material, starting material or intermediate, or as an in‐process control (Option 2) or DS (Option 1) at the acceptable limit should be included.
Another important point made within this specific section relates to impurities introduced in the last synthetic step; it states that an Option 1 control approach would be expected unless otherwise justified. The caveat that other options may be justified is an important caveat and potentially allows other control options to be justified based on a scientific risk assessment as opposed to simplistic dogma.
Earlier regional guidelines had been predicated on the application of “As Low As Reasonably Practicable” (ALARP) even where levels were below the TTC. They also talked about avoidance of the use of mutagenic reagents. ICH M7 addresses both points directly. It is not necessary, if the level of the mutagenic impurity is below acceptable limits, to implement limits based on the ALARP principle. Similarly, it is not necessary to demonstrate that alternate routes of synthesis have been explored.
Where the ALARP principle is applicable is in cases where efforts to reduce the level of a mutagenic impurity to below the acceptable limit have proven unsuccessful. In this instance, that provided levels are ALARP – a higher limit may be justified based on a risk/benefit analysis.
2.2.9.2 Considerations for Periodic Testing
This section seeks to provide guideline in terms of the use of periodic testing; however, it unfortunately lacks real clarity, failing to provide any definite advice as to when such options are to be applied. A specific concern in the absence of real clarity is that such an approach may be requested even when the control process has been fully justified.
2.2.9.3 Control of Degradation Products
Appearing somewhat out of place the control strategy section also includes specific advice relating to the control of degradation products. The guideline states the need to understand the degradation pathway for a mutagenic degradant and its relevance to the DS and DP manufacturing processes and/or their proposed packaging and storage conditions. It also articulates how either accelerated stability studies (e.g. 40 °C/75% relative humidity, six months) or kinetically equivalent shorter term stability studies at higher temperatures in the proposed commercial package may be used to determine the relevance of the degradation pathway prior to initiating longer term stability studies. This of course makes perfect sense, there being a considerable risk in relying on long‐term studies to provide the required assurance of control. Finding out control is inadequate at a late stage, i.e. at the end of long‐term stability studies, is likely to have a serious impact. Earlier identification of any potential issue would certainly allow more time to consider formulation/packaging options for control. Again, as with synthetic impurities, if formulation development and packaging design options are unable to control mutagenic degradation product levels to less than the acceptable limit, it may be possible to justify a higher limit based on a risk/benefit analysis.
2.2.10 Lifecycle Management
This section specifically applies to those products approved after the issuance of this guideline. A considerable portion of the section is taken up by what amounts to a description of lifecycle management and the need for an appropriate quality system. It is perhaps not wholly clear as to why this is included as it is not specific to the control of mutagenic impurities.
What is clear and useful is the statement that any proposed change to the manufacturing process should be evaluated for the impact on the quality of DS and DP. This evaluation should be based on understanding of the manufacturing process and should determine if appropriate testing to analyze the impact of the proposed changes is required.
It also stresses the need throughout the lifecycle of the product to reassess if testing is recommended when intended or unintended changes occur in the process, highlighting the need to consider this in particular where there is no routine monitoring (Option 3 or Option 4).
Mention is also made as to the potential use of statistical process control and trending of process measurements, but in the absence of any clear examples, it is not entirely clear as to how this might be utilized.
2.2.11 Documentation
The final section, Section 9 of the guideline, seeks to provide guidance as to the level of information to include within regulatory submissions pertaining to the assessment and control process for mutagenic impurities. This is split into two sections:
2.2.11.1 Clinical Trail Applications
This is further differentiated based on phase:
1 For Phase 1 studies of 14 days or less, the guidance defines the need to provide a description of efforts to mitigate risks of mutagenic impurities focused on Class 1 and Class 2 impurities and those in the cohort of concern.
2 For Phase 1 clinical trials greater than 14 days and for Phase 2a clinical trials, it states that in addition Class 3 impurities that require analytical controls should be included.
3 For Phase 2b and Phase 3 clinical development trials, a list of the impurities assessed by (Q)SAR now should be included, as well as a description of the systems used. Any Class 1, 2, or 3 actual and potential impurities should be described along with details as to how they are controlled. The results of bacterial mutagenicity tests should also be reported.
It is also stated that chemistry arguments may be used in lieu of analytical data for potential impurities that present a low likelihood of being present; this represents in effect Option 4 control. It is assumed therefore that this is applicable irrespective of the phase, despite this not being specifically stated.
2.2.11.2 Common Technical Document (Marketing Application)
The guideline stipulates:
1 The mutagenic impurity classification and rationale for this classification, for actual and potential process‐related impurities and degradation products, needs to be provided. Particular emphasis is placed in the guideline on the need to justify the classification of impurities into Class 4 and Class 5 impurities.
2 When bacterial mutagenicity assays were performed on impurities, study reports should be provided for bacterial mutagenicity assays on impurities. What is not clear is whether or not this should be included directly in the submission in the relevant section (would this be within the preclinical section or S3.2 Impurities?) of the dossier or as a supplementary reference.
3 Justification for the overall control strategy and any proposed specification. For Option 3 and Option 4 control approaches, a summary of purge factors and identification of factors providing control (e.g. process steps and solubility in wash solutions) needs to be provided.
Within both later stage clinical applications and the Common Technical Document (CTD), there is an explicit need to properly articulate and justify the classification of impurities based on SAR and any subsequent bacterial mutagenicity data. One potential option would be to include a summary table.
2.2.12 Other Aspects
2.2.12.1 Relationship Between ICH M7 and ICH Q3A
Ahead of development of the guideline the question as to the relationship between guidelines pertaining to mutagenic impurities and ICH Q3A [5] was a considerable concern. These concerns centered on the issue of impurity qualification. For a marketed product, any impurity present at level >0.15% requires qualification. In addition to general toxicological qualification such an impurity requires qualification in terms of its genotoxic potential. It is of course obvious that ICH Q3A predates ICH M7 and indeed earlier regional guidelines; however, the question of genotoxic qualification remains. Of particular concern within this was, not only does ICH Q3A ask that consideration be given to conduct of assessment of mutagenic potential, but it also advises that an assessment of chromosomal activity be also considered.
Note