DAVID P. ELDER
David P. Elder Consultancy (formerly GlaxoSmithKline)
110 Fordwich Rise, Hertford, SG14 2DE,
Hertfordshire, United Kingdom

Abstract

Excipients play an important role in drug product processability, stability and in vivo performance. A robust formulation is one that is able to accommodate the typical variabilities likely to be experienced in the API, excipients and process. Thus the critical material attributes (CMAs) of input materials, particularly excipients, can hugely influence critical processing parameters (CPPs) and critical quality attributes (CQAs). There is now a greater focus on risk based approaches as part of the development of robust formulations. However, due to the fact that excipients are typically continuously manufactured, the natural variability within these processes can result in significant inter-batch and inter-vendor excipient variability that can affect CPPs and CQAs of the resultant drug product. Dual sourcing considerations (which are often needed from a business continuity perspective) can necessitate greater variability having to be ‘built in’ to the product compared to a single sourcing strategy. Dual sourcing considerations are particularly important for release controlling excipients in controlled release formulations or structure forming excipients in semi-solid creams and ointments.

INTRODUCTION

The majority of drug products contain excipients in addition to active pharmaceutical ingredient(s) (API). Excipient levels can vary between 1-99% of the total formulation composition. Excipients facilitate and support the manufacture, in vitro performance and the long term stability of the drug product (1). Although, historically excipients were viewed as pharmacologically inert substances, it is clear that many excipients can also modify the in vivo performance of the product (2). Excipients are often chemical commodities and may not be manufactured according to current good manufacturing practice (cGMP) (3, 4). Excipients are tested and released in accordance to the requirements of the various international pharmacopoeia and in-house release criteria. However, the majority of the tests are chemical or microbiological in nature, and there are very few monographs that contain objective functional tests; despite the fact that it is excipient functionality that is primarily responsible for the manufacturing performance of the product. Unfortunately, excipient performance tests are application specific, linked to each different formulation and ...