Regulatory Starting Materials (RSMs)

There have been a number of papers on the subject of how to specify regulatory starting materials, with a bench marking exercise carried out by the IQ Consortium1.  Now a sub-group has published a risk assessment tool to evaluate potential regulatory starting materials2, particularly in early development.

For any proposed RSM a score is built up by counting:

  1. The number of bond forming steps to the API.
  2. Number of isolated steps to the API
  3. % w/w of the API
  4. Number of stereogenic centres
  5. Number of substituted aryls or double bonds
  6. Number of rings
  7. Impurity carry over to the API
  8. Instability

An overall score is built up using the following equation:

Risk score = 4/A  +  8/B  +  (C x 0.6)  + D  +  E  +  F  +  G  +  H

if the score is <8 the risk is considered low.  A score of 8-10 carries a medium risk, and a score of >10 indicates a high risk.

  1. M.M. Faul, W.F. Kriesman, M. Smulkowski, S. Pfeiffer , and C.A. Busacca, Org. Process. Res. Dev., 2014, 18, 587-593.

M.M. Faul, C.A. Busacca, M.C. Eriksson, F. Hicks, W.F. Kriesman, M. Smulkowski, J.D. Orr, and S. Pfeiffer, Org. Process Res. Dev.201418, 594–600;

M.M. Faul, M.D. Argentine, M. Egan, M.C. Eriksson, Z. Ge, F. Hicks, W.F. Kriesman, I. Mergelsberg, J.D. Orr, M. Smulkowski, and G.A. Wachter, Org. Process Res. Dev.201519, 915–924.

2. L. Wigman, R.S. Oestrich, S. Hildbrand, H. Iwamura, F. Gosselin, W. Göhring, F. Schwarb, and J.-P. Crochard, American Pharmaceutical Review, A New Risk Assessment Tool for Regulatory Starting Material Evaluation, posted online on March 17, 2017.