Peptide Therapeutics

Strategy and Tactics for Chemistry, Manufacturing, and Controls

Ved Srivastava, David Rotella, Ved Srivastava

• Publisher: Royal Society of Chemistry
• Year: 2019
• ISBN:
  9781788018692
• Edition: 1
• Topic: Biological Sciences
• Subtopic: Biology
• Index: Biological Sciences

Peptide therapy has become a key strategy in innovative drug development, however, one of the potential barriers for the development of novel peptide drugs in the clinic is their deficiencies in clearly defined chemistry, manufacturing and controls (CMC) strategy from clinical development to commercialization. CMC can often become a rate-limiting step due to lack of knowledge and lack of a formal policy or guidelines on CMC for peptide-based drugs. Regulators use a risk-based approach, reviewing applications on a case-by-case basis.
Peptide Therapeutics: Strategy and Tactics for Chemistry, Manufacturing, and Controls covers efficient manufacturing of peptide drug substances, a review of the process for submitting applications to the regulatory authority for drug approval, a holistic approach for quality attributes and quality control from a regulatory perspective, emerging analytical tools for the characterisation of impurities, and the assessment of stability.
This book is an essential reference work for students and researchers, in both academia and industry, with an interest in learning about CMC, and facilitating development and manufacture of peptide-based drugs.

CHAPTER 1

Regulatory Considerations for Peptide Therapeutics

LARISA WU

Office of Pharmaceutical Quality, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, MD 20993, USA

Email: [email protected]

1.1 Introduction

Being at the borderline between typical small molecules and large proteins, peptides have raised a series of regulatory challenges. Although the use of the term “peptide” varies in the scientific literature outside the regulatory framework, the currently used regulatory definition delineates that peptides are α-amino acid polymers with specific defined sequences, 40 amino acids or fewer in size, and regardless of their production method (synthetic or of recombinant DNA origin). Despite the pharmaceutical industry's interest in peptides as drug candidates, specific regulatory challenges persist, especially related to establishing their quality standards. Moreover, current US Food and Drug Administration (FDA) and International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) guidelines regarding the quality of pharmaceutical products do not include peptides. This chapter presents an overview of the approval process for New Drug Applications (NDAs) and Abbreviated New Drug Applications (ANDAs) as pertaining to the quality of peptide drugs.^1,2

1.2 Peptide Quality Assessment at the FDA

The FDA Center for Drug Evaluation and Research (CDER) is in charge of timely assessment of all data submitted by applicants relevant to the safety, efficacy and quality of peptide drug products. Within the CDER, the quality information in marketing applications [also known as the Chemistry, Manufacturing and Controls (CMC) section] is under the purview of the Office of Pharmaceutical Quality (OPQ). The OPQ assesses the identity, strength, quality and purity of peptide drug substances and products by integrating their review, inspection, surveillance, policy and research and creating the parity of quality between new drug products, generic drug products.³

1.3 Overview of the Current Drug Approval Process Employed for Peptide Applications

When a peptide drug product application is submitted to the FDA, it is the responsibility of the applicant to provide evidence that the peptide product under evaluation is safe, effective, and of high quality. Once an application has been submitted for review, OPQ regulators have the responsibility to assess the quality of the peptide drug with respect to its impact on the safety and efficacy by taking a stepwise risk analysis approach. This approach includes (1) understanding the complexity of the peptide and its clinical use, (2) evaluating the process- and product-related factors that may impact the safety and efficacy of the proposed peptide product and (3) determining whether additional studies (in vitro or in vivo) are needed to address any residual uncertainty related to the safety of the peptide product. This is not a “one size fits all” approach, but rather a case-by-case analysis depending on factors characteristic of each different peptide.²

As with any other drug product, the overall peptide drug development and approval process generally follows pre-defined steps: (1) preclinical investigation, (2) clinical investigation, (3) post-approval marketing surveillance and (4) life-cycle management.¹ An overview of the stages of drug development, relevant application submissions and corresponding regulatory paths as applicable to peptides is provided below.⁴

Before any clinical investigations regarding a new peptide may begin, the applicant must submit an Investigational New Drug (IND) application. Clinical investigations, as planned and documented through the IND process, generally consist of three phases: Phase I, in which safety studies are conducted in a small number of individuals (20–200 people); Phase II, in which efficacy studies begin in volunteers (up to several hundred people) of the target population; and Phase III, in which human testing continues in a significant number of patients (several hundred to several thousand people).⁴ Once Phase III is complete, the applicant will submit an NDA under Section 505(b)(1) of the Federal Food, Drug, and Cosmetic Act (FDCA) including all collected clinical and nonclinical data. If an applicant intends to rely, to any extent, on safety or effectiveness investigations that were not conducted directly by or for the applicant, the NDA may be submitted in accordance with FDCA Section 505(b)(2).¹

Upon approval, the drug product can be marketed. Any subsequent modifications to an approved application should be submitted to the FDA for assessment as post-approval changes or supplements. After NDA approval, the next stage in the life cycle of a drug product happens when all forms of exclusivity (e.g. patent protection) have expired for the “innovator” or “reference listed” drug. At that point, under FDCA Section 505(j), the Reference Listed Drug (RLD) may be cited in an ANDA submitted for marketing a generic version of the drug product. An ANDA contains information to show that the proposed generic product is therapeutically equivalent and thus interchangeable with the RLD, specifically in terms of active ingredient, dosage form, strength, route of administration, labeling, quality, performance characteristics and intended use. “Bioequivalence,” provides the basis for establishing product interchangeability. Through reliance on bioequivalence, generally, ANDAs do not require significant amounts of time and money that would be normally needed for the submission of NDAs.¹

