Strategies for Accelerated Drug Development: An Industry Perspective Based on an IQ Consortium Survey of CMC Considerations.

Over the past decade, there has been an increase in accelerated drug development with successful regulatory approval that has provided rapid access of novel medicines to patients world-wide. This has created the opportunity for the pharmaceutical industry to continuously improve the process of quickly bringing new medicines to patients with unmet medical needs. This can be accomplished through sharing the learnings and advancements in drug development, enhancing regulatory interactions, and collaborating with academics on developing the underlying science to reduce drug development timelines. In this paper, the IQ Consortium - Accelerated Drug Development working group members intend to share recommendations for optimizing strategies that build efficiencies in accelerated pathways for regulatory approval. Information was obtained by surveying member pharmaceutical companies with respect to recent expedited submissions within the past 5 years to gain insights as to which development strategies were successful. The learnings from this analysis are provided, which includes shared learnings in formulation development, stability, analytical methods, manufacturing, and importation testing as well as regulatory considerations. Each of these sections provide a summary illustrating the key data collected as well as a discussion that is aimed to guide pharmaceutical companies on strategies to consider streamlining development activities and expedite the drug to market.

Opposite effects of polyols on antibody aggregation: thermal versus mechanical stresses.

PURPOSE: To investigate the physical stability of antibody-polyol formulations under thermal and mechanical stresses. METHODS: mAb-U was analyzed in buffer, trehalose, sucrose, glycerol and ethylene glycol solutions at pH 7.0. T(m1) of mAb-U was determined using DSC. Thermal stress studies were performed by incubating mAb-U-polyol solutions at 40°C (2 months), 50°C (3 weeks) and 65°C (5 days). Mechanical stress studies were conducted by shaking mAb-U-polyol solutions at 200 rpm for 5 days at 25°C. RESULTS: Trehalose and glycerol increased the T(m1) of mAb-U, whereas ethylene glycol decreased it. The trend observed in the order of increasing aggregation of mAb-U after thermal stress (40°C and 50°C) was buffer = trehalose = sucrose

Application of second-derivative fluorescence spectroscopy to monitor subtle changes in a monoclonal antibody structure.

In this study, the tertiary structure of a monoclonal antibody was analyzed under thermal and chemical stresses using second-derivative fluorescence spectroscopy. The effect of polyols, sucrose, and ethylene glycol on the tertiary structure of monoclonal antibody-U (mAb-U) (pH 7.0) was studied under thermal stress (25°C-75°C). The tertiary structure of mAb-U was also analyzed upon chemical denaturation using urea (2.0-8.0 M). The second derivative of mAb-U showed three bands corresponding to the three spectral classes of tryptophan, class I (330 nm), class II (340 nm), and class III (350 nm). Class II was higher in intensity in the presence of polyols compared with the solution without any polyol. Thermally denatured structure of mAb-U in sucrose and ethylene glycol was distinctly different than that in buffer. Addition of urea resulted in a decrease in intensity of class I and II, and an increase in intensity of class III implying unfolding. This study showed that second-derivative fluorescence spectroscopy is an effective tool to monitor subtle alterations in the tertiary structure of proteins. The unfolding of a protein is reflected as an increase in the intensity of the polar class III accompanied with a decrease in the intensity of class I.

Characterization of antibody-polyol interactions by static light scattering: implications for physical stability of protein formulations.

In this study, the nature of interactions between monoclonal antibodies and polyols was studied using static light scattering. Solutions of mAb-U and mAb-P (4-12 mg/mL) were analyzed using static light scattering in buffer, 10% w/v trehalose and ethylene glycol solutions at pH 5.0, 7.0 and 9.0. Mechanical stress studies were conducted by shaking the mAb-U solutions (5mg/mL, pH 5.0, 7.0 and 9.0) and mAb-P solutions (5mg/mL, pH 7.0) at 200 rpm for 5 days at 25°C. Addition of trehalose and ethylene glycol resulted in a decrease in the attractive interactions between mAb-U molecules at pH 7.0 and 9.0, and at pH 9.0 between mAb-P molecules. At a higher ionic strength (300 mM, pH 5.0) trehalose and ethylene glycol decreased attractive interactions for both mAbs. Mechanical stress studies showed higher aggregation of mAb-U in trehalose solutions than ethylene glycol and buffer solutions at pH 7.0 and 9.0. A converse trend was seen for mAb-P at pH 7.0. This study showed that polyols, conformational stabilizers or destabilizers, decrease attractive interactions between protein molecules. The decrease is a result of masking of the hydrophobic sites on a protein as polyols can have favorable hydrophobic interactions with the surface exposed hydrophobic groups.

Solubilities and transfer free energies of hydrophobic amino acids in polyol solutions: importance of the hydrophobicity of polyols.

The purpose of this work was to investigate the difference in the hydrophobicities of various polyols and the nature of interactions between hydrophobic amino acid side chains and polyols. The interactions were explored by conducting solubility studies of three amino acid derivatives, N-acetyl tryptophanamide (NATA), N-acetyl leucinamide (NALA), and N-acetyl glycinamide (NAGA), in the solutions of sorbitol, sucrose, trehalose, glycerol, ethylene glycol, ribose, and deoxyribose. Hydrophobicity index of polyols was calculated using molecular modeling. An increase in the solubility of the hydrophobic side chains of tryptophan and leucine was observed with an increase in the hydrophobicity index of polyols. Transfer free energies of NATA from water to polyols solutions were negative, whereas those for NALA were positive for all polyols except glycol. This study shows that the hydrophobic nature of polyols plays an important role in polyol-side chain interactions. Solubility behavior observed for NATA and NALA in different polyols indicates that polyols can interact differently with the same side chain depending on the nature of the polyol and the side chain.