Influence of Production Process and Scale on Quality of Polypeptide Drugs: a Case Study on GLP-1 Analogs
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RESEARCH PAPER
Influence of Production Process and Scale on Quality of Polypeptide Drugs: a Case Study on GLP-1 Analogs Arne Staby 1 & Dorte Bjerre Steensgaard 2 & Kim F. Haselmann 2 & Jesper Søndergaard Marino 2 & Christina Bartholdy 2,6 & Nicoline Videbæk 3 & Ole Schelde 4 & Heidrun Bosch-Traberg 5 & Lotte Touborg Spang 4 & Désirée J. Asgreen 4
Received: 12 February 2020 / Accepted: 5 April 2020 # Springer Science+Business Media, LLC, part of Springer Nature 2020
ABSTRACT Purpose Manufacturing processes for polypeptide/protein drugs are designed to ensure robust quality, efficacy and safety. Process differences introduced by follow-on manufacturers may result in changes in quality and clinical outcomes. This study investigated the impact of production methods on the stability and impurities of liraglutide and semaglutide drug substances/products, and the potential impact on drug quality, efficacy and safety. Methods State-of-the-art analytical methods were used to compare physical and chemical stability, and impurity profiles of drug substances/products from different suppliers. Identified polypeptide-related impurities were evaluated for immunogenicity potential by in silico T cell epitope prediction. Semaglutide immunogenicity in clinical trials (SUSTAIN) was evaluated using a tiered antibody analysis. Results Manufacturing scale and process strongly impacted the physical stability of the products. Trace metals increased high-molecular-weight protein formation for liraglutide and semaglutide. Synthetic and recombinant liraglutide produced by five suppliers had distinct impurity profiles compared with the originator. In silico evaluation suggested that new impurities could be immunogenic. Immunogenicity of semaglutide in clinical trials was lower than for liraglutide.
* Arne Staby [email protected]
1
Novo Nordisk A/S, CMC Development, Smørmosevej 17–19, 2880 Bagsværd, Denmark
2
Novo Nordisk A/S, Global Research Technologies, Måløv, Denmark
3
Novo Nordisk A/S, Global Drug Discovery, Måløv, Denmark
4
Novo Nordisk A/S, Product Supply, Bagsværd, Denmark
5
Novo Nordisk A/S, Global Development, Søborg, Denmark
6
Present address: LEO Pharma A/S, Research, Ballerup, Denmark
Conclusions Differences in manufacturing processes affect chemical/physical stability and impurity profile, and may impact immunogenicity. Follow-on versions of liraglutide and semaglutide, and possibly other polypeptides, should be clinically evaluated for efficacy and safety.
KEY WORDS immunogenicity . liraglutide . production . purity . semaglutide
ABBREVIATIONS ADA AU B/T DP DPP-IV DS dSLR EC70–80 GLP-1 GMP HLA HMWP HPLC ICP–OES LC-MS LEAD LOQ MHC MS nAb NTU PEG
Anti-drug antibody Arbitrary units Percentage of bound (B) relative to total (T) radioactivity Drug product Dipeptidyl peptidase-IV Drug substance Digital single-lens reflex 70–80% maximal effective concentration Glucagon-like peptide-1 Good Manufacturing Practice Human leukocyte antigen High-molecular-weight protein High-performance liquid chromatography Inductively
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