Three Things to Know About API Preparation for Phase 3 Clinical Trials

Drug development is a risky business both financially and from a patient safety point of view.  CDMOs try to minimize that risk by spending a great deal of time developing APIs that are safe enough to be given to humans, remaining ever vigilant for potentially harmful toxins or impurities.  A drug candidate’s safety is first tested in small Phase 1

trials, usually with 20-100 volunteers, or a smaller number of patients if the drug is aimed at a rare disease.

According to the FDA, approximately 70% of drug candidates move from Phase 1 to Phase 2.   Much of the effort in developing APIs occurs when the CDMO prepares material for the larger Phase 2 trials. It’s then that any scale up issues that surface are resolved, processes tweaked for optimum yield, and analyticals developed in earnest. 

Phase 2 trials weed out many more drug candidates due to efficacy or safety issues.  Only 33% move on to pivotal Phase 3 clinical trials.  This article will focus on the top three considerations in preparing APIs for Phase 3 clinical trials.

1. An eye toward commercialization.
   As we’ve previously said, the biggest transition in API manufacturing has already occurred in preparing for Phase 2 clinical trials.  At that point a decision was made that it made economic sense to invest in the asset. Accordingly, the chemistry was reviewed, and material scaled up to assure production in larger quantities without new impurities emerging.  The process research conducted aimed at finding the most efficient route, and analytics were also stepped up in preparation for a Phase 2 trial. 
   
   However, there are still things to be done to prepare for manufacturing the greater volume of API material required for Phase 3 trials. Depending on the size of the trial, 10 times as much material may be needed. If it’s a rare disease, perhaps only twice the amount may suffice.  No matter the amount, in preparing for Phase 3 trials we are looking ahead to commercialization and want to lock everything in.  But first there are additional things we may want to try.
   
   By the time we get to Phase 3, we are no longer worried about impurities. Rather, our sights are set on economics.  We want to know as we continue to scale up whether there are opportunities and ways to improve cycle time, yield, and other variables.  Investing in greater efficiencies is the right thing to do.
   
   There are also things we do not want to do in Phase 3. We don’t want to introduce any new materials or different reagents. At this stage we’re just tweaking around the edges – if we can wring more efficiencies by adjusting a process’s time or temperature, that can translate into a significant impact that could improve yield, process throughput and cycle time without impacting product quality.
   
2. Locking down the analytics
   Once we have done all we can within reason to optimize the API’s economics for Phase 3 and beyond, it’s time to lock down the analyticals.  If anything has not yet been validated, we make sure it is.  At this point we should also have a fair amount of stability data, which needs to be checked one more time to make sure everything is in order and that there are no stability issues.
   
3. Ensuring the supply chain
   Every CDMO knows that sourcing raw materials and ensuring the increased supply needed for Phase 3 and commercial manufacturing is critical.  Whether the project requires off-the-shelf or customized ingredients, it is essential to cultivate reliable, trustworthy and high-quality suppliers.  Nurturing those relationships is well worth the any effort involved.

In these days of tariff wars and pandemics, securing high quality supplies and safe raw materials has become even more challenging, yet Good manufacturing practices (GMP) guidelines demand it.  GMP has always been about paying attention to the details in order to minimize issues that can disrupt or delay project completion. Because the stakes are so high, every CDMO should take extra care in selecting and managing suppliers.

I would suggest that of all supply chain best practices, redundancy is among the most critical. Take Apple for example.  One of the biggest U.S. companies, Apple learned the hard way that relying on one country—China—for its iPhone parts and assembly is risky, and the ensuing delays costly. Tesla, whose CEO Elon Musk made all kinds of promises to deliver a certain number of the company’s popular electric cars, was hamstrung by a coronavirus pandemic no one anticipated, which forced closure of factories in both China and the U.S.  Until we have a domestic stockpile of raw materials and supplies to draw from when circumstances such as the pandemic warrant, we can’t take the risk of relying on a single foreign supplier.

Risk assessment discussion with your customers

Finally, when preparing for Phase 3 trials, it’s a good idea to sit down with your customers. The best thing to do is look at everything that’s been done to date. Provide an overview of all the changes that have been made and their impact on the project up to this point. Discuss with sponsors goals for regulatory approval, post-approval volumes, delivery, timelines, etc. Based on that conversation, discuss what justifies additional investment in the asset.  

Although they’ve made it to Phase 3 and already invested quite a bit to get to this point, it’s still risky.  Going forward at this stage still requires a consideration of investment vs. risk, and it’s important that we CDMOs are sensitive to that.  Our extensive experience allows us to give solid advice on the appropriate investment.  This is not the time to be penny wise and pound foolish. We still should be doing things that are needed, particularly analyticals that may have been missed, but not making any process changes.

Summary

As projects enter Phase 3 trials, it’s our job as CDMOs to work with our customers, sharing best practices and our expertise to help minimize risk and speed safe, effective products to market.

If you have questions about Phase 3, please call us at (978) 462-5555 or email us at info@pcisynthesis.com.

About the Author

Ed is President & CEO of SEQENS North America (formerly PCI Synthesis). He serves as a co-chair of the New England CRO/CMO Council and sits on the Industrial Advisory Board for the Department of Chemical Engineering at UMass, Amherst. Ed is also a long standing member of the American Chemical Society and advises the Bulk Pharmaceutical Task Force of the Society of Chemical Manufacturer’s and Affiliates (SOCMA)...

Do you have questions? Talk to Ed.