ANALYTICAL METHOD TRANSFER USING EQUIVALENCE TESTS WITH REASONABLE ACCEPTANCE CRITERIA AND APPROPRIATE EFFORT: EXTENSION OF THE ISPE CONCEPT L. Kaminski§, U. Schepers§, H. Wätzig* §both authors equally contributed to this article Supplementary material Introduction This file shall provide additional information and hence lead to a better understanding of some circumstances presented in the original paper “ANALYTICAL METHOD TRANSFER USING EQUIVALENCE TESTS WITH REASONABLE ACCEPTANCE CRITERIA AND APPROPRIATE EFFORT: EXTENSION OF THE ISPE CONCEPT” by Kaminski, L., Schepers, U. and Wätzig, H.[1] It does not claim to be an exhaustive explanation of equivalence tests. Please refer to the above mentioned work for detailed information about these tests and their use in analytical method transfer. [1] L. Kaminski , U. Schepers and H. Wätzig, J. Pharm. Biomed. Anal (2010), doi:10.1016/j.jpba.2010.04.034 Test principle • Same test principle for classic t-test and for the equivalence test! xT x R t n , ˆ P Y C L Confidence interval CL standardized normal distribution of the θ value C U t n , ˆ P Y CU θ0 = 0 Reference value classic two sided t-test CL CU High precision and/or high number of samples θ0 = 0 Statistically significant but practically irrelevant difference! transfer wrongly rejected The t-test paradoxically rewards imprecise working and low data numbers Statistically insignificant but practically relevant difference! transfer wrongly accepted Low precision and/or low number of samples CL CU θ0 = 0 equivalence test CL CU High precision and/or high number of samples θ0 = 0 -2% +2% Same starting position, but an interval of relevance (acceptance interval) with e.g. ±2% is introduced in addition here! Low precision and/or low number of samples CL CU -2% θ0 = 0 +2% equivalence test CL CU High precision and/or high number of samples θ0 = 0 -2% +2% The whole confidence interval lies within the interval of relevance equivalence! The equivalence test rewards precise working and high numbers of samples The confidence interval lies partially outside the interval of relevance no equivalence! Low precision and/or low number of samples CL CU -2% θ0 = 0 +2% classic two sided t-test (Figure 3) When measurement spread gets higher (e.g. ±2%) the error probability increases to almost 40% at the acceptance limit (approx. 60% acceptance probability)! 100 acceptance probability of 95% 90 acceptance probability [%] 80 error probability of 12% error probability of 5% (ISPE concept) 70 60 50 40 30 20 10 0 0,00 0,50 1,00 1,50 2,00 2,50 true deviation betw een the labs [%] 2,0% 1,0% 0,5% Acceptance tolerance of approx. 2,3% equivalence test (Figure 2) 100 Acceptance limit 90 acceptance probability [%] 80 error probability of 12% error probability of 5% (ISPE concept) 70 60 50 40 30 20 10 0 0,00 0,50 1,00 1,50 ~1,65 2,00 true deviation between the labs (bias) [%] 0.7% 1.0% 1.2% 2,50