R&D Director of PROCOS S.p.A

It’s no secret that within this highly competitive environment, the pharmaceutical companies that are constantly trying to reduce the time-to-market of new chemical entities (NCE’s) and the speed of process development activities are moving towards success.

After jumping into the clinical phases of a project the need for API quantities strongly increases, quickly growing from a few hundred grams to some kilos or tens of kilos of API. At PROCOS, the manufacturing scale progressively goes through the kilo lab reactors (25-50 liters), then to pilot reactors (300 – 1000 liters) and potentially, when a few hundred kilos are requested, up to industrial reactors (3000 – 6000 liters).

Process development through reaction screening, looking for the best reaction conditions, the best catalytic system, obtaining the lowest possible limits for the impurity profile and optimizing reaction selectivity, are fundamental activities for the scale-up of chemical processes.

Besides the technical feasibility of the chemistry in the manufacturing plant, we also need to consider, as basic requirements for the scale-up of the process, the following fundamental factors:

1. Process Safety: The process must be inherently safe, meaning that the calorimetry of each step is strongly investigated, and any kind of runaway reaction is avoided.

2. High Quality: The impurity profile of the final API or advanced intermediate must be deeply known and perfectly under control to match the desired specifications. Origin, fate, and purging studies of all relevant impurities must be performed.

3. Process Robustness: Design spaces of relevant process parameters and, wherever possible, in combination with quality attributes of raw materials are needed to assure consistent reproducibility within the scale-up of the process from the laboratory scale.

4. Process Economy: As long the manufacturing scale increases and with good anticipation in the earlier phases, process economic efficiency needs always to be looked for.

From a modern approach of R&D process development team at PROCOS, the answer to the above challenges is, besides the high level of technical competencies of organic chemists, the implementation of automation and robotic techniques to drastically increase the number of experiments per day. With this idea in mind, we decided to invest in a high-level laboratory automation system:  Chemspeed® Autoplant Prores.

With this equipment, hosting 12 completely independent reactors each equipped with mechanical stirring and up to 72 glass vials system stirred through a shaking movement, we can perform both process optimization and reactions screening activities.

‘Process development through reaction screening, looking for the best reaction conditions, the best catalytic system, obtaining the lowest possible limits for the impurity profile and optimizing reaction selectivity, are fundamental activities for the scale-up of chemical processes.’

The choice of the reactors has been driven by the philosophy to be consistent and like the industrial plant in terms of representativeness of mixing properties. Each reactor is equipped with a mechanical stirrer and is completely independent, in terms of operations, jacket and internal temperature. Glass or PEEK gaskets can be inserted into reactors to allow handling of reaction mixture in acidic conditions. Different kinds of mechanical stirrers (anchor/impeller made of stainless steel, PEEK or teflonated) are available to allow mixing studies along reactions and crystallization steps.

Reactors can work at high pressure (up to 80 bars) and we are using them to screen hydrogenation reaction conditions up to 75 bars and 140 °C both for heterogeneous and homogeneous hydrogenation

Chemspeed® Autoplant Prores equipment is a fully robotic system able to perform either solid dosage or liquid dosage with very high precision.

Solid dosage is performed through a patented technology using a suspended balance which allows to dose solids with very different physical properties (i.e., inorganic salts, charcoal powder, catalysts etc) with very low tolerance.

Liquids can be dosed either by syringe pumps or through peristaltic pumps.

Samples can be pulled from the reaction mixture with disposable tips and then diluted for the chromatographic analysis.

The system works under inertized conditions so we can easily handle oxygen-sensitive materials like organometallic catalysts for cross-coupling reactions or enantioselective hydrogenation etc.

All experimental data (i.e., jacket and internal temperature, pressure, dosing rate, stirring time, rpm) along each trial are fully recorded and available for any further back evaluation.

Chemspeed® Autoplant Prores equipment, installed at PROCOS R&D department, allows us to increase our process knowledge in a shorter time compared to the traditional experimental approach. A thorough process optimization including the challenge of most relevant process parameters, within the concept of process robustness, is fundamental to lowering the risk during the scale-up of chemical processes.

With this level of automation, sets of significant numbers of experiments planned through DOE methodologies i.e., screening of catalytical systems, temperature, pressure and reaction volumes or optimization designs are no longer considered a barrier and they are easily completed in a few working days, thus allowing each researcher to carry out enough replicate experiments to properly assess the experimental variability.

All collected data can be used with a high level of confidence to justify process parameter ranges (proven acceptable ranges - PAR) in DMF filing.

The last upgrade of the Autoplant Prores equipment allowed us to increase our technological portfolio including in the R&D studies, solubility curve determination, crystallizations studies and polymorph screening.

Solubility curve determination in different solvents or solvents composition can be done automatically by sampling and doing quantitative analysis of supernatants at different temperatures.

Example of solubility curve obtained with Chemspeed® automatic preparation.

Sampling is performed using a heatable automatic needle (pre-heated at the same sampling temperature) and an automatic SPE Heatable rack with a 3ml PE cartridge with 10um septa for pressure filtration (polish supernatant filtration before quantitative analysis)

4 needle tools with heatable needle at PROCOS Autoplant Prores

SPE HEATABLE RACK FOR 3ml cartridge at PROCOS Autoplant Prores

Crystallization studies can be performed using automatic vacuum filtration racks where the crystallization mixture can be filtered and washed. In that way, we can check the impurity purging in different conditions like temperature or solvent composition.