Along the drug development pathway, pharmaceutical companies face a host of challenges as they seek to demonstrate a product’s safety and efficacy by understanding the complex ways in which molecules and active pharmaceutical ingredients (APIs) react under different circumstances. Therefore, it is vital that companies have thorough analytical testing capabilities in place and that the experts they trust to assess their molecules are skilled at navigating the complexities of analytical method development and validation throughout the product's lifecycle.
Colman Byrne, Head of Analytical Services at DSI, describes the process as detective work, in which physical chemists assess different pieces of information to solve a puzzle. Questions that must be answered in the process include: What is the product supposed to be and do? What are the impurities? Are they as low as they need to be? Is the product being manufactured properly? Will it be safe when it is in a dose?
“There are always little challenges in terms of how you design the series of tests that are appropriate for any particular product,” Colman says. “How do you make sure that the tests are working appropriately so that you can trust the results? Can you trust the data? Can you support the testing results when you bring your data along to the agencies to get approval for your product?”
When analytical researchers first begin working with a molecule, they will know very little about it. As the development process progresses from pre-IND through clinical trials to commercialization, the researchers learn more and more about the molecule and what can happen to it under different circumstances. In the process, experts adapt the analytical methodology to better understand the molecule and work alongside the synthetic chemists developing the molecule to determine what impurities could potentially be present. Knowing those impurities allows the researchers to create methods to separate the molecule from its known synthesis impurities and challenge those methods to confirm that separation.
“However, you generally don't have access to every minor impurity that can potentially be generated, so you then rely on trying to use analogs or degraded samples that you sometimes manufacture deliberately, either through stress stability studies or chemical degradation, to establish the separation,” Colman says. “You try to establish the potential impurities that can develop within a product and then show that your method(s) can resolve and quantitate the levels of the impurities, both consistently and accurately. That's always the challenge because, quite frequently, impurities and degradation tend to be very similar to the parent compound.”
This is where working with experienced analytical experts who can draw on different techniques to separate and understand those impurities is key. To prevent problems and surprises later on, sponsors should have a test method that has been sufficiently developed by the time they reach the IND phase. During stability studies, it might be necessary to re-evaluate and re-optimize the test method if new issues arise, and then complete validation of the test method during phase two or pre-phase three studies. While is preferable to follow clear timelines, projects differ. In some cases, it might be possible to isolate, characterize, and identify impurities at an early stage, while in others it might only be possible to identify a particular degradant during phase three stability studies.
Often test methods have to be changed midstream, for example, if a new degradant is discovered, in which case a supplemental variation of an existing procedure can be done. Some changes will be negligible but sometimes a more significant change is required.
“A typical case might be where impurities are quantitatively based on their relative amounts when a test procedure was initially developed,” Colman says. “All of the impurities are calculated based on the area percent of a chromatographic response. This is a common way that early-stage methods are developed before standards are available.”
Regulators, however, often don’t approve methods that are area percent based, and will look for an impurity content method that is based on quantitation against a known standard. Sponsors need to be ready to adapt to changing situations to demonstrate the accuracy of their data.
Guidances have been developed by various regulatory authorities to help standardize practices for analytical testing, including on the validation of test methods, which helps to provide clarity for sponsors. While consistently improving the test method is desirable, Colman says the key is to establish valid reasons why these improvements have to be done. That means documenting thoroughly, including the rationale behind the improvement.
“When we present data in a regulatory filing, we do so in a fashion that the regulators can understand, and can see that that you have done the job you're supposed to do well, and that they have confidence that you know what you're doing and the data you're presenting is accurate and trustworthy,” he says. “That's what it's all about if you're an analytical person.”
This blog is based on CMC.Live Episode Number 6 – Analytical Method Development.