A concern had been that existing medicines would be required to comply with all aspects of the new guidance. This could have led to there being a perceived shortfall in control strategies or quality for a significant number of medicinal products that had been developed in the years prior to the development of this guidance and furthermore that had proved to be adequately safe across this period. The published guideline included the following specific statement.
“It also relates to new applications for existing products, where assessment of the route of synthesis, process control and impurity profile does not provide reasonable assurance that no new or higher levels of genotoxic impurities are introduced as compared to products currently authorised in the EU concerning the same active substance. The same also applies to variations to existing Marketing Authorisations pertaining to the synthesis. This guideline does, however, not need to be applied retrospectively to authorised products unless there is specific cause for concern.” As examined below, there was considerable uncertainty as to what this term meant in practice; there being no clear definition, at least not initially.
In practice this proved extremely difficult to interpret consistently, both from an industry and regulators perspective, particularly in relation to the potential “catch all” phrase “cause for concern.” The impact of this uncertainty is explored in detail in the following section.
Another addition within the Recommendations section was advice on the scope of investigations in terms of what impurities should be considered as part of an assessment. The guideline stating:
As stated in the Q3a guideline, actual and potential impurities most likely to arise during synthesis, purification and storage of the new drug substance should be identified, based on a sound scientific appraisal of the chemical reactions involved in the synthesis, impurities associated with raw materials that could contribute to the impurity profile of the new drug substance and possible degradation products. This discussion can be limited to those impurities that might reasonably be expected based on the knowledge of the chemical reactions and conditions involved.
Although entirely sensible and reasonable on the face of it, in practice this was difficult to interpret consistently.
Another significant change was the exclusion of excipients from the finalized guideline, this having present in the 2004 draft. A separate specific position paper addressing excipients has subsequently been issued jointly by the Quality Working Party (QWP) and SWP within European Medicines Evaluation Agency (EMEA) (and will be discussed later in this chapter).
1.1.4.1 Issues Associated with Implementation
Many of the concepts and principles outlined in the finalized guideline were of real significance in achieving a practical guidance. However, many of the concepts outlined in the guideline also required careful implementation and left certain concerns unaddressed.
1.1.4.1.1 The Relevance of the TTC Concept for Short Durational Exposure
The value of the “threshold of toxicological concern” (TTC) concept is undeniable, but many experts were concerned, and remain concerned, that the maximum daily exposure of 1.5 μg was overly conservative (being based on the combination of several “worst case” assumptions in its derivation) and especially conservative if applied to short duration usage and acute‐use therapies. Importantly, the guideline as published did not provide clear guidance on what standards would be expected of investigational medicinal products during the clinical development phases, when controlled and often short duration clinical trials are conducted. It should be unnecessary to apply a control standard applicable to lifetime exposure in such short duration clinical studies, but the guideline gave no specific guidance on what standard would be expected, leaving the implementation of the guideline to be potentially inconsistent. Of primary concern was the lack of any indication as to whether or not the staged TTC concept, as outlined in the Mueller paper [5], was acceptable or not. This led to considerable confusion and uncertainty, which was ultimately resolved with the publication, some 18 months later, of the EMEA staged TTC limits through the SWP Q&A Document [10].
1.1.4.1.2 Application to Existing Products
Similarly, despite the useful focusing of the scope of the applicability of the guideline on “causes for concern” and “significant change” of existing medicinal products, it left unclear what was considered to constitute a “significant cause for concern” or a “significant change.”
Did a “cause for concern” exist if an existing impurity in an existing medicine had known genotoxicity (but the medicine concerned had been safely used for many years)? Did a “cause for concern” exist if an existing impurity in an existing medicine had a structural alert for potential genotoxicity but there was no known toxicological findings associated with the impurity?
Did a manufacturing change bring significant new risks if the same route of manufacture was scaled up or conducted at a different site? Did a manufacturing change bring significant cause for concern if process changes were conducted to optimize manufacture that instituted a change in manufacturing chemistry but not a change in the specification of the active substance? What about a change in manufacture of a starting material for active substance manufacture?
Such topics and a lack of clear, specific guidance in the published text left the guideline open to considerable degrees of interpretation and with it the possibility for inconsistent implementation. As a consequence of this uncertainty, a considerable increase in queries linked to existing products was triggered, many asking for a full evaluation of the MI risk, sometimes triggered by even simple variations not linked to the manufacturing process.
So, one can see that even with elements of the guideline that were viewed as “positive,” like the TTC concept and the risk‐based application to existing products, there were elements of detail that seemed to bring a need for further clarity to support consistent implementation. And of course, there were other aspects of the published guideline that were less well received or were simply not considered in the guideline as it was first published. These too are worthy of consideration.
1.1.4.1.3 Standards Required of Investigational Products
The lack of clear standards that would be expected of investigational products was quickly identified as a gap in the EMA guideline [9]. It could be considered that the original intent of the guideline had been to provide guidance on the management of potentially MIs for marketing applications, not for investigational materials, and thus to make good the “gap” in the ICH impurity guidelines. These ICH guidelines, which provide potential registration requirements for marketing applications, point to a potential need for more rigorous control for some impurity classes (e.g. genotoxic impurities) but do not provide guidance on how to manage such impurities. Given this ICH‐driven provenance, one might consider that the Committee for Human Medicinal Products (CHMP) guideline as published was not intended to apply to investigational materials, but like ICH guidelines, to provide potential registration requirements for commercial products. However, the guideline's applicability was ambiguous, and of course with no further specific guidance for investigational materials, it was most likely that the same standards might begin to be applied to investigational materials, even if this was not the initial intent of the expert authors of the original guidance.
1.1.4.1.4 Circumstances that Support Modification of the TTC Limit
As already described the published guideline also contained guidance to the effect that the general TTC limit (1.5 μg/day) could be modified in certain circumstances (e.g. for short duration treatments, particular indications, or patient groups) to provide for modified control of potential MIs in these products. Unfortunately, while this was potentially a very useful aspect of the guidance, the published guideline provided no further specific advice. Similarly, and importantly, there could be some medicines, indications, or patient groups where it might be unnecessary