Stage 2 – Method Qualification: Confirm that the method is capable of meeting its design intent.
Stage 3 – Continued Method Verification: Gain ongoing assurance to ensure that the method remains in a state of control during routine use.

 

Stage 1 - Method Design

The Method Design stage includes establishing the method performance requirements, developing a method that will meet these requirements and then performing appropriate studies to understand the critical method variables that must be controlled to assure the method is robust and rugged, The method design stage can be an iterative process which is repeated as required in accordance with the lifecycle phase of the product.

Method Performance Requirements
Utilising a QbD approach, it is essential at this stage that sufficient thought be given to the intended use of the method and that the objectives or performance requirements of the method be fully documented. This represents the Analytical Target Profile (ATP) [6] for the method.

To draw a parallel to qualification of new analytical equipment, the ATP for the method is effectively the equivalent of a User Requirement Specification that would be produced to support qualification of new analytical equipment (or the Design Qualification as defined in USP <1058>).

To build the ATP, it is necessary to determine the characteristics that will be indicators of method performance. Typically these characteristics will be a subset of those described in ICH Q2, such as accuracy or precision.

It is important, however, not to use the ICH Q2 characteristics in a check box manner but to consider the method's intended use. For example, the characteristics that are critical to the performance of an HPLC assay method intended to be used to quantify the active ingredient within a tablet might be quite different from those of an NIR method intended to be used to measure the end point of a blending operation. In the second case, accuracy may not be a critical method performance requirement in determining homogeneity.

Once the important method characteristics are identified, the next step is to define the target criteria- in other words, how accurate or precise the method should be. A key factor in choosing the appropriate criteria is the impact of method variation on the overall manufacturing process capability. Knowledge of the proposed specification limits and the expected process mean and variation is helpful in setting meaningful criteria.

Method Development
Once the ATP has been defined, an appropriate technique and method conditions must be selected in order to meet the requirements of the ATP. While method development is a very important part of the method lifecycle, it is not necessary to elaborate here since it has been extensively addressed in the literature.

Method Understanding
Based on an assessment of risk (i.e. the method complexity and the potential for robustness and ruggedness issues) one can perform an exercise focused on understanding the method to better understand what key input variables might have an impact on the method's performance characteristics. From this, one can identify a set of operational method controls.

Experiments can then be run to understand the functional relationship between method input variables and each of the method performance characteristics. Knowledge accumulated during the development and initial use of the method provides input into a risk assessment (using tools such as the Fishbone diagram and FMEA) which may be used to determine which variables need studying and which require controls.

Robustness experiments are typically performed on parametric variables using Design of Experiments (DoE) to ensure that maximum understanding is gained while minimizing the total number of experiments. Depending on the type of method, surrogate measures of characteristics such as accuracy or precision may be evaluated. An example might be peak resolution in a chromatographic method. It follows that well designed System Suitability requirements can be a valuable tool for assuring that a method is operating in a region where the ATP requirements will be met.

When developing an understanding of the method’s ruggedness, it is important to consider variables that the method is likely to encounter in routine use, such as in situations involving different analysts and different instruments. Tools such as measurement system analysis can be useful in providing a structured experimental approach to examining such variables.

Method Design Output
A set of method conditions will have been developed and defined which are expected to meet the ATP. Those conditions will have been optimized based on an understanding of their impact on method performance.

 

Stage 2 - Method Qualification

Once a set of operational method controls has been determined during the design phase, the next step is to qualify that the method will operate as intended. In a similar manner to equipment qualification, method qualification can be broken down into the stages of method installation qualification (MIQ), method operational qualification (MOQ), and method performance qualification (MPQ).

Method Installation
Qualification focuses on ensuring that the facility where the method will be used is prepared to use it. This process includes ensuring that the analytical equipment is qualified and that appropriate knowledge transfer and training of analysts has been performed.

The method conditions and detailed operating controls, along with all the knowledge and understanding generated during the design phase, must be conveyed to staff at the facility in which the method will be used. Performing a “method walkthrough” exercise with both the development and routine analytical teams can be extremely valuable in ensuring all tacit knowledge about the method is communicated and understood.