Pub Date : 2019-08-16DOI: 10.1039/9781788016445-00111
S. Kota
Peptides are manufactured commercially by liquid- or solid-phase peptide synthesis, by hybrid synthesis using both solid- and solution-phase synthesis or by using recombinant DNA technologies. The technology applied to commercial manufacturing is determined by the size and nature of the peptide. Since the impurities in peptides tend to be generally similar to those in the product of interest, downstream processing steps such as purification and isolation are significant for producing highly purified active peptide pharmaceutical ingredients that meet the stringent regulatory requirements.
{"title":"Chapter 5. Peptide Manufacturing Methods and Challenges","authors":"S. Kota","doi":"10.1039/9781788016445-00111","DOIUrl":"https://doi.org/10.1039/9781788016445-00111","url":null,"abstract":"Peptides are manufactured commercially by liquid- or solid-phase peptide synthesis, by hybrid synthesis using both solid- and solution-phase synthesis or by using recombinant DNA technologies. The technology applied to commercial manufacturing is determined by the size and nature of the peptide. Since the impurities in peptides tend to be generally similar to those in the product of interest, downstream processing steps such as purification and isolation are significant for producing highly purified active peptide pharmaceutical ingredients that meet the stringent regulatory requirements.","PeriodicalId":20009,"journal":{"name":"Peptide Therapeutics","volume":"21 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2019-08-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"72814020","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2019-08-16DOI: 10.1039/9781788016445-00472
Suzanne M. D'Addio, J. Bothe, E. Walsh, Marian E. Gindy
Achieving market approval of a new peptide therapeutic requires phase-appropriate demonstration of product safety, efficacy and quality across all stages of development, including raw materials, drug substance and drug product manufacture, product distribution and shelf-life. Of particular importance is the definition of a drug product formulation that meets requirements as defined by the Quality Target Product Profile (QTPP) and mitigates peptide-specific Chemistry, Manufacturing and Controls (CMC) liabilities. Peptide drug product formulations can range widely in complexity, but often require the inclusion of excipients that are selected to perform a number of functions, such as buffering pH, preserving sterility, mitigating chemical and/or physical instabilities of the peptide active substance or controlling the rate of peptide drug release upon administration in people. The choice of excipient(s) and composition(s) can impact multiple drug product attributes, which necessitates appropriate formulation characterization and data-driven decision-making regarding excipient use throughout development and ultimately in the final drug product. This chapter briefly surveys categories of excipients employed in therapeutic peptide formulation development, highlights guidance and regulations related to the selection and evaluation of such excipients and discusses the assessment and justification of excipient use in formulations, from discovery through development, with a focus on peptide-specific challenges in parenteral formulations.
{"title":"Chapter 13. Assessing the Impact of Functional Excipients on Peptide Drug Product Attributes During Pharmaceutical Development","authors":"Suzanne M. D'Addio, J. Bothe, E. Walsh, Marian E. Gindy","doi":"10.1039/9781788016445-00472","DOIUrl":"https://doi.org/10.1039/9781788016445-00472","url":null,"abstract":"Achieving market approval of a new peptide therapeutic requires phase-appropriate demonstration of product safety, efficacy and quality across all stages of development, including raw materials, drug substance and drug product manufacture, product distribution and shelf-life. Of particular importance is the definition of a drug product formulation that meets requirements as defined by the Quality Target Product Profile (QTPP) and mitigates peptide-specific Chemistry, Manufacturing and Controls (CMC) liabilities. Peptide drug product formulations can range widely in complexity, but often require the inclusion of excipients that are selected to perform a number of functions, such as buffering pH, preserving sterility, mitigating chemical and/or physical instabilities of the peptide active substance or controlling the rate of peptide drug release upon administration in people. The choice of excipient(s) and composition(s) can impact multiple drug product attributes, which necessitates appropriate formulation characterization and data-driven decision-making regarding excipient use throughout development and ultimately in the final drug product. This chapter briefly surveys categories of excipients employed in therapeutic peptide formulation development, highlights guidance and regulations related to the selection and evaluation of such excipients and discusses the assessment and justification of excipient use in formulations, from discovery through development, with a focus on peptide-specific challenges in parenteral formulations.","PeriodicalId":20009,"journal":{"name":"Peptide Therapeutics","volume":"29 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2019-08-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"77276767","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2019-08-16DOI: 10.1039/9781788016445-00031
René Thürmer
Synthetic peptides are of increasing importance as a class of substances used in medicinal products and the number of applications for marketing authorization has increased steadily in recent years. Based on European quality guidelines, international quality guidelines and European Pharmacopoeia (Ph. Eur.) requirements, it is discussed which data are relevant for synthetic peptides. The requirements for both marketing authorization applications and for clinical studies are addressed.
