Chemometrics in Protein Formulation : Stability Governed by Repulsion and Protein Unfolding
(2023) In Molecular Pharmaceutics 20(6). p.2951-2965- Abstract
Therapeutic proteins can be challenging to develop due to their complexity and the requirement of an acceptable formulation to ensure patient safety and efficacy. To date, there is no universal formulation development strategy that can identify optimal formulation conditions for all types of proteins in a fast and reliable manner. In this work, high-throughput characterization, employing a toolbox of five techniques, was performed on 14 structurally different proteins formulated in 6 different buffer conditions and in the presence of 4 different excipients. Multivariate data analysis and chemometrics were used to analyze the data in an unbiased way. First, observed changes in stability were primarily determined by the individual... (More)
Therapeutic proteins can be challenging to develop due to their complexity and the requirement of an acceptable formulation to ensure patient safety and efficacy. To date, there is no universal formulation development strategy that can identify optimal formulation conditions for all types of proteins in a fast and reliable manner. In this work, high-throughput characterization, employing a toolbox of five techniques, was performed on 14 structurally different proteins formulated in 6 different buffer conditions and in the presence of 4 different excipients. Multivariate data analysis and chemometrics were used to analyze the data in an unbiased way. First, observed changes in stability were primarily determined by the individual protein. Second, pH and ionic strength are the two most important factors determining the physical stability of proteins, where there exists a significant statistical interaction between protein and pH/ionic strength. Additionally, we developed prediction methods by partial least-squares regression. Colloidal stability indicators are important for prediction of real-time stability, while conformational stability indicators are important for prediction of stability under accelerated stress conditions at 40 °C. In order to predict real-time storage stability, protein-protein repulsion and the initial monomer fraction are the most important properties to monitor.
(Less)
- author
- organization
- publishing date
- 2023-06
- type
- Contribution to journal
- publication status
- published
- subject
- keywords
- colloidal and conformational stability, multivariate data analysis, protein characterization, protein formulation, therapeutic proteins
- in
- Molecular Pharmaceutics
- volume
- 20
- issue
- 6
- pages
- 15 pages
- publisher
- The American Chemical Society (ACS)
- external identifiers
-
- pmid:37146162
- scopus:85163321275
- ISSN
- 1543-8384
- DOI
- 10.1021/acs.molpharmaceut.3c00013
- language
- English
- LU publication?
- yes
- id
- ae1c75e7-16df-4e94-96e2-8624f2eaf90b
- date added to LUP
- 2023-09-15 11:57:50
- date last changed
- 2024-04-26 02:21:24
@article{ae1c75e7-16df-4e94-96e2-8624f2eaf90b, abstract = {{<p>Therapeutic proteins can be challenging to develop due to their complexity and the requirement of an acceptable formulation to ensure patient safety and efficacy. To date, there is no universal formulation development strategy that can identify optimal formulation conditions for all types of proteins in a fast and reliable manner. In this work, high-throughput characterization, employing a toolbox of five techniques, was performed on 14 structurally different proteins formulated in 6 different buffer conditions and in the presence of 4 different excipients. Multivariate data analysis and chemometrics were used to analyze the data in an unbiased way. First, observed changes in stability were primarily determined by the individual protein. Second, pH and ionic strength are the two most important factors determining the physical stability of proteins, where there exists a significant statistical interaction between protein and pH/ionic strength. Additionally, we developed prediction methods by partial least-squares regression. Colloidal stability indicators are important for prediction of real-time stability, while conformational stability indicators are important for prediction of stability under accelerated stress conditions at 40 °C. In order to predict real-time storage stability, protein-protein repulsion and the initial monomer fraction are the most important properties to monitor.</p>}}, author = {{Kulakova, Alina and Augustijn, Dillen and El Bialy, Inas and Gentiluomo, Lorenzo and Greco, Maria Laura and Hervø-Hansen, Stefan and Indrakumar, Sowmya and Mahapatra, Sujata and Martinez Morales, Marcello and Pohl, Christin and Polimeni, Marco and Roche, Aisling and Svilenov, Hristo L. and Tosstorff, Andreas and Zalar, Matja and Curtis, Robin and Derrick, Jeremy P. and Frieß, Wolfgang and Golovanov, Alexander P. and Lund, Mikael and Nørgaard, Allan and Khan, Tarik A. and Peters, Günther H.J. and Pluen, Alain and Roessner, Dierk and Streicher, Werner W. and van der Walle, Christopher F. and Warwicker, Jim and Uddin, Shahid and Winter, Gerhard and Bukrinski, Jens Thostrup and Rinnan, Åsmund and Harris, Pernille}}, issn = {{1543-8384}}, keywords = {{colloidal and conformational stability; multivariate data analysis; protein characterization; protein formulation; therapeutic proteins}}, language = {{eng}}, number = {{6}}, pages = {{2951--2965}}, publisher = {{The American Chemical Society (ACS)}}, series = {{Molecular Pharmaceutics}}, title = {{Chemometrics in Protein Formulation : Stability Governed by Repulsion and Protein Unfolding}}, url = {{http://dx.doi.org/10.1021/acs.molpharmaceut.3c00013}}, doi = {{10.1021/acs.molpharmaceut.3c00013}}, volume = {{20}}, year = {{2023}}, }