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ICH M7 – Regulatory Updates & Industry Practices ICH M7 Indian RoadshowsSub Heading 2020 February 28, 2020 Date March 02, 2020 Muzaffar Khan, Ph.D [email protected] Introduction • Updates to ICH M7 (R2) • Common structural alerts involved in chemical synthesis • Misattributed structural alerts • Aryl-boronic acids & esters • Acyl/sulfonyl chlorides • Sulfonate esters • Nitrosamines • Regulatory deficiencies • ICH M7 best practices 2 ICH M7 R2 • The M7(R2) Expert Working Group (EWG) is developing AI limits / PDEs for new mutagenic impurities and revising AI for impurities already listed in the Addendum. Potential impurities in drug substances: Compound-specific toxicology limits for 20 synthetic reagents and by-products, and a class-specific toxicology limit for alkyl bromides. Regul. Toxicol. Pharmacol. 94 (2018), pp. 172–182. • Adapt the classification of anti-HIV therapeutics to medicines for lifelong treatment. • Elaborate and bring clarity on estimated (theoretical) purge factor for clearance of mutagenic impurity. • Update the M7 text and develop a Question & Answer document to clarify and address Quality and Safety issues and concerns. 3 Additional compound specific limits 4 Mutagenicity, genotoxicity and cancer Indirect mechanisms of genotoxicity; M Kirsch-Volders et al. Tox. Letters 140/141 (2003) 63/74 5 Mutagenicity, genotoxicity and cancer • Mutagens are agents that bind directly with DNA and cause inheritable changes to DNA base pair sequence. • Genotoxicity – Damage to genetic material (DNA and chromosomes). • Genotoxicants that are non-mutagenic typically have threshold mechanisms and usually do not pose carcinogenic risk in humans at the level ordinarily present as impurities. • There is growing evidence of thresholds in mutagenicity (MMS, EMS etc.). For such impurities, compound specific AI/PDE can be justified based on TD50/BMDL10 & NOAEL from the in vivo cancer studies. • Not all mutations lead to cancer. • Oncogenes & tumour suppressor genes play important role in cancer. • Mitigation factors - ADME, detoxification, DNA repair, apoptosis/ autophagy/anoikis to remove damaged cells. • Non-mutagenic carcinogens are outside the scope of ICH M7. 6 Structural Alerts (Mueller; PhRMA white paper) 7 Common structural alerts for mutagenicity Common structural alerts involved in chemical synthesis 1. Alkyl sulfonate esters 2. Alkyl halides 3. Alkyl hydrazines 4. Alkyl aldehydes 5. Alkyl N-nitrosamines 6. Aryl boronic acids 7. Aromatic amines & aromatic Azo groups 8. Aromatic N-oxides 9. Aziridines 10.Carboxylic/Sulfonic acid halides 11.Carbamates 12.Dialkylsulfates 13.Epoxides 14.Michael acceptors 15.Nitro groups 8 Common structural alerts for mutagenicity Common structural alerts involved in chemical synthesis 1. Alkyl sulfonate esters 2. Alkyl halides 3. Alkyl hydrazines 4. Alkyl aldehydes 5. Alkyl N-nitrosamines 6. Aryl boronic acids 7. Aromatic amines & aromatic Azo groups 8. Aromatic N-oxides 9. Aziridines 10.Carboxylic/Sulfonic acid halides 11.Carbamates 12.Dialkylsulfates 13.Epoxides 14.Michael acceptors 15.Nitro groups 9 Misattributed Structural Alerts 1. Alkyl and aryl sulfonic acids or sulfonate anions; only alkyl/aryl sulfonate esters are alerting 2. Aromatic aldehydes; only formaldehyde & some di-aldehydes are alerting; formaldehyde is not carcinogenic through oral route 3. Amines in general; only aromatic amines are alerting 4. Aromatic halides and tertiary alkyl halides – only primary and secondary alkyl halides are alerting; chain length and modifications impact the mutagenic potential of alkyl halides 5. Mesityl oxide and diacetone alcohol 6. Carbamates; only vinyl carbamate/ethyl carbamate (excluded from Derek alerts) (Williams et al.) 7. Michael Acceptors (soft electrophiles) 8. N-Oxides in general; Only 'certain' aromatic N-oxides (e.g. must have > 1 aromatic ring) (Myatt et al.) 9. Carboxylic/Sulfonic acid halides (Derek Alert 315; Equivocal); Acid chlorides react with DMSO to form mutagenic chlorodimethylsulfide (CDMS) 10. N-Methylols (Derek Alert 307; Equivocal) – Genotoxic through hydrolytic formation of formaldehyde (LaVoie EJ, Benigni & Bossa) 10 Mutagenicity of Aryl-boronic acids and esters • Aryl-boronic acids and esters are commonly used synthetic intermediates in pharmaceuticals. • General practice is to control Aryl-boronic acids and esters at TTC levels. • Derek Alert – 746: Arylboronic acid or derivative. • Ames assay: 12 out of 13 compounds tested were mutagenic. DNA adducts were not isolated in 32P-postlabelling studies carried out on two mutagenic compounds. Boronic acids represent “novel class of bacterial mutagen” that may not act by direct covalent binding to DNA. [O'Donovan et al., 2011]. • Many of the active compounds in this class only produce weak positive results in the Ames test, with and without metabolic activation, most commonly with Salmonella typhimurium TA100 and TA1537 and Escherichia coli WP2 uvrA strains. • There is currently no experimental evidence to show that arylboronic acids form adducts with DNA. 11 Mutagenicity of Aryl-boronic acids and esters • Pellizzaro et al. demonstrated that there are electronic and steric factors related to the bacterial mutagenicity of arylboronic compounds, which can be measured via the 11B NMR chemical shift with 86% accuracy for prediction. • Hansen et al. tested 44 arylboronic compounds in bacterial reverse mutation assay to understand the SAR and proposed oxygen mediated oxidation of boron compounds to generate organic radicals as a potential mechanism for mutagenicity. • In another study four benzoxaboroles and one boronic acid ester produced negative results in the Ames assay, chromosomal aberration and in vivo micronucleus study (rat bone marrow). One of these compounds was not carcinogenic in the 2 year mouse and rat bioassay (Ciaravino et al.). • Eight Aryl boronic acid/ester scaffolds mutagenic in Ames test were non- mutagenic in follow-up in vivo studies (Masuda et al.). 