The COVID-19 pandemic has highlighted the importance of expedited development to address medical emergencies and serious or life-threatening conditions. The FDA has four programs for these purposes: fast-track designation, breakthrough therapy designation, accelerated approval, and priority review designation.
In any pharmaceutical development program, there are risk-benefit analyses being done to assist with decision-making processes. Expedited development presents a different balance to a company’s risk-benefit in order to bring a particular molecule forward as quickly as possible because of the potential benefits.
“You may be in a situation where, instead of having 99.9% confidence that the approach that you're taking is correct and that the quality of the data you're generating is as good as it could be, you may only have 99 or 95% confidence,” says Colman Byrne, senior analytical services expert at DSI. “Based on the data you've generated, you have to look at how much confidence you can truly have.”
As with any other program, issues can be mitigated by ensuring that in the pre-IND phase and phase one development, the validation test method is scientifically valid, and that there will be few, if any, surprises in later development.
“Validation of a test method should be a smooth process because you should expect that you know everything that could have gone wrong and have addressed those before you do the validation,” Colman says. “The validation is ideally just a documented process to show that you have, under controlled conditions, done all the work needed to show that your data is accurate, precise, and linear. There should not be any surprises.”
The way to limit surprise is to ensure the method used is well-developed and will stand up to validation, even with a compressed timeline. “This then becomes a simple step with a low probability of a failure and of having a problem that is going to need corrective action,” he says. “The key is to do the due diligence upfront and try to develop a method as thoroughly as possible while working under the constraints of an early-stage development process.”
The challenge will likely be resources and time, which are more limited in the early stages when the focus is on making clinical material, releasing it, and getting it into the clinic. However, by considering the end goal, it is possible to quickly develop methods for the immediate and near-term that can be easily used, validated, and, if necessary, adapted to the more stringent needs in phase three and into commercial.
“It’s about trying to do as much upfront, where you don't necessarily know everything, and you don't necessarily have all the resources that you might have at a later stage,” Colman says.
Where problems can arise is when certain physical-chemical properties affect method development. One example is compounds that are light-sensitive, which is integral to how they perform a specific function. It is this very property that makes the compound a good potential medication, but it also makes it more difficult to work with from an analytical point of view.
“In that situation, you need to do what you can to minimize the product's exposure to light, such as using dark glass containers of low actinic glass or amber glass or use filters on the lab lights to exclude certain wavelengths of light or in very low light intensity areas,” Colman says.
By understanding the physiological or physical properties of the molecule, it’s possible to know if it is light-sensitive so that precautions can be taken when working with it. In this way, when it comes to generating release and stability data on the clinical materials, the data can be trusted, because it isn’t being affected by forces and circumstances that have not been properly controlled.
Another potentially problematic situation is water sensitivity, where if the analytical expert is weighing a quantity of standard to use to quantitate a sample, the assay can change because the standard concentration is not what it's supposed to be.
“Because of water absorption, the same weight standard now has less of the active in it, so the same amount of active in a sample appears to be greater than it is,” Colman notes. “If you know what the physical parameters of the molecule are when you go into a project, you can understand what precautions you need to take to avoid analytical problems.”
Unfortunately, he says that sometimes problems only become apparent when things go wrong, in which case it’s important to develop preventive and corrective actions so the problem doesn’t happen again.
“This is a learning experience, and it is part of what causes methods to sometimes have to be modified and updated throughout the life of a project,” Colman says. “You're finding out things you didn't know at the start, and, overall, that is a good thing. By focusing your development upfront and looking at the available information and the potential pitfalls, you can minimize the possibility of having unfortunate learning experiences, which will cost time and money and cause potential delays.”
This blog is based on CMC.Live Episode Number 6 – Analytical Method Development.