Following a model-centric strategy in the development of a manufacturing process for a new medicine empowers the simultaneous study of a large number of process parameters, which is large enough to exceed the capability of a graphic representation of the interactions across them. This work presents a discussion regarding the identification, description, and communication of multidimensional design spaces of high order. It introduces the reader to mathematical tools developed by the process systems engineering community that become relevant in the challenge to replace graphics as a means to describe and communicate a design space. Concepts like process f lexibility are discussed and illustrated. The paper also introduces geometric projection as a way to capture and describe the shape of the design space in an easier form (than that of the complete mechanistic model) that can be communicated to the regulator. An assessment is presented regarding the key elements communicated by a graphical representation of a design space, and alternate ways of conveying the same information using mathematics are suggested. These ideas are illustrated by applying them to the identification and definition of a design space for a chemical reaction step and the digital risk assessment for a packed bed adsorption step.

This work describes a modeling-aided approach to scale-up high-shear rotor−stator wet milling processes for pharmaceutical applications. A population balance equation was used that applies known breakage distribution functions and specific breakage rate to provide valuable insight into the significance of different scale-up factors to predict milling performance as well as the importance of accounting for flow-induced breakage in recirculation configurations. Case studies involved the size reduction of platelike and rodlike organic crystalline compounds.

Herein, ao ne-pot liquid phase peptide synthesis featuring iterative addition of amino acids to a" nanostar" support, with organic solvent nanofiltration (OSN) for isolation of the growing peptide after each synthesis cycle is reported. Ac ycle consists of coupling,F moc removal, then sieving out of the reaction by-products via nanofiltration in areactor-separator,orsynthesizer apparatus where no phase or material transfers are required between cycles.T he threearmed and monodisperse nanostar facilitates both efficient nanofiltration and real-time reaction monitoring of each process cycle.T his enabled the synthesis of peptides more efficiently while retaining the full benefits of liquid phase synthesis.P EPSTAR was validated initially with the synthesis of enkephalin-like model penta-and decapeptides,t hen octreotate amide and finally octreotate.T he crude purities compared favorably to vendor produced samples from solid phase synthesis.

The large-scale manufacture of complex synthetic peptides is challenging due to many factors such as manufacturing risk (including failed product specifications) as well as processes that are often low in both yield and overall purity. To overcome these liabilities, a hybrid solid-phase peptide synthesis/liquid-phase peptide synthesis (SPPS/LPPS) approach was developed for the synthesis of tirzepatide. Continuous manufacturing and real-time analytical monitoring ensured the production of high-quality material, while nanofiltration provided intermediate purification without difficult precipitations. Implementation of the strategy worked very well, resulting in a robust process with high yields and purity.

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