Complex API sameness
A drug can be considered complex for a variety of reasons such as complex formulations, mixtures with multiple active components or mixtures where the active ingredients are not well defined. Complex drugs often present an intrinsic structural variability caused by slightly different manufacturing procedures or variability of their biological source. For these drugs, classical techniques are often unable to establish their structural characteristics and only the application of orthogonal analytical methods allow to determine their attributes. This strategy enables generic versions and innovator drugs to be compared to aid product development and reduce the need for clinical studies.
Our laboratories have long experience in performing sameness studies of Heparin, Low Molecular weight Heparin, glycosaminoglycans mixtures, glatiramer acetate and pentosan polysulfate using the combination of different techniques:
mass spectrometry coupled with chromatographic techniques of intact and enzymatically depolymerized materials
molecular weight determination using SEC coupled with multidetector array (RI, UV, viscometer and RALLS/MALLS).
immunogenic properties by investigation of the molecular weight dependence of the polymer– protein interaction (heparin, LMWH and pentosan polysulfate).
Because of their roles, primarily in drug development, traditional validation and robustness of analytical methods have not usually been performed on NMR and MS methods. In our laboratories we developed procedures for method validation following ICH Q2(R1), FDA or EMA guidelines. Particularly, quantitative 2D-NMR methods (HSQC) to determine the mono- and disaccharide composition of various complex drugs have been developed and validated.
Chemometric analysis of spectral libraries.
The characteristics of a variable complex drug cannot be related to a single standard, but they must be compared against a library of reference samples that represent the natural variability of the product. A widely used approach to handle a large set of data (i.e. NMR spectra or LCMS profiles) is to first reduce their complexity to those basic elements, which best define the differences among samples by employing chemometric techniques.
Our lab has experience in the construction of validated spectral libraries, explore them by Principal Component Analysis and verify if the structural characteristics of a test samples complies or not with the reference library. This approach resulted very useful in the control of production, control of products from different suppliers (i.e. raw or starting material) or identification of possible contaminants.