12 Aryl-boronic acids & esters– In vivo data Structure & Chemical name CAS No. In vitro Mutagenicity Results In vivo study results Positive (Ames, MLA, comet, Non mutagenic in Pig-a, 156545-07-2 MN) (Callan 2013) Micronucleus, and Comet Results 3,5- Difluorophenylboronic acid (DFPBA) Non mutagenic in Pig-a, Positive (Ames) 98-80-6 Micronucleus, and Comet (Hansen et al. 2015) Results Phenylboronic acid (PBA) Positive (Ames) Non mutagenic in Pig-a, 191162-39-7 (Lhasa Vitic database) Micronucleus, and Comet Results 3-Quinoline boronic acid (QBA) Positive (Ames) 1400668-06-5 (Gilead Sciences) Non mutagenic in Pig-a Imidodicarbonic acid, 2-[6-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-2-pyrazinyl]-, 1,3-bis(1,1- dimethylethyl) ester (IDCPBE) In Vivo Mutagenicity Testing of Arylboronic Acids and Esters (Masuda et al.) 13 Aryl-boronic acids & esters– In vivo data contd. Structure & Chemical name CAS No. In vitro Mutagenicity Results In vivo study results N O H Positive (Ames) Non mutagenic in Pig-a, N B 109299-78-7 (Lhasa Vitic database) Micronucleus, and Comet Results O H Pyrimidinyl boronic acid (PyBA) O H Positive (Ames, MLA) (Callan B Non mutagenic in Pig-a, 2013) H O 5720-07-0 Micronucleus, and Comet Negative (comet, MN) Results (Callan 2013) O 4-methyoxyphenylboronic acid (MPBA) O O B Not available Non mutagenic in Pig-a O S 1092563-25-1 and Comet Results O N Thiomorpholine, 4-[[4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)phenyl]methyl]-,1,1- Dioxide (TTDPMD) N O H O S Not available Non mutagenic in Pig-a B 747413-23-6 O and Comet Results O H Boronic acid, [4-[(1,1- dioxido-4- thiomorpholinyl)methyl]p henyl]- (BADTMP) In Vivo Mutagenicity Testing of Arylboronic Acids and Esters (Masuda et al.) 14 Mutagenicity of Acyl/sulfonyl chlorides • Acyl/sulfonyl halides are often used in chemical synthesis as reactive intermediates. • Acyl/sulfonyl halides are known to react with DMSO to form alkyl halides via the well established Pummerer rearrangement. • Acyl chlorides react with DMSO to yield the corresponding carboxylic acids and chlorodimethylsulfide (CDMS) which is a known mutagen. • Sulfonic acid chlorides can also react with DMSO to form CDMS. 15 Mutagenicity of Acyl/sulfonyl chlorides • The impact of solvent on bacterial mutagenicity of acyl/sulfonyl chlorides was studied in detail by Amberg et al. • Ames data of 39 acyl/sulfonyl chlorides was generated in MeCN, DMSO and other solvents by GSK and Sanofi. • Most of these were Ames +ve in DMSO and Ames -ve in other solvents. • Methane sulfonyl chloride (MsCl) was Ames +ve in DMSO, MeCN, Acetone & MeOH. • MsCl is prone to react with each of these solvents and form known or potentially mutagenic intermediates (CDMS with DMSO, isopropenyl sulfonate with acetone, MMS with methanol, methyl sulfonyl nitrilium with MeCN). • Ames data of acyl/sulfonyl chlorides should be handled with care. • Because of the solvent interactions the Ames test cannot measure the mutagenic potential of this class in most cases. A purge argument may be easier than trying to make this assessment. 16 Regulatory deficiency - Thionyl chloride “You classified thionyl chloride used in the preparation of 2,6-Dimethyl phenoxy acetyl chloride as ICHM7 Class 5 compound, this is not acceptable, since it is potential mutagenic compound (Ames positive). Please amend your discussion and demonstrate that it is controlled in line with ICHM7” (WHO Query). Thionyl chloride Ames data from Toxnet CCRIS (TOXNET): Ames positive [SHORT-TERM TEST PROGRAM SPONSORED BY THE DIVISION OF CANCER BIOLOGY, NATIONAL CANCER INSTITUTE, MS. ELLEN ZAIKA,
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  • Catalytic Silane Nanopatterning Using Scandium Triflate Functionalised PPL Arrays

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    Catalytic Silane Nanopatterning using Scandium Triflate Functionalised PPL Arrays A dissertation submitted to the University of Manchester for the degree of Master of Chemistry by Research in the Faculty of Science and Engineering 2017 David T. Arrowsmith School of Chemistry Table of Contents Title Page ....................................................................................................................................... 1 Table of Contents .......................................................................................................................... 2 Word Count .................................................................................................................................... 4 List of Figures ................................................................................................................................ 5 List of Schemes ............................................................................................................................. 7 List of Tables ................................................................................................................................. 8 List of Abbreviations ...................................................................................................................... 9 Abstract ........................................................................................................................................ 11 Declaration ..................................................................................................................................