Revision of USP <1032> Design and Development of Biological Assays

Background:

The USP has recently published a revision of its chapter <1032> on ‘Design and Development of Biological Assays’. The new draft is based on the official version of the chapter from before 2013 and takes into account feedback from stakeholders. It attempts to achieve better coordination with other USP bioassay chapters and provide practical examples. With regard to the performance of a bioassay, the requirements were orientated towards the life cycle. Equivalence limits based on effect (logarithmic power) are explained in more detail and recommended. Emphasis is placed on design and analysis strategies to control systemic errors in efficacy and to improve monitoring. The discussion of outliers, including references to <1010>, has been expanded. There is more explanation of groups, mixed models and alternative parameterisation, but less focus on weighted models and more discussion of strategic decisions and statistical implications.

Introduction:

Bioassays, or biological test procedures, are used to compare test samples with standard samples using living material. These can be qualitative and/or quantitative comparisons to determine the identity or potency of a sample. Bioassays in general can be used in many areas, but this chapter focuses on a specific area of application, namely quality control for the release of biological products.

Aim and contents:

This chapter <1032> introduces the methodology for bioassay procedures, the results of which can then be analysed using sound statistical principles. The chapter is part of a group of five general chapters dealing with bioassays for determining relative potency. Many of the principles and approaches described in <1032> and other chapters may well be relevant and useful for other analytical methods.

Ideally, a bioassay will reflect or simulate the known or intended mechanism of action of the analyte. In some cases, a bioassay may not include the functional biology that is directly related to the mechanism of action. It may then be necessary to demonstrate a correlation between the efficacy values estimated in the bioassay and the results of another assay or clinical data reflecting the intended functional activity.

Chapter <1032> is intended to assist in the planning and development of bioassays for compounds or products intended for commercial distribution. The focus is on the first part of the life cycle of the respective method as described in ‘An Introduction to the Biological Assay Chapters - Overview and Glossary’ of chapter <1030>. Early consideration of the given recommendations can provide valuable information for product characterisation and to ensure comparability, which should facilitate the development of the assay. However, the examples, methods and perspectives listed in the draft can only outline a section of the possibilities offered by the field of modern bioassays.

Challenges:

Due to the natural variability of biological test systems (such as the variability of animals, cells, instruments, reagents, and variations between days and laboratories), absolute measures of efficacy tend to be more variable than relative measures of efficacy. Since the mechanistic principles and thus the requirements for classical protein therapeutics, cell and gene therapeutics and vaccines can be very different, a comprehensive understanding of the underlying biology is essential. Due to the highly individual nature of the mechanisms of action, there are very few monographs and very few - if any - international reference and control materials. Particularly in the case of cell and gene therapy products, some of which are even produced autologously, a matrix approach over the life cycle with the selection of suitable test procedures is gaining acceptance, which ensures maximum patient safety without unnecessarily complicating the release of individual batches and the fulfilment of all regulatory requirements. The inclusion of orthogonal methods to fulfil the requirements for reproducibility, accuracy and robustness is also often useful.

Whether and to what extent the new draft fulfils the objectives set will probably only become clear after the comments and the resulting final version. Further details on the draft can be found after prior registration on the Webpage der USP.