The ICH M7 guidance provides a series of flexible control options for the control of (potentially) mutagenic impurities (PMIs) that fully align with key risk-based principles. This includes option 4, ...which leverages existing process knowledge and/or data to justify control of PMIs without the need for routine analytical release testing during manufacturing. One such technique highlighted uses systematic, semiquantitative calculations to define the degree of “purge” of PMIs within a synthetic route to an active pharmaceutical ingredient (API) based on physicochemical properties of the impurities in question, and the manufacturing process being undertaken. This paper introduces a consortium-led initiative, Mirabilis, which aims to build on the semiquantitative purge approach, and harmonize industry best practices by enabling the calculations to be conducted in a standardized, consistent, and reproducible manner. The development of an expert-derived knowledge base for the prediction of reactivity by enhancing expert opinion using evidence derived from the published literature and experimental data is also discussed. Furthermore, this paper describes the application of Mirabilis software for the processes involved in the synthesis of verubecestat, naloxegol oxalate, and camicinal.
The ICH M7 Option 4 control of (potentially) mutagenic impurities is based on the use of scientific principles in lieu of routine analytical testing. This approach can reduce the burden of analytical ...testing without compromising patient safety, provided a scientifically rigorous approach is taken which is backed up by sufficient theoretical and/or analytical data. This paper introduces a consortium-led initiative and offers a proposal on the supporting evidence that could be presented in regulatory submissions.
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•ICH M7 Option 4 permits the use of predicted purges in lieu of analytical testing of mutagenic impurities.•Predicted purge factors derived from expert knowledge or experimental data can be derived for stages in a synthesis.•Thresholds of the predicted purge over the required purges can ensure a negligible risk from a mutagenic impurity.•The level of scientific support needed to defend a purge estimate has been proposed.
The assessment and control of genotoxic impurities (GTI) in pharmaceutical products has received considerable attention in recent years. Molecular functional groups that render starting materials and ...synthetic intermediates useful as reactive building blocks for small molecules may also be responsible for their genotoxicity. As a potential safety concern, it is important to understand the various issues related to GTIs and how they can be addressed for clinical and commercial phases of development. Justification that these impurities are controlled to safe levels must be obtained during development. This article will briefly discuss the multiple sources of anticipated impurities in a drug substance (also known as active pharmaceutical ingredient or API) synthetic route and how they are identified as GTIs in early chemical process development. A risk-based approach consistent with regulatory expectations is described for establishing control of GTIs. The approach includes process design considerations, impurity rejection information, and appropriate application of specifications. Analytical considerations for determination of GTIs at low levels are also discussed.
Controlling impurities during drug development improves product quality and minimizes safety risks to the patient. Recent regulatory guidance on genotoxic impurities (GTIs) state that identified GTIs ...are unusually toxic and require lower reporting, identification, and qualification limits than outlined in the International Conference on Harmonization (ICH) guideline “Impurities in New Drug Substances Q3A(R2).” ICH Harmonized Tripartite Guideline: Impurities in New Drug Substances (Q3A), (R2); International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH), 2006. Patient safety is always the underlying focus, but the overall impurity control strategy is also driven by appropriate “as low as reasonably practicable” (ALARP) procedures that include assessment of process capability and associated analytical techniques. In combination with ALARP, safe and appropriate GTI levels are currently identified using chronic toxicology-based limits calculated under the standard assumption of 70-years for exposure duration. This paper proposes a risk assessment approach for developing GTI limits based on shorter-term exposure durations by highlighting marketed anticancer compounds with limited dosing schedules (e.g., 2 years). These limits are generally higher than the defaulted threshold of toxicological concern (TTC of 1.5 μg/day) and can result in more easily developed and less complex analytical methods. The described approach does not compromise safety and can potentially speed life-saving medicines to patients.
