Does monograph compliance of pharmaceutical excipients ensure “fit for purpose” ?

Developing pharmaceutical drugs requires the compliance with several guidelines. A core one is ICH Q8 [1]: Pharmaceutical development. In section 2, Excipients (2.1.2) it is stated ”The excipients chosen, their concentration, and the characteristics that can influence the drug product performance (e.g., stability, bioavailability) or manufacturability should be discussed relative to the respective function of each excipient.” The information on excipient performance can be used, as appropriate, to justify the choice and quality attributes of the excipient and to support the justification of the drug product specification according to CTD Quality Module 3 [2]. Sounds straight forward – on paper, however, do we have the appropriate information at hand in the respective monographs? In USP40/ NF 35 General Notices, it is stated that “(…) substances may conform to USP or NF standard but differ with regard to non-standardized properties that are relevant to their use in specific preparations (…) In many cases the excipient meets the monograph, but the pharmaceutical manufacturer finds that is not fit for purpose.” In other words, does the respective monograph description provide the formulator with the relevant information regarding the suitability of the respective excipient for the intended use – “fit for purpose”? It is the responsibility of the formulator/pharmaceutical company to demonstrate the “required fitness” and to comply with guidelines. If the necessary information can not be drawn from the monograph it has to be done with extensive effort more or less for every development. Why is this becoming more problematic? The current drugs are mainly poorly soluble NCEs, biologicals (peptide/protein based) or even mRNA, therefore the required functionality of the excipients is much higher than earlier. “(…) an API equals the labelled entity plus impurities. Applying the logic to excipients, anything NOT the labelled entity would be an ”impurity”. Most excipients are more complex and less well defined than APIs…The named entity may be a minor component.” according to Moreton et al. 2017 [3]. Polysorbate 80 will be discussed in more detail because of its widespread use due to its versatility, as a non-ionic O/W emulsifier solubilizer, with a high HLB value and a low CMC. The majority of biologics contain Polysorbate 80. Another reason to look into Polysorbate 80 is, that Polysorbate 80 is a complex mixture. Sun et al. 2017 [4] reported 355 chemicals in Polysorbate 80. To identify the components essential for functionality or at least the non-contributors in such a cocktail is complicated. The raw materials and manufacturing processes contribute to Polysorbate 80 variability and quality. The variability can be reduced by on the raw material side with tighter specifications on the fatty acids. Since 2015 the Chinese pharmacopeia (CP) contains a Polysorbate 80 (for injections) monograph that specifies > 98 % of oleic acid. Replacing the classical two step synthesis via sorbitan-monoester and subsequent ethoxylation with a three-step synthesis will reduce the variability further. Thereby also reducing the amount of non-surfactant entities.