title: Application of response surface methodology to maximize the productivity of scalable automated human embryonic stem cell manufacture.
abstract: OBJECTIVE
  Commercial regenerative medicine will require large quantities of clinical-specification human cells. The cost and quality of manufacture is notoriously difficult to control due to highly complex processes with poorly defined tolerances. As a step to overcome this, we aimed to demonstrate the use of 'quality-by-design' tools to define the operating space for economic passage of a scalable human embryonic stem cell production method with minimal cell loss.
  
  
  METHODS
  Design of experiments response surface methodology was applied to generate empirical models to predict optimal operating conditions for a unit of manufacture of a previously developed automatable and scalable human embryonic stem cell production method.
  
  
  CONCLUSIONS
  Two models were defined to predict cell yield and cell recovery rate postpassage, in terms of the predictor variables of media volume, cell seeding density, media exchange and length of passage. Predicted operating conditions for maximized productivity were successfully validated. Such 'quality-by-design' type approaches to process design and optimization will be essential to reduce the risk of product failure and patient harm, and to build regulatory confidence in cell therapy manufacturing processes.
authors.affiliation: Healthcare Engineering Research Group & EPSRC Centre for Innovative Manufacturing for Regenerative Medicine, Centre for Biological Engineering (CBE), Wolfson School of Mechanical & Manufacturing Engineering, Loughborough University, Leicestershire, UK.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Ratcliffe
authors.forename: Paul
authors.initials: P
authors.lastname: Hourd
authors.forename: Juan
authors.initials: J
authors.lastname: Guijarro-Leach
authors.forename: Erin
authors.initials: E
authors.lastname: Rayment
authors.forename: David J
authors.initials: DJ
authors.lastname: Williams
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Thomas
mesh_terms: D001331:Automation; D002452:Cell Count; D018929:Cell Culture Techniques / Q000379:methods*; D049109:Cell Proliferation; D053595:Embryonic Stem Cells / Q000166:cytology*; D006801:Humans; D008954:Models, Biological