Validation of analytical method based on QBD

As shown in Figure 1.1, according to the method life cycle management, using QBD for analysis method validation is similar to using QBD for process validation, which means: during the whole method life cycle from the method design stage, data and knowledge are collected and evaluated, and scientific basis is established, indicating that the method can continuously improve the quality of analysis data The approach is also divided into three stages: Method Design (stage I), method validation (stage 2) and continuous method validation (stage 3) Figure 1.1 QBD classification verification is divided into three stages: (1) stage 1; (2) stage 2; (3) stage 3: (1) method design (stage 1) In the method design phase, firstly, based on the understanding of qtpp, product CQA and process control requirements, the analysis objective profile (ATP) and method key performance characteristics (ATP is the focus of all stages of the method life cycle) should be determined In order to establish ATP, it is necessary to determine all characteristics of the performance of the indicating method, such as accuracy and precision, so as to ensure that the measurement can produce data suitable for the purpose Once the performance characteristics of these methods, especially the key performance characteristics, are identified, then the target criteria of these characteristics can be defined The only key factor in selecting the target standard is the overall process capability Knowledge of the proposed quality standard limits, expected material properties, and mean and variation values of process parameters can help to set meaningful target standards Once ATP and method key performance characteristics are defined, method development and understanding activities can be carried out First, select appropriate analysis technology and method conditions that can meet ATP requirements for method development (a new method can be developed or an existing method can be changed, or the existing method can be directly used) These analytical techniques and methods generally include the principle of analytical method, instrument and its parameters, preparation of reagent test solution and reference solution, measurement process, calculation formula and range limit requirements, etc Then, based on the previous knowledge and risk assessment, appropriate experimental research (DOE if necessary) is carried out to understand the material properties and method parameters to be controlled and their relationship with the performance characteristics of the method, i.e to ensure that the method is durable and robust Finally, a series of method conditions and control measures that are expected to meet ATP are developed and defined to establish method control strategy The process is very similar to the process design （2） Method validation (stage 2) is similar to the definition of process validation Method validation is to collect and evaluate data and knowledge from the method validation stage, and establish scientific basis to show that the method can consistently provide high-quality analysis data Only confirmed methods can be used for inspection of materials and products, as well as for internal quality control and process analysis of products When the same method is used for different inspection items, the determination contents may be different For example, when HPLC is used for identification and impurity quantitative inspection, the requirements for method confirmation may be different The former can focus on confirming the specificity, while the latter can focus on confirming the specificity, accuracy and precision Studies conducted as part of the method validation activities are subject to specific intended use as defined by ATP This validation activity may involve demonstrating that the method has sufficient accuracy and precision in the range of expected analyte concentrations it uses The key of this stage is to confirm that the method can be operated in the daily environment as required by ATP on the basis of a series of method control strategies determined in the method design stage, no matter whether the method is used for R & D or industrial quality control Therefore, this stage involves proving that the defined conditions (including the specified test and control repetition levels and correction methods) can produce data that meet the requirements of ATP, such as precision and accuracy, during routine operation This may involve repeatedly measuring a series of identical samples to confirm the accuracy of the method, and comparing the analysis results with products of known quality to prove that any potential interference will not introduce unacceptable deviation （3） Continuous method validation (stage 3) the main purpose of continuous method validation is to continuously ensure that the established analytical method can be kept under control in daily use, including the continuous method performance in routine application of the method and the related subsequent method performance validation Continuous method confirmatory performance monitoring refers to the continuous arrangement of collecting and analyzing data related to method performance characteristics from duplicate samples, including trend analysis of system applicability test data, evaluation of stability research data and trend analysis of daily test data of samples, etc Once operated in a normal environment, close attention should be paid to any OOS or OOT results generated by this method Ideally, by using the QBD approach of method lifecycle management, laboratories should encounter less OOS related analysis data Once OOS data is encountered, the root cause should be identified or eliminated Continuous method performance monitoring is also used to control method adjustments (i.e., changes within the method design space) The purpose of method performance verification is to confirm that the change of analysis method outside the design space has no adverse effect on method performance These verification activities need to be carried out through risk assessment to meet ATP requirements The possible scope of these activities ranges from the assessment that the operation after the method change can continuously meet the system applicability requirements to the comparative study to prove that the change has no adverse effect on the precision or accuracy of the method The purpose is to provide confidence that the results of the changed method still do not meet the target standards