Complexity in biological products – Applications to QbD

Most biological products, whether derived from natural sources or recombinantly expressed, are heterogeneous mixtures of distinct molecular entities and hence, complex. The heterogeneity is a result of dynamic and subtle variations in the biological systems used to manufacture them. For example, post translational modifications of a protein expressed in a mammalian expression system can introduce significant complexity – in a very reproducible fashion. However, predicting and designing processes to deliver a specific target distribution is challenging due to the non-linear and dynamic interactions involved in the cellular processes. We believe that complexity can be beneficial if appropriately harnessed and controlled, especially to tune drug performance for the complex human repertoire of disease manifestation.

Quality by design for complex products begins with an accurate and high resolution description of the target, going beyond a point by point description of the different attributes. The variations in the attributes are not random – hence quantitative mapping of the connectivity of the different attributes provides insights into design and control strategies. Approaches to understanding and deconvoluting complexity in products, biology and in manufacturing process and will be discussed.