May the Outsource Be With You

The breadth and availability of cell and gene therapies (CGTs) is advancing at a historic pace as more of these treatments move from research to full-scale manufacturing. Though FDA-approved CGTs represent only a small fraction of conventional drugs, the forecasted growth rates are staggering. Sales of conventional drugs and non-CGT biologics are expected to achieve five percent compound annual growth rate (CAGR) from 2022 to 2028, while CGTs are forecasted to achieve a CAGR of up to 46 percent, an estimated $86 billion in sales, by 2028. (1)

It’s an exciting but also challenging time. The high expense of manufacturing these therapies stresses the economic viability of scaling to commercial production and broad clinical usage. To solve these cost and scaling issues, we will need to address many technical, quality, and logistical issues – including a lack of manufacturing capacity and regulatory adherence.

One solution that has risen to the top for CGT companies, small and large, is outsourcing development and manufacturing. CDMOs have specialized manufacturing knowledge, as well as the right infrastructure and quality control processes – and the option is always open for customers to bring manufacturing back in house.

Here, we discuss what we believe to be some of the key advantages that outsourcing can bring to cell and gene therapy development. 

The raw material benefits
 

Manufacturing workflows for cell and gene therapies increasingly require specialized lipids, proteins, and reagents that are not related to traditional therapeutic modalities. With the importance of cost efficiency clear, chemical and single-use providers are receiving more and more requests for cGMP grades of materials that previously were not needed at scale or to cGMP specifications. As CDMOs often manage several sponsor projects, their scale can drive collaboration with providers to develop new materials and to implement improvements in raw material inputs – balancing the additional costs of cGMP grade raw materials with potential savings in time and labor. 

Although there is considerable raw material expense associated with some components, such as plasmid DNA, transfection reagents, and enzymes (2), the greater danger lies in changing any materials at a late stage in clinical development. Late changes can result in batch failure or process variability, leading to delays and added expense. In addition, cell and gene therapies are more sensitive to degradation than other modalities. In the case of cellular therapies, biological activity must be retained, which limits the use of harsh purification methods. This special sensitivity requires raw materials that meet critical performance specifications from the supplier, so potentially harmful or adventitious agents are kept out of the supply chain. Reliable access to materials of the correct analytical grade is, therefore, more critical than ever before to overcome potential supply bottlenecks. Working with material suppliers during CGT therapeutic process development and using external suppliers for hydration management and other customized materials allows for greater portability of therapeutic manufacturing to other partners and global manufacturing sites. 

To do this effectively, choosing a globally established material supplier is best, because they will likely offer necessary redundancies and supply chain security, such as multiple sites qualified for materials, access to new sources of materials, and the ability to hold inventory in strategic locations. CDMOs are also very good at choosing the right material suppliers. 

Efficiencies in manufacturability
 

If cell and gene therapies are to become widely used across the population, innovation in process technology is essential. Process standardization has helped other biologics, such as monoclonal antibodies, advance – increasing recoveries consistently to 90 percent or more (3). In cell and gene, making the leap to standardized production systems in downstream workflows, through a platform approach, can also improve yields at scale. This gain in efficiency has been seen across the CDMO industry with flexible platforms being marketed in the viral vector space. But furthermore, outsourcing with a contractor that is both a materials and single-use manufacturer provides additional guidance on where to adopt technical, quality, and regulatory best practices from more established therapies.

Implementing closed and automated systems can lead to significant process improvements and help eliminate risk. Any manual operation represents a significant failure mode and could be overcome with a custom-designed process using a closed system. Vector propagation, purification, and cell line optimization are additional examples of steps that need improvement. Here, an effective partner that has a solid understanding of the contribution of labor, overheads, and possible economies of scale from reducing processes will be able to help accelerate development. 

In a constantly changing landscape, large biopharmaceutical manufacturers producing traditional therapies have a deep bench of experts to optimize workflows in several important areas, including process engineering, production chemicals and excipients, and single-use technologies. In the cell and gene space, expertise is still limited. Many of the companies developing these therapeutics are small to medium size (4), making them more likely to benefit from the expertise of a service provider.

To invest in infrastructure – or not
 

Internal manufacturing of biologics requires a substantial investment that can tie up capital for years before a return is realized – if the product makes it to market. The specialized manufacturing facility itself, high-end equipment, procurement, and warehousing of consumables, and specially trained and qualified employees, require an enormous amount of cash to establish. 

Large pharma with established facilities can often re-purpose manufacturing capacity to new trial therapeutics and are more insulated from single candidate trial failures. On the other hand, many new cell and gene companies have no or few therapeutics on the market. Additionally, as these therapeutics pipelines are likely in an early phase and the performance of the candidates is uncertain, there are many unknowns regarding the size of manufacturing space needed. When considered with the high turnover of company acquisition and dissolution, individual investment in large-scale manufacturing facilities may be seen as nonviable for many players in the cell and gene space.

To meet the need of companies with investigational pipelines, some CDMOs specialize in single-batch, rapid production of therapeutic candidates and have specialized scaling methodologies. For late phase and commercial production, other CDMOs offer reserved suites for long-term manufacturing. 

However, there has also been recent examples of companies with on-the-market cell and gene therapeutics bringing manufacturing back in-house. This is likely due to the desire to further control quality in-house and that the need to regularly produce the same therapeutic significantly reduces the financial risk of investment into specialized manufacturing facilities. Further, the mentioned benefits of having, and paying for, an external manufacturer may, in some instances, fade as processes are firmly established and optimized, while the benefit of having complete control of production timelines to meet consumer demand increases. In other circumstances, some companies may also need to move their therapeutic from one CDMO to another. If companies rely solely on their CDMO partner for all development, material handling, and preparation, they may experience significant delays and challenges when shifting manufacturing bases. In this case, it may be more effective to partner with an independent service provider/material supplier that can service both the therapeutic developer and the CDMO manufacturer.

It is certainly an exciting time for the cell and gene therapy field – with many therapeutics in trials using a plethora of technologies and being developed by an innovative, young pharma sector. With rapidly evolving pipelines that are predominately pre-revenue, these cell and gene companies are better equipped to expend resources on therapeutic development rather than take on the challenges associated with clinical trials and commercial-scale manufacturing. This phase is resource intensive and has a concerted focus on staffing with experienced production engineers.

Outsourcing to experienced manufacturers and chemical/material suppliers that can better implement workflow technologies and quality standards is an effective option. In our view, collaboration between independent manufacturers, suppliers, and therapeutic inventors will be key to driving down cost reduction and increasing global market access.