Preface

Peptide therapy has become a key strategy in innovative drug development. However, one of the potential barriers for the development of novel peptide drugs is that they may lack a clearly defined Chemistry, Manufacturing and Controls (CMC) strategy encompassing pre-clinical development through to commercialization. CMC can often become a rate-limiting step for peptide-based drug development owing to a deficiency in knowledge and/or a lack of formal policies or CMC guidelines.

More than 70 peptide drugs have been approved for marketing and more than 150 peptide molecules have entered into clinical trials for a wide variety of therapeutic indications, including metabolic, cardiovascular, oncological and central nervous system diseases. Most of the commercial successes have been in metabolic diseases and oncology and include the insulin analogs NovoLog^® (insulin aspart), Humalog^® (insulin lispro), Victoza^® (liraglutide), Byetta^® (exenatide), Lupron^® (leuprolide), Sandostatin^® (octreotide) and Forteo^® (teriparatide). In recent years, peptidomimetic inhibitors of intracellular proteases such as Kyprolis^® (bortezomib) and Ninlaro^® (ixazomib) have also been approved for commercialization. Despite these successes, specific regulatory challenges remain that are often related to managing quality standards. These challenges are due in part to a lack of official regulatory guidelines for peptide drugs, as there are no current FDA or ICH guidelines that address the quality of pharmaceutical peptide products. Regulators frequently use a risk-based approach applied on a case-by-case basis when reviewing NDAs (New Drug Applications) or ANDAs (Abbreviated New Drug Applications).

The system for regulating medicines in Europe is unique. It is based on a closely coordinated regulatory network of competent national authorities in the Member States of the European Economic Area (MS-EEA) working together with the European Medicines Agency (EMA) and the European Commission. A network of more than 4500 experts appointed by the EU Member States guarantees the high-standard of scientific assessment of medicines.

This book on peptide therapeutics provides a holistic approach to strategy and tactics for CMC. The book is focused on covering four key areas in 14 chapters: (1) the regulatory process in both the USA and Europe and guidelines including immunogenicity evaluation strategy (Chapters 1–3), (2) challenges in the manufacturing process, CMC overview and economic and environmental impact (Chapters 4–6), (3) holistic quality control strategy, novel techniques for characterization of peptide impurities and stability testing (Chapters 7–11) and (4) peptide design, the impact of functional excipients on peptide formulation and nanoparticles for peptide delivery (Chapters 12–14). The extensive references cited in each chapter offer additional detail on the subject matter.

This book is an essential reference for students and researchers, in both academia and industry, to facilitate development and manufacturing of peptide-based drugs using regulatory requirements. The goal of this book is to provide a valuable resource and reference, not only for the peptide researcher engaged in peptide-based drug development and peptide manufacturing, but also for young scientists learning the CMC and regulatory process as it relates to the development of peptide-based medicines.

The chapters are written by well-known key opinion leaders from the US Food and Drug Administration (FDA), the Federal Institute for Drugs and Medical Devices in Europe, Lilly, Merck, Amgen, Contract Manufacturing Organizations (CMOs) – Polypeptide and Bachem, and analytical chemistry Contract Research Organization (CROs) – Teva and Almac, etc. Short synopses of each chapter are presented below.

1. The chapter on Regulatory Considerations for Peptide Therapeutics in the USA presents an up-to-date overview of the approval process for New Drug Applications (NDAs) and Abbreviated New Drug Applications (ANDAs) as it pertains to peptide drugs at the FDA. The chapter also provides a review of practice, format and content of NDAs and ANDAs, including challenges with Drug Master Files (DMFs). It emphasizes the special approval pathways such as orphan drug designation programs and pediatric exclusivity, post-approval activities and life-cycle management of peptide drugs.

2. The chapter on Regulatory Perspective on Synthetic Peptides in Europe addresses European Quality guidelines and International Quality guidelines, including European Pharmacopoeia (Ph. Eur.) requirements. The chapter also covers control strategy and the requirements for clearly differentiated relevant data and documentation for synthetic peptides for a clinical trial application or a marketing authorization dossier for Investigational Medicinal Products (IMPs).

3. The Biological and Immunogenicity Evaluation Strategy for Therapeutic Peptides: CMC Perspective chapter covers immunogenicity evaluation as an essential part of peptide-based therapeutic development and assessment of the immune response against therapeutic biologics using various methodologies such as enzyme-linked immunosorbent assay (ELISA), surface plasmon resonance (SPR), chemiluminescence and flow cytometry assays for binding antibodies and cell-based assays for neutralizing antibodies.

4. The Chemistry, Manufacturing and Controls: Active Pharmaceutical Ingredient (API) and Drug Product (DP) chapter summarizes the CMC topics for active pharmaceutical ingredients and drug products in general and discusses the distinct activities required, including the risk management at each clinical phase (Phase I, Phase II and Phase III) from development to commercialization.