defined by ATP The possible changes and measures in the life cycle of the method are shown in the figure: after the method is confirmed, it may involve operation in a new field and be transferred to another laboratory In order to ensure that the receiver can apply the method accurately and reliably, and ensure the continuity and integrity of the analysis results, it is necessary to carry out appropriate method installation and method performance verification in accordance with QBD requirements The degree of method installation activities is based on risk assessment （4） Compared with the traditional way, the traditional analysis method verification has the similarity with the traditional process verification The traditional verification of analytical methods is usually completed by the R & D personnel involved in method development Method verification is often considered as a one-time event Based on the general method characteristics and standards, the verification is carried out in the way of check box rather than for its purpose The verification process is more focused on producing the verification documents of acceptable laws and regulations than on ensuring that the methods can be better in daily use Execution often leads to poor accuracy and reliability of analysis results After method validation, it may be transferred to another laboratory The traditional analysis method validation takes less consideration of the conventional method operating environment, and lacks the process of effectively collecting and transferring the implicit knowledge of method developers As a result, the method may not operate as expected by the receiver Then it takes a lot of effort to identify the variables that cause the performance problems of the method, and repeat them Method transfer activities are usually carried out as a one-off process, and the risk is that the activity focuses more on producing method transfer reports than on ensuring the recipient's accurate and reliable use of the method, and ensuring the continuity and integrity of the analysis results Based on the specific ATP defined for the intended use of the method, the QBD approach to method validation is more flexible in carrying out all validation activities, which will eliminate the unnecessary and valueless work mode of creating a robust validation in a check box manner Because the QBD approach can be adopted by users of analysis methods, it can also provide the possibility of industry terminology standardization and create a coordinated method validation approach QBD approach is to align terms with those of process validation, support life cycle management, delete existing vague terms, and clarify the requirements to be met for each part of the method validation process Taking the research methods of related substances as an example, the traditional way is a passive thinking mode Starting from the results of impurity analysis, only the relevant substances detected by a certain detection method belong to their sources, but the potential impurities that may exist are not fully analyzed and determined The established analysis method can not detect these impurities comprehensively, so it is easy to miss the detection of impurities, which is difficult to complete Master the impurity profile of the product The QBD approach based on MS analysis is a source based active control mode Starting from the source of impurities, starting from the analysis of preparation process, chemical structure and product composition, we evaluate and predict the possible and potential by-products, intermediates, degradation products, reagents, catalyst residues and other impurities in the products, supplemented by appropriate forced degradation and control By means of substance addition, the established analytical methods can be detected one by one and verified by corresponding methods The comparison between QBD and traditional methods of analytical method validation (5) conclusion: the design, validation and continuous validation of analytical method validation by QBD are the sufficient guarantee for the effectiveness, safety and quality control of drugs It should be used for the design and confirmation of analytical method confirmation based on the QBD concept of scientific knowledge and risk assessment to ensure the scientificity, accuracy and feasibility of analytical method, and then through the continuous confirmation of analytical method, consistently provide high-quality analytical data to effectively control the internal quality of drugs and reduce the risk of drug safety It is of great significance for analysts in pharmaceutical industry to adopt the QBD method of life cycle management Both the pharmaceutical industry and regulators need to improve the approach of ICH Q2 (validation of analytical methods: text and methodology) Ideally, with more and more QBD verified by analytical methods, the revision of ICH Q2 will be promoted to be consistent with the concept of product and process life cycle management proposed by ICH q8-q11, and the reliability of analytical methods and continuous improvement of analytical methods will be effectively improved （6） Key words 1 Analysis objective overview analysis objective overview (ATP): all performance standard combinations required for the expected analysis application of the guidance method validation process ATP defines the method performance characteristics (such as precision) that must be measured and the level to be achieved by the measurement (such as the target standard of precision) ATP requirements are general requirements, mainly related to the expected purpose rather than a specific method Any ATP compliant method is considered appropriate 2 Method validation, that is, analytical method validation: in the whole life cycle of its use, necessary collection activities are carried out to prove that the method can meet its ATP Method validation includes three stages: method design, method validation and continuous method validation 3 Method design: carry out collection activities to define the expected purpose of the method, select appropriate technology, and identify the key variables to be controlled to ensure the durability and robustness of the method Method design includes method development and method understanding 4 Method development: carry out collection activities to select appropriate analysis technology and method conditions that meet the requirements of ATP 5 Method understanding: acquire knowledge from collection activities to understand