Formulation, manufacturing and regulatory strategies for extracellular vesicles-based drug products for targeted therapy of central nervous system diseases

ABSTRACT

Introduction

Extracellular vesicles (EVs) are a family of natural nanosize vesicles that transport biological cargos, including DNA, RNA, protein, and lipids. In recent years, EVs have attracted a lot of attention for their capability to function as a drug delivery system (DDS). While clinical trials have been conducted, the techniques to formulate, process, and quality control EVs-based drug products still have the potential to be improved, especially in large scale production.

Areas covered

We will introduce and discuss EVs biology, their potential role in CNS pathologies under different conditions, and recent methods of isolation. We will then provide a detailed discussion on current benchtop formulation methods, quality control methods, and regulatory affairs for EVs-based drug products.

Expert opinion

Despite being a hot topic, EVs-based drug products have not received any approval from regulatory agencies. In this review, we will provide general guidance to help EVs-based drug products to ‘move from bench to bedside’.

KEYWORDS:

• Extracellular vesicles
• CNS pathologies
• drug delivery systems
• drug encapsulation
• quality control
• large scale production
• regulatory approval
• cleanroom technology
• facilitated regulatory pathways
• cGMP

Article highlights

• Extracellular vesicles (EVs) are natural carriers for biological molecules. They can be used as drug delivery systems (DDS) to provide target delivery and reduce systemic side effects.

• Extracellular vesicles (EVs) have been proved to successfully carry small molecules, nucleic acids, peptides, and proteins for drug delivery.

• Direct inoculation, sonication, electroporation, freeze-thaw, extrusion are the most investigated drug loading methods into EVs. Drug loading capacity and efficiency are determined by the cargo’s characteristics, processing method, and final purification method.

• Quality control is the major missing section for current EVs based drug products, which is required by most pharmaceutical regulatory agencies including US-FDA.

• EVs based drug products may be eligible for special regulatory pathways to translate from ‘bench’ to ‘bed’ in a faster manner.

• In the current COVID-19 pandemic, EVs can be used to provide target delivery of anti-retroviral agents LPV/RTV to reduce systemic side effects in high doses.

Reviewers disclosure

Peer reviewers on this manuscript have no relevant financial relationships or otherwise to disclose.

Declaration of interest

The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Additional information

Funding

The funding was obtained from the National Institute of Health grant [DA047178]; The Plough Center for Sterile Drug Delivery Solutions, Universiy of Tennessee Health Science Center.