ICH M7

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Although relatively quiet in terms of any specific regulatory activities, the last 6 months have seen a plethora of publications that are associated with the ICH M7 guideline. Prominent within these was the Special Edition of Organic Process Research & Development in November 2015. This special edition focused on mutagenic impurities, examining the challenges and also opportunities faced when seeking to implement ICH M7.(5) This was timely as it aligned with the effective date for ICH M7 of January 2016; the guideline when finalized in June 2014 having a defined implementation phase of 18 months. ICH M7 is, in general, a well-written guideline that provides a flexible and pragmatic framework by which the risk posed by mutagenic impurities can be effectively managed. The flexibility provided by the guideline and the opportunities this presents in terms of science and risk based thinking are examined in depth through a series of articles within the special edition.

A tabulated summary of the special edition is described in Table 1.

Table 1

subject	highlights	authors
Is Avoidance of Genotoxic Intermediates/Impurities Tenable for Complex, Multistep Syntheses?	A survey of over 300 synthetic publications in OPR&D over a 10 year period clearly demonstrated that the synthesis of synthetic APIs was untenable without the use reactive, potentially mutagenic reagents/intermediates. That the principle of avoidance was fundamentally flawed	Elder, D. P.; Teasdale, A.(6)
Strategies To Address Mutagenic Impurities Derived from Degradation in Drug Substances and Drug Products	The paper outlines a strategy for the systematic assessment of the risk posed by mutagenic degradants, describing how this relates to stress testing and long-term stability studies. Within this it seeks to define appropriate thresholds for identification directly related to the extent of degradation	Kleinman, M. H.; Teasdale, A.; Baertschi, S. W. et al.(7)
Assessing the Risk of Potential Genotoxic Degradation Products in a Small Molecule Kinase Inhibitor Drug Substance and Drug Product	The degradation profile resulting from stress testing of galunisertib is described, focusing on formation of two N-oxides, examining the site of oxidation and the relevance of the pathway under typical storage conditions.	Strege, M. A.; Osborne, L. M.; Hetrick, E. M. et al.(8)
Mutagenic Alkyl-Sulfonate Impurities in Sulfonic Acid Salts: Reviewing the Evidence and Challenging Regulatory Perceptions	Provides a comprehensive review of the existing evidence relating to sulfonate esters, examining the comprehensive mechanistic and kinetic studies and safety data. It also examines the current regulatory approaches and how this appears misaligned with the data.	Snodin, D.; Teasdale, A.(9)
Mutagenic Impurities: Precompetitive Collaborative and Data Sharing Initiatives	Examines the nature, impact, and successes of a series of cross industry initiatives covering areas such as structural evaluation (Q)SAR, data sharing–aromatic amines, boronic acids, purging and degradation.	Elder, D. P.; Williams, R.; Harvey et al.(10)
Do Carboxylic/Sulfonic Acid Halides Really Present a Mutagenic and Carcinogenic Risk As Impurities in Final Drug Products?	Examines evidence that indicates that in the case of both sulfonyl and acyl chlorides that Ames positive results relate to generation of a reactive species, halodimethyl sulphides (HDMSs) through reaction with DMSO and that this is the root cause of a positive response. Confirmatory negative data from other test solvents is also provided	Amberg, A.; Harvey, J.; Spirkl, H.-P. et al.(11)
Boronic Acids and Derivatives—Probing the Structure–Activity Relationships for Mutagenicity	The primary purpose is to raise awareness of the potentially mutagenic nature of boronic acids and stimulate further discussion/research in the areas. It provides mutagenicity data for some 40+ examples, examining the current status of in silico predictions and postulates a potential mechanism related to oxidation of boronic acids to yield oxygen radicals	Hansen, M. H.; Jolly, R. A.; Linder, R. J.(12)
A Kinetics-Based Approach for the Assignment of Reactivity Purge Factors	Details an experimental approach that utilizes kinetic analysis to facilitate assignment of reactivity purge values.	Betori, R. C.; Kallemeyn, J. M.; Welch, D. S.(13)
A Generic Industry Approach to Demonstrate Efficient Purification of Potential Mutagenic Impurities (PMIs) in the Synthesis of Drug Substances	Based on vortioxetine and its associated PMIs predicted purge values based on the system described by Teasdale et al.(15) are compared with experimental values. The results show good correlation concluding that theoretical purge values can be used to predict purging of PMIs.	Lapanja N, Zupanĉiĉ B, Toplak Ĉasar R et al(14)
Evaluation and Control of Mutagenic Impurities in a Development Compound: Purge Factor Estimates versus Measured Amounts	The purging of MIs associated with the synthesis of MK-8876 were assessed using the approach described by Teasdale et al.(15)These predicted values were compared to measured values and shown to be conservative in comparison to experimental data.	McLaughlin, M.; Dermenijan, R. K.; Jin, Y. et al.(16)

