The analytical detective: Benefit-risk balance and the analytical testing process
The COVID-19 pandemic has emphasized the grave importance of accelerated pharmaceutical development to combat serious or life-threatening diseases and cope with medical emergencies.
Image Credit: DSI, a PLG Company
The FDA has four programs for these instances: fast-track designation, accelerated approval, priority review designation and breakthrough therapy designation.
To assist with decision-making processes, a risk-benefit analysis is carried out in any pharmaceutical development program. Expedited development – the notion of bringing forward a particular molecule as rapidly as possible because of its immediate benefits – presents a change in balance to a company's risk-benefit.
"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 the senior analytical services expert at DSI, Colman Byrne.
Byrne continues: "Based on the data you've generated, you have to look at how much confidence you can truly have."
Problems that arise can be addressed during the pre-IND phase and phase one development by validating the test method, thus ensuring it is scientifically robust and reducing the number of 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 explains.
"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."
By ensuring the selected method is well developed and withstands validation, even with a compressed timeline, will help to reduce surprise.
"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," Colman 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."
Challenges that arise are often related to time and resources. During the early stages, time and resources are more limited because development is focused on producing clinical material, releasing it and getting it into the clinic.
However, it is possible to rapidly develop methods for the immediate and near-term by considering the long-term goal. Those methods can then be easily applied, validated and, where necessary, modified to the more stringent requirements of 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 Byrne, Senior Analytical Services Expert, DSI
Problems with novel compounds
Issues can arise when specific physical-chemical properties affect method development. For example, compounds can be light-sensitive, and such properties allow them to perform a specific function.
Those specific properties make a compound a good potential medication, but from an analytical perspective, it also makes the compound more difficult to work with.
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 Byrne, Senior Analytical Services Expert, DSI
With an understanding of the physical or physiological properties of the molecule, it is possible to determine if it is sensitive to light, and if so, what precautions should be taken.
The release and stability data on the clinical materials can be trusted by taking such precautions since the acting forces and circumstances have properly been controlled.
Another potential issue is water sensitivity. This can occur when the analytical expert is weighing a quantity of a standard to use to quantitate a sample; the assay can change because the standard concentration is not correct.
"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 explains.
"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, Colman notes, some issues only become apparent once they have occurred. In this case, it is important to develop preventive and corrective actions to ensure that the same issues do not reoccur.
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 Byrne, Senior Analytical Services Expert, DSI
"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," Colman concludes.
Acknowledgments
Produced using material originally authored by Meranda Parascandola from DSI InPharmatics, and is based upon CMC.Live Episode Number 6 – Analytical Method Development.
About DS InPharmatics 
DS InPharmatics (DSI) provides regulatory, technical, and project management consulting services to healthcare product companies that manufacture and/or market pharmaceuticals, biopharmaceuticals, and cellular and gene therapy products.
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