Development of a Control Strategy for a Final Intermediate to Enable Impurities Control

Ramı́rez, Antonio; Hallow, Daniel M.; Fenster, Michaël D. B.; Lou, Sha; Domagalski, Nathan; Tummala, Srinivas; Srivastava, Shalini; Hobson, L.

doi:10.1021/acs.oprd.6b00253

Cited by 9 publications

(8 citation statements)

References 7 publications

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“…As a relevant example, scientists at Bristol Myers-Squibb developed a DS approach to manufacture asunaprevir (to treat chronic hepatitis C infection). [22] In this case, once the impurities and the critical factors were determined, the dynamic model of DS was built through a critical assessment of the elementary step kinetics, cross checked, and validated with several relevant experiments. The system of study involves the interaction of the polyfunctional alcohol derivative 1 with α-haloisoquinoline 2 in an aromatic nucleophilic substitution, using a strong base to generate the alkoxide reactive intermediate (Figure 2A).…”

Section: Process Chemistrymentioning

confidence: 99%

Reaction Space Charting as a Tool in Organic Chemistry Research and Development

Baró,

Nadal Rodríguez,

Juárez‐Jiménez

et al. 2024

Adv Synth Catal

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Abstract. The chemical and reaction spaces are incredibly vast and special procedures are required to study them. Their complex and multiparametric nature encompass myriads of compounds and interactions and endless modifications involving the distinct impact of relevant variables (temperature, solvent, stoichiometry, etc.). This often calls for the design, collection, and analysis / interpretation of large datasets. Reaction charting, the systematic scanning, description, analysis, and guided modifications of a given process, stands as the most promising approach. It offers fast and accurate solutions as well as expanding the knowledge about the systems. This deeper understanding enables reliable predictions, improvement of the productivity (yields, scope), eventually leading to sustainable, economic, and safe applications. The present review introduces the topic, analyzing selected examples and recent advancements in different organic chemistry‐related fields. The covered methodologies range from classical experimentation modifying one factor at a time, to Design of Experiments and more modern computational approaches involving Machine Learning and Artificial Intelligence. In this way, the impact of charting in process development, biological and medicinal chemistry, catalysis, reaction discovery and computational methods is accounted. Finally, the conclusion / outlook section gives a general appraisal and a prospect on the future implementation of the methodology. 1. Introduction 2. Process Chemistry 3. Biological and Medicinal Chemistry 4. Catalysis 5. Reaction discovery and development 6. Computational Approaches 7. Conclusions and Outlook

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Section: Process Chemistrymentioning

confidence: 99%

Reaction Space Charting as a Tool in Organic Chemistry Research and Development

Baró,

Nadal Rodríguez,

Juárez‐Jiménez

et al. 2024

Adv Synth Catal

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“…Another approach for the definition of a design space that is typically more resource-intensive is based on kinetic and mechanistic investigations; it is described in ICH Q11 and has been reported in the literature …”

Section: Statistical Design Of Experimentsmentioning

confidence: 99%

Recommendations for Effective and Defendable Implementation of Quality by Design

Zlota¹

2021

Org. Process Res. Dev.

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Quality by Design (QbD) is a systematic, holistic, and proactive approach to development that begins with predefined objectives and emphasizes product and process understanding and process control based on sound science and quality risk management. In the past decade, an increasing number of pharmaceutical companies have been practicing QbD, enabling the successful development and scale-up of active pharmaceutical ingredient processes. QbD implementation is more complicated than desired in part because of the nonprescriptive nature of the QbD guidelines, which requires interpretation for the appropriate application of QbD, including regional regulations. In this paper, on the basis of observations made during two decades of QbD training and project support as well as frequently asked questions, certain practical recommendations are made regarding effective use of three QbD methods: risk analysis, statistical Design of Experiments, and scale-up investigations. Although QbD is still evolving, because of its business and technical benefits, including the definition of effective control strategies and the development of robust processes, the pharmaceutical industry is embracing the use of QbD elements while maintaining realistic expectations for the evaluation of QbD success.

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“…This is accomplished by having a solid understanding of the chemistry and processes and knowing the origin of and being able to control the impurities formed in the synthetic route. 1 The process control strategy, a specific and well-defined set of parameters, is developed to ensure product quality. 2 Across the synthetic sequence, impurity formation is governed by the chemistry undertaken, the quality of reagents, and reaction parameters such as temperature and concentration.…”

Section: ■ Introductionmentioning

confidence: 99%

“…For the commercial manufacturing of a drug substance, ensuring quality, patient safety, and uninterrupted drug supply are paramount. This is accomplished by having a solid understanding of the chemistry and processes and knowing the origin of and being able to control the impurities formed in the synthetic route . The process control strategy, a specific and well-defined set of parameters, is developed to ensure product quality .…”

Section: Introductionmentioning

confidence: 99%

Development of a Control Strategy for Hydrogenation of Aryl Nitro Analogs by Kinetic Justification

Kotecki,

Franczyk,

Allian

et al. 2023

Org. Process Res. Dev.

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This article describes the development of a control strategy for controlling potentially mutagenic impurities that result from the hydrogenation of aryl nitro analogs, utilizing concepts outlined in the International Conference on Harmonisation guidelines (ICH M7, Option 4). A kinetic model was developed in conjunction with a detailed understanding of gas−liquid mixing principles and heterogeneous catalyst properties to provide a process for commercial manufacturing control included in the manufacturing of pibrentasvir.

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Development of a Control Strategy for a Final Intermediate to Enable Impurities Control

Cited by 9 publications

References 7 publications

Reaction Space Charting as a Tool in Organic Chemistry Research and Development

Reaction Space Charting as a Tool in Organic Chemistry Research and Development

Recommendations for Effective and Defendable Implementation of Quality by Design

Development of a Control Strategy for Hydrogenation of Aryl Nitro Analogs by Kinetic Justification

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