Chemical Process Development & Scale-Up

Chemical process development is focused on the development, scale-up and optimization of a chemical synthetic route, leading to a safe, reproducible and economical chemical manufacturing process.  Following the identification of a target molecule by chemists, the initial stages of chemical process development are laboratory based and focus on route scouting, i.e. investigating the best synthetic approach, and in later stages, to produce larger investigative quantities of the molecule for additional studies, such as pre-clinical and clinical studies.

After the synthesis route is chosen, the focus shifts to scaling up the synthesis including defining the process design space, i.e., defining a set of variables and parameters that result in a process that ensures a reliable, quality product.

Chemical process development activities focus on process understanding and control to support Quality by Design objectives.  Process variables that affect critical quality attributes of the product are defined, measured and monitored as are those that optimize product yield.  A Design of Experiment approach is often utilized to aid in accomplishing these goals. Furthermore, Process Analytical Technology is employed to measure and monitor those parameters that define key quality attributes as well as for supporting process optimization studies.  Scale-up efforts involve investigation into potential process hazards, understanding reaction kinetics and thermodynamics, identifying and characterizing impurities, mixing and mass transfer studies, heat transfer and heat removal studies as well as crystallization and polymorph control.

Chemical process development is important because it is the means by which a synthetic route is transformed into a reliable, cost-efficient chemical process, yielding a high quality product. In discovery phase, chemists synthesize a small amount of a target compound and if preliminary studies look promising, there will be a requirement for larger quantities of the compound. As the molecule moves to Development, chemists often find that the Discovery Route is not the best choice for larger scale production since it may require expensive reagents, be performed under challenging conditions or create potential safety hazards. Process chemists will begin work on the development of a synthetic route that achieves the quantity, quality, safety, robustness, and cost objectives that are required for larger scale synthesis. After the best route is selected, the focus is on optimizing and scaling up the route. Work will begin on simplification, e.g., can steps be combined, identifying a catalyst enabling the reaction to be performed under milder conditions, etc. Scale dependent variables such as dosing rates, mixing and mass transfer are investigated. There will be concerted effort on understanding process limits and creating an effective design space for the process.  Part of defining process limits is investigating potential safety hazards and to ensure that exotherms generated by the reaction at scale are understood and effectively controlled. As an element in an effective QbD strategy, on-line PAT methods will be developed and deployed to ensure product quality via process reproducibility and stability. Understanding how to effectively control the crystallization of a molecule is also a critical part of chemical process development since it effects drug activity (e.g., polymorphism) as well as ease of filtering, isolating and drying the final product.

The chemical development and the scale-up of processes pose many challenges for researchers, starting with the selection of the route, via the QBD topic, to process scale-up and process safety investigation. Among others, these include for example:

• Selection of the Synthesis Route
• Quality by Design (QbD) – An Approach Supporting Chemical Process Development
• Process Analytical Technology (PAT)
• Understanding Chemical Reaction Kinetics
• Importance of Mixing and Mass Transfer
• Relevance of Heat Transfer
• What is Reaction Calorimetry?
• What is the Heat of Reaction?
• Why is Process Safety Relevant in Chemical Process Development?
• Process Scale-up
• Controlling Crystallization
• Process Optimization

Once a target molecule is chosen for synthesis and the effectiveness is proven, finding the most efficient synthetic route quickly is essential. Typically, the scientist first looks at the required compound trying to find the suitable starting materials. Often, the complexity select the synthetic route is high as the drug candidates range from relatively simple structures to complex ones, including chemistries or starting materials that are dangerous or never used before.

Often, the starting point for chemical process development is the medicinal chemistry route, which still allows access to a variety of targets. However, the medicinal chemistry route is not typically designed for scale-up into a large manufacturing process. It is likely that the synthetic route changes multiple times as development progresses. But, the first time right is the goal as time to market is critical.

Quality-by-Design (QbD) is effective to develop products in the industry. Its purpose is to ensure that the intended effect of a product is achieved as expected, and it is of constant quality in terms of purity and efficacy. QBD in chemical process development aims for targeted error identification, efficient error reduction, and thus a highly reproducible, high quality and safe process.

In the concept of QbD quality control is an integral part and thus, requires an in-depth understanding of the process and the critical process parameters (CPP) that influence the process. So that the CPPs and their influence can be determined reproducibly, precisely and efficiently, they need to be examined using tools that control parameters precisely by design. For chemical process development personal synthesis workstations are the ideal solution as these allow to control the reaction parameters accurately providing data-rich experiments reproducibly.

Confirmation that the process is being carried out within the design space is obtained through online Process Analytical Technologies (PAT), such as heat flow trend, pH measurement, online IR or Raman spectroscopy, particle size characterization, online sampling and many more.

Process Analytical Technology (PAT) is a key element in QbD and is deployed to ensure product quality and stability, and continuously monitors the key variables and triggers corrective actions if necessary. Thus, various PAT technologies are employed to track the critical process parameters supporting the QbD concept.

