Uncertainty Estimates of Purity Measurements Based on Current Information: Toward a “Live Validation” of Purity Methods

Abstract

PurposeTo predict precision and other performance characteristics of chromatographic purity methods, which represent the most widely used form of analysis in the biopharmaceutical industry.MethodsWe have conducted a comprehensive survey of purity methods, and show that all performance characteristics fall within narrow measurement ranges. This observation was used to develop a model called Uncertainty Based on Current Information (UBCI), which expresses these performance characteristics as a function of the signal and noise levels, hardware specifications, and software settings.ResultsWe applied the UCBI model to assess the uncertainty of purity measurements, and compared the results to those from conventional qualification. We demonstrated that the UBCI model is suitable to dynamically assess method performance characteristics, based on information extracted from individual chromatograms.ConclusionsThe model provides an opportunity for streamlining qualification and validation studies by implementing a “live validation” of test results utilizing UBCI as a concurrent assessment of measurement uncertainty. Therefore, UBCI can potentially mitigate the challenges associated with laborious conventional method validation and facilitates the introduction of more advanced analytical technologies during the method lifecycle.Electronic supplementary materialThe online version of this article (doi:10.1007/s11095-012-0836-z) contains supplementary material, which is available to authorized users.

Prediction of Precision for Purity Methods

“…Hydrophilic interaction chromatography (HILIC) glycan map was performed as previously described. 10 In brief, glycans were released by adding 1 mL of PNGase F to 25 mg of protein and incubating for 2 h at 37 C. The released glycans were labeled with 50 mL solution containing 12 mg/mL 2-aminobenzoic acid, 0.2 M sodium cyanoborohydride, 0.8% (w/v) sodium acetate, and 0.4% (w/v) boric acid. The reaction was allowed to proceed for 75 min at 80 C. After the reaction, the samples were filtered and centrifuged.…”

“…An inadequate number of replicates can result in a significant overestimation or underestimation of method performance. 7,10 The work of Hayashi and Matsuda on function of mutual information theory [11][12][13][14][15][16] and Apostol et al 10 using Uncertainty Based on Current Information (UBCI) model showed that the precision of chromatographic methods can be predicted. However, owing to complexity and limited demonstration of applicability, these approaches have not been widely practiced.…”

“…In this manuscript, we present an assessment of uncertainty for purity measurements using a refined UBCI model. 10 A fundamental, underlying principle of this approach recognizes that the execution of a method is always associated with specific circumstances; therefore, the UBCI model accounts for the changing operational conditions of the method, hardware, and software settings. Historically, method lifecycle management did not take these fundamental considerations into account, resulting in performance drift.…”

Analytical Method Validation for Biopharmaceuticals

“…Typically, method precision is established from replicate analyses of the same sample. However, methods for predicting precision have recently been published that allow the assessment of precision based on a single chromatogram (Apostol, Kelner et al 2012).…”

“…Apostol et al (Apostol, Kelner et al 2012) proposed a new approach to assessing the uncertainty of purity analyses that uses a more holistic approach that is called Uncertainty Based on Current Information (UBCI). The model allows for real-time assessment of all performance characteristics using the results of the specific separation of interest.…”