Design and Statistical Analysis of Method Transfer Studies for Biotechnology Products

Abstract

During biotechnology product development, the analytical instrumentation and methodology are often carefully selected based on the intended purpose and the scope of the analytical method. Specifically, parameters such as specificity, linearity, limit of detection (LOD) and limit of qualification (LOQ), range, accuracy and precision are evaluated [1]. After an analytical method is successfully validated and implemented, the updates of the method with the standard operating procedure will be conducted during the life-cycle of the product. The life-cycle management of analytical methods includes, but is not limited to, the following:• trend analyses of the method performance at regular intervals;• evaluation of the need to optimize the analytical method by requalification or even revalidation of all or a part of the analytical procedure due to any proposed changes (e.g., critical raw material supplier change);• development and validation of a new or an alternative analytical method for a new impurity;• transferring a validated analytical method from a sending laboratory to a testing laboratory.A method transfer is common practice during the life-cycle management of pharmaceutical products. Since the analytical method to be transferred has been already thoroughly evaluated and fully validated for its intended purpose at the sending laboratory, the main purpose of method transfer studies is usually the qualification to evaluate if the two laboratories generate comparable results across the parameter ranges of interest, and to assure that the method after the transfer is still suitable for its intended use.While the US FDA guidance to industry [1,2] and further publications [3][4][5][6][7][8][9][10][11][12][13][14][15] discuss the general principles for the design, analysis and evaluation of method transfer studies, they do not explicitly specify the acceptance criteria by which assay transfers are considered acceptable. Although these general principles apply to the majority of assay transfer studies, depending on the type and the intended purpose of the assays, different statistical analysis methods have been proposed to suit specific needs. Below, we briefly summarize published proposals with regard to testing materials, study [6,7]. Wieling [6] proposed to split the sample into two subsets. Lin et al. [7] recommended that bioanalytical methods use the incurred samples or a set of QC samples prepared to cover the low, medium and high concentrations in both laboratories. Samples of commercial production batches are recommended to be used [5,[8][9][10][11][12][13] as testing materials. Samples from at least one batch are recommended to be tested [4,[9][10][11][12].With regard to the study designs, method transfer studies should evaluate the impact of factors including analysts, days, number of runs, equipment (brand and/or model), environment and reagent suppliers on the results obtained in the sending and receiving laboratories, using the same testing materials. Wieling proposed to keep the methods, chemicals, rea...

Improved Wald Test for Equivalence Assessment of Analytical Biosimilarity

“…Shen and Xu [5] proposed 0.85 f = in designs of method transfer studies for biotechnology products to compare means between the sending laboratory and the receiving laboratory. In their study, T µ and R µ represent the population mean of the measurements under normality distributions obtained at the receiving laboratory and the sending laboratory, respectively, and R σ represents the population SD of the measurements obtained at the sending laboratory.…”

“…Two one-sided hypothesis tests with a parameter margin that is a function of the variability of the reference product have been applied to equivalence assessments in several pharmaceutical areas [3][4][5]. The two one-sided hypotheses can be written as follows.…”