Managing Risk in API R&D Requires Strategic Planning, Collaboration and Experience

In drug development, there is an inherent amount of uncertainty, which translates into risk.  Uncertainty is caused by the organic nature of raw materials, making it impossible to predict how an Active Pharmaceutical Ingredient (API) will behave, how much yield can be achieved and how effective it will be, even for molecules having an otherwise perfect profile. A lack of efficacy can, for example, be the consequence of the wrong choice of target, the use of models that are not predictive for human disease, or failure of the molecule to engage the target in the clinical situation. Risks can come from an inability to characterize the right compound, the lack of suitable bioassays, an inability to generate the correct reagents or toxicity in the molecules.

Adding to this uncertainty are increasing pressures due to rising research and development (R&D) costs, expiring patents, increasing competition and regulatory requirements eroding profit margins.

In fact, developing a new prescription medicine that gains marketing approval is estimated to cost drug makers $2.6 billion according to a recent study by Tufts Center for the Study of Drug Development and published in the Journal of Health Economics. And, new drug discovery projects can take more than 12 years before they are commercialized.

As we’ve seen recently because of the pandemic, unforeseen factors can also impact risk, such as disrupted supply chains, plant shutdowns or reduced FDA review of non-COVID-related drug candidates.

Managing Risk Begins in the R&D Lab

A key area where risk can be minimized however, is in the R&D phase where APIs are created and Kilo-lab production takes place.  An interesting line of thinking was addressed in an article in NCBI, which stated that, “in contrast to widespread scientific practice, experiments should be designed and executed to clearly demonstrate that the initial hypothesis is wrong—so called No-Go experiments.”  The thinking is that failing in the earliest stages is less costly and resource-intensive than waiting until the project enters GMP manufacturing to fail.

Despite this “No-Go experiments” philosophy, there are many steps that can be taken to not only set up a project for success in the earliest stages, but to ensure that success continues beyond those stages and throughout the project’s lifecycle.

Managing risk in API R&D requires picking the right CDMO for the job, one that can carefully vet suppliers, implement the most robust methods and testing processes and that acutely understands your project and leverages its own experience and insights to ensure the best outcomes. 

Consider the following five best practices to ensure success in R&D:

1. Plan the regulatory strategy. From the beginning, a clear and realistic regulatory strategy should be planned, that will guide the scope and lifecycle of the project, as well as its associated costs.  A good way to accomplish this is to hire a consultant who has done this before and who knows all the latest requirements. You can also request a meeting with the FDA and they can guide you. Once you have your regulatory strategy in place, the key is to share it with your CDMO in order to accurately execute  chemical development processes.
2. Think carefully about raw materials.Quality raw materials can make or break your project, so it’s important to have good relationships with reputable suppliers, as well as multiple ones to increase your chance for securing required materials in the event of delays. The more impurities found during stability testing, the longer the project will be delayed, and often, so quality from the outset is key.
3. Implement rigorous documentation. All experimental details necessary to replicate a set of experiments should be rigorously documented, including outcomes, protocols, analysis and raw data. This data, also includes Quality Assurance documents, SOP strategy, batch records, test methods, specifications and logbooks.
4. Quality control.  Led by experienced Quality Assurance (QA) and Quality Control (QC) teams, quality control procedures for reagents and materials used in experimental studies should be consistent from the earliest stages of R&D. The QA group should be the final authority, providing the ultimate checks and balances and final say over raw materials quality, batch quality, writing and compiling all batch records, and signing off on all certificates of analysis.
5. Don’t put cost above success. Cutting corners without a good understanding of the potential consequences almost never saves money, but often adds to the cost of the project in the long run.  An experienced CDMO should have a good understanding of what will and will not pass muster with the FDA, so it’s important to work closely to determine where savings can and cannot be generated. One place not to skimp is in Phase 3 clinical trials, which have a more than 50-percent chance of success.  At that point, there are clear clinical results, leading to solid funding and a good chance you are on the right path to commercialization.

While drug development can be filled with risk that cannot be controlled, there are many ways that risk can be reduced in R&D.  Strategically managing this risk at the earliest stages can help to save costs and valuable resources, as well as offer greater chances for success across the drug development journey. 

For more insights on risk management in drug development, read What Should You Look for in a Consultant to Manage Your API Project?; Incomplete Documentation Can Make or Break Projects in API Manufacturing; or  The Top 5 Reasons API Projects Fall Behind Schedule.