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The guidance also contained very specific expectations that the pharmaceutical development efforts should first and foremost “avoid” genotoxic materials or impurities and take every effort to select a manufacturing process that avoids there being potential genotoxic risks associated with the product.

A justification needs to be provided that no viable alternative exists, including alternative routes of synthesis …

If a genotoxic impurity is considered to be unavoidable in a drug substance, technical efforts (e.g. purification steps) should be undertaken to reduce the amount of the genotoxic residues in the final product in compliance with safety needs or to a level as low as reasonably practicable.

These were elements of the guideline that had provoked considerable comment during the drafting process. Assembling drug substances by chemical synthesis is predicated on the combination of simple chemicals into more complex drug substance structures. This synthesis involves chemical reactions often driven by reactive functional groups that as a consequence of their reactivity (e.g. alkylating functionality) can be potentially toxic and indeed potentially genotoxic. Thus, to have “complete avoidance” as the fundamental principle of chemical process development would be extremely problematic. In extremis the effect of such an approach could be that many important, necessary (and well‐understood) reactions would suddenly be declared unsuitable or at the very least subject to intense scrutiny. Not only would avoidance be problematic as a fundamental principle but avoidance can also be appreciated to be inherently unnecessary, in risk management terms, when one considers that a manufacturing process can be designed in such a way as to ensure that the residues of these reactive materials are not significantly present in the drug substance.

An important consequence of the intrinsic reactivity of the materials “to be avoided” is that they can easily break down to innocuous materials during isolation of intermediates, for example by hydrolysis. This would mean that one would be being told to avoid a useful synthetic material that would anyway be destroyed and removed during manufacture. This removal would make “avoidance” unnecessary. Furthermore, manufacturing processes can be designed with the removal of potential genotoxic reagents, intermediates, or impurities in mind, either by using such reagents early in a multistep manufacturing process or by designing isolation processes or purification processes specifically to remove materials of concern. Thus, having “avoidance” as a fundamental design criterion for drug substance manufacture could be considered to be an overreaction and extremely precautionary. When all aspects of risk management and scientific understanding are considered, avoidance can be seen to be nonscientific. The risks being avoided can be managed in other scientifically sound ways and furthermore can also be controlled to appropriate levels, if need be, by analytical testing. The primary consideration of the chemical manufacture of drug substances (and medicinal products) should be the safety (and efficacy) of the medicine, and since the adoption of the TTC principle establishes a basis of adequate safety (or acceptable risk), then control strategies and control tests on specifications can be established to “control” the adequate safety of manufactured drug substances without imposing a “ban” on the use of many important reagent and reaction types.

Let’s be sure we are absolutely precise and fair to the wording of the guideline. In the guideline, “avoidance” was stated to be a fundamental principle but was not required if the applicant had shown that no other manufacturing process free of attendant genotoxic risk factors could be employed

A justification needs to be provided that no viable alternative exists …

If a genotoxic impurity is considered to be unavoidable…

While on the face of it a seemingly reasonable request, in practice this particular aspect of guidance is in reality a case of “how long is a piece of string?” in terms of the expected extent of such investigations. How many alternative routes of synthesis need to be evaluated and discarded before one can conclude “there is no viable alternative”? How many potential routes should one explore if a drug substance is made by a manufacturing process that uses “risky” reagents like alkylating reagents but contains no trace of the impurity that would have potential genotoxicity? If a route of synthesis not employing “at risk” materials can be shown to be feasible but the drug substance cannot be made economically, or in an environmentally acceptable manner, by that route, should that potential medicine be “avoided”? Having development chemists chasing alternative routes to one medicine is a sure fire way to prevent development chemists developing other medicines. Thus this guidance by placing “avoidance” above “control” could very well have prevented the innovation of new medicines or new manufacturing routes (with improved environmental benefits).