Strategic framework for education and training in Quality by Design (QbD) and process analytical technology (PAT).

The regulatory and technical landscape of the pharmaceutical field is rapidly evolving from one focused predominantly on development of small molecules, using well established manufacturing technologies towards an environment in which biologicals and complex modalities are being developed using advanced science and technology coupled with the application of modern Quality by Design (QbD) principles. In order that Europe keeps pace with these changes and sustains its position as major player in the development and commercialization of medicines, it is essential that measures are put in place to maintain a highly skilled workforce. A number of challenges however exist to equipping academic, industrial and health agency staff with the requisite knowledge, skills and experience to develop the next generation of medicines. In this regard, the EUFEPS QbD and PAT Sciences Network has proposed a structured framework for education, training and continued professional development, which comprises a number of pillars covering the fundamental principles of modern pharmaceutical development including the underpinning aspects of science, engineering and technology innovation. The framework is not prescriptive and is not aimed at describing specific course content in detail. It should however be used as a point of reference for those institutions delivering pharmaceutical based educational courses, to ensure that the necessary skills, knowledge and experience for successful pharmaceutical development are maintained. A positive start has been made and a number of examples of formal higher education courses and short training programs containing elements of this framework have been described. The ultimate vision for this framework however, is to see widespread adoption and proliferation of this curriculum with it forming the backbone of QbD and PAT science based skills development.

Towards a European strategy for medicines research (2014-2020): The EUFEPS position paper on Horizon 2020.

As to the alignment of "Horizon 2020", ir is a more integrated approach to European science policy than expressed in the proposals previously drafted, and specifically considers: (i) promoting excellence in Science, (ii) establishing a sound industrial leadership and (iii) expressing an ambition to address current and future societal challenges. In this respect, the quest for a knowledge-based economy in Europe should result in proposals for industrial and employment policies that will consolidate the major European advantages in the biomedical, healthcare and pharmaceutical sectors. Horizon 2020 also provides the possibility of adopting a more flexible and simplified management route to drive European research through innovation, research and development. What should be additionally considered? Unmet medical needs, under pressure from demographic changes, await the generation of new medicines and health technologies which will evolve into a driver for a unified European policy. We believe that this should be focused on harnessing pharmaceutical knowledge for clinical use, as part of a response to accommodate patient needs and economic growth based on a robust, scientific approach. The bolder ambition for European research is to unlock key bottlenecks currently undermining European competitiveness. The historical lack of an appropriate business/innovation environment with reduced access to adequate risk finance instruments has severed the path for economic growth and industrial development. These issues are of critical importance and a solution is urgently needed to foster translation from the university to the healthcare sector through the generation and support of start-ups, spin-offs, university-industry consortia, and other platforms, which support translational research. The ultimate goal is implementation of holistic programmes: the 'bench to bedside' paradigm of medicines and other healthcare products. The European Research Council supports the basic biomedical research programmes of long term importance for development of medicines; however, fundamental research initiatives on medicines development will not be competitive in such an environment. In order to strengthen the long term outlook, we must foster innovative research within the university sector, EUFEPS proposes that a fund for such research be set up within Horizon 2020, which would be open for individual research groups and which would include Public-Public Partnerships (complementing already existing Public-Private Partnerships). How do we look for implementation? There is an established research agenda for medicines research that is globally focused, and which incorporates a cooperative model between universities and industry, facilitating integration of complex technologies. Regulatory Science will play an important role in this integration. This agenda uses tools arising from systems approaches (including discovery with systems biology and also systems pharmacology) and has the potential for providing better knowledge management, as well as technological innovation (including manufacturing). It also addresses the drive towards personalised medicines and can, with support from both public and private sectors, foster translation of knowledge to new technologies and from that, to new medicinal products and complex integrated systems. This is a part of a strategy capable of solving unmet medical needs, which would increase the quality of life of patients suffering from chronic and debilitating diseases. The instruments to allow the development of a research agenda should strengthen existing partnerships such as the IMI-JU model; allow for the creation of European-network infrastructures that can bring together existing competences with adequate European coordination, thus promoting advanced training and continuous professional development for the pharmaceutical sciences. This will be the cornerstone of a knowledge management strategy, providing education and training for healthcare professionals and scientists. A key role for EUFEPS is to help the research community to embrace these new holistic policies applied to the spectrum of pharmaceutical, medical and cognate sciences.

Synthesis, X-ray analysis, and biological evaluation of a new class of stereopure lactam-based HIV-1 protease inhibitors.

In an effort to identify a new class of druglike HIV-1 protease inhibitors, four different stereopure ß-hydroxy γ-lactam-containing inhibitors have been synthesized, biologically evaluated, and cocrystallized. The impact of the tether length of the central spacer (two or three carbons) was also investigated. A compound with a shorter tether and (3R,4S) absolute configuration exhibited high activity with a K(i) of 2.1 nM and an EC(50) of 0.64 µM. Further optimization by decoration of the P1' side chain furnished an even more potent HIV-1 protease inhibitor (K(i) = 0.8 nM, EC(50) = 0.04 µM). According to X-ray analysis, the new class of inhibitors did not fully succeed in forming two symmetric hydrogen bonds to the catalytic aspartates. The crystal structures of the complexes further explain the difference in potency between the shorter inhibitors (two-carbon spacer) and the longer inhibitors (three-carbon spacer).

Two-carbon-elongated HIV-1 protease inhibitors with a tertiary-alcohol-containing transition-state mimic.

A new generation of HIV-1 protease inhibitors encompassing a tertiary-alcohol-based transition-state mimic has been developed. By elongation of the core structure of recently reported inhibitors with two carbon atoms and by varying the P1' group of the compounds, efficient inhibitors were obtained with Ki down to 2.3 nM and EC50 down to 0.17 microM. Two inhibitor-enzyme X-ray structures are reported.