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 (e.g., pre-clinical and clinical studies in the pharmaceutical industry). 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 supporting 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 the 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 telescoped, 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 Quality by Design (QbD) strategy, online 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.

Synthesis Route Selection

Selecting the best route for commercial process development of a molecule goes beyond the actual chemical synthesis.  Factors influencing the decision include the scalability of the process, understanding the factors influencing process safety, assuring a high quality product, the costs and availability of raw materials, production costs associated with the route, and environmental and waste considerations.  Batch and/or continuous flow approach to the process needs to be considered and explored since this decision influences many of the cost, safety and quality factors.   

Understanding Reaction Kinetics

Reaction kinetics provide a measurement of reaction rates, factors that affect the speed of a chemical reaction, and insight into reaction mechanisms.  Understanding the kinetics of a reaction is critical for being able to control a reaction and direct the desired outcome of the reaction.  By testing and identifying how variables affect the rate of a reaction, products are optimized and by-products are reduced. 

Mixing and Mass Transfer

At the heart of scale-up in chemical process development is the fundamental understanding of the mixing process.  Influencing mixing efficiency is the physical properties of the material being mixed, the design of the stirrer and the reactor, the mixing regime, and the position of the feed tube and the operating conditions.  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.

Process Scale-up and Heat Transfer

Heat dissipation in a stirred tank reactor is vital for the scale-up and safe operation of a chemical process. Scaling-up a chemical process from lab to manufacturing requires accurate heat transfer coefficients. Heat transfer variations will impact the scaling of a chemical process, design of the plant vessel, cooling system and potential safety considerations.

Process Safety

Chemical process safety uses a framework of different techniques, technologies, and models and requires an understanding of the desired and potentially undesirable reactions possible during the process. This includes the investigation of thermal events, heat transfer, mixing, mass transfer, and gas evolution, as well as stability of the starting material, the reaction mass, and the resulting products.

Controlling Crystallization

Understanding how process parameters influence crystal nucleation, growth, and size distribution is of critical importance to ensure the quality, efficacy and cost-efficient manufacturability of a product.

Achieving Quality by Design (QbD)

A QbD control strategy signifies that quality cannot be achieved by simply testing, it must be designed into the process from the beginning.   In QbD, well defined Critical Quality Attributes (CQAs) are identified for the product, and Critical Process Parameters (CPPs) to support the attainment of the CQAs are established. Science and risk-based methods are used to define process parameters that may impact CQAs.  Both Process Analytical Technology and orthogonal modeling such as Design of Experiments have important roles in achieving QbD goals.

At the heart of scale-up in chemical process development is the fundamental understanding of the mixing process.  Influencing mixing efficiency are the physical properties of the material being mixed, the design of the stirrer and the reactor, the mixing regime, and the position of the feed tube and the operating conditions. Chemical reactions in a stirred tank reactor may include reagents with more than one phase and/or state (liquid, gaseous or solid).  These reactions 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.

The heat dissipation in a stirred tank reactor is vital for the scale-up and safe operation of a chemical process. Batch and semi-batch reactors are still the most frequently applied type of reactors in the chemical and pharmaceutical industries. Variations of heat transfer may impact the scaling of a chemical process, design of the plant vessel, cooling system and potential safety considerations.

The earlier that non-scalable conditions are recognized, the more easily a process can be modified with improvements for safety. A webinar presented by Lubrizol focuses on how to improve process development and scale-up by leveraging calorimetry and in situ process analysis. Lubrizol redefined traditional process development to reduce the time and complexity of scale-up/scale-down.

A chemical reaction is affected by multiple parameters, such as concentration, addition rate, temperature, the solvent, catalyst and pH.  Further, reactions may also be affected by the stirrer type or speed which impact the mass transfer and further influence the result of the experiment. Rather than adopting a "trial-and-error" approach, where each parameter is examined individually and interactions between them cannot easily be detected, scientists apply the DoE methodology in the synthetic organic chemistry lab.

Case studies from the Zurich University of Applied Sciences (ZHAW) and Lonza SA apply the Design of Experiments (DoE) methodology to:

• Identify the Impact of Reaction Parameters
• Reduce Process Variability
• Shorten Chemical Development Cycles
• Support the Quality-by-Design (QbD) Approach

Within chemical process development, program timing often dictates making informed decisions with limited process understanding, especially in the early clinical delivery space. To facilitate this, Merck & Co Pharmaceutical Process Development Intensification Laboratory presents how to acquire deeper, more fundamental process understanding in a resource-sparing manner. 

• Chemical Reaction Kinetics
• Impurity Profiling of Chemical Reactions
• Flow Chemistry
• Heat Transfer and Scale-up
• Mass Transfer and Reaction Rate
• Crystallization and Recrystallization

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.