is one of defining what is considered reasonable when defining impurities, particularly MIs. Within the framework of the original guideline, it was also unclear as to how many steps within a process should be taken into consideration when performing such an assessment. This was a specific topic returned to when the ICH M7 [1] guideline was elucidated.
1.1.4.5 The Principle of Avoidance
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).
1.1.4.6 The ALARP Principle
The EMA guideline [9] also suggested that if avoidance was not possible, then residues of any mutagenic materials to be used should be removed to a level that was “as low as reasonably practicable” (the so‐called ALARP concept). This concept too sounds immediately reasonable, especially in the context of the original request to control to as low as technically feasible, but is flawed when one begins to consider aspects of its implementation. Consider a case when an applicant has developed a process to deliver an active ingredient that contains a measurable, but low, level of a potentially MI. The applicant has established a control strategy in accordance with a TTC‐based limit. Should the assessor approve this application or require the applicant to further modify the process to lower the residual level yet further? How much more work would be required to be considered “reasonably practicable”? Can such a judgment be consistently applied, by all assessors, to all applicants? Will some applicants or assessors expect more to be done than others? All such considerations could introduce inconsistencies in what needs to be a level regulatory landscape. Given the conservative nature of the guideline, there should simply be no need to further improve quality if a TTC‐based control strategy has been established. After all the TTC is considered a virtually safe dose.
1.1.4.7 Overall
Potentially the most troublesome aspect of the EMA guideline [9] was the scope for inconsistent interpretation even in relation to the many apparently “well‐developed” concepts. Adding to this challenge of interpretation and consistent implementation are some further gaps that became evident the more one started to consider the kind of scenarios that would be encountered as the guideline was implemented. It is perhaps not surprising that regulators and industry alike struggled to fully understand how to interpret and apply it in its entirety.
To begin to resolve the difficulties described, further work and discussion took place after the final publication of the guidance in both regulatory circles (CHMP SWP and European Directorate for the Quality of Medicines) and in industry and industry trade associations (European Federation of Pharmaceutical Industry Associations – EFPIA) as all parties involved looked to examine these important topics, in depth, principally through a Question and Answer [10] process initiated by the EMA SWP.
1.1.5 SWP Q&A Document
The SWP Q/A document [10] (published 26 June 2008 as EMEA/CHMP/SWP/431994/2007) sought to address several key areas within the original EMA guideline, these included:
1.1.5.1 The Application of the Guideline in the Investigational Phase and Acceptable Limits for GIs Where Applied to Studies of Limited Duration
Through the Q&A document [10], it was clarified that durational adjustments to the TTC limit are acceptable for investigational studies. This approach of extrapolating the lifetime‐based TTC limit to shorter