The Relationship between the Risk of Catastrophic Failure and the Size of the Scale Up Steps in Chemical Process Development

What do I Mean by Catastrophic Failure?

In the context used herein, I am defining a catastrophic failure of a process step trial as a very large loss of product quality and/or isolated yield from which there is no recovery. That is, by definition, there is no patch known and reprocessing is not viable. Characteristically, the failure, when it occurs, comes as a complete surprise. Catastrophic failures at scale usually create serious financial losses and make project schedule extension necessary. It is the risk we face when we ‘put too many eggs in one basket’.

How is the Size of the Scale Up linked to the Risk of Catastrophic  Failure?

What is risked when a process step is increased in scale? It is fair l widely accepted that at first and quite normally, for any reaction step the yield is likely to fall somewhat. More serious, but still not unexpected, is that the type and quantity of impurities in the isolated product may change in unanticipated ways. Worse still and getting to the catastrophic, the reaction may create a mixture that cannot be purified enough to give an isolable physical form. Still worse, the reactor contents may become unprocessible (can’t cut, can’t stir, can’t cool, can’t filter can’t distil). When these latter things, for which there has been no preparation occur, unacceptable time and money is lost. More material must be ordered. The project milestone are missed. These possibilities limit the size of the scale up steps in development. Consequently, as the cost of the inputs at risk and/or the probability of catastrophic failure fall, the size of the steps in scale up can increase.

The approximately optimal conditions determined with laboratory equipment can still be quite different with respect to a  number of variables from what must be done in a pilot plant. Just for starters, some parameters such as heating, cooling, stirring and the times for reagent additions most often cannot be physically matched after increasing scale because of  equipment limitations. Surprises can occur as one increases the  size of operations and these lead to product with unacceptable properties.

How does One Rank Risks?

Any risk to workers’ physical safety must be made inconsequential. It would be immoral to knowingly add to risks to health and safety. Even from a completely selfish perspective, a lost time industrial accident can put a chemist manager’s professional career at risk. Safety issues are paramount and signs of a hazard dictate slow scaling.

A loss of starting material is both a loss of time and of money. The budget can perhaps be repaired but the time required for the delivery and qualification of  fresh starting materials is lost forever. If the inputs are inexpensive as a proportion of total costs and are quickly available from multiple sources, one risk of more aggressive scaling is reduced. It is usually the early steps in a process where inputs can be replaced cheaply and quickly and other things being approximately equal, early steps can be scaled up in larger increments for that reason.

Can One Estimate the Likelihood of a Particular Type of Scale-Up Failure?

Perhaps we ought to ask instead: How well am I able to  scale down the pilot plant environment and reproduce it in my laboratory equipment? Scaling down is the exercise of selecting the bench-scale equipment, operating conditions, and mathematical models to successfully simulate pilot or production scale operations in the lab.

Risk can be reduced by testing with such equipment. If the experimentation has been conducted using exactly the same quality for solvents, reagents, processing aids and catalysts, the biggest sources of deviation in scale-up are removed. If the processing times including times of addition, times for transfers, and time for filtrations approximate those necessitated in the pilot plant, risk is reduced. If the corrosiveness and abrasiveness of the reactants have been tested on the reactor’s materials of construction, it reduces risk. If the procedure is insensitive to rate over a wide range of agitation speeds then another sensitivity has been allowed for. If the sensitivity to traces of air and moisture is known and taken into consideration, life is simplified. If none of the reactants reagents or coproducts in the process step are more completely swept out of the reactor at one scale compared to the other, another frequent source of deviation is accounted for.

There are auguries of danger that can be divined while still in the laboratory and addressed before moving to higher scale:

·        Addition or removal of a gas

·        High viscosity of the reaction medium

·        High exothermicity

·        Need for a low reaction temperature

·        Drown out quenching

·        Rapid addition rates

·        Fast reaction relative to the rate of addition of a reacting component

·        Decomposition on the reactor walls

·        Presence of byproduct polymer

·        Use of polymer reagents that may disintegrate with stirring

·        High speed stirring

·        Asymmetric synthesis catalysis

When one scales up, it is advantageous if the first step is of sufficient size that all the changes in the main discontinuous variables (reactor materials, reactor shape, minimal stirrable volume, type of agitation, heat transfer etc.) are introduced together. Making these changes together often can be better accommodated by also including initially an increase in the amount of solvent in the reactor, to give an overall dilution. Often the biggest risk impediment to moving into the pilot plant is the cost of materials to operate at the minimum stirrable volume in the larger reactor. Making an initial dilution that can later we reversed, may set up a more acceptable combination of risks at a more acceptable price.

Said another way, it may be better to delay the optimization of the throughput, which is very often the result of the consequence of increasing the concentration of the reactants and reducing the amount of diluents (ie solvent) until after  the transition to the pilot plant or manufacturing equipment. This will result in a less expensive transition from laboratory to pilot plant. It will require less of the expensive chemical to reach the minimum stirrable volume at the start of the reaction.

Catalyst poisoning will be treated in a separate article.