A new roadmap for biopharmaceutical drug product development: Integrating development, validation, and quality by design.

Quality by design (QbD) is a science- and risk-based approach to drug product development. Although pharmaceutical companies have historically used many of the same principles during development, this knowledge was not always formally captured or proactively submitted to regulators. In recent years, the US Food and Drug Administration has also recognized the need for more controls in the drug manufacturing processes, especially for biological therapeutics, and it has recently launched an initiative for Pharmaceutical Quality for the 21st Century to modernize pharmaceutical manufacturing and improve product quality. In the biopharmaceutical world, the QbD efforts have been mainly focused on active pharmaceutical ingredient processes with little emphasis on drug product development. We present a systematic approach to biopharmaceutical drug product development using a monoclonal antibody as an example. The approach presented herein leverages scientific understanding of products and processes, risk assessments, and rational experimental design to deliver processes that are consistent with QbD philosophy without excessive incremental effort. Data generated using these approaches will not only strengthen data packages to support specifications and manufacturing ranges but hopefully simplify implementation of postapproval changes. We anticipate that this approach will positively impact cost for companies, regulatory agencies, and patients, alike.

Raman spectroscopic characterization of drying-induced structural changes in a therapeutic antibody: correlating structural changes with long-term stability.

We characterized the secondary structure of a therapeutic recombinant humanized monoclonal antibody (rhuMAb), formulated with different concentrations of sucrose, trehalose, and histidine and in solution, lyophilized, and spray-dried states. Quantitative secondary structure estimates were obtained using amide I band Raman spectroscopy and a previously developed spectral deconvolution procedure. On lyophilization or spray drying in the absence of sugar, the antibody underwent significant structural perturbation. The beta-sheet content decreased with corresponding gain in the turn and unordered content. With increasing amount of sucrose or trehalose, the extent of structural perturbation decreased. Eventually, at sugar-to-protein molar ratios of > or =360, almost complete structural preservation was observed. Histidine also protected the antibody against lyophilization-induced structural changes. The extent of structural perturbation immediately after lyophilization or spray drying exhibited good correlation with the rate of aggregation for the antibody during long-term storage under accelerated conditions. The results demonstrate that amide I band Raman spectroscopy could be a quick and reliable way to screen excipients and their concentrations during lyophilized or spray dried formulation development.