Several papers focused on control options, specifically ICH option 4, involving evaluation of the impact of process conditions upon the purging of mutagenic impurities. This concept was first described by Teasdale et al. in 2010(17) and augmented by a cross-industry evaluation published in 2013.(15) The practical use of such tools is examined through two papers, that of Nevenka et al.(14) and McLaughlin et al.(16) This is augmented by a further publication by Welch et al.(13)that describes work now being undertaken by an industry consortium to develop this tool still further as a robust in silico tool (Mirabilis). Welch et al. describe the work being undertaken to fully evaluate the potential fate of MIs under a range of common chemical transformations. A critical finding of these studies, examined through the reaction of benzyl bromide with triethylamine, was alignment between the rate constants and half-lives of the reaction of benzyl bromide with triethylamine in isolation and as a low-level impurity in the TBS protection of benzyl alcohol (Figure 2). This established the proof of concept that the kinetic information obtained from the stand-alone reaction can be used to predict impurity conversion in a more complex reaction.

Figure 2. Alignment between the reaction of benzyl bromide with triethylamine in isolation and as a low-level impurity in the TBS protection of benzyl alcohol.

Another area addressed in the special edition is that of sulfonate esters. This relates to the use of a sulfonic acid, used to form an API salt and the potential formation of sulfonate esters through reaction with alcoholic solvents. Snodin and Teasdale(9) have reviewed the available literature information concluding that the extensive evidence supports the view that such concerns are grossly exaggerated. In parallel to this publication there have been a series of correspondences involving the EMA quality working party, the following points were released following discussion at the CVMP committee.(18)

“The Committee endorsed the QWP response to the EDQM request for an opinion on new information on alkyl sulfonates. The QWP reviewed the article from Snodin et al. QWP acknowledges the scientific rationale in this article and that the formation of alkyl sulfonates is very low and very much depends on the reaction conditions. This makes the presence of these mutagenic impurities at toxicologically significant levels unlikely. However, as the presence and formation of these alkyl sulfonates cannot be totally excluded, QWP proposes the following approach: marketing authorization holders should justify via Risk Assessment that alkyl sulfonates are not expected to be present for their product, which may be sufficient.”

Of concern within this text is the comment that the presence and formation cannot be totally excluded; this is despite the evidence pointing clearly to fact that it can.

Similarly at the end of February EDQM issued a press release relating to the Mesilates Working party.(19) Included within this, as well as information relating to analytical methods, was the following revision of the production statement.

“In addition to the elaboration of these methods, the Ph. Eur. Commission had also decided to revise the Production section of monographs on those active substances to further assist users: “It is considered that [XXX esters] are genotoxic and are potential impurities in [name of the API]. The manufacturing process should be developed taking into consideration the principles of quality risk management, together with considerations of the quality of starting materials, process capability and validation. The general method [2.5.XX] is available to assist manufacturers.”

This also goes on to state that:

“Marketing Authorisation Applicants are not obliged to perform the testing when they can justify via risk assessment that alkyl sulfonates are not expected to be present in their product.”

Although both the QWP deliberation and the EDQM statement fall short of concluding minimal risk, they nevertheless represent for the first time at least tacit recognition that control is possible.

read ………….https://www.aaps.org/uploadedFiles/Content/Sections_and_Groups/Regional_Discussion_Groups/Southern_California_Pharmaceutical/SCPDG%20Impurities_Olsen%20Jan%20event.pdf

Q7 Good Manufacturing Practice
Code Document Title Previously coded
- Q7Good Manufacturing Practice Guide for Active Pharmaceutical IngredientsQ7A
- Q7 Q&AsQuestions and Answers: Good Manufacturing Practice Guide for Active Pharmaceutical Ingredients
http://www.ich.org/products/guidelines/quality/article/quality-guidelines.html
Finalised Q&As: June 2015

