Tag Archives: Chemical Business

For Students. Thoughts on Chemical Process Scale-Up.

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Chemical process scale-up is a product development activity where a chemical or physical transformation is transferred from the laboratory to another location where larger equipment is used to run the operation at a larger scale. That is, the chemistry advances to bigger pots and pans, commonly of metal construction and with non-scientists running the process. A common sequence of development for a fine chemical batch operation in a suitably equipped organization might go as follows: Lab, kilo lab, pilot plant, production scale. This is an idealized sequence that depends on the product and value.

Scale-up is where an optimized and validated chemical experimental procedure is taken out of the hands of R&D chemists and placed in the care of people who may adapt it to the specialized needs of large scale processing. There the scale-up folks may scale it up unchanged or more likely apply numerous tweaks to increase the space yield (kg product per liter of reaction mass), minimize the process time, minimize side products, and assure that the process will produce product on spec the first time with a maximum profit margin.

The path to full-scale processing depends on management policy as well. A highly risk-averse organization may make many runs at modest scale to assure quality and yield. Other organizations may allow the jump from lab bench to 50, 200, or more gallons, depending on safety and economic risk.

Process scale-up outside of the pharmaceutical industry is not a very standardized activity that is seamlessly transferable from one organization to another. Unit operations like heating, distillation, filtration, etc., are substantially the same everywhere. What differs is administration of this activity and the details of construction. Organizations have unique training programs, SOP’s, work instructions, and configurations of the physical plant. Even dead common equipment like a jacketed reactor will be plumbed into the plant and supplied with unique process controls, safety systems and heating/cooling capacity. A key element of scale-up is adjusting the process conditions to fit the constraints of the production equipment. Another element is to run just a few batches at full scale rather than many smaller scale reactions. Generally it costs only slightly more in manpower to run one large batch than a smaller batch, but will give a smaller cost per kilogram.

Every organization has a unique collection of equipment, utilities, product and process history, permits, market presence, and most critically, people. An organization is limited in a significant way by the abilities and experiences of the staff who can use the process equipment in a safe and profitable manner. Rest assured that every chemist, every R&D group, and every plant manager will have a bag of tricks they will turn to first to tackle a problem. Particular reagents, reaction parameters, solvents, or handling and analytical techniques will find favor for any group of workers. Some are fine examples of professional practice and are usually protected under trade secrecy. Other techniques may reveal themselves to be anecdotal and unfounded in reality. “It’s the way we’ve always done it” is a confounding attitude that may take firm hold of an organization. Be wary of anecdotal information. Define metrics and collect data.

Chemical plants perform particular chemical transformations or handle certain materials as the result of a business decision. A multi-purpose plant will have an equipment list that includes pots and pans of a variety of functions and sizes and be of general utility. The narrower the product list, the narrower the need for diverse equipment. A plant dedicated to just one or a few products will have a bare minimum of the most cost effective equipment for the process.

Scale-up is a challenging and very interesting activity that chemistry students rarely hear about in college. And there is little reason they should. While there is usually room in graduation requirements with the ACS standardized chemistry curriculum, industrial expertise among chemistry faculty is rare. A student’s academic years in chemistry are about the fundamentals of the 5 domains of the chemical sciences: Physical, inorganic, organic, analytical, and biochemistry. A chemistry degree is a credential stating that the holder is broadly educated in the field and is hopefully qualified to hold an entry level position in an organization. A business minor would be a good thing.

The business of running reactions at a larger scale puts the chemist in contact with the engineering profession and with the chemical supply chain universe. Scale-up activity involves the execution of reaction chemistry in larger scale equipment, greater energy inputs/outputs, and the application of engineering expertise. Working with chemical engineers is a fascinating experience. Pay close attention to them.

Who do you call if you want 5 kg or 5 metric tons of a starting material? Companies will have supply chain managers who will search for the chemicals with the specifications you define. Scale-up chemists may be involved in sourcing to some extent. Foremost, raw material specifications must be nailed down. Helpful would be some idea of the sensitivity of a process to impurities in the raw material. You can’t just wave your hand and specify 99.9 % purity. Wouldn’t that be nice. There is such a thing as excess purity and you’ll pay a premium for it. For the best price you have to determine what is the lowest purity that is tolerable. If it is only solvent residue, that may be simpler. But if there are side products or other contaminants you must decide whether or not they will be carried along in your process. Once you pick a supplier, you may be stuck with them for a very long time.

