Learning How to Navigate Biologics Development

Biologics are becoming more established in the development pipeline as a result of their ability to treat a variety of conditions and diseases in a targeted and effective way. The increasing prevalence of diseases, such as cancer, autoimmune diseases, and genetic diseases, globally is driving continued growth for biologic therapies (1).

However, the inherent complexities associated with biologics makes formulation and development uniquely challenging when compared with small-molecule drug products. To learn more about the formulation challenges associated with biologics, potential solutions and approaches that are helping to overcome these challenges, the regulatory landscape, and how outsourcing partners can be beneficial, BioPharm International® spoke with Aaron Frimel, manager, Process Development at Thermo Fisher Scientific.

Formulation challenges

BioPharm: Could you highlight the main challenges associated with biologics formulation development?

Frimel (Thermo Fisher Scientific): With early phase development, the hardest challenge can be getting enough representative material early enough in the development lifecycle to support a thorough formulation study (time and size) to achieve the target product profile. Another challenge is having methods ready for the formulation studies so that method performance is understood well enough to know whether a change in product quality is due to assay performance or formulation performance.

With late-phase development, routes of administration, dosing, and degradation products on long-term stability are better understood and may necessitate changes that can sometimes be difficult to accommodate and may even require altering the target product profile.

Strategic solutions

BioPharm: What strategies can companies employ to overcome these challenges?

Frimel (Thermo Fisher Scientific): High-throughput, characterization-type assays [can be employed] to uncouple the start of formulation work from method development, as well as reduce material per sample in order to screen larger design spaces, which sets the project up for earlier success with less potential for re-development. [Additionally, with] in-house cell line development, the material requirements and representativeness are dealt with by using high-titer cell lines and targeted integration. Process development groups can then perform material generation runs using the center-point of their platform processes to generate material early in the project lifecycle so that the final formulation is selected at or before the conclusion of process development activities.

With late-phase projects, material representativeness and availability are much less of a problem, but clients may choose to go to a higher concentration for dosing purposes or to change the route of administration. With an existing formulation, and known degradation patterns, [it is possible to] stage a small-scale robustness study with the critical stability indicating assays to achieve the target concentration while mitigating the most significant liabilities.

If the client is trying to blunt the formation of a degradant, [then it is beneficial] to have an analytical suite that is larger than just release analytics. [Thermo] had a program recently that saw some charge heterogeneity issues and [by using a] multi-attribute-method (MAM) [it was possible] to understand that the shift in the acidic shift in a cIEF [capilliary isoelectric focusing] profile was a trade-off between deamidation and oxidative modifications, and [it was possible] to reduce both degradation patterns by raising the pH 0.5 units while adding methionine—something [that] would have never been [possible without] such a powerful analytic to tease apart these modifications on the amino acid level.

Innovative options

BioPharm: Have there been any technological innovations or novel approaches implemented that have helped with biologics formulation?

Frimel (Thermo Fisher Scientific): With biologics formulation, the range of available excipients is limited, and a lot of the advancements come from the development of more sensitive, stability-indicating analytics that are precise and trend with a high degree of linearity. [Because] the range of excipients that are available (and not patent protected, if possible) is small, being able to achieve the maximum potential of what is available is the best option.

Increases in throughput or decreases in material requirement and touch time are the things that allow a formulator to screen wider ranges and are what gives a project a good chance of finding a global optimum, rather than a local optimum, when screening formulations.

Regulatory landscape

BioPharm: Has the regulatory landscape changed for biologics formulation? If so, how can companies navigate these regulations with ease?

Frimel (Thermo Fisher Scientific): The most common thing [being seen] since the pandemic is an increase in the amount of early phase projects targeting a subcutaneous format, many times using a pre-filled syringe. The benefits are obviously easier self-administration, and opinions on self-administration have rapidly changed both as a result of the pandemic and as a result of the Type 2 diabetes drugs that are being used to treat obesity.

Pre-filled syringes are regulated as combination products. While this isn’t a new regulatory landscape, FDA has clarified its guidance on combination products and streamlined the process for triaging whether the primary mode of action of the product classifies it as either a drug or a device while eliminating the need to get approvals for both.

Partnership benefits

BioPharm: How can partnerships benefit in biologics formulation development? Are there any best practices you can share?

Frimel (Thermo Fisher Scientific): A great thing about outsourcing biologics formulation work is that the teams at these outsource facilities see a wide range of molecules and molecule behavior and can act on this breadth of experience. What separates a good partnership from a great one is how well the outsource partner works to understand the client’s goals and mentality when it comes to risk in order to customize the approach to meet the customers goals while incorporating the technical knowledge gleaned from previous projects into the design. Some of the most productive conversations we have with clients are the informal sidebar discussions where a project member casually mentions the long-term goal for the project. It is surprising how many times pieces of information from informal conversations can be incorporated into the existing work and eliminate the need for future studies.

Both the technical experience and establishing rapport come down to the same thing, listening. Both listening to the data during study execution and actively listening and questioning the client to understand their long-term goals so that they can be addressed in the project design.

Being on the outsource side, [Thermo encounters] a range of client mentalities, both in terms of clients shopping projects as well as clients that commit to a workscope with [a particular] team. The clients who put in the work to understanding a CDMO’s [contract development and manufacturing organization’s] technical capabilities, resourcing, and any client-specific considerations prior to committing to a CDMO tend to be the more satisfied clients. Specifically, the customer that takes the time to evaluate, understand, and articulate their internal needs as best as possible tend to be more skilled at evaluating whether a particular CDMO will match these needs as closely as possible.

Reference

1. Grand View Research. Biologics Market Size, Share, and Trends Analysis Report by Source (Microbial, Mammalian), by Product (MABs, Recombinant Proteins, Antisense & RNAi), by Disease Category, by Manufacturing, by Region, and Segment Forecasts, 2023–2030. Market Report, May 2023.

About the Author

Felicity Thomas is the European/senior editor for BioPharm International.