WHEN DO WE NEED TO ACHIEVE MASS BALANCE OF 100%?

This is the eternal question.  Guidance is Guidance, so the ICH and FDA never really tell you.  The goal is to gain better and better understanding of degradation pathways and methodology as the development program proceeds, so at any point in a program the measured mass balance is a kind of surrogate measurement of how much you know.   Some compounds required many routes of investigation before they yield all their degradation chemistry secrets, and the agencies leave it up to you to justify the clinical development plan by demonstrating an understanding and control of the chemistry.  New drugs are approved with mass balance less than (or greater than) 100%, but not without some understanding of the variance.

HOW DO WE ACHIEVE MASS BALANCE?

We start with stress degradation studies and HPLC method development. Initial goals are to differentiate related substance degradants from unrelated, to identify key stressors (and thus learn about chemistry), to get MS and UV spectra on degradants (and thus learn about chemistry), and to develop a simple method to resolve them from the drug and from each other.  Calculating mass balance from this initial study tells us something about how much or how little we understand.

From here, we investigate different detectors, and we look to GC and GC/MS for possible volatile degradants.  Later steps might include isolation of specific degradants to determine structure and response factors, giving us better understanding of chemistry and a quantitative correction to the degradant’s response. 

Mass balance is a goal, but it’s only a surrogate for the real goal – a complete, analytically based understanding of the chemistry of the drug under conditions produced in manufacturing and storage.  

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