Lifecycle management in pharmaceutical analysis: How to establish an efficient and relevant continued performance...

It is the objective of a systematic and holistic Quality-by-Design approach to demonstrate and ensure that an analytical procedure is fit for its intended purpose over its entire lifecycle. Such a lifecycle approach, as proposed for a new USP General Information Chapter includes the three stages Procedure Design and Development, Procedure Performance Qualification, and Continued Procedure Performance Verification, in alignment to manufacturing process validation. A decisive component of this approach is the Analytical Target Profile, which defines the performance requirements for the measurement of a Quality Attribute as the target for selection, development and optimization of the respective analytical procedures. Although the most benefit can be gained by a comprehensive Quality-by-Design approach establishing the Analytical Target Profile in the very beginning of a drug development project, it may also be established retrospectively for analytical procedures long in routine use, in order to facilitate future lifecycle activities such as continual improvements, transfers, monitoring and periodic performance evaluations. In contrast to the first two stages of the analytical lifecycle with usually limited amount of data, the Continued Procedure Performance Verification stage offers the possibility to utilize a much more reliable data base to collect, analyze, and evaluate data that relate to analytical procedure performance. This monitoring program should be aligned as far as possible with other quality systems already in place and may include performance indicators such as Conformity (i.e. out-of specification test results with analytical root-cause), Validity (i.e. failure to meet method acceptance criteria, e.g. system suitability tests), and (numerical) analytical performance parameters (e.g. ranges for replicate determinations, control sample results, etc). In addition to the monitoring of analytical control parameters by means of control charts, average (pooled) performance parameters can be calculated. Over time, a large number of data can be included and thus the reliability of these estimates is increased tremendously. Such reliable estimates for the true performance parameters, e.g. repeatability or intermediate precision are essential to identify systematic effects (also called special cause variation) with good confidence. The intent of the analytical procedure performance evaluation is to identify substandard performance, identify root cause through investigations, and determine when additional activities are required to improve it. Examples are provided for the monitoring and evaluation of performance parameters for the compendial drug substance Furosemide and for biopharmaceutical applications.