An Optimized Scalable Fully Automated Solid-Phase Microwave-Assisted cGMP-Ready Process for the Preparation of Eptifibatide

Giuseppina Sabatino,Matteo Zini,Annunziata D’Ercole,Anna Maria Papini,Alfredo Paio,Paolo Rovero,Arianna Ribecai,Lorenzo Pacini

doi:10.1021/acs.oprd.0c00490

Abstract

We investigated several strategies, based on the use of microwave-assisted solid-phase peptide synthesis (MW-SPPS) and scalable to kilogram-scale manufacturing, for the preparation of Eptifibatide,...

Highlights

The need of new, specific, safe and well-tolerated medicines led several pharmaceutical companies to move toward peptidebased drugs.[1,2] In the past few years the U.S Food and DrugAdministration (FDA) approved 15 new peptides or peptidecontaining drugs (7% of the total number of drugs).[3]since many patents of peptide drugs are expiring, a large number of generic peptide drugs are entering the market or are expected to do so in the near future
Peptide manufacturers need to improve their processes both chemically and economically, that is, in terms of profitability: such remarkable advancement can be achieved being able to optimize the solid-phase synthesis of an active peptide as pharmaceutical ingredient on a laboratory scale and to perform the same synthesis on the larger scale, up to hundreds of times, with the same efficiency in terms of peptide quality and impurities profile. This unique goal can be reached by automated microwave-assisted solidphase peptide synthesis (MW-solid-phase peptide synthesis (SPPS)), as proven by several experimental evidence (Jon Collins’ personal communications from CEM, U.S.A.)
Intermediate-scale peptide synthesis is no longer required and the optimized synthetic strategy can be directly scaled up from grams to multigrams/ kilograms. With these considerations in mind, in the present paper we focused our interest to the scale-up from R&D multigram-scale of the active peptide ingredient Eptifibatide by the microwave-assisted solid-phase synthesizer (Liberty Blue CEM, Charlotte, NC, U.S.A.), affording and solving both technical and economic issues, to transfer the technology to an industrial kilogram-scale production plant based on the recently engineered Liberty PRO (CEM, Charlotte, NC, U.S.A.), allowing fully automated, production scale, microwave synthesis with full current Good Manufacturing Practice (cGMP) compatibility

Summary

Introduction

The need of new, specific, safe and well-tolerated medicines led several pharmaceutical companies to move toward peptidebased drugs.[1,2] In the past few years the U.S Food and DrugAdministration (FDA) approved 15 new peptides or peptidecontaining drugs (7% of the total number of drugs).[3]since many patents of peptide drugs are expiring, a large number of generic peptide drugs are entering the market or are expected to do so in the near future. Administration (FDA) approved 15 new peptides or peptidecontaining drugs (7% of the total number of drugs).[3]. The large-scale manufacturing of peptides as APIs, requiring full compliance with cGMP regulations,[7] leads pharmaceutical companies to face many challenges related to the complexity of peptide synthesis in terms of size, modifications, conjugation methods, stability, and purity. This requires on one hand the development of robust manufacturing processes and on the other hand keeping production costs at a reasonable level

Objectives

Results

Conclusion