limit concentration, the relative standard deviation of 6 solution impurities peak retention time should not be greater than 2.0%, and the relative standard deviation of peak area should not be greater than 5.0%.
7. Durability
the proportion change of flow phase ±5%, the change of flow phase pH ±0.2, the change of column temperature ±5 degrees C, the change of wavelength ±5nm, relative flow rate. Changes in ±20% of the value and the determination using three different batch numbers ofcolumn, the instrument chromatography behavior changes, under each condition twice.
the acceptable criteria are: the trailing factor of each impurity peak shall not be greater than 2.0, the impurity peak and other component peaks must reach baseline separation, the relative standard deviation of impurity content data (n-6) under various conditions shall not be greater than 2.0%, and the absolute value of impurity content shall be within ±0.1%.
8, system adaptability
preparation of 6 copies of the same concentration of impurity solution analysis, the impurity peak area of the relative standard deviation should not be greater than 2.0%, the retention time of the relative standard deviation should not be greater than 1.0%. In addition, the trailing factor of impurity peak shall not be greater than 2.0, and the number of theoretical tower plates shall conform to the quality standards.
9. Solution stability
according to the analysis method, respectively,control product solution and test solution, parallel determination of the content of two main components and impurities, and then the above solution stored at room temperature and refrigerator refrigerator refrigerator (4 degrees C), in 1, 2, 3, 5 and 7 days, respectively, two parallel measurement of the main components and impurities content.
acceptable criteria are: the absolute value of the content change of the main ingredient should not be greater than 2.0%, the absolute value of impurity content should be within ±0.1%, and no new impurities greater than the reported limit should appear.
content determination analysis method verification
abstract: This paper describes the analytical method used in the content determination method method method methodological verification, the indicators of acceptable standards, in order to help determine the feasibility of the analysis method.
Keywords: Content measurement analysis method verification receivable standard
In the process of quality research, the important work is to carry out methodological verification of the analysis methods involved in the quality standard, to ensure that the analytical method used can indeed be used in the study of drugsquality control In order to standardize the verification requirements of various analytical methods, China has promulgated the guiding principles for the verification of analytical methods in 2005.
guidelines describe the analytical methods that need to be verified and the specific indicators that need to be verified. However, the document does not address the acceptable criteria for the validation of specific indicators, and the relevant requirements are not found in the guidelines that have been issued internationally.
On the other hand, several drug research and development units in quality research, has gradually recognized the necessity and importance of analytical method verification, most of them are also in accordance with the requirements of the guidelines for analysis method verification, but after verification, but because there is no clear acceptable standards, it is difficult to determine whether the analysis method meets the requirements. Based on the requirements of some large foreign drug research and development enterprises in this aspect, this paper puts forward acceptable standards for the verification of content measurement methods for reference by domestic drug research and development units in their research.
1. The accuracy
this indicator is mainly reflected by the recovery rate. During the verification, it is generally required to prepare three serving solutions with concentrations of 80%, 100% and 120%, respectively, to determine their content, to compare the measured values with the theoretical values, and to calculate the recovery rate.
acceptable criteria are that the average recovery rate at each concentration should be between 98.0% and 102.0%, and the relative standard deviation (RSD) of the nine recovery rate data should be no greater than 2.0%.
2. Linear
generally represented by linear regression equations. The specific verification method is:
in the concentration range of 80% to 120% of the preparation of 6 different concentrations of the test fluid, respectively, to determine the area of its main peak, calculate the corresponding content. Linear regression analysis is performed with the content as horizontal coordinates (X) and the peak area as the ordinate coordinates (Y).
acceptable criteria are: the correlation coefficient (R) of the regression line must not be less than 0.998, the Y-axis intercept should be within 2% of the 100% response value, and the relative standard deviation of the response factor should not be greater than 2.0%.
3. Precision
1) Repeatability
6 samples of the same concentration of test solution, tested by an analyst under the same conditions as possible, the resulting 6 serving liquid content of the relative standard deviation should not be greater than 2.0%.
2) Intermediate Precision
6 sample solutions of the same concentration were made, tested by two analysts using different instruments and reagents, and the relative standard deviation of the resulting 12 content data should not be greater than 2.0%.
4. The acceptable
of the exclusive properties are: blank control should be non-disturbing, the main component and the relevant substances should be completely separated, the degree of separation shall not be less than 2.0. When analyzing purity with a diode array detector, the purity factor of the main peak should be greater than 980.
5. The intensity ratio
the main peak and the noise peak signal should not be less than 3.
6. The strength ratio
the main peak and the noise peak signal should not be less than 10. In addition, the relative standard deviation of the retention time of the main peak of the 6 parts of the solution measured should not be greater than 2.0% for the preparation of 6 solutions with a minimum quantitative limit concentration.
7. The durability
the ratio change of flow phase ±5%, the pH change of flow phase ±0.2 and column temperature respectively.
