Non-inferiority testing for qualitative microbiological methods:Assessing and improving the approach in USP <1223>

ABSTRACT

The United States Pharmacopoeia (USP) presents two approaches for showing non-inferiority of an alternate qualitative microbiological method versus a compendial method. One approach compares the positive rates for the alternate and compendial methods at one spike level, while the other one compares multiple most probable number (MPN) estimates from a multi-spike design using a t-test. In this paper, we discuss these approaches under certain assumptions and propose a third approach that can be used for both single and multiple dilutions, which we call the generalized MPN (gMPN) approach. Simulations, using Poisson distributed numbers of microorganisms in test samples, confirm that the USP approach based on rates is not suitable, that the USP approach based on MPNs is appropriate for non-inferiority, but the gMPN approach outperforms the MPN-based approach and is therefore recommended.

KEYWORDS:

• Binomial detection
• detection proportion
• limit of detection
• microbiological validation
• most probable number
• sterility tests

Disclosure statement

No potential conflict of interest was reported by the author(s).

Additional information

Funding

This work is part of the research program Rapid Micro Statistics with project number 15990, which is (partly) financed by the Dutch Research Council (NWO).