An efficient and divergent synthesis of C4α- and C4β-methyl-substituted analogues of 2-aminobicyclo3.1.0hexane 2,6-dicarboxylate, which are important tools in the study of metabotropic glutamate ...receptor function, has been achieved. By taking advantage of an unanticipated facial selectivity of the bicyclo3.1.0hexane ring system, either the C4α- or C4β-methyl substituent was introduced in a highly stereoselective and high-yielding manner.
This article describes the development and optimization of chemical reactions and subsequent multikilogram preparation of the glucokinase activator (R)-1 to fund clinical evaluation as a potential ...therapeutic for type II diabetes. The major process developments presented here are a Wittig olefination isomerization based synthesis of an E-acrylic acid, an optimized enantioselective hydrogenation of the E-acrylic acid, and a challenging final amide coupling.
Cryptophycins-1 and 52 (epoxides) were discovered to have in-vitro and in-vivo antitumor activity in the early 1990s. The chlorohydrins of these, Cryptophycins-8 and 55 (also discovered in the early ...1990s) were markedly more active, but could not be formulated as stable solutions. With no method to adequately stabilize the chlorohydrins at the time, Cryptophycin-52 (LY 355073) entered clinical trials, producing only marginal antitumor activity. Since that time, glycinate esters of the hydroxyl group of the chlorohydrins have been synthesized and found to provide stability. Three of the most active were compared herein. Cryptophycin-309 (C-309) is a glycinate ester of the chlorohydrin Cryptophycin-296. The glycinate derivative provided both chemical stability and improved aqueous solubility. After the examination of 81 different Cryptophycin analogs in tumor bearing animals, C-309 has emerged as superior to all others. The following %T/C and Log Kill (LK) values were obtained from a single course of IV treatment (Q2d x 5) against early staged SC transplantable tumors of mouse and human origin: Mam 17/Adr a pgp (+) MDR tumor: 0%T/C, 3.2 LK; Mam 16/C/Adr a pgp (-) MDR tumor: 0%T/C, 3.3 LK; Mam 16/C: 0%T/C, 3.8 LK; Colon 26: 0%T/C, 2.2 LK; Colon 51: 0%T/C, 2.4 LK; Pancreatic Ductal Adenocarcinoma 02 (Panc 02): 0%T/C, 2.4 LK; Human Colon HCT15 a pgp (+) MDR tumor: 0%T/C, 3.3 LK; Human Colon HCT116: 0%T/C, 4.1 LK. One additional analog, Cryptophycin-249 (C-249, the glycinate of Cryptophycin-8), also emerged with efficacy rivaling or superior to C-309. However, there was sufficient material for only a single C-249 trial in which a 4.0 LK was obtained against the multidrug resistant breast adenocarcinoma Mam-16/C/Adr. C-309 and C-249 are being considered as second-generation clinical candidates.
A pilot-plant scale desymmetrization of the cyclic meso-epoxide 4b, using a chiral lithium amide prepared from symmetrical diamine 17, was designed and implemented to provide allylic alcohol 3b in ...high yield and greater than 99% ee. This chiral alcohol was converted to ketone 2b, a key intermediate in a new asymmetric synthesis of LY459477. Chiral diamine 17 was prepared from a readily available chiral precursor, (R)-α-methylbenzylamine, and could be recovered from the reaction mixture and reused. Studies performed to probe the mechanism of the rearrangement reaction of epoxide 4b showed that diamine 17 provided an optimal combination of selectivity and scaleability for this process.
Syntheses of the potent 5-HT1A agonists 2 and 3 were accomplished in several steps from the 6-iodo partial ergoline alkaloid 8. Disparate tactics available for construction of differentially ...substituted oxazoles led to the development of new and general methodology critical to the efficient preparations of 2 and 3. A novel palladium(0)- and copper(I)-cocatalyzed cyanation reaction provided efficient access to the nitrile 10, a key intermediate in the synthesis of 2. A palladium(0)-catalyzed cross-coupling reaction of 16 with oxazol-2-ylzinc chloride formed the potent 5-HT1A agonist 3.
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