Division Spotlight: Process Chemistry

Posted on September 29, 2021

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What are some of the new projects/initiatives that the GMP process chemists are currently working on?

We recently completed the process validation of DSPCII and our entire department is now involved with the planned process validations of CMPEG2, N-TETAMINE, and ALC-0159 which are all products related to the COVID vaccine. We have completed the first manufacturing campaign for ALC-307 which is another novel cationic lipid used in lipid nanoparticle formulations. Development of DSPE PEG2K COOH, which is used as a platform delivery vehicle for established chemotherapeutics to hypoxic tumors, is ongoing and its first cGMP batch is slated to begin in early Q1 2022. Development of the three-step POPG process is underway and it entails the enzymatic hydrolysis of DPPC to furnish 16:0 Lyso PC, followed by coupling with oleic acid to provide POPC, and culminates with a head group exchange with glycerol. The manufacturing pathway utilizes process improvements to the legacy process, which include replacing chromatography with partitions and precipitation for 16:0 Lyso PC, precipitation and triturations for POPC, and precipitations for POPG.

Describe the general process that our process chemists use to take a project from small scale to commercial scale.

Once the small-scale batch of a product is complete, we normally evaluate the process holistically to identify any reactions or downstream processing/purification steps that would not transfer successfully at scale. Key areas that we focus on are yield, safety, equipment limitations, impurity formation, and processing inefficiencies. If any are identified, alternatives are proposed and we then evaluate their viability in the lab. Solvent selection for the process is also considered to determine if safer and more environmentally friendly solvents could be employed. Once we have successfully implemented any changes and improvements, two developmental batches are manufactured using a draft batch production record (BPR) at the anticipated cGMP scale. During this time, and following completion of the developmental batch manufacturing, we work closely with the Quality Control group to develop robust analytical methods to adequately determine the purity of the material. After a suitable analytical method is developed, the draft BPR is revised to incorporate any findings identified during manufacture of the developmental batches and any new raw materials are qualified. Once these activities are completed, cGMP manufacturing can begin.

How has the process chemistry team been able to work with the broader Croda team so far?

Initially, Avanti worked closely with the Process Development team at Leek, Staffordshire (UK), namely Andy Sellars, Steve Mellor, and Rebecca Murray, to completely transfer the ALC-0315 process to the Leek site. This was a crucial step in providing the manufacturing capacity capable of supplying Pfizer with suitable quantities of lipid excipients for Comirnaty, the Pfizer/BioNTech COVID-19 vaccine, from both the Alabaster and Leek sites. As part of the Croda secondment program, the Avanti Process Development team worked extensively with Heather McMahon, part of the Croda Mill Hall Process Development team. A great many of the interactions with Heather focused on the rationale for the process route selection for ALC-0159 and she had the opportunity to share with our team the capabilities and equipment at the Mill Hall site. We also routinely work with Bas Wells from the Croda Nederland BV site. He is an integral part of our team that has responsibilities for overseeing external manufacturing and scale-up of raw materials, intermediates, and, in some cases, final products.

In an effort to implement sustainable and environmentally friendly processes, we have shared information and results from some preliminary feasibility studies with Tesia Chciuk, Peter Kaplan, and Sreejit Menon at Atlas Point to determine the viability of centrifugal partitioning chromatography (CPC). This is a relatively new industrial scale methodology we are evaluating with a company in Hungary as a potential greener method for purification. We are collaborating with Rachel Scullion from the Croda Process Innovation Team in Ditton, England on the feasibility of immobilizing phospholipase enzymes for recovery and reuse. Most recently, we have shared detailed technology transfer packages with the engineering team at Mill Hall that will guide the transition of the ALC-0159, DSPC, and Synthetic Cholesterol processes to the new Lamar site in Pennsylvania.