Developing and Validating Complex Methods

Summary

Agenda1 were selected by a United States based client to transfer and validate a method to quantify the level of crystallinity present in an API starting material and the finished drug product. Using the experience gained from previous similar validation programmes and recognizing the varying levels of validation possible, Agenda1 developed a cost-effective, client-specific, uncomplicated method. Previous techniques had provided Agenda1 with the experience needed to ensure the end result was accurate whilst meeting the client’s requirements.

Background

A US based client needed to transfer and validate a method to quantify the level of crystallinity in both an API starting material, and the related finished drug product. Both starting material and drug product had the potential to contain a proportion of amorphous API as an impurity.  Even at low levels (10%) the existence of such content was detrimental in terms of product safety and efficacy, and at above 10% the product would not meet required quality standards.

Given the above, the client was very specific when considering acceptable levels of crystallinity which meant method precision and accuracy were crucial when establishing the limit of detection and limit of quantification.

Agenda1 were selected by the client in place of their previous collaboration with a US based local (to the client) company, who  had developed what was felt to be an overly complicated, non cost effective method. The client was also cautious about becoming too reliant on a single supplier using a single type of Diffractometer and wanted a methodology which could be readily transferred between instrument and laboratories.

Resources used

Agenda1 have a range of in house equipment and processes which are  GMP compliant. The equipment is operated by an experienced team of analysts who are also fully trained in using the analytical techniques and in this case the client customized test sample preparation procedures.

For this work, a Bruker-AXS D8 Advance X-Ray Diffractometer was used with the X-Ray peak intensity and position standards sourced from NIST (National Institute of Standards and Technology). An internal standard was also supplied for incorporation into all test and calibration samples.

The client supplied a range of standard materials including a 100% API standard and samples of the inactive excipients.

Agenda1 have extensive experience developing XRD methods for quantitative crystallinity determination gained from previous work carried out,  which experience was applied to support the client’s work.

Approach and program

The first part of the program involved understanding and successfully transferring a sophisticated powder blending technique, which was employed to generate the test and calibration samples. This required all staff to be fully trained against the blending procedures used by the client.

The XRD method was then transferred and its application demonstrated by comparing results from the two sites.  It was necessary that XRD setting and sample presentation very precisely reflected the process at both sites, generating comparable results in terms of relative peak intensity and peak position. This required very precise equipment control and method development.

Once it was established that accurate and precise results were being obtained, Agenda1 then developed the existing client method to more appropriately reflect the client’s needs.

Results

Analysis of multiple samples and sample replicates demonstrated the success of the method transfer for both analytical and blending methods.

The method is now more readily transferable between instruments and sites as a result of  the work carried out by Agenda1.  |The understanding and documenting of instrument configuration and relative peak intensities (calibrated against  NIST standards) was of particular importance to support the client’s long term goals.