Finally, remember that the most important reaction in all of chemistry is the one where you turn chemicals into money. That is always the imperative.

Convincing Industry of the Utility of Your Chemical Method or Reagent

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It is not uncommon to read in chemistry papers or hear speakers from academic institutions making the assertion that certain problems exist that their method or reagent may solve. Perhaps a particular catalyst may give rise to a set of useful transformations or said catalyst may be fished out and reused in many other runs. Or, maybe the reagent in development affords spectacular yields or stereoselectivity. Given that an industry might have blockbuster products that share certain features or pharmacophores, an efficient method for synthesizing that feature is likely to be of genuine interest.

Chemical research coming from an academic institution in the USA is almost always executed by students and/or postdocs. In the case of graduate students, the work is done as part of their degree program and is designed to achieve certain goals or to explore a question. Regardless, it is not done to achieve a commercial purpose with product sales in mind. Student research is conducted with training and publication success as the goal. Graduate success and publication are the work products of academics.

If it transpires that a particular academic wants to do work that is also of commercial interest, that work should include certain commercial sensibilities associated with chemical production. Every business has its own list of development criteria in use. It will have a basis on in-house equipment and skills, company policy, safety, economic imperatives, working capital, required profit margins, environmental permits, available economies of scale, specialty or commodity products, etc.

Adopting a new reagent for an existing chemical product can be very problematic for a business. For production pharmaceuticals, it is likely to be impossible for management to actually contemplate the trouble involved in changing an approved process. For other industries a similar problem exists. Changing a reagent in an existing process will likely require the customer to approve the change and the drafting of an updated specification. And, for their trouble they are going to demand a reduced price. I’ve received and given that talking to on a few occasions myself.

If the change is very early in the reaction sequence of a lined-out process, there may be a chance to do a replacement or change a step. Maybe. Remember that customers usually do not like change in regard to the chemical product they are purchasing. They want and need consistency. Even improving purity can be bad if it results in the final product surprising the end-user in some way.

I would offer that if an academic worker wants to make a difference in commerce, they should concentrate on the final product in the application. It may be that an existing product could be made cheaper by your wonder reagent, or perhaps some me-too congener. Your reagent may be superior in a functional group transformation, but that is likely to draw yawns. How does your reagent add value to a process in concrete terms?

By adding value I mean to say, increasing profit margins. Costs in manufacturing are broadly divided into raw materials, labor, cost of sales and other overhead. They are not all easy to minimize. For instance, a mature product may be priced according to commodity scale pressures. That is, there are numerous suppliers and low margins in the market for producers. If the cost of goods sold is driven strongly by raw material costs, unless you can wangle a breakthrough in raw mat prices, staying price competitive may involve a race to the bottom of the lake. However, if labor is the major driver of cost, you may have a chance to increase margins by reduction in man-hours per unit. That reduction would come from any of a number of labor saving strategies.

Labor savings can come in many forms. More efficient use of existing equipment can lead to an increase of capacity and throughput over the year if the turnaround time between runs is shortened. Process intensification can also increase throughput and consequently reduced labor hours per kg of product. Higher reaction temperatures benefit kinetics as do increased space yields by running at higher concentrations. Just beware of the reaction enthalpy per kg of reaction mass (specific enthalpy). It is very possible to over-intensify and bring on problems with safe operation and side reactions.

For the academic aiming to be technologically relevant in a concrete way you have to think like the owner of big equipment. Idle equipment is not earning revenue. Busy equipment at least has a chance if it is done efficiently. Telescoping a process so that more steps can be run in the same vessel without solvent changes or excessive purification is always desirable. Moving material between vessels is time consuming and likely labor intensive.

More questions to consider. Does a reaction really require an overnight stir-out. And at reflux? Do you have a method of in-process checks that allow the next step to proceed? What is the minimum solvent grade you can get away with? Can you replace methylene chloride with anything else? What is the minimum purity raw material you can get away with? Unnecessarily high purity specs can be very expensive. Your customer will suffer from this as well.

Learn to get pricing from bulk suppliers. Use those unit prices for your cost calculations. For God’s sake, don’t use the Aldrich catalog for pricing. Remember, you’re trying to make a case for your technology. There should be a costing spreadsheet in your write up.

That’s enough for now. I gotta go home.