Increasing the Reuse of Protein Non-Naïve Nonhuman Primates in Pharmaceutical Drug Discovery and Development: An Overview and Industry Position on the Challenges and Benefits.

The IQ Consortium NHP Reuse Working Group (WG) comprises members from 15 pharmaceutical and biotechnology companies. In 2020, the WG developed and distributed a detailed questionnaire on protein non-naïve NHP reuse to the WG member companies. The WG received responses from key stakeholders including principal investigators, facility managers, animal welfare officers and research scientists. This paper's content reflects the consolidated opinion of the WG members and the questionnaire responses on the subject of NHP reuse within nonclinical programs at all stages of research and development. Many of the pharmaceutical companies represented in the working group or participating in the questionnaire have already achieved some level of NHP reuse in their nonclinical programs, but the survey results suggested that there is significant potential to increase NHP reuse further and a need to understand the considerations involved in reuse more clearly. The WG has also focused carefully on the inherent concerns and risks of implementing protein non-naive NHP reuse and has evaluated the best methods of risk assessment and decision-making. This paper presents a discussion on the challenges and opportunities surrounding protein non-naïve NHP reuse and aims to stimulate further industry dialogue on the subject and provide guidance for pharmaceutical companies to establish roadmaps and decision trees enabling increased protein non-naïve NHP reuse. In addition, this paper represents a solid basis for collaborative engagement between pharmaceutical and biotechnology companies with contract research organizations (CROs) to discuss how the availability of protein non-naïve NHP within CROs can be better leveraged for their use within nonclinical studies.

A high throughput metabolic stability screening workflow with automated assessment of data quality in pharmaceutical industry.

One of the most commonly performed in vitro ADME assays during the lead generation and lead optimization stage of drug discovery is metabolic stability evaluation. Metabolic stability is typically assessed in liver microsomes, which contain Phase I metabolizing enzymes, mainly cytochrome P450 enzymes (CYPs). The amount of parent drug metabolized by these CYPs is determined by LC/MS/MS. The metabolic stability data are typically used to rank order compounds for in vivo evaluation. We describe a streamlined and intelligent workflow for the metabolic stability assay that permits high throughput analyses to be carried out while maintaining the standard of high quality. This is accomplished in the following ways: a novel post-incubation pooling strategy based on cLogD(3.0) values, coupled with ultra-performance liquid chromatography/tandem mass spectrometry (UPLC/MS/MS), enables sample analysis times to be reduced significantly while ensuring adequate chromatographic separation of compounds within a group, so as to reduce the likelihood of compound interference. Assay quality and fast turnaround of data reports is ensured by performing automated real-time intelligent re-analysis of discrete samples for compounds that do not pass user-definable criteria during the pooling analysis. Intelligent, user-independent data acquisition and data evaluation are accomplished via a custom visual basic program that ties together every step in the workflow, including cassette compound selection, compound incubation, compound optimization, sample analysis and re-analysis (when appropriate), data processing, data quality evaluation, and database upload. The workflow greatly reduces labor and improves data turnaround time while maintaining high data quality.