Regulatory Perspectives on Continuous Pharmaceutical Manufacturing: Moving From Theory to Practice

Continuous manufacturing is a key enabler for modernization of pharmaceutical manufacturing. This emerging technology has the potential to improve agility, flexibility, and robustness in the manufacture of pharmaceuticals. As expected, with the introduction of new technologies in the pharmaceutical sector, there are regulatory uncertainties in adopting a continuous manufacturing process. These include material traceability, process design, monitoring, and control that require consideration beyond established practices. More importantly, some uncertainties exist regarding how product quality is evaluated and assured in the context of continuous manufacturing technology within the current regulatory frameworks. To meet these challenges, key stakeholders, including drug manufacturers, suppliers, research institutions, and regulatory agencies, met at the 1st International Symposium on Continuous Manufacturing of Pharmaceuticals (ISCMP), sponsored by the Novartis-MIT Center for Continuous Manufacturing and the Continuous Manufacturing and Crystallisation Consortium on May 27-28, 2014 to discuss existing knowledge, opportunities, challenges, technology gaps, and regulatory aspects related to continuous manufacturing. The meeting resulted in a series of White Papers intended to drive the pharmaceutical industry toward reaping the true benefits of continuous manufacturing and adopting this emerging technology. The pharmaceutical industry, research institutions, and regulatory agencies are collaborating to overcome challenges related to the development and implementation of continuous manufacturing. Significant progress has been achieved since the 2014 ISCMP. Nearly all major innovator pharmaceutical companies are working on continuous manufacturing technologies. Only 2 years have passed since the first symposium, and already there have been tremendous advances in terms of the number of companies committed to continuous manufacturing. The degree of their commitment can be measured by the number of continuous manufacturing projects that they are pursuing. Of the top 15 pharmaceutical companies, nearly all have publicly declared their commitment to continuous manufacturing. The number of continuous equipment vendors is increasing. Most significantly, the U.S. Food and Drug Administration (FDA) approved Orkambi (lumacaftor/ivacaftor), which is a new cystic fibrosis drug produced using continuous drug product manufacturing methods (i.e., the active pharmaceutical ingredient [API] is still produced via batch) including real-time release testing (RTRT). In 2016, the US FDA also approved a manufacturer’s switch in its production method from batch to continuous drug product manufacturing for the existing product Prezista (darunavir). These 2 examples represent a significant step in integrating continuous manufacturing into commercial pharmaceutical production. They illustrate the feasibility of using continuous manufacturing for a new drug development and commercial production under an accelerated regulatory pathway and for implementing this emerging technology for manufacturing existing products as post approval changes. Building upon the 2014 ISCMP meeting and consequential implementation progress, the 2nd ISCMP meeting was held on September 26-27, 2016. The objective of the 2016 ISCMP included providing real case studies from stakeholders to illustrate progress that has been made since 2014, identifying the remaining gaps, and developing appropriate solutions and next steps to address them. In addition, the symposium aims to develop and provide practical guidelines based on real case studies to support a future International Conference for Harmonisation (ICH) guidance on continuous manufacturing. This paper represents the main output of the 2016 ISCMP. In support of the 2014 Regulatory White Paper,1 this paper will not repeat the detailed regulatory and quality issues previously described in the 2014 paper, but will instead focus on providing updates on topics specifically discussed during the 2016 meeting, including scientific and regulatory aspects related to the development, implementation, and evaluation of continuous manufacturing from both industry and regulatory agency perspectives. In addition, this paper identifies opportunities to further advance and accelerate the implementation of continuous manufacturing for pharmaceuticals.