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Lauren Marie
Lauren Marie

(QbD) Approach For Analytical Method Development [REPACK]


Pharmaceutical industry has been emerging rapidly for the last decade by focusing on product Quality, Safety, and Efficacy. Pharmaceutical firms increased the number of product development by using scientific tools such as QbD (Quality by Design) and PAT (Process Analytical Technology). ICH guidelines Q8 to Q11 have discussed QbD implementation in API synthetic process and formulation development. ICH Q11 guidelines clearly discussed QbD approach for API synthesis with examples. Generic companies are implementing QbD approach in formulation development and even it is mandatory for USFDA perspective. As of now there is no specific requirements for AQbD (Analytical Quality by Design) and PAT in analytical development from all regulatory agencies. In this review, authors have discussed the implementation of QbD and AQbD simultaneously for API synthetic process and analytical methods development. AQbD key tools are identification of ATP (Analytical Target Profile), CQA (Critical Quality Attributes) with risk assessment, Method Optimization and Development with DoE, MODR (method operable design region), Control Strategy, AQbD Method Validation, and Continuous Method Monitoring (CMM). Simultaneous implementation of QbD activities in synthetic and analytical development will provide the highest quality product by minimizing the risks and even it is very good input for PAT approach.




(QbD) Approach for Analytical Method Development



Scientific QbD Approach for Synthesis and Analysis. ICH Q11 has explained the QbD approach for API synthetic process development but there is no specific discussion on AQbD. However, it is recommended to implement QbD approach in analytical method development termed as AQbD. These two scientific approaches (QbD and AQbD) can be progressed in equal time. Figure 2 represents the necessary steps in API synthesis and analytical development with QbD implementation. This simultaneous implementation produces high quality product. It may give better input for initiation of process analytical technology (PAT).


Differences for Traditional and Scientific Approach. Analytical method development traditional and scientific approaches have large difference. Traditional approach does not use statistical calculations and risk assessment. AQbD approach will proceed with scientific tools such as ATP, CQA, DoE and Risk Assessment, Control strategy and Risk Assessment and AQbD Method Validation, and Continuous Method Monitoring. Figure 3 represents the steps for traditional and scientific approaches for analytical development.


ATP [7, 8] identification includes the selection of method requirements such as target analytes (product and impurities), analytical technique category, and product specifications. Initial risk assessment would be performed for anticipation of the method requirements and analytical criticalities. General ATP for analytical procedures is as follows:(a)target analytes selection (API and impurities),(b)technique selection (HPLC, GC, HPTLC, Ion Chromatography, chiral HPLC, etc.),(c)method requirements selection (assay or impurity profile or residual solvents).


Example. A model synthetic route is presented in Figure 4 with ATP impurities. This synthetic route has been considered for analytical method development by HPLC/UPLC, HPTLC, or GC techniques with AQbD implementation. DS synthetic route has eight steps from the starting material. Additional new raw materials are added at stages 4 and 6. Byproducts are forming at stages 5 and 7. Stage 4 product is a degradation of final drug substance. Stage 6 is a carryover to final DS.


(i) CQA (Critical Quality Attributes). CQA for analytical methods includes method attributes and method parameters. Each analytical technique has different CQA. HPLC (UV or RID) CQA are mobile phase buffer, pH, diluent, column selection, organic modifier, and elution method. GC methods CQA are gas flow, oven temperature and program, injection temperature, sample diluent, and concentration. HPTLC method CQA are TLC plate, mobile phase, injection concentration and volume, plate development time, color development reagent, and detection method. Nature of impurities and DS can define the CQA for analytical method development such as solubility, pH value, polarity, charged functional groups, boiling point, and solution stability. Table 3 represents the common ATPs and CQA for an HPLC method.


(ii) Risk Assessment. Risk Assessment is a science-based process used in quality risk management and it can identify the material attributes and method parameters (ATP). Risk Assessment can be performed from initial stage of method development to continuous method monitoring. AQbD approach involves the risk identification at early stages of development followed by appropriate mitigation plans with control strategies that will be established. In general, Ishikawa fishbone diagram can be used for risk identification and assessment. See Figure 5 that shows fishbone risk identification approach for typical analytical test procedure.


