A QbD framework for analytical lifecycle management

QbD is defined as "A systematic approach to development that begins with predefined objectives and emphasizes product and process understanding based on sound science and quality risk management" (9). FDA has proposed a definition for process validation that is "the collection and evaluation of data, from the process design stage throughout production, which establishes scientific evidence that a process is capable of consistently delivering quality products" (3). When considering a lifecycle approach to method validation a similar definition could be adopted, "the collection and evaluation of data and knowledge from the method design stage throughout its lifecycle of use, which establishes scientific evidence that a method is capable of consistently delivering quality data" (1). A method, as defined in this article, is a synonym for analytical procedure and includes all steps of the procedure (e.g., sample preparation, analytical methodology, calibration, definition of the reportable result, and specification limits). From these definitions, it can be seen that there are a number of key factors that are important in a QbD lifecycle approach. These include:

• The importance of having predefined objectives
• The need to understand the method (i.e., having the ability to explain the method performance as a function of the method input variables)
• The need to ensure that controls on method inputs are designed such that the method will deliver quality data consistently in all the intended environments in which it is used
• The need to evaluate method performance from the method design stage throughout its lifecycle of use.

In alignment with the approach proposed in the FDA guidance for process validation, it is possible to envisage a three-stage approach to method validation.

Measurement requirements

Before commencing method validation, it is key to understand what the product critical quality attributes and process control requirements are. These requirements form the basis for the development of an Analytical Target Profiles (ATP) (10). While the paper in reference 10 introduced the concept of an ATP and described how it could have potential as a tool to facilitate regulatory oversight of change, its principal aim is to act as the focal point for all stages of the analytical lifecycle including method validation, which is the focus of this paper.

To build the ATP, it is necessary to determine the characteristics that will be indicators of method performance. These should include all of the characteristics that will ensure the measurement produces fit-for-purpose data and are likely to be a subset of those described in ICH Q2 (e.g., accuracy, precision) (5).

Once the important method characteristics are identified, the next step is to define the target criteria for these (i.e., how accurate or precise the method needs to be). After ensuring safety and efficacy, a key factor in selection of the appropriate criteria is the overall manufacturing process capability. Knowledge of the proposed specification limits and the expected process mean and variation is helpful in setting meaningful criteria. To draw a parallel to qualification of new analytical equipment, the ATP is similar to a user requirement specification that would be produced to support qualification of new analytical equipment.