Maybe There is a Reason After All!!

Getting back to the elemental impurities (EI) issue, we received additional interesting feedback from one ANDA sponsor.  They said sometimes “this stuff gets tricky.”  The sponsor related a situation of a capsule ANDA product that could be administered multiple times a day at high maximum daily dose.  The empty capsule shell had the standard limit for lead; however, given at the maximum daily dose approved in the labeling of the reference listed drug, the exposure at the standard lead limit was above the permissible total daily lead limit. While the capsule actually had a much lower level of lead than the standard limit, the sponsor had to go back to the capsule manufacturer and ask them to lower the limit, as the actual lead level was far below the standard limit, which they agreed to do.  The sponsor noted maybe this is where the trust issue comes in relative to providing data demonstrating acceptable EI limit, especially where appropriate risk mitigation steps are taken in this case where there could have been a risk assessment that showed and actual risk.

This is likely the exception rather than the rule and, even in this case, it was the limit set by the capsule supplier and not the actual amount of EI exposure that caused the potential concern.  As I have always said – to steal a phrase – you learn something new every day.  But what we also learned is that it was a theoretical risk and not an actual risk.  I wonder how often a real risk comes along?  The question then becomes, does OGD have a valid point in waiting until the actual data is provided or is a post-approval commitment, like those issued by the new drug folks satisfactory?  What do you think? Email me at

Sorry if you are getting tired of the EI saga, but given the impact it has had on ANDA approvals over the last couple of months, I believe the discussion is worth having.