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Things to Consider in Early Development for Late-Stage NCE Success – Part One

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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. The conversation has been broken into a three-part series that shares details of the process, key considerations, potential challenges and on quality systems and how Societal may be able to help you will round out the series.

What are the key considerations for the successful development of NCEs?

NCE development is a wide-ranging topic. This conversation focused on the CDMO perspective and highlighted a few key practical considerations for early product development strategies to help ensure late-stage success. 

Raw Materials 

Let’s start with the raw materials: the API and the excipients. Always make sure that you have identified an established and reliable source for GMP-compliant API and excipients. We recommend that when in preclinical development, always use GMP grade and GMP quality excipients, preferably the same sources you expect to use throughout development. 

If importing API for clinical use, import under your issued IND number. API not imported under an IND generally cannot be legally used in humans.

Early prototype stability studies are often associated with go/no-go decisions determining which formulations move forward. Changing material sources later can impact the relevance of those feasibility batches and decisions. If you use a substandard grade of excipients, you might see degradation profiles that are not indicative of how your formulation will behave with proper GMP-grade materials. You might make an erroneous go/no-go decision that could be painful. 

Always try to select excipients listed in the FDA’s inactive ingredient database for your route of administration. Also, make sure the amounts you use are covered. That does not mean that you should not use novel excipients. Still, you must be mindful that there will be extra time and expense for additional toxicology studies if you want to advance a novel excipient into the market. 

Preformulation and Formulation Development

The subsequent phases are pre-formulation and formulation development. This is one of the most crucial stages for early product development, and it forms the foundation for late-stage success.

Preformulation work is crucial in developing safe, effective, and stable formulations. It’s good to gather as much data as you can. Solubility, lipophilicity, pH stability profiles, excipient compatibility, forced degradation studies, and solid-state characterizations like particle-size distribution, morphology, and crystallinity are all useful depending on your intended product type and anticipated process. Make sure that you lay a strong foundation for formulation development. 

When making prototype formulations, don’t base them on random trials, but rather take a scientifically driven approach. Use the preformulation data, target product profile, and expert experience to narrow the design space. Then, use statistical design of experiments to test and document the formulation space. Having done all of this, you should have some promising lead candidates. 

This may be all you need to identify a lead candidate for simple formulations. For more complex situations, like developing an injectable of a water-insoluble compound where you need to use a lot of organic solubilizers, solvents, and co-solvents, make sure to gather some early toxicological data. If there is not a lot of safety data available for the combination of materials you’ve used, it’s very important to get an early read on safety.

You don’t want to go too far into development only to find your perfect stable formulation cannot be used in vivo. 

Processability and Scalability

Even when you are in the formulation development phase, always be forward-looking and mindful about what process you will implement. Is the equipment train you will utilize in development suitable for your drug product in later stages? How can you implement quality by design in your process? How can you define your critical process parameters and critical quality attributes? The earlier you can start to answer these questions, the more likely it is you can avoid problems and roadblocks later on. It’s also very important to keep your QA and regulatory team members in the loop.

They are the ones who are going to guide you in making sure that you cover all the bases. Take care to understand your regulatory landscape. Choose a phase-appropriate CMC strategy and be aware of what restrictions and requirements there might be for your target market. Step back at every stage of development, assess and analyze your risk, and consider how to mitigate it. In part two of the series, you will learn more about potential challenges in developing NCEs.

In part two of the series, you will learn more about potential challenges in developing NCEs.

Richard Sidwell, Ph.D.
Senior Vice President and Chief Scientific Officer
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