illustration of scientists in lab

How to Scale Up a New Synthesis Reaction

A successful scale-up requires input from a variety of team members to produce a safe and effective product

Michael J. Williams

The first step to successfully scaling up from bench research to production requires building the right team. A wide variety of skills is needed, including chemists, chemical engineers, analytical chemists, environmental health and safety (EHS) experts, supply chain managers, and even sales and marketing specialists. The team will set the tone for the entire scale-up process. 

As products are introduced into the production environment, the questions that need to be answers have evolved. The supply chain team is no longer simply tasked with finding the raw materials on the market. They also consider the distance from the supplier to the production site to reduce the carbon footprint. Raw materials can be obtained from both a bio-renewable source and a synthetic source and have the same material specifications. However, the materials may not perform identically due to “unspecified specifications.” Seasonal fluctuations of bio-renewable materials may affect supply chain distribution and impact the production process.  

Steps for the chemist

The chemist’s role starts with understanding the basic chemistry and working with the product development team or application team to know how the product must perform in a given application. The chemist needs sufficient experience with the reaction in the lab to know what caused an upset in the plant, and most importantly, how to fix the problem. This means making material that is at the edge of and beyond the product’s specifications. As part of the runs, the chemist needs to learn what influences the product and test the robustness of the synthesis. For example, if a reaction requires a temperature of 150C, what happens if the plant’s control system actually maintains a temperature range of 145C to 155C? Will the product have the desired conversion? When running through these trial lab batches, the chemist must consider all of the product specifications, which are reflected in the product’s Certificate of Analysis. 

To have a successful scale up, a product needs to have clearly defined analytical targets and the appropriate ranges for those targets. As a product is scaled up to the plant, it needs to be analyzed on equipment the plant has, using the methods that the plant utilizes. The specifications that the team sets must fall within the accuracy limits of the analytical tests being used. The team needs to ensure that the analytical methods exist in the production environment before scale-up. 

After the chemist has thoroughly vetted the process, they will develop the bill of materials. Unfortunately, this typically is not just scaling up the reaction quantities because plants prefer to consume whole containers of materials. When developing batch sizes, the chemist must consider what material is hardest to handle in the process. The batches are then scaled around consuming whole containers of this material. If the material is a solid, is it available as a pellet or hot melt? If it is a hot melt, does the plant have the right equipment to charge it? If it is only available as a solid and the plant cannot handle the material, then this may mean the  process has to start again and the chemist must develop a new process that can work within the plant’s limitations. 

Factors that influence a scale-up

When a product moves from benchtop scale to production, it is not as simple as multiplying the reactant quantities by 200x. Most lab scale reactions are sized so that their reaction vessels can quickly dissipate any heat that is evolved during the reaction. Heat-up and cool-down cycles are much longer in production scale vessels. This additional reaction time may impact a product’s properties. If the reaction is performed in glassware, it is often vented to atmosphere or flows through a condenser, so that pressure is not a concern. If the lab scale work is done in pressure vessels, the vessels are usually rated for well beyond any expected pressure. For this reason, it is important to investigate and document the vapor pressure of a reaction mixture through the entire process. As the process experiences the complete temperature cycle, the viscosity of the material may change. While it is hard to measure the viscosity during the entire process, the chemist can measure the viscosity of the starting materials and final products. The chemical engineers need to know the viscosity profile over the course of the reaction. 

For example, a raw material with the viscosity of water may work well in the reactor’s pump at room temperature; however, as the temperature rises, the viscosity may be too low to properly lubricate the pump seals on the reactors. If the viscosity of the product rises over the course of the reaction, the product may flow without issue through the pump at elevated temperatures but become too viscous for the pump to adequately circulate the material as it cools. 

Safety considerations

When a product is developed in the lab, all the work is typically done inside a fume hood. In a production environment, the ventilation is usually natural ventilation; the wind and air moving around the vessels. As the process is prepared for scale up, the EHS group will look at the materials and processes. It is important to identify if the product and all of its isolated intermediates are on the US Toxic Substances Control Act (TSCA). If the material is on TSCA, but has never been produced at production scale before, has the preliminary manufacturing notification (PMN) been completed? If the material has a PMN, does it have a significant new use rule (SNUR).  Another concern is staying within the production facilities’ air permits. Many common chemicals in use in the lab will exceed air permits if they are vented to the atmosphere during a reaction. Simply heating water has the potential to exceed a production vessel’s pressure rating if the water is present in high enough concentration. Lower boiling solvents can exacerbate this effect even more. 

Topics such as maximum allowable working pressure (MAWP) and vessel pressure ratings are just two of the many topics that need to be discussed when the safety team member leads the process hazards analysis (PHA) of a new product. The PHA team will take into account material compatibility, vessel pressure and temperature ratings, control systems, plant interlocks, relief device settings, and many other risk factors. The technical team of the product introduction team normally participates. The goal is to ensure that the new process fits within the safety capabilities of the existing plant equipment. If the product or process falls outside of the existing systems, recommendations are made to improve the equipment. Protocols differ among production facilities, but all of them undergo some type of ‘management of change’ process when new materials are introduced to the plant. 

A successful first production run can take many shapes. It may simply be completing the first large scale run of a product in the plant or it may be making millions of pounds of product for a customer. No matter what the definition of success is, it is only possible when the organization works as a team to get it finished. This team includes many departments, such as chemists, chemical engineers, EHS, supply chain, and more. The chemist plays a significant role in kickstarting the project by defining targets and vetting the process. Once the process is under way, other departments can assists with evaluating all the factors and safety considerations that need to be prioritized to ensure a successful scale-up run.

Michael J. Williams

Michael J. Williams received his MSc in organic chemistry from the University of Oregon in 1995. Immediately after school he worked in the pharma industry doing process development and scale-up. In 1998, Mike became a production chemist at a small surfactant company called Tomah Products in Milton, WI. Since then, he has been a synthetic research chemist, group leader and senior group leader. After several corporate name changes, Mike still sits at the same desk, but he works for the Evonik Corporation where he now manages two synthetic and one analytical R&D groups. He is additionally responsible for scale-up and product transfer activities at five production sites in the Americas.