5. The chapter Peptide Manufacturing Methods and Challenges illustrates different manufacturing technologies on a commercial scale, addressing the challenges of meeting regulatory standards while satisfying commercial viability and challenges in the upstream synthesis and downstream purification process of manufacturing.

6. The Economic and Environmental Factors Affecting the Sustainability of Peptide Manufacturing chapter provides an analysis of the causes of industry consolidation through an examination of current economic and environmental issues that affect peptide therapeutic manufacturing. The chapter also discusses the generic and NCE markets trend for peptide therapeutics, advances in commercial manufacturing methods, the economics of peptide manufacturing, factors for sustaining a profit and green chemistry, and waste disposal. Finally, it emphasizes the need for a more efficient and rational use of resources.

7. The chapter A Holistic Quality Control Strategy for Peptide APIs outlines the principles of process design and development as a comprehensive control strategy and emphasizes how to achieve critical quality attributes (CQAs) consistently given the complexity and variability of the manufacturing process. It addresses the idea that “consistent quality cannot be tested-in, but rather must be built-in by design,” according to FDA guidance. The approach utilizes process design through the practical application of a quality target product profile (QTPP), quality by design (QbD) and identification and mitigation of risks.

8. The chapter on Higher-Order Structure Characterization and Comparability Assessments for Peptides addresses the advantages and limitations of different analytical methodologies for the study of higher-order peptide structures. The application of orthogonal techniques such as intrinsic fluorescence spectroscopy and differential scanning calorimetry for secondary and tertiary structure and the application of techniques such as self-association, micro-flow imaging (MFI), asymmetric flow field-flow fractionation (AF4) and compositional gradient multi-angle light scattering (CG-MALS) for elucidating quaternary structure are reviewed.

9. The chapter on Impurity Characterization and Quantification by LC-HRMS covers liquid chromatography coupled with high-resolution mass spectrometry (LC-HRMS) as an approach that can be used as part of the analytical framework to ensure proper quality control of peptide drug products, including the assessment of peptide-related impurities. The chapter illustrates the suitability of LC-HRMS with three case studies: salmon calcitonin, bivalirudin and exenatide drugs.

10. The chapter on Mass Spectrometric Analysis for the Quality Control of Peptide Conjugate Therapeutics summarizes advances in HRMS and provides an overview of special techniques (e.g. ion stripping and isotopic labeling) that are employed for the analytical characterization and quantitation of peptides, including conjugates such as PEGylated peptides and antibody–drug conjugates.

11. The chapter on Identity, Content and Purity of Therapeutic Peptides by NMR Spectroscopy describes the application of 1D and 2D NMR spectroscopy for the determination of the identity, content, structure and purity of peptides and how NMR is used for the determination of unrelated impurities such as process-related impurities and extractable/leachable compounds.

12. The chapter on Transport, Stability and Delivery Considerations for the Design of Peptide Drugs addresses key stability and pharmacokinetic considerations for the development of peptide drugs and identifies approaches and methodologies for their assessment in preclinical research and development. The chapter also covers current and emerging chemistry strategies, assumptions for druggability with a peptide modality and alternative routes of administration, such as oral, pulmonary, nasal and transdermal, using cost-effective dosage forms.

13. The chapter Assessing the Impact of Functional Excipients on Peptide Drug Product Attributes During Pharmaceutical Development discusses drug product formulation with appropriate choices of excipient(s) and composition(s) impacting the Quality Target Product Profile (QTPP) and mitigating peptide-specific CMC liabilities. This chapter highlights guidance and regulations related to the selection and evaluation of novel excipients, quality risk assessment and management and risk evaluation and mitigation in formulation development from discovery through development phases.

14. The final chapter, on Formulations of Microspheres or Nanoparticles for Peptide Delivery, describes the significance of nanoparticles for an alternative delivery system for peptide and protein drugs. Different types of microspheres, their preparation, characterization, factors affecting drug delivery and mechanism of drug delivery are described. Case studies using peptide drugs such as leuprolide, triptorelin, octreotide, lanreotide, human growth hormone, buserelin, abarelix and exenatide are provided.

I would like to thank and express my sincere gratitude to all the authors who have contributed to this edition of Peptide Therapeutics: Strategy and Tactics for Chemistry, Manufacturing and Controls for their hard work in writing each chapter and most importantly for sharing their expertise with a broad spectrum of readers. Thanks are also due to Drew Gwilliams and Katie Morrey at the Royal Society of Chemistry for their guidance and support.

My special thanks go to Professor Bradley Pentelute, Massachusetts Institute of Technology, for providing editorial recommendations for the book. I dedicate this book to my parents (Shravan and Kusum) for their encouragement and my wife (Nisha) and children (Aaron and Nikita) for their continued support.

Ved Srivastava

Intarcia Therapeutics

Research Triangle Park, Durham, NC, USA