EDITORIAL

KLAUS LAUE
Solvias AG, Rmerpark 2, 4303 Kaiseraugst, Switzerland
Member of Chimica Oggi Chemistry Today Scientific Advisory board

Klaus Laue

The art of rapid scale-up

During early-phase development usually a point is reached where for the first time kilogram amounts of a new compound are needed
quickly. However, the so far used lab-scale synthesis was intended for synthesis of grams and is often lengthy but flexible allowing also the
synthesis of analogous compounds. When the first kilogram is needed either this non-optimized research route can be used or a better
process can be developed. It has to be decided if already now a significant investment in time and money for process development is
appropriated in view of the fact that less than 10% of the early phase compounds reach commercial application. In an environment where
companies are following the faster time to market principle with rigid timelines and budget control, this gets an even more difficult task.
From a process chemists view there must be clear definition of the targets (timelines, budget restrictions, amount and quality) before he can
analyse the different options and a production campaign can be planned. At first the current research rout should be challenged under
different aspects, such as scalability and safety of chemistry, purification issues, required/available production equipment and raw materials.
Are there any show-stoppers, like e.g. non-available starting materials or thermal hazards (e.g. Grignard reactions in diethylether or
azide chemistry)? Where are critical steps (reproducibility, yield, reaction volume) or are there any extensive work-up procedures (e.g.
large scale chromatographies)? And where are still possibilities for a quick optimization (e.g. reduction of reaction volumes or
streamlining of the processes). Finally the total effort necessary for a short process development and production should be estimated.
In parallel also alternative processes should be considered. Based on literature examples and own experience an evaluation should
be performed similar to the known research route. Of course uncertainties here are higher but also the necessary efforts can
roughly be estimated.
Once the different options are evaluated, risks, timing and costs can be compared. Usually the decision is a trade-off between different
aspects. If a scale-up of the research synthesis seems like the best way forward (which is often the case), how can you organize a successful
campaign? Strategic project management and good working habits in your organization (and CMO) can make the difference!
A good preparation already starts in the earliest research phase. Well documented protocols and analytical methods are the
starting point for an efficient process development later. These protocols should also report problems like e.g. strong exothermic
reactions, bad phase separations or filtrations. Reagents and solvents which can be used in a kilo lab should be the first choice
while critical solvents or reagents should be second choice, like e.g. diethyl ether or dichloroethane. All information should be
completely documented including negative results allowing a smooth knowledge transfer. If available retain samples are important
extras to speed up analytical development and critical up-front testing during a rapid scale-up.
Once it is decided to run a rapid scale-up, critical starting materials should immediately be ordered as delivery times can be long.
Do not wait until the project is transferred to a scale-up team, as this takes time. It is advisable to order 20 to 30% extra material. This
wont increase costs significantly but gives a good safety-buffer in the campaign.
A professional scale-up team is key, especially if a tech transfer to a CMO is needed. There is more to consider than just pricing and
planned delivery dates. The team must be reliable and experienced with a reasonable track record and there must be a culture of
risk awareness in combination with good communication and planning skills. Also an appropriate infrastructure is essential which
allows a seamless transfer from laboratory (~5L) to medium sized equipment (~10 to 50 L) and pilot plant (100L to 1m3). Equipment
should be organized as flexible as possible allowing parallel working with quick adaptations during an ongoing campaign. For the
worst case also suitable chromatography equipment should be available up to pilot plant.
Even when moving quickly through different steps, safety and quality risk evaluation is important and must be done adapted to the
intended scale. An evaluation for 100L should be more detailed than for a 10L reaction. Such evaluation can be simple stress tests or DSC
analytics. More sophisticated tests like RC1 are usually only necessary for critical reactions.
Basically, effective process development is only possible with a reliable analytic. Analytical equipment like NMR, HPLC, GC, LC/MS,
DSC should be freely accessible. As mentioned above, samples of the intermediates and products from early research are very
helpful allowing analytical development to be ahead of process development and avoiding interruption of development work or a
production campaign due to analytical issues which is time consuming and should be avoided. Or even worse, fail batches can be
caused by a not-reliable analytic.
However each scale-up includes potential risk to fail regarding lower yield, new impurity profile or time delays, but also project
adjustments like change of target amounts or specifications may be necessary. Therefore, an open regular communication and
good reporting are important to keep the stake holder well informed about all risks and in a driver seat position for important
decisions. A timely and open communication including also bad results leads to trust and acceptance.
Last, but not least, everyone should be aware that a rapid scale-up provides you with the first kilogram amounts but will hardly
provide you with a further scalable process which can be even validated. So, when you obtained the first kilogram, that doesnt
mean you can use the same process also for manufacturing of 50 kg or more.

Chimica Oggi - Chemistry Today - vol. 33(3) May/June 2015

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