Modeling and Experimental Model Parameter Determination with Quality by Design for Bioprocesses

Abstract

Process development and design in a strictly regulated environment need effi cient methods to generate product quality as early as possible, and to prove the reproducibility and reliability of process operation at the production scale afterwards. For pharmaceuticals, regulatory authorities like US Food and Drug Administration ( FDA ) and European Medicines Agency (EMA) have demanded Quality by Design ( QbD ) approaches in order to fi le information -based decisions. This chapter describes the state -of -the -art of QbD by statistical design of experiments. and actual developments to improve the predictive power and accuracy in combination with a reduction of later efforts by physicochemical -based process modeling. The benefi ts are pointed out exemplifi ed by an examplea typical hydrophobic interaction chromatography step in monoclonal antibody ( mAb ) downstream processing.A model has to be generated that is suffi ciently predictive within a given process operation parameter range with a known suffi cient accuracy. Therefore, a physicochemical -based mathematical process model is derived including nonidealities like fl uid dynamics by axial dispersion, mass transfer kinetics by fi lm and pore diffusion, and multicomponent equilibrium phase by interferences.The model parameters are determined experimentally at the laboratory scale (about a few milliliters) in order to gain an acceptable experimental error of lower then ± 5%. The model ' s accuracy is defi ned with the aid of Monte -Carlo simulations, which are described in detail. Afterwards, the model is validated at the laboratory scale and production scale with a set of different operation parameters to determine the predictive range and accuracy. Finally, some parameter studies are described in order to illustrate the method, discuss benefi ts, and point out limitations.

Efficient Engineering and Production Concepts for Products in Regulated Environments – Dream or Nightmare?

“…-First approaches to develop such innovative manufacturing plant concepts are under construction already. But still the technical transfer into industrialization under resource-and energy-efficient optimization strategies needs improvement [39,43,50,52,57,58]. Maturing manufacturing technologies tend to move from batch to continuous operation, often driven by economy-ofscale scenarios.…”

“…These techniques are applied in research, but still have to be transferred into daily project development work. This means that more industrial and project orientated education and training is needed [50].…”

“…(5) National funding concepts have already put a focus on strengthening SME's for good reasons [50,52,53]. -SME's, in contrast to global companies are predominantly locally orientated due to their size.…”

Quality-by-Design (QbD) process evaluation for phytopharmaceuticals on the example of 10-deacetylbaccatin III from yew

“…risk assessment and sensitivity studies, has shown that separation may be influenced by variability in flow-rate, load, solvent composition and adsorbent properties among others [19]. According to QbD-principles, a suitable solvent composition and adsorbent should be chosen based on scientific insight and proven product knowledge.…”

“…Especially, the implementation of rigorous process models provides an effective method to establish the required process knowledge. They ensure comparability between process scales within rigorous models, which is why they represent the missing link, connecting process risk assessment and process characterization [17][18][19].…”