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Decision-making in drug development benefits from an integrated systems approach, where the stakeholders identify and address the critical questions for the system through carefully designed and performed studies. Biopharmaceutics Risk Assessment Roadmap (BioRAM) is such a systems approach for application of systems thinking to patient focused and timely decision-making, suitable for all stages of drug discovery and development. We described the BioRAM therapy-driven drug delivery framework, strategic roadmap, and integrated risk assessment instrument (BioRAM Scoring Grid) in previous publications (J Pharm Sci 103:3377–97, 2014; J Pharm Sci 105:3243–55, 2016). Integration of systems thinking with pharmaceutical development, manufacturing, and clinical sciences and health care is unique to BioRAM where the developed strategy identifies the system and enables risk characterization and balancing for the entire system. Successful decision-making process in BioRAM starts with the Blueprint (BP) meetings. Through shared understanding of the system, the program strategy is developed and captured in the program BP. Here, we provide three semi-hypothetical examples for illustrating risk-based decision-making in high and moderate risk settings. In the high-risk setting, which is a rare disease area, two completely alternate development approaches are considered (gene therapy and small molecule). The two moderate-risk examples represent varied knowledge levels and drivers for the programs. In one moderate-risk example, knowledge leveraging opportunities are drawn from the manufacturing knowledge and clinical performance of a similar drug substance. In the other example, knowledge on acute tolerance patterns for a similar mechanistic pathway is utilized for identifying markers to inform the drug release profile from the dosage form with the necessary “flexibility” for dosing. All examples illustrate implementation of the BioRAM strategy for leveraging knowledge and decision-making to optimize the clinical performance of drug products for patient benefit.

The October 2015 FDA/PQRI Conference on Advancing Product Quality provided a forum for the exchange of ideas focused on drug product quality between regulatory agencies, the pharmaceutical industry, and academia. Key topics of the 2015 conference were (i) emerging regulatory initiatives; (ii) regulatory submission, assessment, and inspection; (iii) product and process development; and (iv) manufacturing, risk management, and quality assurance. Key discussion points and recommendations for each track and session have been captured. With powerful advancements in product quality encompassing regulatory, industrial, and technological elements, an era of rapidly improving pharmaceutical quality is underway. At the conference, one theme prevailed through all sessions: regulators, industry, and academia are aligned in their desire for drug product quality on behalf of the ultimate stakeholder–the patient. 3D three dimensional, ANDA abbreviated new drug application, API active pharmaceutical ingredient, ASTM American society for testing and materials, BCS biopharmaceutics classification system, BLA biological license application, CGMP current good manufacturing practice, CMA critical material attribute, CMC chemistry manufacturing and controls, CPP critical process parameters, CQA critical quality attribute, CU content uniformity, DLS dynamic light scattering, DOE design of experiment, EMA European Medicines Agency, EWG Expert Working Group, FDA Food and Drug Administration, GDUFA generic drug user fee amendments, HCl Hydrogen Chloride, ICH International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use, IND investigational new drug, IQA integrated quality assessment, IR immediate release, IR information request, ISPE International Society for Pharmaceutical Engineering, MIT Massachusetts Institute of Technology, NDA new drug application, NIPP new inspection protocols project, NIR near-infrared spectroscopy, OPQ office of pharmaceutical quality, PAI pre-approval inspection, PAT process analytical technology, PDUFA prescription drug user fee act, PHS public health service, PQRI Product Quality Research Institute, PQS pharmaceutical quality system, QbD quality by design, QMS quality management system, QRM quality risk management, QTPP quality target product profile, RPM revolutions per minute, RTRT real time release testing, SUPAC scale-up and post-approval changes, UDU uniformity of dosage units, USP U.S. Pharmacopeial Convention.