Regulatory Highlights pubs.acs.org/OPRD
Regulatory Highlights
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INTRODUCTION In the last regulatory review1 it was commented that there had been a significant amount of regulatory activity during the second half of 2013, much of which was directly relevant to chemists involved in the pharmaceutical industry. The first six months of 2014 has again seen an intense period of regulatory activity within the CMC area (Chemistry Manufacturing and Controls). Activities relate to areas such as impurities: elemental impurities (ICH Q3D) and mutagenic impurities (ICH M7), manufacturing (dedicated facilities, GMP ICH Q7), and quality by design (ICH Q11). This article seeks to describe the key progress made over the last six months within each area and examine the possible implications.
material is known) the f inal steps of the starting material synthesis should be evaluated for potential mutagenic impurities. It may be argued that this does not entirely answer the question posed: what, after all, is meant by “final steps”? However, I believe this provides a flexible framework and a suitable basis upon which a pragmatic assessment can be based, including the definition of a sensible start point for the assessment. Further flexibility is gained by a clear recognition within the guideline of the need to assess risk in the context of the intended use, the guideline making specific reference to ICH S9, Nonclinical Evaluation of Anticancer Pharmaceuticals.4 The guideline also allows for far greater flexibility in respect to options to demonstrate control; section 8 of the guideline defines four options ranging from Option 1 (Test for the impurity in the drug substance) to Option 4 (So reactive that no testing is required). Option 4 permits the assessment of risk based on an understanding of the physical-chemical properties of the impurity and the process conditions it is exposed to, i.e., its reactivity, solubility, etc. Of particular importance in relation to this option is the retention of the reference to the purge factor approach described by Teasdale et al.,5 within the finalized guideline. The remaining critical area to highlight within the finalized guideline is the inclusion of a specific section relating to implementation. This defines an implementation time scale for full compliance of 18 months, although earlier adoption is, as would be expected, encouraged. Of particular relevance is the inclusion of specific guidance relating to “late stage” programs, this states that When development programs have started phase 2b/3 clinical trials prior to publication of M7 these programs can be completed up to and including marketing application submission and approval, with the following exceptions to M7. • No need for two QSAR assessments as outlined in Section 6. • No need to comply with the scope of product impurity assessment as outlined in Section 5. • No need to comply with the documentation recommendations as outlined in Section 9. This should prove beneficial to those organisations currently trying to juggle the additional requirements predicated by ICH M7 at the same time as concluding current development programs. Likely to be the most significant of these is the delay in the need to utilize two QSAR methods in the assessment of mutagenic potential. The introduction of such systems was considered by many to be problematic both in terms of time/ cost, and the phasing of its implementation allows organisations more time to ensure this is managed effectively. As someone heavily involved in this area, I personally believe that ICH M7 strikes a sensible balance between the need to protect the safety of patients while at the same time avoiding the implementation of excessive regulatory requirements that hinder the effective development of new medicines.
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DNA REACTIVE (MUTAGENIC) IMPURITIES ICH M7 ICH M7,2 Assessment and Control of DNA Reactive (Mutagenic) Impurities In Pharmaceuticals to Limit Potential Carcinogenic Risk, was approved (Step 4) as expected, in June 2014. In the main the changes made to the document between the previous step 2 document and the final guideline are relatively minor; much of the activity focusing on clarification of the guideline as opposed to a significant shift in the fundamental principles upon which the guideline is predicated. In the previous review,1 I focused on some of the key areas within the guideline and their impact on the risk assessment process from a chemist’s perspective. These remain essentially unaffected by changes made to the issued step 4 guideline. The single most important aspect of the guideline from a chemist’s perspective is the scope in terms of “which impurities do I need to assess”? It is critical to realize that the guideline does not expect an attempt to be made to identify and assess the mutagenic potential of every actual or theoretical impurity that might be present in an active substance. The guideline clearly outlines the scope; this includes materials used within the synthesis, e.g., starting materials, intermediates, reagents, solvents, processing agents, etc., as well as probable impurities formed during the process. It also includes drug substance and drug product degradants. Another important point to emphasize is the relationship between ICH M7 and ICH Q3A. 3 The identification threshold remains that defined in ICH Q3A, further underlining the scope of the guideline. An often asked question relating to the risk assessment is “how far back in the synthesis should the assessment start”? Although empirical, there is a clear logic to the view that the further back in the synthesis a mutagenic reagent is utilized, the lower the potential risk of carryover to the final product at levels of concern. This still leaves open the question posed above; is it three steps/four steps or even five steps? What is even defined as a step? Must this involve bond formation? One change to the guideline since the step 2 document is a specific attempt to address this, at least in the context of starting materials. Section 5.1, synthetic impurities, now includes this specific statement: For starting materials that are introduced late in the synthesis of the drug substance (and where the synthetic route of the starting © XXXX American Chemical Society
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dx.doi.org/10.1021/op5002963 | Org. Process Res. Dev. XXXX, XXX, XXX−XXX
Organic Process Research & Development
Regulatory Highlights
Table 1. Summary of ICH, US, and European elemental impurities alignment USP/FDA
EMEA/Ph Eur
permitted limits
anticipated to be finalized September 2014
ICH Q3D
reported to have reached agreement on aligned limits with ICH
analytical methods defined
not defined (reference to pharmacopoeial methods) yes, Q3D includes detailed process not defined2015?
