Case study
As part of the life cycle management of our products , regular reviews of the processes are performed with a multi-disciplinary team to identify potential for improvements in terms of process efficiency , sustainability , and safety . At commercial stages , all process modifications are carefully assessed to balance the potential benefits in terms of impact on the regulatory filing .
The current manufacturing process of a commercial API , which has been produced in one of our facilities since 2014 , was reviewed with the objective of finding areas of improvement to increase efficiency . Several opportunities for process development and optimisation were identified :
• The two-step process used up to five different solvents for reaction and downstream processing , including some solvents of concern due to their inherent toxicity
• Tetrahydrofuran ( THF ) was considered a non-optimum solvent for the reaction because of the difficulty of recovering and recycling it , due to the risk of peroxide formation
• The process PMI was considered very high for such a process . The reduction of solvent consumption was a key objective , including the possibility of recovering and recycling solvents in the same process
• The intermediate obtained after step 1 was isolated . This led to a long and inefficient filtration at production scale , due to the generation of fine particles after precipitation During optimisation work , the impact on the production and control of potential genotoxic impurities and nitrosamines according to current ICH guidelines needed to be assessed and controlled . As the regulatory dossier was filed in multiple countries , a key regulatory challenge was to keep the specifications and physical
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Comparison of yield
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Existing process
Figure 1 - Key process efficiency metrics comparison
properties unchanged for the API . Hence process improvements studies were performed with the aim of keeping the final API isolation procedures unchanged .
Very importantly , the regulatory support teams were involved throughout the whole project to advise on the modification and support in building the required documentation to support the dossier modification . With these identified objectives agreed , our goal was to design a clear path for process development to reach the identified improvements .
Our teams recognised that telescoping of the two steps , without intermediate isolation , would greatly streamline the process while giving opportunities to rationalise the number of solvents and eliminate the use of toxic hexanes currently used in the precipitation and washings of the intermediate . However , the
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New process
removal of an isolation step in the API manufacturing needed to be carefully investigated to ensure that this optimisation would not jeopardise the robustness of the process in matching the specifications .
Change of solvent
Replacing the current reaction solvent , THF , was considered in order to reduce the consumption of solvent and facilitate solvent recovery and recycling . Partial solubility in water and strong susceptibility to peroxide formation were identified as potential issues .
2-Methyl THF ( MeTHF ) is a greener alternative to THF . 4 It is obtained from non-edible , renewable resources and possesses better properties in terms of decreased water solubility , higher boiling temperature , and better tolerance to acid and base conditions . Despite a higher initial solvent cost , it was considered
26 SPECIALITY CHEMICALS MAGAZINE ESTABLISHED 1981