An NMR-Based Similarity Metric for Higher Order Structure Quality Assessment Among U.S. Marketed Insulin Therapeutics

Wang, Deyun; Park, Junyong; Patil, Sharadrao M.; Smith, Cameron J.; Leazer, John L.; Keire, David A.; Kang, Chul

doi:10.1016/j.xphs.2020.01.002

Cited by 18 publications

(22 citation statements)

References 30 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The Mahalanobis distance (D M ) calculated from the first three principal components ( Table S2 ) using Equations (1) and (2) were 1.95 and 3.15, when the 850 MHz data and the 600 MHz data were used, respectively. Both values were below the established similarity threshold D M value of 3.3 [ 27 ], suggesting similar HOS between the two products. Ninety percent (90%) confidence interval ellipses were drawn for the Rituxan ® DP lots in PC1/2 space ( Figure 2 , right).…”

Section: Resultsmentioning

confidence: 87%

“…Although the 1D 1 H spectra can be used to assess protein HOS qualitatively, a quantifiable similarity metric is of interest to demonstrate comparability after manufacturing changes or similarity between any two drug brands [ 38 ]. Previously, 1D 1 H spectra between the reference insulin and the follow-on insulin DPs were chemometrically compared using principal component analysis (PCA) and Mahalanobis distance (D M ) metrics, which were derived from PCA space [ 27 ]. The previous results on insulin DPs suggested a D M value of 3.3 as the similarity threshold [ 27 ], where above 3.3 value there were clear differences in the HOS, while below that there were no discernable differences.…”

Section: Resultsmentioning

confidence: 99%

“…Previously, 1D 1 H spectra between the reference insulin and the follow-on insulin DPs were chemometrically compared using principal component analysis (PCA) and Mahalanobis distance (D M ) metrics, which were derived from PCA space [ 27 ]. The previous results on insulin DPs suggested a D M value of 3.3 as the similarity threshold [ 27 ], where above 3.3 value there were clear differences in the HOS, while below that there were no discernable differences. Here, the rituximab DPs Rituxan ® and Reditux ® were compared using the same approach.…”

Section: Resultsmentioning

confidence: 99%

“…The question of the level of similarity that is practically measurable remains to be answered quantitively. Previous attempts were made to collect NMR spectra on a DS enriched formulation of filgrastim [ 26 ] and DP formulations of insulin [ 27 ]. A combined chemical shift difference of 8 ppb or less was proposed as the threshold for experimental precision in 2D-NMR comparisons of biosimilars using data between the US and Indian marketed filgrastim DPs [ 26 ].…”

Section: Introductionmentioning

confidence: 99%

“…A combined chemical shift difference of 8 ppb or less was proposed as the threshold for experimental precision in 2D-NMR comparisons of biosimilars using data between the US and Indian marketed filgrastim DPs [ 26 ]. The principal component analysis (PCA) of the insulin DP NMR spectra revealed the practically achievable similarity threshold expressed in Mahalanobis distance (D M ) to be 3.3 or less [ 27 ]. These values were achieved when 600 MHz spectrometer with room temperature probe was used, therefore, the derived metrics were practical (in terms of the availability of instruments) and could be useful in establishing the acceptance criteria for a certain DP before and after a manufacturing change and for the comparison between a generic or biosimilar protein and the reference DP.…”

Section: Introductionmentioning

confidence: 99%

See 4 more Smart Citations

NMR Spectroscopy for Protein Higher Order Structure Similarity Assessment in Formulated Drug Products

et al. 2021

Self Cite

View full text Add to dashboard Cite

Peptide and protein drug molecules fold into higher order structures (HOS) in formulation and these folded structures are often critical for drug efficacy and safety. Generic or biosimilar drug products (DPs) need to show similar HOS to the reference product. The solution NMR spectroscopy is a non-invasive, chemically and structurally specific analytical method that is ideal for characterizing protein therapeutics in formulation. However, only limited NMR studies have been performed directly on marketed DPs and questions remain on how to quantitively define similarity. Here, NMR spectra were collected on marketed peptide and protein DPs, including calcitonin-salmon, liraglutide, teriparatide, exenatide, insulin glargine and rituximab. The 1D 1H spectral pattern readily revealed protein HOS heterogeneity, exchange and oligomerization in the different formulations. Principal component analysis (PCA) applied to two rituximab DPs showed consistent results with the previously demonstrated similarity metrics of Mahalanobis distance (DM) of 3.3. The 2D 1H-13C HSQC spectral comparison of insulin glargine DPs provided similarity metrics for chemical shift difference (Δδ) and methyl peak profile, i.e., 4 ppb for 1H, 15 ppb for 13C and 98% peaks with equivalent peak height. Finally, 2D 1H-15N sofast HMQC was demonstrated as a sensitive method for comparison of small protein HOS. The application of NMR procedures and chemometric analysis on therapeutic proteins offer quantitative similarity assessments of DPs with practically achievable similarity metrics.

show abstract

Section: Resultsmentioning

confidence: 87%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

NMR Spectroscopy for Protein Higher Order Structure Similarity Assessment in Formulated Drug Products

et al. 2021

Self Cite

View full text Add to dashboard Cite

show abstract

Assessment of the Higher‐Order Structure of Formulated Monoclonal Antibody Therapeutics by 2D Methyl Correlated NMR and Principal Component Analysis

et al. 2020

View full text Add to dashboard Cite

Characterization of the higher‐order structure (HOS) of protein therapeutics, and in particular of monoclonal antibodies, by 2D 1H‐13C methyl correlated NMR has been demonstrated as precise and robust. Such characterization can be greatly enhanced when collections of spectra are analyzed using multivariate approaches such as principal component analysis (PCA), allowing for the detection and identification of small structural differences in drug substance that may otherwise fall below the limit of detection of conventional spectral analysis. A major limitation to this approach is the presence of aliphatic signals from formulation or excipient components, which result in spectral interference with the protein signal of interest; however, the recently described Selective Excipient Reduction and Removal (SIERRA) filter greatly reduces this issue. Here we will outline how basic 2D 1H‐13C methyl−correlated NMR may be combined with the SIERRA approach to collect ‘clean’ NMR spectra of formulated monoclonal antibody therapeutics (i.e., drug substance spectra free of interfering component signals), and how series of such spectra may be used for HOS characterization by direct PCA of the series spectral matrix. © 2020 U.S. Government.Basic Protocol 1: NMR data acquisitionBasic Protocol 2: Full spectral matrix data processing and analysisSupport Protocol: Data visualization and cluster analysis

show abstract

Structural Fingerprinting of Antisense Oligonucleotide Therapeutics by Solution NMR Spectroscopy

2022

View full text Add to dashboard Cite

An NMR-Based Similarity Metric for Higher Order Structure Quality Assessment Among U.S. Marketed Insulin Therapeutics

Cited by 18 publications

References 30 publications

NMR Spectroscopy for Protein Higher Order Structure Similarity Assessment in Formulated Drug Products

NMR Spectroscopy for Protein Higher Order Structure Similarity Assessment in Formulated Drug Products

Assessment of the Higher‐Order Structure of Formulated Monoclonal Antibody Therapeutics by 2D Methyl Correlated NMR and Principal Component Analysis

Structural Fingerprinting of Antisense Oligonucleotide Therapeutics by Solution NMR Spectroscopy

Contact Info

Product

Resources

About