Once the potential and critical analytical method variables are defined with initial risk assessment, then DoE can be performed to confirm and refine critical method variables based on statistical significance. It can be determined per unit operation or combination of selected multiple method variables and their interactions and responses (critical method attributes). This approach provides an excellent opportunity to screen a number of conditions generated from a limited number of experiments. Then, data evaluations by using statistical tools are very important to identify critical method variables and the appropriate optimal ranges for method variables where a robust region for the critical method attributes could be obtained.


Life cycle management is a control strategy used for implementation of design space in commercial stage. CMM is final step in AQbD life cycle; it is a continuous process of sharing knowledge gained during development and implementation of design space. This includes results of risk assessments, assumptions based on prior knowledge, statistical design considerations, and bridge between the design space, MODR, control strategy, CQA, and ATP. Once a method validation is completed, method can be used for routine purpose and continuous method performance can be monitored. This can be performed by using control charts or tracking system suitability data, method related investigations, and so forth. CMM allows the analyst to proactively identify and address any out-of-trend performance.


Quality by design (QbD) refers to the achievement of certain predictable quality with desired and predetermined specifications. A quality-by-design approach to method development can potentially lead to a more robust/rugged method due to emphasis on risk assessment and management than traditional or conventional approach. An important component of the QbD is the understanding of dependent variables, various factors, and their interaction effects by a desired set of experiments on the responses to be analyzed. The present study describes the risk based HPLC method development and validation of ceftriaxone sodium in pharmaceutical dosage form.


The central composite design experimental design describes the interrelationships of mobile phase and pH at three different level and responses to be observed were retention time, theoretical plates, and peak asymmetry with the help of the Design Expert 11.0 version. Here, a better understanding of the factors that influence chromatographic separation with greater confidence in the ability of the developed HPLC method to meet their intended purposes is done. The QbD approach to analytical method development was used for better understanding of method variables with different levels.


Using the CCD approach, these method conditions were assessed. At the first step, the conditions for retention time, theoretical plates, and peak asymmetry were evaluated. For ceftriaxone sodium, this resulted in distinct chromatographic conditions. The proven acceptable ranges from robust regions where the deliberate variations in the method parameters do not affect the quality. This ensures that the method does not fail downstream during validation testing. If the modeling experiments do not have the desired response, the variable needs to be optimized at different levels until the responses were within the acceptable ranges [19]. The best suited chromatographic conditions shall be optimized using the Design Expert tools.


A control strategy should be implemented after the development of method. The analytical target profile was set for the development of the analytical control strategy. The analytical control strategy is the planned set of controls that was derived from the understanding of the various parameters, i.e., fitness for purpose, analytical procedure, and risk management. All these parameters ensure that both performance of the method and quality outputs are within the planned analytical target profile. Analytical control strategy was planned for sample preparation, measurement, and replicate control operations [22].


Method validation is a documented evidence which provides a high degree of assurance for a specific method that the process used to confirm the analytical process is suitable for its intended use. The developed HPLC method for estimation ceftriaxone sodium was validated as per ICH Q2 (R1) guidelines [24].


The analytical quality-by-design HPLC method for the estimation of ceftriaxone sodium in pharmaceutical formulation has been developed. The analytical target product profile were retention time, theoretical plates, and peak asymmetry for the analysis of ceftriaxone sodium by HPLC. The two variables namely the mobile phase composition and pH of buffer solution were identified as the critical quality attributes that affect the analytical target product profile. The central composite design was applied for two factors at three different levels with the use of the Design Expert Software Version 11.0. The risk assessment study identified the critical variables that have impact on analytical target profile [26,27,28]. In chromatographic separation, the variability in column selection, instrument configuration, and injection volume was kept controlled while variables such as pH of mobile phase, flow rate, and column temperature were assigned to robustness study. 041b061a72


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