The Manufacturing Process Route Selection: The Inclusion of Phase Switching and its Relationship to Validation

Neal G. Anderson in his monograph, Practical Process Research & Development, says nothing about validation but he does speak about the need “to freeze the final process early, that is, to identify early the most desirable final chemical transformation to prepare the drug substance.” He credits this concept to P. Shutts. [“Freeze the Commercial Process-Issues and Challenges” a talk contributed at the Third International Conference on Process Development Chemistry, Amelia Island, FA, March 26 1997].

Earlier in his book, Anderson says specifically:  “In order to establish routine impurity profiles and levels, ideally the final isolation of drug substance should be optimized, and this process should be used for the preparation of material destined for toxicological studies and later Phase I studies. The types of impurities found in drug substance will be largely determined by the starting materials and reagents used in the final step to prepare the drug substance. Thus the ideal penultimate compound should be identified in investigations, and parallel development work should converge on this penultimate compound.”

In this particular passage that the last step Anderson is talking about is not the formation of a pharmaceutical salt. Almost certainly he is talking about a covalent bond forming step that completes the final structure.

Also Anderson is speaking about the ideal situation, but what this assumes is not just that the last step, from penultimate compound to actual API, does not change, but also that this final intermediate is so efficiently purified that the steps preceding do not contribute to its impurity profile other than as inconsequential trace substances such as would be below 0.1%. It would only be in such instance that different routes to this penultimate compound would not leave behind any of their own impurities in the drug substance. If this is translated into the vocabulary of process validation, this would declare that there should be no critical steps before the purification of the ultimate intermediate! This is indeed a truly ideal situation and would constitute an impractical goal for real-life penultimate compound purifications to routinely seek.

Even though Anderson does not actually use the word validation in his book, even if we accept that validation is the most significant economic outcome of a developed pharmaceutical process; Anderson does convey the idea that certain characteristics of the final process step that simplify validation, are very, very important.

To achieve this requires a very selective choice of the penultimate compound. It must be easily and efficiently isolated and purified. As Kilomentor has argued this suggests that the step in which it is prepared and worked up involve several phase switches, because it is phase switches that provide purification and it is compounds containing acid and/or basic functionalities that provide the most common opportunities for simple phase switches.