Throughput Optimization of Continuous Biopharmaceutical Manufacturing Facilities

PDA J Pharm Sci Technol. May-Jun 2017;71(3):189-205. doi: 10.5731/pdajpst.2016.006882. Epub 2016 Dec 14.


In order to operate profitably under different product demand scenarios, biopharmaceutical companies must design their facilities with mass output flexibility in mind. Traditional biologics manufacturing technologies pose operational challenges in this regard due to their high costs and slow equipment turnaround times, restricting the types of products and mass quantities that can be processed. Modern plant design, however, has facilitated the development of lean and efficient bioprocessing facilities through footprint reduction and adoption of disposable and continuous manufacturing technologies. These development efforts have proven to be crucial in seeking to drastically reduce the high costs typically associated with the manufacturing of recombinant proteins. In this work, mathematical modeling is used to optimize annual production schedules for a single-product commercial facility operating with a continuous upstream and discrete batch downstream platform. Utilizing cell culture duration and volumetric productivity as process variables in the model, and annual plant throughput as the optimization objective, 3-D surface plots are created to understand the effect of process and facility design on expected mass output. The model shows that once a plant has been fully debottlenecked it is capable of processing well over a metric ton of product per year. Moreover, the analysis helped to uncover a major limiting constraint on plant performance, the stability of the neutralized viral inactivated pool, which may indicate that this should be a focus of attention during future process development efforts.LAY ABSTRACT: Biopharmaceutical process modeling can be used to design and optimize manufacturing facilities and help companies achieve a predetermined set of goals. One way to perform optimization is by making the most efficient use of process equipment in order to minimize the expenditure of capital, labor and plant resources. To that end, this paper introduces a novel mathematical algorithm used to determine the most optimal equipment scheduling configuration that maximizes the mass output for a facility producing a single product. The paper also illustrates how different scheduling arrangements can have a profound impact on the availability of plant resources, and identifies limiting constraints on the plant design. In addition, simulation data is presented using visualization techniques that aid in the interpretation of the scientific concepts discussed.

Keywords: Continuous manufacturing; Plant throughput; Process modeling; Production scheduling.

MeSH terms

  • Batch Cell Culture Techniques / standards
  • Biological Products / chemistry*
  • Biopharmaceutics / instrumentation
  • Biopharmaceutics / methods
  • Biopharmaceutics / standards*
  • Bioreactors / standards
  • Chromatography / standards
  • Drug Compounding
  • Drug Industry / instrumentation
  • Drug Industry / methods
  • Drug Industry / standards*
  • Facility Design and Construction*
  • Filtration / standards
  • Models, Theoretical
  • Pharmaceutical Preparations / chemistry*
  • Quality Control*
  • Technology, Pharmaceutical / instrumentation
  • Technology, Pharmaceutical / methods
  • Technology, Pharmaceutical / standards*
  • Time Factors
  • Workflow*


  • Biological Products
  • Pharmaceutical Preparations