{"title":"Chapter 2. Regulatory Perspective on Synthetic Peptides in Europe","authors":"René Thürmer","doi":"10.1039/9781788016445-00031","DOIUrl":"https://doi.org/10.1039/9781788016445-00031","url":null,"abstract":"Synthetic peptides are of increasing importance as a class of substances used in medicinal products and the number of applications for marketing authorization has increased steadily in recent years. Based on European quality guidelines, international quality guidelines and European Pharmacopoeia (Ph. Eur.) requirements, it is discussed which data are relevant for synthetic peptides. The requirements for both marketing authorization applications and for clinical studies are addressed.","PeriodicalId":20009,"journal":{"name":"Peptide Therapeutics","volume":"86 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2019-08-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"75832172","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2019-08-16DOI: 10.1039/9781788016445-00343
O. Chahrour, Anna Meljon, D. Cobice
The development of suitable analytical tools is required to study the stability, manufacturability and bio-performance of peptide conjugate therapeutics. Mass spectrometric analysis provides essential knowledge for understanding and building the critical quality attributes and regulatory specifications of peptides. The purpose of this chapter is to provide an overview/update of mass spectrometric techniques (e.g. ion stripping and isotopic labelling) that are employed for the analytical characterization and quantitation of peptides and their conjugates such as PEGylated peptides and antibody–drug conjugates. Advances in high-resolution mass spectrometry (HRMS) have considerably increased the quality of analytical data on antibody–peptide drug conjugates [e.g. average drug-to-antibody ratio (DAR), drug loading distribution, unconjugated drug and impurity characterization via peptide mapping] that can be used for product and process development, lot release and stability testing. Similarly, the quality of PEGylated peptides can be evaluated via qualitative and quantitative mass spectrometric analysis to ensure that the PEGylated therapeutics have the desired properties such as molecular mass and polydispersity. In addition, relative or absolute mass spectrometric-based quantitation of peptides/peptide conjugates is very useful for assessing stability, label claim and batch-to-batch variability. Different strategies exploiting stable isotope labelling and isotope dilution are possible, each having specific strengths and weaknesses. Inductively coupled plasma mass spectrometry (ICP-MS) has recently emerged as a complementary technique to the previous methods allowing absolute protein quantification using suitable elemental-based tags.
{"title":"Chapter 10. Mass Spectrometric Analysis for the Quality Control of Peptide Conjugate Therapeutics","authors":"O. Chahrour, Anna Meljon, D. Cobice","doi":"10.1039/9781788016445-00343","DOIUrl":"https://doi.org/10.1039/9781788016445-00343","url":null,"abstract":"The development of suitable analytical tools is required to study the stability, manufacturability and bio-performance of peptide conjugate therapeutics. Mass spectrometric analysis provides essential knowledge for understanding and building the critical quality attributes and regulatory specifications of peptides. The purpose of this chapter is to provide an overview/update of mass spectrometric techniques (e.g. ion stripping and isotopic labelling) that are employed for the analytical characterization and quantitation of peptides and their conjugates such as PEGylated peptides and antibody–drug conjugates. Advances in high-resolution mass spectrometry (HRMS) have considerably increased the quality of analytical data on antibody–peptide drug conjugates [e.g. average drug-to-antibody ratio (DAR), drug loading distribution, unconjugated drug and impurity characterization via peptide mapping] that can be used for product and process development, lot release and stability testing. Similarly, the quality of PEGylated peptides can be evaluated via qualitative and quantitative mass spectrometric analysis to ensure that the PEGylated therapeutics have the desired properties such as molecular mass and polydispersity. In addition, relative or absolute mass spectrometric-based quantitation of peptides/peptide conjugates is very useful for assessing stability, label claim and batch-to-batch variability. Different strategies exploiting stable isotope labelling and isotope dilution are possible, each having specific strengths and weaknesses. Inductively coupled plasma mass spectrometry (ICP-MS) has recently emerged as a complementary technique to the previous methods allowing absolute protein quantification using suitable elemental-based tags.","PeriodicalId":20009,"journal":{"name":"Peptide Therapeutics","volume":"46 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2019-08-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"82235486","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2019-08-16DOI: 10.1039/9781788016445-00151
E. Lax, T. Shah
The outlook for peptide therapeutic drugs is bright. The range of medical indications is expanding and the rate at which peptide therapeutic drugs are being approved is increasing. New formulations and alternative delivery modalities are overcoming many of the inherent weaknesses of peptide-based pharmaceuticals. From many perspectives, peptide therapeutics are benefiting from the success of biologics. However, the sustainability of independent contract manufacturing of peptide-based new chemical entities (NCEs) for approved products and candidates in clinical trials is open to question given the consolidation in the industry over the last 20–30 years. At present, this specialized type of manufacturing activity is performed by only a few companies. This chapter analyzes the causes of the consolidation and examines the current economic and environmental issues that affect peptide therapeutic manufacturing.
{"title":"Chapter 6. Economic and Environmental Factors Affecting the Sustainability of Peptide Therapeutic Manufacturing","authors":"E. Lax, T. Shah","doi":"10.1039/9781788016445-00151","DOIUrl":"https://doi.org/10.1039/9781788016445-00151","url":null,"abstract":"The outlook for peptide therapeutic drugs is bright. The range of medical indications is expanding and the rate at which peptide therapeutic drugs are being approved is increasing. New formulations and alternative delivery modalities are overcoming many of the inherent weaknesses of peptide-based pharmaceuticals. From many perspectives, peptide therapeutics are benefiting from the success of biologics. However, the sustainability of independent contract manufacturing of peptide-based new chemical entities (NCEs) for approved products and candidates in clinical trials is open to question given the consolidation in the industry over the last 20–30 years. At present, this specialized type of manufacturing activity is performed by only a few companies. This chapter analyzes the causes of the consolidation and examines the current economic and environmental issues that affect peptide therapeutic manufacturing.","PeriodicalId":20009,"journal":{"name":"Peptide Therapeutics","volume":"29 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2019-08-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"90851400","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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