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Why Is Batch Processing Still Dominating the Biologics Landscape? Towards an Integrated Continuous Bioprocessing Alternative

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Why Is Batch Processing Still Dominating the Biologics Landscape? Towards an Integrated Continuous Bioprocessing Alternative processes Perspective Why Is Batch Processing Still Dominating the Biologics Landscape? Towards an Integrated Continuous Bioprocessing Alternative Ashish Kumar 1 , Isuru A. Udugama 2, Carina L. Gargalo 2 and Krist V. Gernaey 2,* 1 Pharmaceutical Engineering Research Group (PharmaEng), Department of Pharmaceutical Analysis, Ghent University, 9000 Gent, Belgium; [email protected] 2 Process and Systems Engineering Center (PROSYS), Department of Chemical and Biochemical Engineering, Technical University of Denmark, 2800 Kongens Lyngby, Denmark; [email protected] (I.A.U.); [email protected] (C.L.G.) * Correspondence: [email protected] Received: 9 November 2020; Accepted: 10 December 2020; Published: 12 December 2020 Abstract: Continuous manufacturing of biologics (biopharmaceuticals) has been an area of active research and development for many reasons, ranging from the demand for operational streamlining to the requirement of achieving obvious economic benefits. At the same time, biopharma strives to develop systems and concepts that can operate at similar scales for clinical and commercial production—using flexible infrastructures, such as single-use flow paths and small surge vessels. These developments should simplify technology transfer, reduce footprint and capital investment, and will allow to react readily to changing market pressures while maintaining quality attributes. Despite a number of clearly identified benefits compared to traditional batch processes, continuous bioprocessing is still not widely adopted for commercial manufacturing. This paper details how industry-specific technological, organizational, economic, and regulatory barriers that exist in biopharmaceutical manufacturing are hindering the adoption of continuous production processes. Based on this understanding, the roles of process systems engineering (PSE), process analytical technologies, and process modeling and simulation are highlighted as key enabling tools in overcoming these multi-faceted barriers in today’s manufacturing environment. Of course, we do recognize that there is also a need for a clear set of regulations to guide a transition of biologics manufacturing towards continuous processing. Furthermore, the role played by the emerging fields of process integration and automation as well as digitalization is explored, as these are the tools of the future to facilitate this transition from batch to continuous production. Finally, an outlook focusing on technology, management, and regulatory aspects is presented to identify key concerted efforts required to drive the broad adaptation of continuous manufacturing in biopharmaceutical processes. Keywords: continuous manufacturing; bioprocessing; process systems engineering; single-use technology 1. Introduction: Where Are We Now There is a growing interest in continuous biologics manufacturing in the pharmaceutical sector, encouraged by regulatory entities such as the Food and Drug Administration (FDA) and the International Council for Harmonization (ICH) [1–4]. Continuous manufacturing (CM) constitutes the critical aspect of process intensification which endeavors to reduce the time, cost, and complexities of bioprocess development and manufacturing. Several potential benefits are to be expected from its implementation, such as sustained and steady-state operation, the promise of more consistent product Processes 2020, 8, 1641; doi:10.3390/pr8121641 www.mdpi.com/journal/processes Processes 20202020,, 88,, 1641x FOR PEER REVIEW 2 of 19 consistent product quality and high productivity, reduced equipment size, and streamlined process qualityflow, thus and lowering high productivity, operating reduced and capital equipment costs [5,6]. size, An and overall streamlined increase process in sustainability flow, thus lowering can, in operatingprinciple, andbe achieved capital costs by switching [5,6]. An overallto continuous increase manufacturing, in sustainability in can, line in with principle, the UN’s be achievedSustainable by switchingDevelopment to continuous Goals to adopt manufacturing, better and in more line withsustai thenable UN’s processes. Sustainable However, Development despite Goals the immense to adopt betteropportunities and more of sustainablecontinuous processes.over batch However,operation, despite technical the and immense operational opportunities challenges of continuousneed to be overaddressed batch and operation, overcome technical for integrated and operational continuous challenges bioprocessing need toto bebecome addressed a reality. and Like overcome any other for integrateddisruptive continuous“new” technology, bioprocessing