(671f) Rational Strategies for Physical Characterization of Amorphous Solid Dispersions during Drug Product Development and Manufacture

As amorphous solid dispersions become more widely exploited in pharmaceutical products to enhance active ingredient solubility, strategies to more efficiently confirm the absence of undesired crystallinity during manufacture and shelf life become necessary. In recent years, rapid improvement in the application of solid state characterization techniques, such as calorimetry, spectroscopy, XRPD and ssNMR, has permitted order-of-magnitude increases in method sensitivity and development of reliable quantitative limit tests to justify control strategy selection. Verification of these strategies by transfer of solid state techniques to traditional quality control laboratories remains a challenge. Companies seeking to avoid extensive use of solid state techniques in routine manufacturing release testing may instead choose to leverage such techniques in well-designed development experiments based upon fundamentals.

Using several recent cases of drug products (prepared with hot melt extrudate or spray dried intermediates), we outline efficient approaches for identification of credible phase transition risks and development of methods to explore the propensity for such risks to occur. We find methods can often achieve limits of detection of ~5% amorphous to crystalline conversion on an active ingredient basis (particularly when the drug loading exceeds 10wt%). Experience from both marketed and late stage development programs are used to illustrate a rational, risk-based strategy can be demonstrated during process validation. In contrast to extensive, multi-dimensional stability studies and measurements aiming to anticipate the infinite set of excursion scenarios that might be anticipated during the product lifecycle, we instead advocate a more fundamental exploration of physical stability boundaries. These are often associated with solid dispersion glass transition temperatures. We emphasize the use of well-designed product characterization studies to understand the failure modes of solid dispersion intermediates and drug products, and compare a more limited set of experiential measurements to predictions from nucleation and growth theories. Specialist solid state methodologies can then be confined mainly to development laboratories, yet manufacturing facilities are still provided with robust amorphous control strategies and the knowledge to react to manufacturing excursions comprehensively and efficiently.