Analytical Control Strategies for Process Chemists

Abstract

Published as part of Organic Process Research & Development special issue “Analytical Control Strategies for Process Chemists”. Increased resource utilization, which can be achieved through atom economy leading to higher selectivity and high yields, minimization of byproducts formation (impurity rejection), and hence waste reduction. Simplicity and safety of processes, which means the involvement of minimal steps and use of readily available, safe, and environmentally friendly reagents and solvents. Also, the use of mild temperatures, pressures, and reagents leads to minimized energy consumption, reduced risk of hazardous conditions, and hence low environmental impact and better sustainability. Scalability and robustness, where the requirement is that the process should be readily scalable from laboratory to industrial production without significant changes in yield or selectivity and insensitive to minor variations in operating conditions or raw materials, ensuring consistent product quality. Cost-effectiveness, which refers to minimizing the overall cost of the process, including raw materials, energy, and waste disposal, to ensure economic viability. Regulatory compliance, in line with increasingly stringent policies from worldwide regulatory bodies toward assurance of product quality and patient safety in the case of pharmaceuticals and biopharmaceuticals. Use of strategies like constant monitoring and precise control of reaction conditions, such as temperature, pressure, pH, cooling rate, rotation speed, etc. The reactions with multiple steps and competing pathways can be challenging to control. In these situations, strategies like selective catalysis, precise dosing of reagents, and real-time monitoring of key intermediates can be used to steer the reaction toward the desired product. Analytical control strategies are essential for ensuring the quality of the product and consistency of organic processes. These strategies involve the use of various analytical techniques to monitor and optimize reaction conditions, track the formation of products and byproducts, and ensure that the final product meets the required specifications. Variations in raw materials, equipment performance, or operating conditions can lead to inconsistencies in product quality between different batches. To address this, strategies like statistical process control, detailed documentation of process parameters, and robust process design are employed. For example, in the production of an active drug substance, monitoring critical process parameters can help ensure consistent product quality across different batches. By providing real-time information about the composition of the reaction mixtures, analytical techniques enable scientists to gain a deeper understanding of reaction mechanisms and kinetics for controlling the product quality and cycle time. This knowledge is crucial for developing efficient and robust processes. Analytical techniques help identify inefficiencies and optimize reaction conditions to improve yield and product quality, reduce waste, and enhance overall process efficiency. This optimization leads to cost reductions in production by minimizing raw material and energy consumption. When deviations from expected results occur, analytical techniques are used to identify the root cause of the problem and provide an appropriate mitigation strategy. This troubleshooting capability is essential for maintaining consistent product quality and minimizing downtime. Analytical techniques are employed to monitor the release of hazardous substances and ensure compliance with environmental regulations. They also play a vital role in identifying and mitigating potential safety hazards, reducing the risk of accidents, and ensuring a safe working environment. Critical quality attributes (CQAs) and critical process parameters (CPPs) are the terms used in pharmaceutical and biopharmaceutical production to describe product quality and process variables. CQAs are physical, chemical, biological, and/or microbiological characteristics, which usually are product-specific and vary widely across drug modalities and manufacturing processes. These ensure that a desired quality level within specifications is met and thus are monitored as part of a Chemistry Manufacturing and Control (CMC) strategy. Identifying CQAs requires careful evaluation of manufacturing practices and selection of key product specifications. CPPs are process variables that affect a CQA. CPPs must be monitored or controlled using analytical tools to ensure that the final product is within set specifications. In the current era, the requirement of precise process control has increased enormously because of intolerance to impurities in pharmaceutical substances. There is an evident shift from purity to trace and minor impurities, whether organic, inorganic, solvents and those that are mutagenic/genotoxic by nature, including a focus on nitrosamines and nitrosamine drug substance related impurities (NDSRIs) since mid-2018. Moreover, impurities appearing as artifacts pose bountiful analytical challenges. For these little impurities, whose levels are now considered as key CQAs, recommended strategies involve their monitoring and control in raw/starting materials and intermediates and the optimization of purification steps, including crystallization. Analytical techniques allow for the identification and quantification of impurities through the process life cycle and ensure that the final drug product meets the required specifications. The determination of stereochemical composition and stereochemical purity is highly dependent on the use of simple to advanced analytical tools. There are multiple instances where a regulatory agency refuses to allow registration of a generic or a product approved several decades ago by an innovator unless there is complete analytical characterization. Similar is the case with biopharmaceuticals, including biosimilars, where the availability of relevant multiple analytical techniques decides the fate of the project. By accurately measuring and analyzing various parameters, analytical techniques help companies meet regulatory standards and requirements of risk management, thus helping to avoid potential legal issues and penalties. Saranjit Singh received his Bachelor’s and Master’s degrees and also completed his Ph.D. at the University Institute of Pharmaceutical Sciences, Panjab University (Chandigarh, India) under the mentorship of Professor S. K. Baveja. He got the opportunity to serve at the same institution as a faculty member for 13 years. Subsequently, he moved to National Institute of Pharmaceutical Education and Research (NIPER) (Sahibzada Ajit Singh Nagar, Punjab, India), where he served for 27 years as Associate Professor, Professor, Dean, and Acting Director before superannuating in 2021. Currently he is partner in PwB Holdings and is involved in industrial consultancy and training. This article has not yet been cited by other publications.