Process Analytical Technology (PAT) is a methodology to develop and produce high value chemicals and pharmaceuticals. Critical parameters (CPPs) and key performance indicators (KPIs) of the process are thoroughly understood, well-defined and continually monitored in order to ensure that the pre-defined critical quality attributes (CQA) of the final product are consistently achieved. PAT measures key quality and performance indicators in raw materials, in-process materials and processes in real-time. A well designed PAT-based process is stable, ensuring that the critical parameters and indicators remain within pre-described limits to ensure product quality and process safety. PAT is an important element in a Quality by Design (QbD) system, in which quality is not tested into product, but rather inherent, by-design.

Process Analytical Technology (PAT) utilizes a variety of tools, such as spectroscopic and chromatographic compositional analyzers, fixed purpose sensors, automated and statistical data analysis and overall knowledge management methods.  All of these technologies and methods are designed to provide information in a real-time or near real-time manner. Since the purpose of PAT is to improve the safety and quality of manufactured products, it must be incorporated into efforts leading to large-scale production, such as early and late stage process development and process scale-up.

Chemical process development combines a multitude of disciplines in order to identify the best possible reaction conditions resulting in an optimal process. Among others, this also includes reaction kinetics which provides insights of rate dependencies of the chemical reaction on variables, such as concentration, temperature, pressure, the presence of catalysts, or the physical state of the reactants.

In order to perform chemical reactions effectively and to obtain the desired products in the right quality at large scale, the understanding of the reaction kinetics is an important pillar. Kinetic parameters, such as the reaction rate, the rate constant or the activation energy are independent of the scale and are determined experimentally.

From the investigation of the reaction kinetics, both the order of the individual reaction steps as well as the overall order of the reaction is determined.  The order of a reaction is essential because it defines the relationship between the concentration of reactants and the rate of reaction.

Knowing the reaction kinetics and its parameters impact the progress of the reaction, and thus also the time or yield can be predicted. However, this is not the only value as reaction kinetics also supports the mathematical modeling of a reaction.

The fundamental understanding of the mixing process is crucial for scale-up in chemical development. Mixing is the reduction or elimination of inhomogeneity of phases that are either miscible or immiscible. The goal is to either reduce or eliminate temperature or concentration gradients, or to ensure good dispersion of multiple phases. Good mixing is desirable for several reasons, including side-reactions or by-product formation, improving mass transfer in multi-phase systems, or ensuring fast heat transfer. Mixing efficiency is influenced by the type of material to be mixed, the design of the stirrer and the reactor, the mixing regime, but also the position of the feed tube and the operating conditions. [Handbook of Industrial Mixing, Science and Practice. Paul, E. Wiley (2004)]. Chemical reactions in a stirred tank, where the reagents may be present in more than one phase (liquid, gaseous, or solid), require intensive interfacial contacting to facilitate optimal mass transfer. Improper or poor mixing may result in a low reaction rate, low yield, poor selectivity, or increased concentration of impurities, which increase the costs of manufacturing significantly. Mass transfer and kinetics can compete and contribute to the overall reaction rate. Process scale-up and optimization require that the impact of mixing on the reaction rate be quantified. Laboratory reactors must be operated under conditions that will allow meaningful process characterization and scale-up.

Scaling-up a chemical process from lab to manufacturing only gives useful results with accurate heat transfer coefficients. If thermal resistances and reaction rates are only approximate, large safety margins must be applied later resulting in larger investments or longer batch times, lowering the productivity of the process or an increased concentration of undesired by-products or impurities. In stirred tank reactors, the mechanism of heat transfer is forced convection, and it is of particular interest when scaling a process from the lab to the plant. The overall heat transfer coefficient in the reactor consists of three partial resistances (reactor film, reactor wall, oil film), which are determined in reaction calorimeters. Measuring the jacket and reactor temperature during the release of a well-defined amount of heat allows researchers to accurately compute the thermal resistance, which is used to model the heat transfer and to make critical predictions for reactors at larger scale

Process development and scale-up workstations, such as OptiMax HFCal, RC1e with HFCal and RTCal, provide scientists with thermodynamic data in real time.  Combined with in situ FTIR spectroscopy for real time reaction kinetics measurements, scientists and engineers can understand and model chemical reactions allowing the rapid scaling of a process from lab to plant. 

Fusing data-rich in situ analytical measurements and DynoChem modeling provides a breakthrough to speed development and scale-up of processes and support Quality by Design (QbD) objectives. Dynochem simplifies the acquisition of key kinetic and thermodynamic information from data-rich experiments. In optimization studies, Dynochem modeling provides knowledge to optimize unit operations, including reactor design, process safety, crystallizations, distillations and solvent swaps. Dynochem minimizes time-consuming trial-and-error experimentation and facilitates transfer of process understanding to key organizational stakeholders.   

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