PHARMACEUTICALS
The next step will be the plant design phase , where any necessary adaptations to plant and equipment will be evaluated based on data and information accumulated during the previous developmental studies . A further hazard review will then establish whether the process can be run safely within the parameters of the desired design .
Quality by Design ( QbD ) became mandatory for New Drug Application filings in 2013.2 It acknowledged the integral role of process design in laying the foundation for outstanding quality and safety . As a project moves from development through to manufacture and process optimisation , continued hazard evaluation is necessary and new risks should be assessed in line with subsequent changes , with the customer advised accordingly . Under the foundations of the QbD framework , this continued , proactive risk assessment continues throughout a product ’ s lifecycle .
Case study
Sterling Pharma Solutions was approached by an existing customer looking to carry out a manufacturing process which involved diazomethane as a crucial reagent in the synthesis of an intermediate . Although the process had been carried out on a small scale , the ultimate aim was for commercialscale manufacturing campaigns requiring 100 kg of diazomethane .
All alternative reagents had shown to be incompatible with the chemistry , leaving the customer with no other option than to use diazomethane . As it had worked with Sterling on other projects , our record of handling hazardous materials and experience in chemistry gave the customer the confidence that Sterling would be in a position to undertake the work safely .
Diazomethane is a powerful methylating agent , with many potential uses in synthetic chemistry , API development and manufacturing . However , it is both highly toxic and explosive , being capable of detonating even in the absence of air . Its toxicity for personnel carries with it a permissible exposure limit of only 0.2 ppm time-weighted average . 3 This makes it very dangerous to work with at large scale , resulting in many manufacturing organisations refusing to handle it .
In some cases , diazomethane is the optimal reagent for carrying out synthetic transformations , but a further consideration is that it is not commercially available as an off-theshelf product and instead must be synthesised in situ for use in reactions . In addition , for large-scale use , the handling dangers naturally increase in line with volume . Most published research on diazomethane comes from academic studies conducted at small scale and has marginal correlation with larger-scale handling and production protocols .
As the first step of working on the project , development chemists at Sterling reviewed all of the available literature on the use of diazomethane at scale . The auto ignition temperature of the reagent was cited as being below 100 ° C , but many sources stated it as unknown and the flammable limit had no published data . One source , which was over 25 years old , put the flammable limit at 15 % nitrogen , but the test standard could not be verified .
Sterling approached several companies that specialise in explosive limit testing but none was willing to take on the project and handle diazomethane . The company then undertook its own preliminary hazard studies , building a test rig using pressurised vessels with remote operation and monitoring equipment to keep staff at a safe distance .
We installed a one-litre , highpressure reactor to generate the gas , and a bespoke 20-litre gas testing sphere with gas flow and concentration sensors to measure the diazomethane and determine the lower flammable limit ( LFL ). After 12 months of work assessing the process in a variety of conditions , the LFL was established to be 8 % in air and 15 % in nitrogen ,
SEP / OCT 2024 SPECCHEMONLINE . COM
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