yes ⟨233⟩ N/A
currently for new product limits defined in current EMA guideline9 agreement to align limits with ultimate limits in ICH Q3D. to be captured in. chapter 5.20 yes, Chapter 2.4.20PDG commitment to align with USP N/A
not directly applicable
not directly applicable
risk assessment process implementation deadline (new products) implementation deadline (existing marketed products) products) withdrawal of “heavy metals” test
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no centralized positionrefer Dec 2015 to local schedules Dec 2015
ELEMENTAL IMPURITIES Unlike ICH M7, ICH Q3D6 was not finalized at the June ICH meeting, it is though unofficially reported that the ICH Q3D expert working group plan to finalize the guideline by the end of September. Externally no further formal draft version of the guideline has been circulated, but it has been reported that revisions have been made, including harmonization of limits, as well as changes to the categorization of some elements. It is hoped that this finally addresses one of the most significant concerns pertaining to guidance in this area, that of alignment. As described previously,1 in parallel to the development of ICH 3QD, the United States Pharmacopoeia (USP) has developed two general chapters ⟨232⟩7 and ⟨233⟩8 focused on the control of elemental impurities. Up to this point the ICH guideline and USP general chapters have not been aligned, either in terms of the metals or the permissible limits. Both differ substantively from current EMA guidelines.9 A further complication has been the different timelines for implementation, the original timeline for implementation of the USP general chapters being a wholly unrealistic date of May 2014. This was subsequently revised and postponed until December first 2015.10 Despite this, many organisations have been faced with the challenge of assessing risk using processes aligned to likely future requirements, and this has led to considerable uncertainty as to just what limits apply and what elements should be considered. While harmonization is to be welcomed, substantive changes in terms of limits and reclassification of certain elements may impact on assessments conducted to date and may result in the need for yet further testing. It has also been reported that an implementation working group (IWG) will be established to support the rollout of the finalized guideline ICH Q3D guideline, this including the production of training material to support the process. Further encouraging signs of alignment in this key area were provided by recent output from the European Directorate for the Quality of Medicines and Healthcare (EDQM) specifically through the European Pharmacopoeial Commission. The associated press release stated that, in its June session, the European Pharmacopoeia Commission endorsed the proposed revision strategy of the current “Heavy metals chapters” and decided as a first step to revise chapter 5.20, to replace its content by the ICH Q3D guideline as soon as it has moved to Stage 5 in the European Union.11 It also described plans relating to the need to remove reference to wet chemical tests for “heavy metals” from all individual monographs. The list of all impacted monographs will be published in Pharmeuropa, in January 2015 (issue 27.1).
tbc Jan 2017
The press release also stated that the current plan is to publish the revised individual monographs in the ninth edition of the EP with an implementation date of 1 January 2017. In addition the pharmaceutical discussion group (PDG) announced plans11 to harmonize their general chapters on methods related to elemental impurities with other bodies, with USP serving as the coordinating pharmacopoeia. These announcements were followed by an announcement by the USP12 outlining their own implementation plans. This re-emphasized the Dec first 2015 deadline and provided oversight as to the practical implementation of the proposed changes, focusing on the removal of the current heavy metals test
