Product Formulation & Characterization

The advent of biotechnology led to the development and introduction of biologics-based therapies (For example, Enbrel, Humira, Keytruda to name a few). In the past decade, new advances have brought several advanced therapeutic modalities (ATMs) including engineered cell therapy (Breyanzi®, Kymriah®), gene therapy (Imlygic®, Glybera®, Zolgensma® and Luxturna®) and LNP-based therapies (Onpattro®, Comirnaty®, SpikeVax®), which are uniquely positioned to address unmet medical needs and improve public health. ATMs account for approximately 20% of the global therapeutics pipeline and drove about $90 billion of potential deal value from 2020 through 2022 with drug sales (excluding Covid-19 vaccines) forecasted to reach up to $60 billion by 2027. 

 

A common thread across several cell and gene therapies, and LNP-based therapeutics is the requirement of frozen storage due to the limited stability of these modalities at refrigerated or room temperature conditions. This, in turn, poses significant cold chain challenges to enable the manufacture, storage, and distribution of these drug products. Such challenges include high cost, underdeveloped infrastructure, and limited capacity. In addition, certain ATMs like cell and gene therapy products need to be manufactured in multiple smaller batches rather than a single large batch, whereas LNP-based vaccines typically require the manufacture of millions of doses per year. In both cases, standard biomanufacturing and supply chain economics do not apply. 

 

To realize the full potential of ATMs, it will be critical to develop them as refrigerated lyophile product presentations. Very often, however, significant reformulation efforts may be required to enable freezedrying of cells, gene therapy vectors, and LNPs. As fundamental understanding of the mechanisms to stabilize these modalities in dried solids is lacking, the development of stable solid ATMs products requires significant efforts, which rely primarily on trial and error. The first step to address this gap is to systematically understand the solid-state behavior of ATMs especially as it relates to the impact of formulation components and processing conditions on quality attributes. While there have been efforts in the academia (Ref. 5-9) and the industry in the recent years to develop lyophile products of cells, viral vectors and LNPs, this field remains far from established, which underscores the need for a collective effort to advance it. 

 

The freeze-drying community is uniquely positioned to address this gap through fostering a collaborative effort across the biopharmaceutical industry, academia, regulators, government agencies and private foundations. To attain such collaboration, advocacy for research in this area to be a strategic priority for funding institutions in the government as well as the private sector is essential in order to incentivize academia to actively pursue this field of study. Biopharmaceutical companies will also need to leverage their development experience and work collaboratively to develop best practices in formulation and process development, and characterization of ATMs drug products. Finally, research advances and industry-driven best practices would naturally lead the development of regulatory guidance to address the novel aspects of ATM solid drug products. 

 

In parallel to efforts to advance the science of formulation and process development of solid ATMs, new analytical tools, drug delivery systems and primary packaging will also need to be developed to respond to such advances to enable patient-centric medicines. Bringing such products to patients will also require advances in emerging drying technologies and a trained workforce, which are also two focus areas of this roadmap that are closed tied to new product modalities.

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References:

1. HBR - A New Generation of Drug Therapies Requires New Business Strategies.

2. Boston Consulting Group - New Drug Modalities Offer Promise and Peril.

3. Deloitte - Distribution and Supply Chain Models in the Cell & Gene Therapy Landscape.

4. Zhang et al. Development of a stable lyophilized adeno-associated virus gene therapy formulation.

5. Rieser et al Systematic Studies on Stabilization of AAV Vector Formulations by Lyophilization.

6. Zhi et al. Lyophilization as an effective tool to develop AAV8 gene therapy products for refrigerated storage.

7. Muramatsu et al. Lyophilization provides long-term stability for a lipid nanoparticle-formulated, nucleoside-modified mRNA vaccine.

8. Shi et al. lyophilized lymph nodes for improved delivery of chimeric antigen receptor T-cells.