Table 1. Validation Characteristics per ICH Q2A and Q2B and Relevant Product Specifications
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ANALYTICAL METHOD SELECTION
Many new technologies are now available for biopharmaceutical development.5 These analytical advances and their appropriate application are discussed in detail in the literature.7-9 Since these technologies are constantly improving — resulting in shorter testing times and increased throughput, ease of
use, sensitivity, selectivity, and precision — at some point existing methods will be replaced with better ones. Automating
a procedure, resulting in long-term savings and fewer operator errors, is one reason to undertake this process. A more-sensitive
method may increase the likelihood of observing impurities at an upstream process stage where corrective action is less expensive.
Whether it is the initial license procedure, an update, or a replacement to a licensed procedure, qualified personnel should
carefully select a new test methodology and its appropriate instrumentation. Changing biological assays (for instance, impurity
testing by ELISA) requires extra care. Muire-Sluis documented that accuracy (analyte recovery) of biological assays is often
highly dependent on the standard and method used.5 Literature should be reviewed before selecting a new method. Accuracy is a prime consideration, since any bias in results
must be reflected in the release specifications.10 When replacing existing technologies with automated or more sensitive ones, alert and action levels and associated specifications
must be adjusted if needed. In-process and product specifications should reflect production-process consistency and analytical
capabilities — unless otherwise dictated by regulatory authorities.10
Current GMP guidelines state that GMP documentation and the detail of validation activities should increase as the production
process progresses.11 Testing upstream stages may actually be more critical than many final container release tests because it provides evidence
of fermentation quality and the efficiency of impurity removal — although the tests are more uncertain and variable. Final
container testing attests that formulation excipients remain at predicted levels with little variability.
Science-and risk-based testing should carefully evaluate different product quality attributes that can impact overall product
quality. Testing for in-process impurities (like host cell proteins) should emphasize overall measurement sensitivity, selectivity,
and precision. In other words, the analytical method should clearly detect batch-to-batch variations; whether the measurements
are extremely accurate (100% recovery) is not as important. This contravenes current GMP guidelines that state that the level
of GMP documentation and the details of validation activities should somehow increase with the progression of the production
process.11
Figure 2: Graphical Representation of In-Process and Product Specifications
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Some of the most advanced and innovative analytical technologies may be extremely informative for characterization of product,
impurities, or the product matrix but may not be appropriate for product release testing. When selecting an appropriate quality
control (QC) method, the pros and cons should be carefully weighed against each other. Solid evidence that the new method
will provide equivalent or better results is necessary when submitting a license change to regulatory authorities. The method's
requirements should be similar to instrument requirements and based on the expected capability of the new method, as determined
by a careful data review and identification of critical assay characteristics.
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