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
- 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.
Stage one: method design. The method requirements and conditions are defined according to the measurement requirements given in the analytical target
profile and the potential critical controls are identified.
Stage two: method qualification. During this stage, the method is confirmed as being capable of meeting its design intent and the critical controls are established.
Stage three: continued method verification. Ongoing assurance is gained which ensures the method remains in a state of control during routine use. This includes both
continuous method performance monitoring of the routine application of the method as well as a method performance verification
following any changes.
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