Q7 Questions and Answers

Concept Paper

Work Plan

Finalised Guideline:
November 2000

Q7

Concept Paper

References

1.ICH Q3D Guideline for Elemental Impurities.http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Quality/Q3D/Q3D_Step_4.pdf(Dec 16, 2014).
2.http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Quality/Q3D/Training_package_Module_0-7.zip
3.Analysis of Oligonucleotides and their related substances; Okafo, G., Elder, D., and Webb, M., Eds.; Chapter 2, pp 22– 28; ChromSoc Separation Sciences Series ISBN 9781906799144.
4.http://www.usp.org/sites/default/files/usp_pdf/EN/USPNF/key-issues/m5192.pdf
5.ICH M7 Assessment and Control of DNA Reactive (Mutagenic) Impurities in Pharmaceuticals to Limit Potential Carcinogenic Risk.http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Multidisciplinary/M7/M7_Step_4.pdf (June 23, 2014).
6.Elder, D. E.; Teasdale, A. Org. Process Res. Dev. 2015, 19, 1437– 1446, DOI: 10.1021/op500346q
7.Kleinman, M. H.; Teasdale, A; Baertschi, S. W. Org. Process Res. Dev. 2015, 19, 1447– 1457, DOI: 10.1021/acs.oprd.5b00091
8.Strege, M. A.; Osborne, L. M.; Hetrick, E. M. Org. Process Res. Dev. 2015, 19, 1458– 1464, DOI: 10.1021/acs.oprd.5b00112
9.Snodin, D; Teasdale, A. Org. Process Res. Dev. 2015, 19, 1465– 1485, DOI: 10.1021/op500397h
10.Elder, D. P.; Williams, R; Harvey Org. Process Res. Dev. 2015, 19, 1486– 1494, DOI: 10.1021/acs.oprd.5b00128
11.Amberg, A.; Harvey, J.; Spirkl, H.-P. Org. Process Res. Dev. 2015, 19, 1495– 1506, DOI: 10.1021/acs.oprd.5b00106
12.Hansen, M. H.; Jolly, R. A.; Linder, R. J. Org. Process Res. Dev. 2015, 19, 1507– 1516, DOI: 10.1021/acs.oprd.5b00150
13.Betori, R. C.; Kallemeyn, J. M.; Welch, D. S. Org. Process Res. Dev. 2015, 19, 1517– 1523, DOI: 10.1021/acs.oprd.5b00257
14.Lapanja, N.; Zupanĉiĉ, B.; Toplak Ĉasar, R. Org. Process Res. Dev. 2015, 19, 1524– 1530, DOI: 10.1021/acs.oprd.5b00061
15.Teasdale, A.; Elder, D.; Chang, S.-J. Org. Process Res. Dev. 2013, 17, 221– 230, DOI: 10.1021/op300268u
16.McLaughlin, M.; Dermenjian, R. K.; Jin, Y. Org. Process Res. Dev. 2015, 19, 1531– 1535, DOI: 10.1021/acs.oprd.5b00263
17.Teasdale, A.; Fenner, S.; Ray, A Org. Process Res. Dev. 2010, 14, 943– 945, DOI: 10.1021/op100071n
18.http://www.ema.europa.eu/docs/en_GB/document_library/Minutes/2015/12/WC500198748.pdf (Dec 8, 2015).
19.https://www.edqm.eu/sites/default/files/press_release_on_mutagenic_impurities_february_2016.pdf (Feb 25, 2016).
20.Pharmaceutical CGMPS for the 21st Century—A Risk-Based Approach.http://www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/Manufacturing/QuestionsandAnswersonCurrentGoodManufacturingPracticescGMPforDrugs/UCM176374.pdf (Sept 2004).
21.Technical and Regulatory Considerations for Pharmaceutical Product Lifecycle Management.http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Quality/Q12/Q12_Final_Concept_Paper_July_2014.pdf (July 28, 2014).
22.ICH Q9—Quality Risk Management.http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Quality/Q9/Step4/Q9_Guideline.pdf (Nov 9, 2005).
23.ICH Q10—Pharmaceutical Quality System.http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Quality/Q10/Step4/Q10_Guideline.pdf (June 4, 2008).
24.Established Conditions: Reportable CMC Changes for Approved Drug and Biologic Products,http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM448638.pdf?_sm_au_=iNH61FD2WjHZP02F (May 2015).