Taking In-Licensed Biologics to Market

Why are in-licensed products especially challenging for a sponsor to bring to market?

I will walk you through a typical scenario. Let us say that Sponsor A developed a monoclonal antibody 15 years ago and manufactured clinical trial material at a Contract Development and Manufacturing Organization (CDMO) we will call CDMO 1. Sponsor A then used the material to conduct a Phase I clinical trial, but in the end did not pursue any further development of the antibody.

Years later, Sponsor A decides to sell that asset. A virtual sponsor, Sponsor B, buys the asset with the intent of restarting the development program using the clinical material produced and data obtained from the Phase I trial that Sponsor A filed with the Food and Drug Administration (FDA). In this way, Sponsor B will not have to repeat the Phase I trial; however, this approach is generally not straightforward due to the CMC constraints.

In order to successfully restart the development program and initiate Phase II clinical trials, Sponsor B would have to use the same clinical material that was used in Phase I. All too often that is not possible, because, as in the example above, material manufactured by CDMO 1 for Sponsor A is expired. Should non-expired material be available, Sponsor B would have to look at associated stability study data and test the material to determine its product quality after years of storage.

What happens if the original material is available in limited quantities or has expired?

If the original clinical trial material from Sponsor A has expired and is not available for use, Sponsor B will have to manufacture new material.

The most straightforward path would be to reengage CDMO 1 to execute the same process that was used years before.  While it might be a possibility to reengage CDMO1, CDMO 1 can probably not replicate the manufacturing process with the technology it originally used many years ago, since advances in technology are rapid and CDMOs upgrade their technology to remain competitive with their peers.

Thus, the likely path forward will be to produce new clinical material using a manufacturing  process that incorporates new technology, while simultaneously ensuring that such will not affect the quality of the product.

Why is changing the manufacturing process a big deal?

With biologics, changes introduced into a manufacturing process can impact product quality. If the changes introduced by Sponsor B alter critical quality attributes of the product, the in vivo behavior of the drug may not be the same as what was observed with prior product batches from Sponsor A.  This is turn could complicate matters, especially if Sponsor B is relying on using Phase I clinical data obtained with the original material.  As a consequence of the introduction of these process changes, Sponsor B will have to show equivalence of the new material in comparison to the original.

Since recombinant glycoproteins are structurally complex macromolecules, this is not a trivial task.  A monoclonal antibody, for example, has an average molecular weight of 150,000 daltons. In comparison to small molecules—for example, aspirin—with a molecular weight of 180, the structural complexity is put into perspective.

Showing equivalence of the new versus the old material in order to continue the development process and bring the product to the market must be a key goal for the CMC activities of Sponsor B. If Sponsor B fails to do so, this will result in Sponsor B filing what will be considered a new product—not the same as what Sponsor A had previously filed with the regulatory agency—and risk having to repeat Phase I clinical studies.

Can you give examples of a manufacturing process change a sponsor might need to undertake?

A modest process change might be to select raw materials sourced from different manufacturers. For example, instead of using sodium chloride from one vendor, we might opt for that from another provider at a lesser cost.  These decisions may be budget-driven. Raw materials need to be of GMP grade; however, differences between manufacturers do occur and if so, additional raw material testing will be needed, as well as demonstrating that the inclusion of the ‘new’ raw material has no effect on overall product quality.

A very significant process change is to create a new production cell line—a change made to a manufacturing process driven by the need for higher productivity. A biologics process begins with a cell line, and thus the most important step in developing the process is to generate and characterize a highly productive cell line. Cell line development in turn has also progressed over the years, and a level of productivity that might have been state-of-the-art 15 years ago, would likely be considered modest by today’s standards. A highly expressing cell line is key to effectively manufacturing material at the desired output level and allows for easier optimization of the remaining upstream and downstream processes.

Productivity is key.  When a sponsor has a poorly expressing cell line but is looking at a clinical indication with an unmet need and a large patient population that requires a lot of product, the sponsor will fail to meet market demand. In this instance we would recommend development of a second, highly productive cell line and design of a newly optimized process around it.

But again, there is a huge caveat. The resulting product from any and/or all process changes still must be biochemically and functionally comparable to the original product.

As step-wise changes to the process are introduced, you have to test the quality of the product in search of the best process resulting in the manufacture of comparable material. While this may be labor intensive, the outcome will result in a more productive process delivering material that is comparable to that from the initial process.

What are other challenges that a sponsor might face while taking in-licensed biologics to market?

Changing a CDMO is another challenge. A sponsor might want to change CDMOs for a variety of reasons. In our example, Sponsor A engaged CDMO 1 for the manufacture of Phase I trial material, requiring far less clinical material than later phases would have. CDMO 1 might not have the capacity to go beyond the 500 litre scale; thus in order for Sponsor B to scale up manufacture of its in-licensed product for Phase II or III, CDMO 2 with > 500 litre capacity will need to be engaged.  Lead times and available manufacturing slots remain an issue, and sponsors need to reserve slots with their chosen CDMOs for the manufacture of their test articles 8-10 months in advance.

Transferring a process from one CDMO to another should be done as a last resort.  CDMO 1 has no incentive to cooperate with the sponsor to transfer a process.  One reason is that CDMO 1 won’t want to divulge its know-how and technology to CDMO 2, so it will likely hold back details that might otherwise make transfer go more smoothly.

Good CDMOs operate like well-oiled machines.  CDMOs understand the elements of their own processes; they are generally well stocked on raw materials and have efficient supply chains in place.  So if we try to get CDMO 2 to adopt a process from CDMO 1, using methods and raw materials they don’t normally use, it’s automatically going to be less efficient, it will take longer and mistakes will be made.

If we want to work with CDMO 2, we would prefer them to use their own platform methods and design a process that will yield the desired outcome.  Again, changes to the process can be made, whether it’s to design of process or selection of manufacturer; however, these changes cannot affect the overall product quality in any substantial way or you are back to Phase I clinical testing. This constraint remains ever-present.

Need help selecting a CDMO? Review our CDMO Selection best practices.

How can Alira Health’s seasoned CMC experts help sponsors that would like to bring in-licensed products to the market?

I founded and led Chamow and Associates for 12 years before joining Alira Health in 2020, building out our CMC capabilities, technical proficiency and biologic expertise. Our CMC knowledge and experience was the missing piece to Alira Health’s suite of services and with our integration, the company can now provide comprehensive support to meet the needs of pharmaceutical companies at any stage of the drug development lifecycle. My team’s primary purview is working with sponsors—often those who lack in-house CMC capabilities or those who seek our help to supplement their own capabilities–in developing new drugs.

Sponsors, especially those new to biologics or hailing from a small molecule background, may not be aware of all the complexities we have discussed here. The development process of a biologic is vastly different from that of a small molecule; a situation that always needs to be considered and that we can assist with along the way. We act as an advisory committee, providing education and guidance, and we facilitate outsourcing for virtual companies, helping them to get off the ground to initiate clinical manufacture of their products.