Things to Consider in Early Development for Late-Stage NCE Success – Part Two: Potential Challenges

Adapted by Richard Sidwell, Ph.D., Chief Scientific Officer, from a previously recorded panel discussion with Pharmaceutical Technology 

Societal’s Neha Shah, Director of Product Development, Shweta Sinkar, Senior Product Development and Manufacturing Scientist, and Eduardo Uribe, (former) Senior Director of Quality Assurance, sat down with Pharmaceutical Technology to discuss various things to consider in early development. We shared details of the process and key things to consider in part one of the series, and we look forward to sharing more about potential challenges as we move into part two.

What are some challenges in the development of NCEs?

With these foundational ideas in place, let’s talk about a few of the significant challenges we can encounter in developing an NCE. 

API Availability

The first common challenge during the development of the NCE is limited API availability. The lack of an optimized process to manufacture pure API in sufficient quantities makes it to do in-depth studies in the early stages of development, often leading to limited pre-formulation study. This can leave you vulnerable to surprises later during development. 

The ability to manufacture API of sufficient purity is also critical. Some impurities are pharmacologically active, which can cause false efficacy signals, while others can cause undesirable side effects. 

Analytical Methods

If sufficient consideration is not given early on to the analytical methods to quantify the API and impurities, not only do you leave technical debt that must be resolved later, but you may also make bad decisions about the viability of your prototypes.

We are dealing with tight timelines, so another challenge in early development is a balancing act of understanding what we don’t know, what we need to know, and what we can afford to investigate. 

A good understanding of an API’s physical-chemical properties, polymorphs, excipient interactions, degradation pathways, and the overall performance of the formulation can help avoid problems and, ultimately, repeat formulation steps during later stages. 

Funding

Financial resources are typically limited for small pharma companies, restricting their ability to conduct in-depth preclinical formulation screens. The added upfront costs may slow down early-phase development and increase costs for smaller pharma companies. That’s why it’s so important to work with an experienced and diverse development team so you can balance the investment of time and effort with the critical questions that need to be answered for your development project. 

As a bonus, working with a reputable CDMO to get a detailed proposal or budgetary estimate can bolster your credibility with investors.

Process Development and Scale-up Path

Not having the technology or capacity for scale-up could be another challenge that would delay the development of a drug product. Suppose your early-development group cannot make larger-scale cGMP clinical supplies. In that case, it’s essential to identify the required capabilities and capacity early so you can start the necessary due diligence, negotiation, and knowledge transfer well before you need those next batches in the clinic. Crafting the necessary development protocols, risk assessments, and control strategies at various product development milestones takes time and effort that could hurt your overall timeline if you delay. It’s best to parallel-track these efforts with your earlier work so that the readout from one stage can immediately trigger manufacturing and testing work for the next instead of waiting for a new team to get up to speed.

Supply Chain

COVID has taught us a lot about the fragility of global supply chains. In post-pandemic times, with uncertain geopolitical factors at play, supply chain issues have impacted a lot of items like the delivery of specialty and high-demand excipients, capsule shells, and primary packaging components such as sterile vials. These things can significantly delay project timelines and be very costly. Thinking carefully about the supply chain during early product design and formulation development pays dividends. Now that you know what can be expected throughout the process and components that may delay your project, you will need to learn more about quality. In part three, you will learn more about quality systems and how Societal might be able to help you.

In part three of the series, you will learn more the importance of strong quality systems.