Process analytical technique (PAT) miniaturization for monoclonal antibody aggregate detection in continuous downstream processing

Mariana N. São Pedro, Marieke E. Klijn, Michel H.M. Eppink, Marcel Ottens*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

25 Citations (Scopus)


The transition to continuous biomanufacturing is considered the next step to reduce costs and improve process robustness in the biopharmaceutical industry, while also improving productivity and product quality. The platform production process for monoclonal antibodies (mAbs) is eligible for continuous processing to lower manufacturing costs due to patent expiration and subsequent growing competition. One of the critical quality attributes of interest during mAb purification is aggregate formation, with several processing parameters and environmental factors known to influence antibody aggregation. Therefore, a real-time measurement to monitor aggregate formation is crucial to have immediate feedback and process control and to achieve a continuous downstream processing. Miniaturized biosensors as an in-line process analytical technology tool could play a pivotal role to facilitate the transition to continuous manufacturing. In this review, miniaturization of already well-established methods to detect protein aggregation, such as dynamic light scattering, Raman spectroscopy and circular dichroism, will be extensively evaluated for the possibility of providing a real-time measurement of mAb aggregation. The method evaluation presented in this review shows which limitations of each analytical method still need to be addressed and provides application examples of each technique for mAb aggregate characterization. Additionally, challenges related to miniaturization are also addressed, such as the design of the microfluidic chip and the microfabrication material. The evaluation provided in this review shows why the development of microfluidic biosensors is considered the key for real-time measurement of mAb aggregates and how it can contribute to the transition to a continuous processing.

Original languageEnglish
Pages (from-to)2347-2364
JournalJournal of Chemical Technology and Biotechnology
Issue number9
Early online date15 Sept 2021
Publication statusPublished - Sept 2022


  • continuous biomanufacturing
  • microfluidics
  • monoclonal antibodies
  • process analytical technology (PAT)
  • protein aggregation


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