1.3.1 The New Drug Application Assessment Process

NDAs submitted to FDA for assessment should comprehensively provide all clinical and nonclinical data collected during drug development efforts that were undertaken by or on behalf of the applicant. CDER assessors will evaluate these data to decide whether adequate evidence has been established with regard to safety, efficacy, risk–benefit profile, proposed labeling and quality.⁶

1.3.1.1 INDs and Presubmission of NDAs

Before starting any of the clinical trials essential for providing data to be included in the NDA, applicants are required to have submitted an IND; the IND should summarize evidence of safety and efficacy from preclinical studies and should demonstrate the preparedness of investigators for clinical trials.⁷ The most relevant INDs to broad discussions of drug development and regulations are “investigator” INDs. An investigator IND is initiated by a physician who leads the investigation and decides how the investigational drug is administered. An investigator IND can be submitted for an unapproved drug or to investigate an approved drug for a new indication or new patient population. Other IND types, such as emergency use INDs (for patients who do not meet enrollment criteria for an existing study protocol) and treatment INDs (for patients with serious and life-threatening conditions), are also essential in terms of public health as they expand access to experimental drugs.¹

Good communication between an applicant and the FDA can greatly facilitate the process of “filing” an IND. A “fileable” IND must provide information about the investigational drug manufacture, data from animal pharmacology and toxicology studies, and the proposed clinical investigation protocols, including investigator information. The IND should be submitted to the FDA at least 30 days before the in-human trials are initiated. If an answer is not received from the FDA within 30 days, the applicant may proceed with clinical trials according to the IND. If the FDA has any concerns about the way clinical trials are conducted or about their resultsin the IND, a “clinical hold” may be imposed. Successfully elaborated clinical development, per IND regulations, will typically originate from complete Phase I, II, and III clinical investigations.⁵ The FDA assessment of Phase I focuses on product safety, whereas assessment of Phase II and III submissions includes evaluation of efficacy, clinical investigations, and the prospect of meeting the regulatory standards for marketing approval.¹

In a peptide IND, FDA regulators evaluate the quality information by assessing whether chemistry and manufacturing data related to the peptide drug substance and peptide drug product may indicate health risks to subjects enrolled in IND trials.⁸ Quality information related to peptide drug substance and peptide drug product is provided in a summary report, containing physical, chemical and biological characteristics relevant to the peptide, composition of the peptide drug product, a brief description of the manufacturing process, and acceptable controls and analytical methods used to assess peptide identity, strength, quality, purity and stability.¹ The applicant should also demonstrate that it can adequately produce and supply batches of the peptide drug product, that the proposed peptide drug product is reasonably safe for initial testing in humans, and that the clinical investigators are qualified to perform their responsibilities as assigned during the trial. The amount of the quality information usually varies with the phase and scope of the clinical investigation, but it is expected that this information will be thoroughly documented upon submission of a peptide NDA.¹

1.3.1.2 Format and Content of the NDA

The intent of the NDA is to provide FDA with documentation of data gathered during animal and human clinical investigations. The format and content of NDAs submitted to the FDA are specified in regulations (21 CFR 314.50) and reflected in the form FDA 356(h), used for all drug products including peptides.⁹ The contents and the specifics of a peptide NDA are as follows.¹

• 1. Index – The index gu...

Table of contents

• Cover
• Title Page
• Copyright
• Preface
• Editor Biography
• Contents
• Chapter 1 Regulatory Considerations for Peptide Therapeutics
• Chapter 2 Regulatory Perspective on Synthetic Peptides in Europe
• Chapter 3 Biological and Immunogenicity Evaluation Strategy for Therapeutic Peptides: Chemistry, Manufacturing and Controls Perspective
• Chapter 4 Chemistry, Manufacturing and Controls: Active Pharmaceutical Ingredient and Drug Product
• Chapter 5 Peptide Manufacturing Methods and Challenges
• Chapter 6 Economic and Environmental Factors Affecting the Sustainability of Peptide Therapeutic Manufacturing
• Chapter 7 A Holistic Quality Control Strategy for Peptide Active Pharmaceutical Ingredients (APIs)
• Chapter 8 Higher-order Structure Characterization and Comparability Assessments for Peptides
• Chapter 9 Impurity Characterization and Quantification by Liquid Chromatography–High-resolution Mass Spectrometry
• Chapter 10 Mass Spectrometric Analysis for the Quality Control of Peptide Conjugate Therapeutics
• Chapter 11 Determination of the Identity, Content and Purity of Therapeutic Peptides by NMR Spectroscopy
• Chapter 12 Transport, Stability and Delivery Considerations for the Design of Peptide Drugs
• Chapter 13 Assessing the Impact of Functional Excipients on Peptide Drug Product Attributes During Pharmaceutical Development
• Chapter 14 Formulations of Microspheres and Nanoparticles for Peptide Delivery
• Subject Index