besides to becomethe scientific a reality. element, Like any there other are disruptive also business “new” and technology, human besidesaspects theinvolved scientific in element,decision-making there are alsothat businessneed attention. and human Of aspectscourse, involvedsome changes in decision-making are already thathappening, need attention. and people Of course, are currently some changes working are to already develop happening, more of the and continuous people are biomanufacturing currently working totechnology. develop moreHowever, of the such continuous development biomanufacturing is generally occurring technology. at a much However, slower such pace development than expected. is generallyThe main occurringquestion to at be a much answered slower is pacethen thanwhy expected.adopting continuous The main question biomanufacturing to be answered technology is then whyis, in adoptinggeneral, continuousextremely slow, biomanufacturing despite the obvious technology potential is, in benefits general, that extremely can be slow, achieved despite by theits obviousimplementation. potential benefits that can be achieved by its implementation. This manuscriptmanuscript aims aims to exploreto explore this unknownthis unkn conundrumown conundrum behind thebehind slow adoptionthe slow ofadoption continuous of processingcontinuous inprocessing commercial in biologicscommercial manufacturing biologics manufacturing despite known despite business known benefits, business innovations, benefits, technicalinnovations, support, technical and support, regulatory and push regulatory (Figure 1push). (Figure 1). Figure 1. Key forces that must be taken into considerationconsideration when introducing process technologies to biologics manufacturing. 1.1. Critical Views on Current Practices On the one hand, the manufacturingmanufacturing of biologics is the epitome of thethe contemporarycontemporary industry with cutting-edge research and development, resultin resultingg in the steady discovery of novel molecules. On the other hand, there are the manufacturing proce processessses of these biologics, which which are, are, even even today, today, to aa largelarge extent,extent, basedbased onon ineinefficientfficient batchbatch productionproduction platforms.platforms. Since biotechbiotech production started developing gradually, the firstfirst reactors were typicallytypically relatively small, inspired, e.g., by the dairy industry. However, throughoutthroughout thethe years,years, thethe needneed for reactor capacity and control has been growing steadily, whichwhich hashas resultedresulted inin bioreactorbioreactor vessels that are oftenoften upup toto severalseveral hundredhundred cubiccubic meters in capacity. Operating these processes in a batchbatch mode has its advantages.advantages. Namely, batch processes require lessless preciseprecise and and robust robust controls controls to to make make the the desired desired product product than than continuous continuous operation. operation. At theAt samethe same time, time, the the key key disadvantages disadvantages are are the the inherent inherent ine inefficienciesfficiencies of of batchbatch fermentationfermentation processes. For example,example, several several studies studies [7, 8[7,8]] have have shown shown that continuous,that continuous, or for that or matter,for that even matter, semi-continuous, even semi- fermentationcontinuous, fermentation processes are processes more e ffiarecient more than efficient batch than processes batch processes due to promoting due to promoting gains both gains in space-timeboth in space-time yield and yield raw and material raw material usage. usage. To thisthis end,end, bothboth academiaacademia andand industryindustry havehave beenbeen deliberatingdeliberating the adoptionadoption of continuouscontinuous biologics manufacturing for over half a century. Challenges with regards to various aspects of operation and control control of of the the biolog biologicsics process process in in a acontinuous continuous mode mode were were identified identified in inthis this period. period. A significant number of mechanistic insights translated into several technological advancements. On the other hand, regulatory agencies have also been evolving in support of continuous manufacturing Processes 2020, 8, 1641 3 of 19 A significant number of mechanistic insights translated into several technological advancements. On the other hand, regulatory agencies have also been evolving in support of continuous manufacturing from the FDA guidance on process analytical technologies (PATs) in 2004 for the adoption of a science- and risk-based approach allowing quality by design (QbD) [9] to the recent draft guidance dedicated to continuous manufacturing [2,10]. Despite explicit knowledge, technological advancement, and regulatory support, the implementation of continuous bioprocessing is and has been slow [11]. At
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