Stephan O. Krause, Ph.D.
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Many industry professionals know that analytical testing for biopharmaceuticals for all raw materials, production in-process
stages, and final containers must be validated, and they generally understand how this can be achieved. Many of us even understand
the basic concepts of laboratory compliance and production process quality. However, how exactly are analytical test method
performance and process robustness related and how do they depend on each other? Furthermore, how do we monitor and maintain
the accuracy and reliability of analytical methods long after validation completion to ensure the suitability of these methods
for measuring process quality?
Most monitoring and maintenance activities should be controlled within a validation master plan (VMP) program. A good VMP
in quality control (QC) should include not only detailed strategies and timelines for initial validation activities but also
tools for maintaining compliance for years to come. The lifecycle of an analytical method should be captured from beginning
to end. The beginning can be defined to lie somewhere between early-stage and finished method development, whereas the end
is usually the replacement of one method with a better one. Currently, relatively little guidance exists for maintaining compliance
and validity for analytical testing. This article focuses on how to run a practical program for analytical method maintenance
(AMM) and how to ultimately integrate it into the production process. Detailed suggestions for analytical method development
(AMD), analytical method validation (AMV), and analytical method transfer (AMT) as well as regulatory submissions are discussed
elsewhere.1-7
Figure 1 illustrates a simplified ideal sequence of QC qualification and validation activities to bring an analytical method
initially into compliance. If executed as written, a compendial method does not require AMD, but it will require test method
verification, which demonstrates method suitability under the actual condition of use. The concept and data requirements
for test method verification are described in the new draft chapter <1226> Verification of Compendial Procedures for the United States Pharmacopoeia (USP).8 The data requirements for compendial method verifications are similar to those required to demonstrate method comparability
for each test method category (for example, quantitative limit test).7
VMP FOR ANALYTICAL METHODS
Figure 1. Process Map for Analytical Method Validation
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All compendial and non-compendial test methods should be listed in the QC VMP, together with the supporting instrumentation
and equipment, computer software and hardware, critical reagents, assay standards and controls, and operator training. Although
the listing of these details is time-consuming and constitutes a front-heavy planning activity, it is essential later for
maintaining a compliant QC validation and testing program. All supporting test system components that are prerequisites for
AMV should be identified and connected to each test method in the VMP. To be practical and effective for prioritizing, and
therefore, the assignment of target completion dates, all AMV prerequisites should match the same priorities as the supported
AMV. When considering timelines in preparing the overall QC VMP and all individual project plans, keep in mind that components
of a validation project could fail and therefore have an associated risk to the timely completion of the overall project.
Figure 1 identifies some of the prerequisites (for example, instrument qualification) that should be completed before initiating
an AMV. Using Gantt charts or other similar project management tools assists in the layout of efficient sequences of validation
activities and helps ensure sufficient resources and time for completion.
