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Automated method validation of early drug candidates increases QC efficiency

	Customer Case Study: Bayer Schering Pharma AG, Berlin, Germany

By Katja Kornetsky
Agilent Lab Informatics Product Manager

Creating a validated method for a drug is a complex task. If the drug candidate is eliminated during the later stages of drug development, all the method validation work is irrelevant. To avoid this wasted effort, Bayer Schering Pharma investigated fast and simple ways to create sufficiently reproducible and stable methods during the early stages of drug development. The company’s quality control (QC) unit found a unique way to deploy the macro programming capability of Agilent ChemStation to automate method validation.

	Figure 1. The AUTOVAL macro directs the autosampler to make sample dilutions, as shown in this scheme for automated dilution of a stock solution for basic validation. (Click here to see this image larger.)

Macro directs autosampler to perform dilutions

"The most tedious part in method development is to create different dilutions of a stock solution and to modify method parameters for assessing whether the method is stable," explained Dr. Michael Pfeffer, lab manager at Bayer Schering Pharma.

Dr. Pfeffer’s objective was to automate as many steps in this workflow as possible. His lab chose an Agilent HPLC system equipped with a thermostatted autosampler and controlled through Agilent ChemStation software for development of the analytical method. The lab used the macro programming language of Agilent ChemStation to write a macro, named “Validation Generator” or AUTOVAL, which creates a dilution routine for the autosampler (Figure 1) and a sequence table for the diluted samples. After samples have been run, data is exported to Excel for calculation of results.

	“The system is simple to use and gives accurate and precise results.”

Figure 2. The macro provides a dialog for selection of the validation type, which then triggers the automated dilution procedure. (Click here to see this image larger.)

Figure 3. The AUTOVAL macro saves time by automatically generating a sequence table. (Click here to see this image larger.)

Simple user interface for setting up validation

The AUTOVAL macro checks basic validation parameters such as linearity, system precision, limit of detection (LOD), and limit of quantitation (LOQ). The macro creates a user interface (Figure 2) for selection of the scope of validation and the HPLC method to be used.

Macro generates sequence table

When the validation information is entered, the macro automatically generates a sequence table with the vials that contain the specific dilution levels (Figure 3). The sequence table contains 11 lines. The methods in lines 1 to 3 control the automated dilution. Solvent is injected in line 4 and analyzed according to the HPLC method. In lines 5 through 10, solutions of the six levels (0.1 to 150 %) are analyzed. Finally, solvent is injected again (line 11). The right column shows how often each vial is analyzed. If necessary, the injection volumes can be changed.

Automation increases efficiency

This high level of automation makes it possible to run analyses overnight, resulting in significant time-savings for Dr. Pfeffer and his lab personnel. "The system is simple to use and gives accurate and precise results," comments Ralf Golejewski, method developer at Bayer Schering Pharma.

Automated dilution and standardized evaluation proved to be integral components of effective method validation. "This whole set-up has saved us significant time, which can be used for more demanding work," remarks Dr. Pfeffer. The automated workflow provides reproducible results and eliminates manual pipetting mistakes. The AUTOVAL macro is a simple, robust, and efficient tool for generating validation data systematically.

For more information about use of ChemStation macro programming to automate method validation of early drug candidates, read the entire success story (5989-7874EN).