Abstract:
:Protein higher order structure (HOS) is an essential quality attribute to ensure protein stability and proper biological function. Protein HOS characterization is performed during comparability assessments for product consistency as well as during forced degradation studies for structural alteration upon stress. Circular dichroism (CD) spectroscopy is a widely used technique for measuring protein HOS, but it remains difficult to assess HOS with a high degree of accuracy and precision. Moreover, once spectral changes are detected, interpreting the differences in terms of specific structural attributes is challenging. Spectral normalization by the protein concentration remains one of the largest sources of error and reduces the ability to confidently detect differences in CD spectra. This work develops a simple method to enhance the precision of the CD spectral measurements through normalization of the CD spectra by the protein concentration determined directly from the CD measurement. This method is implemented to successfully detect small CD spectral changes in multiple forced degradation studies as well as comparability assessments during biologics drug development. Furthermore, the interpretation of CD spectral changes in terms of HOS differences are provided based on orthogonal data in conjunction with structural insights gained through in silico homology modeling of the protein structure.
journal_name
J Pharm Scijournal_title
Journal of pharmaceutical sciencesauthors
Barnett GV,Balakrishnan G,Chennamsetty N,Meengs B,Meyer J,Bongers J,Ludwig R,Tao L,Das TK,Leone A,Kar SRdoi
10.1016/j.xphs.2018.06.007subject
Has Abstractpub_date
2018-10-01 00:00:00pages
2559-2569issue
10eissn
0022-3549issn
1520-6017pii
S0022-3549(18)30340-Xjournal_volume
107pub_type
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