Emerging Technologies

Innovation is one of several key aspects that differentiates good processes and products from great processes and products. Novel technologies are required to enable and support innovation, to address the technical challenges presented as research and commercialization projects evolve across industries, and to ensure success of product launches and supply. The development of emerging technologies requires a myriad of skillsets, from new ways of designing, executing, and analyzing experiments to understanding how to implement these emerging technologies at scale. The development also often requires new ways of collaborating cross-functionally. This innovative thinking that is essential for emerging technologies fuels success and competitive advantage. In this session, we will discuss how novel and emerging technologies have progressed a variety of projects, and how challenges were overcome in implementing these new processes, equipment, or methodologies.

Session Chairs:

• Anne Mohan, Merck
• Omid Ebrahimpour, DuPont

Tentative Schedule:

Abstracts:

We Are Building It .. and They Are Coming

Manish Kelkar, AbbVie; Nandkishor Nere, AbbVie

With increased complexity of molecules in the pharmaceuticals pipeline, including ADCs and biologics, manufacturing processes increasingly need to rely on technologies beyond just the standard batch or “dump-and-stir” operations. These next generation or emerging technologies not only include technologies that help in synthesis or separation of the species of interest, but also include the technologies that help us better understand the system at hand.

In this presentation, we will highlight various emerging technologies that are being explored and developed at AbbVie. We will focus on a couple of these technologies that were used to develop more robust processes in a shortened timeline. These examples also show how willingness to experiment with innovative technologies, coupled with intimate cross-functional collaboration and a focus on fundamentals, could enable solutions.

Both authors are employees of AbbVie and may own AbbVie stock. The design, study conduct, and financial support for this research were provided by AbbVie. AbbVie participated in the interpretation of data, review, and approval of the publication.

Development of a Sustainable Biocatalytic Process for the Manufacture of an Amino-Alcohol Intermediate in the Synthesis of Netabrutinib (MK-1026)

Jacob Forstater, Merck; Karla Camacho Soto, Merck; Michael Di Maso, Merck; Jeffrey Kuethe, Merck; Nadine Kuhl, Merck; Karthik Narsimhan, Merck; Christopher Prier, Merck

Enzymes are capable of highly unique and selective transformations that can enable sustainable chemical production. While many efficient industrial processes have been developed using free enzymes in aqueous solutions, immobilization of enzymes on a solid support can offer considerable advantages, including improved reaction efficiency, improved enzyme stability, the ability to perform reactions in non-aqueous media, and simplified separation of products from catalysts Here, we describe the development of packed bed reactor-based process which uses an immobilized transaminase to synthesize a key amine intermediate of a BTK inhibitor, nemtabrutinib (MK-1026). Enzyme immobilization streamlines protein-product isolation and enables transamination in an organic solvent which is critical to the isolation of the product. In this talk, we discuss how data-rich process development approaches and scale-down experimental models enabled rapid development and scale-up of a robust process that combines two renewable bio-based solvents (Cyrene and 2-MeTHF) with isopropylamine and an immobilized, evolved transaminase catalyst to produce a key pharmaceutical intermediate.

Pharmaceutical Peptide Drug Substance Purification Using Nanofiltration

Paridhi Agrawal, Eli Lilly; Kevin Seiber, Eli Lilly

Membrane-based separation is a widely used filtration technology for liquids and gases that serves industries ranging from wastewater treatment to food and agriculture, fine chemicals, and pharmaceutics. Pressure-driven membrane separation can be categorized based on membrane pore size and desired degree of separation. Organic solvent nanofiltration has recently garnered attention in the pharmaceutical industry for drug substance manufacturing. It is used for concentration, purification by removal of low molecular weight species, and solvent exchange by applying high pressure across a nano-porous membrane orthogonal to the bulk flow. For the processing of larger molecules such as proteins, monoclonal antibodies, and peptides where intermediate or final isolation becomes challenging, membrane filtration can be a powerful tool. It also aligns well with other upstream and downstream continuous unit operations to make the overall synthesis telescoped and aids in improving process control and throughput.

The metrics to assess NF process performance are cycle time and yield. The parameters that impact these include feed flow and crossflow rate, transmembrane pressure (TMP), temperature, membrane material and pore size (molecular weight cut off or MWCO), and viscosity of solvent system. Membrane selection is guided by the physical and chemical properties of the solvents and solutes involved in the process. If chemistry modifications are not possible, the only controllable process parameters are flowrate and TMP. Being a high-pressure technology, one challenge in NF is the loss of solute molecules to the permeate even after selection of a tight membrane. For applications of solvent purification, this can cause undesired contamination, and when solute retention is the application, this can cause undesired yield loss. To address the challenge of solute retention, membrane conditioning is performed using the process solution in total recycle mode wherein a solute layer forms on the membrane which acts as a secondary sieve. Since this polarization layer adds resistance in the system, it causes reduction of permeate flux and increases cycle time. Operating conditions such as TMP and crossflow rate need to be adjusted to balance the flux decay and yield loss. Another challenge in NF is the high working capital cost associated with frequent membrane replacement due to fouling.

In this work, we studied the effect of operating parameters on membrane fouling and solute retention during the concentration and purification of an ~2500 Da peptide molecule using 450 Da hydrophilic ceramic membranes. TMP and crossflow rate were modified to span the flow regime spectrum from laminar to turbulent, and low to high pressure. From experiments, we show that for this ratio of peptide size to membrane pore size, high crossflow velocity and low TMP aid in not only peptide retention but also prevention of membrane fouling. This in turn gives a robust purification process with high yield, fast cycle time, and improved membrane longevity.