Comparability Protocols – One Age-Old Question Answered

Over the years I have been trying to convince firms that certain changes to approved ANDAs must always be filed as a Prior Approval Supplement (PAS) or, in some cases, these changes may be handled as a Comparability Protocol that is approved in an ANDA.  At the GPhA Fall Technical Conference yesterday, Dr. Lucinda (Cindy) Buhse, Director, Office of Testing and Research, in the Office of Pharmaceutical Quality, discussed this issue in the context of dos and don’ts for Comparability protocols.

Dr. Buhsa noted that these protocols are useful in ANDAs or PAS for the following types of changes:

  • Additional manufacturing site for drug substance and/or product
  • Additional testing site for drug substance and/or product
  • Additional packaging configuration(s) for drug product
  • Additional supplier for packaging component(s)
  • Removal of blend uniformity test

She went on to state that “adding a new drug substance source (i.e., new DMF to the application) is inappropriate for comparability protocols”.  The reason for this is that that there could be significant differences in quality attributes of the API manufactured from a new source and a different DMF including particle size distribution, process impurities, degradation products, etc., that may have a direct impact on the quality of the finished dosage form that the API is used to manufacture.   (Note that the “don’t” in this case is use of a different source of API, and not the change in site of manufacture under the same DMF.)  I can’t tell you the number of times that this discussion has occurred with clients who said they do this all the time as a CBE-30. Well, if you can’t do it in a comparability protocol, youcan’t do it in a CBE-30, and it must be done in a PAS.

The other example that Dr. Buhse noted was not appropriate for a comparability protocol is when the proposed change requires the submission of new clinical or bioequivalence data.

I hope this clear up this age-old question of how one must submit a change in source of supply of API. But a site change under the same DMF can be the subject of a comparability protocol or a CBE-30 (as long as the site has been inspected and found acceptable to the FDA).