By Marites T. Woon (Associate Director, Nonclinical), Mialy Ramaroson (Director, CMC), Jessica Lee (Principal, Global Head Cell & Gene Therapy)
Welcome back to our exploration of the transformative world of exosomes in the second installment of our blog series. In our initial dive, we uncovered the intriguing potential of exosomes as dynamic messengers in intercellular communication, setting the stage for a deeper understanding of their applications in health and disease. Now, we shift our focus to a critical facet of exosome development in the context of cell and gene therapies: Chemistry, Manufacturing, and Controls (CMC). As we venture into the intricate landscape of CMC-specific considerations, we unveil the complexities involved in developing exosomes as cell-free therapeutic agents and delivery vehicles.
Join us on this journey as we dissect the vital components of Investigational New Drug (IND) applications, exploring the nuances of source and process, raw materials, reagents, and the pivotal role of characterization and specification. Navigating through the intricacies of CMC, we shed light on the challenges, recommendations, and forward-looking perspectives that pave the way for the development of these innovative products. Let’s delve into the core of CMC considerations for exosomes and uncover the pathway to harness their full therapeutic potential.
Exosomes are nanosized extracellular vesicles (EVs) with the potential to address various unmet medical needs. From neurological diseases to cancer, the potential of exosomes as therapies and drug delivery systems continues to gain momentum1. However, there are presently no exosome product(s) approved by the FDA2,3. Here, we share insights into CMC-specific considerations when navigating the complex nature of developing exosomes as cell-free therapeutic agents and delivery vehicles.
CMC Considerations for Investigational New Drug (IND) Applications
As we previously communicated4, CMC applies to the entirety of a product’s development lifecycle and, as such, it is critical that adequate information is provided during regulatory submissions. Within an IND application, CMC information is submitted as part of Module 3 for paper- and electronic Common Technical Document (eCTD)-based submissions to the appropriate review division. The CMC component of an IND application for products such as exosomes is typically comprised of drug substance (DS) and drug product (DP) manufacturing processes, analytical controls, characterization information, and stability data5.
At this juncture, it is critical that the CMC program demonstrate the reproducible or consistent manufacture of the high-quality product. This is typically achieved by developing highly controlled processes with qualified methods to characterize and assess the safety of the investigational product. To this end, we recommend taking into consideration various aspects of the CMC program below, early during development:
Source and Process
- Are the exosomes derived from plants or animals and from which cells?
- Is the cell source of GMP quality?
- Is the cell bank adequately qualified?
- Is human cell/tissue donor eligibility determination in compliance with Title 21 Code of Federal Regulations Part 1271 Subpart C?
- How are the exosomes separated from other EVs (or non-EV material) and enriched?
- Are adequate controls in place to prevent contamination at all stages of manufacturing?
- In the case of loaded exosomes, is the active substance genetically pre-loaded (e.g., producer cells expressing recombinant protein) or by other loading techniques (e.g., electroporation)?
- How is the loading process controlled to enable batch-to-batch reproducibility?
Raw Materials and Reagents
- What is the quality of the raw materials and process reagents used?
- Is a process in place to control for contamination or sterility?
- Are any animal-derived raw materials or excipients appropriately sourced and controlled to minimize risk of adventitious agents and transmissible diseases, including but not limited to spongiform encephalopathy?
- Is functional and impurity testing part of the raw materials/reagents specifications to control for batch-to-batch variability?
Characterization and Specification
- Which quality attributes are specific to the exosome product?
- What qualified method(s) is/are used to ensure the proper identity, potency, and purity of the product?
- How do the impurity profiles of the clinical and nonclinical lots differ?
During development, CMC-related aspects of the product may change and will need to be communicated to the FDA. Changes in manufacturing sites, processes, or formulation – for example – may:
- impact the critical quality attributes (CQAs) of the investigational product (e.g., identity, purity, stability, and potency)
- affect other essential aspects of product development such that additional nonclinical studies, for example, may be needed6
- require additional considerations regarding:
- the information needed to assure the investigational product’s characteristics given the potential inherent uncertainty with respect to product purity/identity; and
- how to best communicate such changes to the FDA.
Moving Forward with Exosomes
Given the complex nature of these investigational products and their potential clinical application, it is unsurprising that the path forward may not be as defined as other programs. To this end, it is important that Sponsors developing such innovative products are:
- well-organized – the availability and completeness of relevant CMC-related source documents (e.g., batch records and standard operating procedures) are critical in the authoring and submission of Module 3, and subsequent review by the FDA.
- collaborative – achieving key milestones such as an IND submission is often the result of a highly collaborative effort alongside subject matter experts (e.g., technical, and regulatory) across industries (e.g., CRO and CDMO).
As we conclude this blog looking at exosome development in Cell and Gene Therapy (CGT), the significance of Chemistry, Manufacturing, and Controls (CMC) comes into sharp focus. From IND applications to source specifics and reproducible manufacturing, we’ve navigated the complexities shaping exosome therapeutics. Looking forward, the evolving nature of CMC-related aspects prompts us to consider uncertainties and changes, emphasizing effective communication with regulators. Despite the less-defined path ahead, organizational efficiency and collaboration can pave the way for innovative products in the dynamic field of CGT.
To learn more about Cell & Gene Therapy product development, particularly regulatory considerations in the preclinical phase, check out our blog “A Regulatory Perspective on Cell and Gene Therapy in Oncology | Allucent
At Allucent, we shine a light on breakthrough therapies by solving the distinct challenges of small and mid-sized biotech companies. As a global provider of comprehensive drug development solutions, we offer a robust set of services including regulatory consulting, clinical operations, clinical pharmacology, and biometrics across a multitude of diverse therapeutic areas. Our individualized partnership approach provides experience-driven insights and expertise to assist clients in successfully navigating the complexities of delivering novel treatments to patients. Learn how the A-Team can support your drug development programs by exploring our website.
References
1 Rezaie J, Feghhi M, Etemadi T. A review on exosomes application in clinical trials: perspective, questions, and challenges. Cell Commun Signal. 2022 Sep 19;20(1):145.
2 U.S. Food & Drug Administration. Public Safety Notification on Exosome Products. Dec. 6, 2019. https://www.fda.gov/vaccines-blood-biologics/safety-availability-biologics/public-safety-notification-exosome-products.
3 U.S. Food & Drug Administration. Consumer Alert on Regenerative Medicine Products Including Stem Cells and Exosomes. Jul. 22, 2020. https://www.fda.gov/vaccines-blood-biologics/consumers-biologics/consumer-alert-regenerative-medicine-products-including-stem-cells-and-exosomes.
4 “The Essential Role of the CMC Expert.” Resources, Sept. 6, 2022. Allucent. https://www.allucent.com/resources/blog/the-essential-role-of-the-cmc-expert
5U.S. Food & Drug Administration. Guidance for Industry. Chemistry, Manufacturing and Control (CMC) Information for Human Gene Therapy Investigational New Drug Applications (INDs). Jan 2020. https://www.fda.gov/media/113760/download.
6 U.S. Food & Drug Administration. Guidance for Industry. Preclinical Assessment of Investigational Cellular and Gene Therapy Products. Nov 2013. https://www.fda.gov/media/87564/download.