The European Union requires final container testing of US-manufactured biopharmaceutical products to be performed in Europe
for release into the European market. Similarly, but less strictly enforced, the US requires final container testing in the
US for European-manufactured biopharmaceutical products before release.
Final container release tests only need to be validated at the sending laboratory with the exception of microbiological and
animal test methods, which are not transferable and must be validated at each testing site (US and Europe). The receiving
laboratory must be qualified to release product using validated procedures, available personnel, and equipment, but validation
does not need to be repeated at the point of product release.
The manufacturing company should validate all its analytical methods at the production site and sending unit according to
ICH Q2A and Q2B guidelines.1-3 In addition to complying with regulatory requirements, this ensures that the production process and product quality are
fully supported by testing results for in-process material and final containers using identical testing conditions. It is
not required to ICH-validate analytical methods in Europe as long as they are identical - or at least equivalent - to those
of the sending laboratory. However, it is necessary to demonstrate that all analytical test results are reproducible by both
testing laboratories. Therefore, the objective of analytical method transfer (AMT) is to demonstrate that the release laboratory
is qualified and suitable to release US-manufactured biopharmaceuticals into the European market (and vice versa).
This article - a practical guide to transferring analytical methods - uses the International Society for Professional Engineering's
Good Practice Guide: Technology Transfer (regulatory agencies accept the methods in this guide).4 Through a practical case study, this article shows how to perform and document the transfer of an analytical method that
will be compliant (that is, qualified) for release into Europe and, furthermore, is fully integrated in order to control the
production process and product quality.
Table 1: AMT execution matrix
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Transfer Strategy Qualifying a release laboratory requires demonstrating inter-laboratory reproducibility of test results. The method transfer
strategy should be captured under a method transfer master plan or protocol. This document should cover the general AMT execution
matrix (Table 1), the reported transfer results, calculations and statistics used, and the general source for the acceptance
criteria.5 A typical AMT is accomplished by round-robin testing at the sending and receiving laboratories. Testing is performed on three
different lots over three days using two operators and two instruments at each testing site.5 (See Table 1. Partial or full factorial designs are not applicable here as we cannot pool data. Besides, switching or rotating
operators or instruments would fall under partial or fractional factorial.)
Example of an MTP Section
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Reproducibility of test results, within and between both laboratories, is demonstrated by evaluating intermediate precision
(different operators, instruments, days, and product lots at each site) and the differences in mean results for each lot between
both sites.6 The results of both laboratories are statistically compared by an analysis of variance (ANOVA). Pre-set acceptance criteria
for intermediate precision and the absolute differences between sites are derived and justified from the validation at the
sending laboratory for each method transferred.7,8 Reports will include descriptive statistics (means, standard deviations, and coefficients of variance), comparative statistics
(ANOVA p-values) for comparison of inter-laboratory results, and the differences-of-mean values for both laboratories.
Individual method transfer protocols (MTPs) must describe in detail how to execute each AMT indicating the samples to be tested
and the spiking experiments to be done in order to demonstrate accuracy, using appropriate biological or chemical reference
materials (that is, accepted European standards, if applicable). MTPs should provide detailed information on the testing conditions
and acceptance criteria to be met. If spiking experiments are performed with European standards, the accuracy and precision
of the results of the receiving unit should be similar to those of the sending unit.4 All pre-set acceptance criteria - derived and justified from any combination of method validation, historical data, or product
specifications - should be given in each MTP.7 Data and results for each AMT are summarized in individual method transfer reports (MTR). Each MTR documents evidence that
a particular test method is suitable (qualified) for product release into the designated market.
Table 2: Historical CZE assay performance for the assay control and BioProduct
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All AMTs must demonstrate reproducibility between test results from the sending and receiving laboratories, as indicated by
single-factor ANOVA at the 95% confidence level (p > 0.05). In cases where p ≤ 0.05, acceptance criteria must be established for the comparison-of-means and variability of the results in order to demonstrate
the overall lab-to-lab reproducibility of test results. It is advisable to include a numerical limit (or percentage) because
the likelihood of obser-ving statistical differences increases with the precision of the test method. In addition, some differences
(bias) between instruments, operator performances, and days are normal.6 The absolute difference of the observed-mean percentages between instruments can be related to the product specifications
and historical-mean results; this should be derived (and justified) from method validation.8 We should tailor our acceptance criteria for overall (intermediate) precision and for the maximum tolerated difference between
laboratory results in order to minimize the likelihood of obtaining out-of-specification (OOS) results.8 The setting and justification of all acceptance criteria must strike a balance and is a critical part of each MTP. The AMT
case study which follows compares results from sending and receiving laboratories to illustrate how reproducibility acceptance
criteria are derived and justified in the MTPs.
