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By Ajit S. Narang, Mike Tobyn, and Robert A. Reed

Ajit Narang-finalExcipient variability has been studied in areas such as particle characteristics, cross-linking, or reactive impurities with the goals of (a) identifying and quantitating potential variability in commonly used excipients, and (b) either designing formulations and processes that can accommodate expected variability or developing an understanding of the excipient variability design space and a control strategy for drug product and excipients. These efforts in many different drug products and scenarios have raised a common question: Is excipient variability a fuss, or is it a big deal?

Join us at this year’s 2015 AAPS Annual Meeting and Exposition for the session Excipient Variability: A Fuss or a Big Deal? where Mike and Bob will take us through a roller-coaster ride of a lively debate—sampled below.

Mostly a Fuss…

Mike Tobyn

Variability in excipients should be part of any risk register for a solid dosage form. Excipient variability can be shown to have caused failures, chemical and physical, in solid oral dosage forms. The question is, what is the rate of those failures for a robust, well understood product, and, therefore, what rating should be given to that variability in the risk register? For those sensible enough to have used “standard” excipients from well-established vendors in the manner which the vendor intends them to be used, a very low residual risk can be assigned. Higher risk may need to be assigned if one is using a highly novel process or application, or if one does not have the faith in the vendor that you might like. However, in those cases, is it the excipient vendor that is to blame for a “failure,” or should we look at our business practices?

Read more about this topic in a recent Tablets & Capsules article by Mike.

A Big Deal!

Bob Reed

Robert A ReedSignificant effort is aimed at the design and selection of suitable forms (salt, solvate, crystal habit, etc.) of a drug substance to select and develop an active pharmaceutical ingredient (API). Formulation scientists then expose the API to a pool of poorly characterized excipients, providing intimate exposure to a soup of potential reactive impurities (such as organo-peroxides, aldehydes, organic acids, metals, and residual solvents). Furthermore, exposure of API/excipient blends to sprays, shears, and pressures (tablet compression, roller compaction, etc.) make the API more susceptible to undesired chemistries through increasing amorphous content, or creating reactive fissures in the crystal lattice, etc. It is not uncommon that the excipient supplier has not fully characterized the impurity profile or developed a comprehensive database of their own materials, so buyers beware. Early program stage development may not be predictive of late stage products, due to the involvement of reactive excipient impurities in the critical quality attributes of a drug product.

Read more about this topic in a recent Tablets & Capsules article by Bob.

Ajit S. Narang, Ph.D., is a principal scientist in the Drug Product Science & Technology Department at Bristol-Myers Squibb. He works for the Parenteral Science Technology function on pharmaceutical development of biologics.
Mike Tobyn is a research fellow Materials Science and Engineering within Bristol-Myers Squibb (BMS). His team studies API and excipient properties and their interaction with pharmaceutical processes; he has been at BMS for 10 years.
Robert (Bob) A. Reed is currently vice president, Regulatory (CMC) & Quality at Aradigm Corporation, Hayward, CA. He oversees CMC aspects for the development of liposomal drug products and has supported regulatory discussions with the FDA, EMA, and sFDA.