The analytical detective: Understanding impurities in the molecule assessment process
Pharmaceutical companies encounter numerous challenges during drug development as they strive to demonstrate a product's safety and efficacy.
Image Credit: DSI, a PLG Company
To achieve this, pharmaceutical companies must understand the complex ways in which molecules and active pharmaceutical ingredients (APIs) respond under different scenarios.
Therefore, companies must have thorough analytical testing capabilities and skilled experts that can assess their molecules and navigate the difficulties of analytical method development and validation throughout a product's lifecycle.
Colman Byrne, Head of Analytical Services at DSI, describes molecule assessment as detective work, where physical chemists consider a variety of information to solve a puzzle.
Questions that must be answered in the process include, what is the product meant to be? What is its purpose? What are its impurities, and are they as low as they need to be? Is it safe once in a dose? Is the product being correctly manufactured?
"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?."
Colman Byrne, Head of Analytical Services, DSI
Learning along the way
Before working on a new molecule, analytical researchers will know little about it. Researchers learn increasingly more about the molecule and what it can do under different scenarios, all the way through the development process – from pre-IND and clinical trials through to commercialization.
Experts will adjust the analytical methodology to further understand the molecule and work with synthetic chemists who develop the molecule to identify and potential impurities during this process.
Once identified, researchers can develop methodologies to separate the molecule from the impurities generated during synthesis and test those methods to ensure a successful 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 explains.
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."
Colman Byrne, Head of Analytical Services, DSI
This is why working with analytical experts is critical. Such experts can rely on their experience and knowledge of different techniques to separate and understand the synthesis impurities. To avoid problems further into the development, sponsors should have an adequately developed test method before they reach the IND phase.
It can be necessary, during stability studies, to re-evaluate and re-configure the test method if novel problems are encountered. The re-optimized test method can then be completely validated during phase two or pre-phase three studies.
Whilst it is preferable to keep to clear timelines, projects will differ. In some instances, it may be possible to isolate, characterize, and identify impurities at an early stage. While in other projects, identifying a particular degradant might only be possible during phase three stability studies.
Changing your methods
Test methods often require changes midstream. For example, if a new degradant is identified, a supplemental variation of an existing procedure can be produced. Some changes can be minor, but often more substantial changes are required.
A typical case might be where impurities are quantitatively based on their relative amounts when a test procedure was initially developed. 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."
Colman Byrne, Head of Analytical Services, DSI
However, regulators will often not approve methods based on area percent. Instead, regulators will look for an impurity content method based upon quantitation against a known standard.
Sponsors need to be prepared to demonstrate the accuracy of their data how the regulators see fit. Sponsors must be able to adapt their methods to changing situations.
Guidance is available from various regulatory authorities to help standardize analytical testing. This guidance seeks to provide clarity to sponsors and provides details on the validation of the test method.
While the constant improvement of test methods is desirable, Colman says it is important to establish why such improvements are required. This necessitates thorough documentation, including the rationale behind any improvements.
"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," Colman says. "That's what it's all about if you're an analytical person."
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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