Why Sharpen Your Focus on API Analytic Methods?

When creating new Active Pharmaceutical Ingredients (APIs) in the lab, developing and documenting analytic methods is considered just a routine part of the job. It shouldn’t be. Analytic method development deserves far more attention given the important role these methods play in two of the most sought-after objectives of any drug development project – efficiency and timeliness.

Efficiency impacts drug development timelines, a critical and carefully management function for the vast majority of programs. Efficiency also impact costs significantly.

The most effective analytic method development, then, assures that lab resources are optimized and that the methods developed can be validated, meeting the requirements of each progressive step in the process.

This article will focus on why analytic methods are so important, the role they play and the key factors in optimizing them.

The role of analytic methods

The role of analytic methods is to establish:

• A drug candidate’s identity
• Its purity (quality)
• Its physical characteristics
• Its efficacy
• Its safety

The analytic methods developed enable these key factors to be tested again and again as drug development progresses to assure that the eventual transfer to the manufacturing suite  progresses as smoothly as possible. Meeting manufacturing specifications and standing up to the long-term stability studies will be required as drug development progresses.

Most common analytical procedures

According to the International Conference on Harmonization’s (ICH) quality guidelines, a standard used by the pharmaceutical industry, the most common analytic procedures (among many) are:

• Identification tests
• Quantitative tests of the active moiety in the API, drug product, or component of the drug product
• Quantitative tests for impurities
• Limits tests for the control of impurities

Analytic method development process

Although the above analytic procedures may be common, the steps involved in developing these analytic methods are anything but routine. For one, they differ based on the type of methods being developed. And each analytic method must be suitable for the compound’s intended use and its phase of development. Remember, each project develops a brand new chemical entity that behaves differently from any other drug candidate.

Questions typically answered during Process Research, when methods are being developed, include:

• What is the purpose of the method being developed? Is it for assay? Purity? Residual solvents? Particle size?
• What is the nature of the compound – is it an API? An excipient?
• Which technique seems most appropriate after initial system evaluation – High Pressure Liquid Chromatography (HPLC)? Gas chromatography? Other?
• What are the characteristics of any analytes, e.g. their solubility; reactivity; pH; stability in media; sensitivity to air, heat, humidity and light?
• What is the polarity of the molecule and its impurities that will be the starting point for column selection?
• What type of HPLC column should be used based on above parameters?
• What type of detector is most appropriate? Is it UV, DAC, CAD, RID, FLD, MS?

As the drug product evolves, methods progress. The methods developed should parallel each phase of the development of the API.

Early drug development methods

In early drug development, methods might focus on the API’s behavior¹. They should be suitable to support:

• Pre-clinical safety evaluation
• Pre-formulation studies
• Product stability

Method optimization

Once initial studies look promising for the sample’s intended use, method optimization begins. Typical HPLC method optimization, for example, involves increasing specificity, sensitivity, and solution stability.  The system suitability determination is also made.

Usual HPLC parameters such as method wavelength, column temperature, autosampler temperature, flow rate, gradient, etc. are being studied as Process Research continues.

As we previously described in “Early and Late Phase Drug Development,” as drug development progresses the analytic methods that will form the backbone of the regulatory submission should be constantly optimized for increased yield and efficiency.

Separation methods: the key determinants of purity and stability

 If we had to single out one analytic method that is particularly important, it would be separation. There’s an entire science devoted to separation. Many chromatographic and mass spectrometric techniques for this ever– and quickly-evolving field are discussed here.

Once an NCE is reasonably well characterized from a physical-chemical point of view, and the synthetic route defined well enough to allow process development of a scale-up synthetic route, one of the first tasks of the analytical chemist is development of a stability-indicating HPLC assay to investigate the purity and stability of the drug substance².

Without doing so in order to meet ICH standards for purity, there is no pathway to regulatory approval. Consequently, much attention is paid to separation methods that remove impurities.

The main decision in efforts to separate out impurities is the selection of the column (C8, C18, etc.) and method chosen must be sensitive enough to detect very low levels of impurities < 0.05%.

Summary

At PCI Synthesis we take great care to assure analytic method development is continuous and phase appropriate. No development step is routine given how vital time, cost and efficiency is to sponsors and programs. Analytic methods that are scientifically sound, well understood and documented with the regulatory pathway in mind do pay off in the end.

References

1. Analytic Method Development and Validation. Particle Sciences, Technical Brief Volume 5, 2009.
2. Dong, Michael W. Separation Science in Drug Development, Part III: Analytical Development. LCGC 33: Issue 10, 764–775, October 1, 2015.

About the Author

Ed is the President and CEO of PCI Synthesis (PCI), 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.