ChemInform Abstract: Control Strategies for Synthetic Therapeutic Peptide APIs. Part II. Raw Material Considerations

Eggen, Ivo F.; Gregg, Brian T.; Rode, Harold; Swietlow, Aleksander; Verlander, Michael S.; Szajek, Anita

doi:10.1002/chin.201435278

Cited by 8 publications

(12 citation statements)

References 1 publication

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“…The industrialisation and regulation of Fmoc‐protected amino acid derivatives have led to a significant improvement in the quality of the 20 standard Fmoc‐protected amino acid building blocks . Most Fmoc amino acids are now available in remarkably high RP‐HPLC purity of >99% although a number of well‐documented side reactions can occur during the introduction of the Fmoc group to the N α ‐amine of an amino acid.…”

Section: Introductionmentioning

confidence: 99%

Advances in Fmoc solid‐phase peptide synthesis

Behrendt

White

Offer

2016

Journal of Peptide Science

589

426

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Today, Fmoc SPPS is the method of choice for peptide synthesis. Very‐high‐quality Fmoc building blocks are available at low cost because of the economies of scale arising from current multiton production of therapeutic peptides by Fmoc SPPS. Many modified derivatives are commercially available as Fmoc building blocks, making synthetic access to a broad range of peptide derivatives straightforward. The number of synthetic peptides entering clinical trials has grown continuously over the last decade, and recent advances in the Fmoc SPPS technology are a response to the growing demand from medicinal chemistry and pharmacology. Improvements are being continually reported for peptide quality, synthesis time and novel synthetic targets. Topical peptide research has contributed to a continuous improvement and expansion of Fmoc SPPS applications. Copyright © 2015 European Peptide Society and John Wiley & Sons, Ltd.

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Section: Introductionmentioning

confidence: 99%

Advances in Fmoc solid‐phase peptide synthesis

Behrendt

White

Offer

2016

Journal of Peptide Science

589

426

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“…As Boc‐SPPS requires the highly hazardous HF for cleavage of peptide resins [16] in recent decades Fmoc/ t ‐Bu SPPS [17] emerged as the prevalent peptide synthesis method. In fact, aided by efficient protocols [18,19] as well as wide availability of inexpensive Fmoc amino acids (AAs) on large scales [20] in qualities required for good manufacturing practice (GMP) manufacturing, [21] it is conceivable that the overwhelming use of the Fmoc as the preeminent α‐protecting group in peptide synthesis will continue for decades to come [22] . Nevertheless, from sustainability standpoint Fmoc/ t ‐Bu SPPS suffers from severe drawbacks, most notably the reliance on large quantities of hazardous dipolar aprotic (DA) solvents such as dimethylformamide (DMF) [12,23] .…”

Section: Methodsmentioning

confidence: 99%

Circular Aqueous Fmoc/t‐Bu Solid‐Phase Peptide Synthesis

Pawlas

Rasmussen

2021

ChemSusChem

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Circular economy and aqueous synthesis are attractive concepts for sustainable chemistry. Here it is reported that the two can be combined in the universal method for peptide chemistry, fluorenylmethoxycarbonyl(Fmoc)/t‐Bu solid‐phase peptide synthesis (SPPS). It was demonstrated that Fmoc/t‐Bu SPPS could be performed under aqueous conditions using standard Fmoc amino acids (AAs) employing TentaGel S as resin and 4 : 1 mixture of water with inexpensive green solvent PolarClean. This resin/solvent combination played a crucial dual role by virtue of improving resin swelling and solubility of starting materials. In a model coupling, TCFH and 2,4,6‐collidine afforded a full conversion at only 1.3 equiv. AA, and these conditions were used in SPPS of Leu enkephaline amide affording the model peptide in 85 % yield and 86 % purity. A method to recycle the waste by filtration through a mixed ion exchange resin was developed, allowing reusing the waste without affecting quality of the peptide. The method herein obviates the use of unconventional or processed AAs in aqueous SPPS while using lower amounts of starting materials. By recycling/reusing SPPS waste the hazardous dipolar aprotic solvents used in SPPS were not only replaced with an aqueous medium, solvent use was also significantly reduced. This opens up a new direction in aqueous peptide chemistry in which efficient use of inexpensive starting materials and waste minimization is coupled with the universal Fmoc/t‐Bu SPPS.

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“…Various unintended impurities can be produced under the complex and harsh conditions present throughout the manufacturing process for synthetic peptide therapeutics, from starting materials, synthesis, and purification as well as during the storage of the drug substance and drug product. ,,, These impurities can result from insertion, deletion, substitution, adduction, oxidation, dehydration, deamidation, isomerization, and racemization, etc. ,, Many of these impurities can be difficult to remove by the purification process.…”

Section: Synthetic Peptide Impuritiesmentioning

confidence: 99%

“…6,9,11,12 These impurities can result from insertion, deletion, substitution, adduction, oxidation, dehydration, deamidation, isomerization, and racemization, etc. 6,9,11 Many of these impurities can be difficult to remove by the purification process. Currently, there is no clear guidance on the threshold of identification, quantitation, and qualification of the impurities in peptide therapeutics.…”

Section: ■ Synthetic Peptide Impuritiesmentioning

confidence: 99%

Characterization of Synthetic Peptide Therapeutics Using Liquid Chromatography–Mass Spectrometry: Challenges, Solutions, Pitfalls, and Future Perspectives

Lian

Wang

Tian

et al. 2021

J. Am. Soc. Mass Spectrom.

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Synthetic peptides represent an important and expanding class of therapeutics. Despite having a relatively small size as compared to monoclonal antibodies and other proteins, synthetic peptides are subject to many complex structural modifications originating from the starting materials, manufacturing process, and storage conditions. Although mass spectrometry has been increasingly used to characterize impurities of synthetic peptides, systematic review of this field is scarce. In this paper, an overview of the impurities in synthetic peptide therapeutics is provided in the context of how the knowledge from detailed characterization of the impurities using liquid chromatography–mass spectrometry (LC–MS) can be used to develop the manufacturing process and control strategy for synthetic peptide therapeutics following the critical quality attribute (CQA)-driven and risk-based approach. The thresholds for identifying and controlling the impurities are discussed based on currently available regulatory guidance. Specific LC–MS techniques for identification of various types of impurities based on their structural characteristics are discussed with the focus on structural isomers and stereoisomers (i.e., peptide epimers). Absolute and relative quantitation methods for the peptide impurities are critiqued. Potential pitfalls in characterization of synthetic peptide therapeutics using LC–MS are discussed. Finally, a systematic LC–MS workflow for characterizing the impurities in synthetic peptide therapeutics is proposed, and future perspectives on applying emerging LC–MS techniques to address the remaining challenges in the development of synthetic peptide therapeutics are presented.

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ChemInform Abstract: Control Strategies for Synthetic Therapeutic Peptide APIs. Part II. Raw Material Considerations

Cited by 8 publications

References 1 publication

Advances in Fmoc solid‐phase peptide synthesis

Advances in Fmoc solid‐phase peptide synthesis

Circular Aqueous Fmoc/t‐Bu Solid‐Phase Peptide Synthesis

Characterization of Synthetic Peptide Therapeutics Using Liquid Chromatography–Mass Spectrometry: Challenges, Solutions, Pitfalls, and Future Perspectives

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