PMID- 30378770
OWN - NLM
STAT- MEDLINE
DCOM- 20200313
LR  - 20200313
IS  - 1520-6033 (Electronic)
IS  - 1520-6033 (Linking)
VI  - 35
IP  - 2
DP  - 2019 Mar
TI  - At-line raman spectroscopy and design of experiments for robust monitoring and 
      control of miniature bioreactor cultures.
PG  - e2740
LID - 10.1002/btpr.2740 [doi]
AB  - The biopharmaceutical industry is moving toward a more quality by design (QbD) 
      approach that seeks to increase product and process understanding and process 
      control. Miniature bioreactor systems offer a high-throughput method enabling the 
      assessment of numerous process variables in a controlled environment. However, 
      the number of off/at-line samples that can be taken is restricted due to the 
      small working volume of each vessel. This limitation may be resolved through the 
      use of Raman spectroscopy due to its ability to obtain multianalyte data from 
      small sample volumes fast. It can, however, be challenging to implement this 
      technique for this application due to the complexity of the sample matrix and 
      that analytes are often present in low concentration. Here, we present a design 
      of experiments (DOE) approach to generate samples for calibrating robust 
      multivariate predictive models measuring glucose, lactate, ammonium, viable cell 
      concentration (VCC) and product concentration, for unclarified cell culture that 
      improves the daily monitoring of each miniature bioreactor vessel. Furthermore, 
      we demonstrate how the output of the glucose and VCC models can be used to 
      control the glucose and main nutrient feed rate within miniature bioreactor 
      cultures to within qualified critical limits set for larger scale vessels. The 
      DOE approach used to generate the calibration sample set is shown to result in 
      models more robust to process changes than by simply using samples taken from the 
      "typical" process. (c) 2018 American Institute of Chemical Engineers Biotechnol. 
      Prog., 35: e2740, 2019.
CI  - (c) 2018 American Institute of Chemical Engineers.
FAU - Rowland-Jones, Ruth C
AU  - Rowland-Jones RC
AUID- ORCID: 0000-0002-3678-2791
AD  - BBTC, Newcastle University, Newcastle, Upon Tyne, NE1 7RU.
FAU - Jaques, Colin
AU  - Jaques C
AD  - Research and Development, Lonza Biologics plc, 228 Bath Road, Slough, SL1 4DX.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20181210
PL  - United States
TA  - Biotechnol Prog
JT  - Biotechnology progress
JID - 8506292
RN  - 0 (Ammonium Compounds)
RN  - 33X04XA5AT (Lactic Acid)
RN  - IY9XDZ35W2 (Glucose)
SB  - IM
MH  - Ammonium Compounds/*analysis/metabolism
MH  - Animals
MH  - Bioreactors/*microbiology
MH  - CHO Cells
MH  - Cells, Cultured
MH  - Cricetulus
MH  - Equipment Design
MH  - Glucose/*analysis/biosynthesis
MH  - Lactic Acid/*analysis/biosynthesis
MH  - Spectrum Analysis, Raman/instrumentation
MH  - Time Factors
OTO - NOTNLM
OT  - Chinese hamster ovary cultures (CHO cultures)
OT  - Raman spectroscopy
OT  - control
OT  - design of experiment
OT  - process analytical technology (PAT)
EDAT- 2018/11/01 06:00
MHDA- 2020/03/14 06:00
CRDT- 2018/11/01 06:00
PHST- 2018/03/14 00:00 [received]
PHST- 2018/10/08 00:00 [revised]
PHST- 2018/10/29 00:00 [accepted]
PHST- 2018/11/01 06:00 [pubmed]
PHST- 2020/03/14 06:00 [medline]
PHST- 2018/11/01 06:00 [entrez]
AID - 10.1002/btpr.2740 [doi]
PST - ppublish
SO  - Biotechnol Prog. 2019 Mar;35(2):e2740. doi: 10.1002/btpr.2740. Epub 2018 Dec 10.