Formulation mitigations for particle formation induced by enzymatic hydrolysis of polysorbate 20 in protein-based drug products: insights from a full-factorial longitudinal study
Abstract Hydrolytic degradation of the polysorbate 20 (PS20) surfactant in protein-based liquid formulations releases free fatty acids (FFAs), which can accumulate to form particles in drug products during real-time (long-term) storage. To identify formulation conditions that mitigate the risk of pa...
| Main Authors: | , , , , , , , |
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| Format: | Article |
| Language: | English |
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SpringerOpen
2022-11-01
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| Series: | AAPS Open |
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| Online Access: | https://doi.org/10.1186/s41120-022-00064-3 |
| _version_ | 1797983963625553920 |
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| author | Inn H. Yuk Theo Koulis Nidhi Doshi Kathrin Gregoritza Constanze Hediger Vanessa Lebouc-Haefliger Jamie Giddings Tarik A. Khan |
| author_facet | Inn H. Yuk Theo Koulis Nidhi Doshi Kathrin Gregoritza Constanze Hediger Vanessa Lebouc-Haefliger Jamie Giddings Tarik A. Khan |
| author_sort | Inn H. Yuk |
| collection | DOAJ |
| description | Abstract Hydrolytic degradation of the polysorbate 20 (PS20) surfactant in protein-based liquid formulations releases free fatty acids (FFAs), which can accumulate to form particles in drug products during real-time (long-term) storage. To identify formulation conditions that mitigate the risk of particle formation, we conducted a longitudinal study using purified recombinant monoclonal antibody (mAb) formulated in 24 conditions. In this real-time stability study at 5 °C, three key formulation parameters—mAb concentration, initial PS20 concentration, and pH—were varied across representative ranges in a full-factorial design. A longitudinal regression analysis was used to evaluate the effects of these parameters and their interactions on PS20 degradation (via measurements of PS20, FFAs, and PS20 ester distribution) and on particle formation (via visible particle observations and subvisible particle counts). The time-dependent onset of visible particles trended with the rise in subvisible particle counts and FFA levels and fall in PS20 concentration. In the ranges studied here, lower mAb concentration and higher initial PS20 concentration delayed the onset of particles, whereas pH had a negligible effect. These observations were consistent with the general trends predicted by our previously published FFA solubility model. Taken together, these findings highlight the complex relationships between formulation parameters, PS20 degradation, and particle formation. |
| first_indexed | 2024-04-11T06:54:19Z |
| format | Article |
| id | doaj.art-309e1482153a44eda5ca7dc1603040aa |
| institution | Directory Open Access Journal |
| issn | 2364-9534 |
| language | English |
| last_indexed | 2024-04-11T06:54:19Z |
| publishDate | 2022-11-01 |
| publisher | SpringerOpen |
| record_format | Article |
| series | AAPS Open |
| spelling | doaj.art-309e1482153a44eda5ca7dc1603040aa2022-12-22T04:39:04ZengSpringerOpenAAPS Open2364-95342022-11-018112210.1186/s41120-022-00064-3Formulation mitigations for particle formation induced by enzymatic hydrolysis of polysorbate 20 in protein-based drug products: insights from a full-factorial longitudinal studyInn H. Yuk0Theo Koulis1Nidhi Doshi2Kathrin Gregoritza3Constanze Hediger4Vanessa Lebouc-Haefliger5Jamie Giddings6Tarik A. Khan7Pharma Technical Development US, Genentech Inc.Nonclinical Biostatistics, Product Development, US, Genentech Inc.Pharma Technical Development US, Genentech Inc.Pharma Technical Development Europe, F. Hoffmann-La Roche Ltd.Pharma Technical Development Europe, F. Hoffmann-La Roche Ltd.Pharma Technical Development Europe, F. Hoffmann-La Roche Ltd.Pharma Technical Development US, Genentech Inc.Pharma Technical Development Europe, F. Hoffmann-La Roche Ltd.Abstract Hydrolytic degradation of the polysorbate 20 (PS20) surfactant in protein-based liquid formulations releases free fatty acids (FFAs), which can accumulate to form particles in drug products during real-time (long-term) storage. To identify formulation conditions that mitigate the risk of particle formation, we conducted a longitudinal study using purified recombinant monoclonal antibody (mAb) formulated in 24 conditions. In this real-time stability study at 5 °C, three key formulation parameters—mAb concentration, initial PS20 concentration, and pH—were varied across representative ranges in a full-factorial design. A longitudinal regression analysis was used to evaluate the effects of these parameters and their interactions on PS20 degradation (via measurements of PS20, FFAs, and PS20 ester distribution) and on particle formation (via visible particle observations and subvisible particle counts). The time-dependent onset of visible particles trended with the rise in subvisible particle counts and FFA levels and fall in PS20 concentration. In the ranges studied here, lower mAb concentration and higher initial PS20 concentration delayed the onset of particles, whereas pH had a negligible effect. These observations were consistent with the general trends predicted by our previously published FFA solubility model. Taken together, these findings highlight the complex relationships between formulation parameters, PS20 degradation, and particle formation.https://doi.org/10.1186/s41120-022-00064-3Free fatty acidsFormulation designParticlesPolysorbate degradationStabilityStatistical analysis |
| spellingShingle | Inn H. Yuk Theo Koulis Nidhi Doshi Kathrin Gregoritza Constanze Hediger Vanessa Lebouc-Haefliger Jamie Giddings Tarik A. Khan Formulation mitigations for particle formation induced by enzymatic hydrolysis of polysorbate 20 in protein-based drug products: insights from a full-factorial longitudinal study AAPS Open Free fatty acids Formulation design Particles Polysorbate degradation Stability Statistical analysis |
| title | Formulation mitigations for particle formation induced by enzymatic hydrolysis of polysorbate 20 in protein-based drug products: insights from a full-factorial longitudinal study |
| title_full | Formulation mitigations for particle formation induced by enzymatic hydrolysis of polysorbate 20 in protein-based drug products: insights from a full-factorial longitudinal study |
| title_fullStr | Formulation mitigations for particle formation induced by enzymatic hydrolysis of polysorbate 20 in protein-based drug products: insights from a full-factorial longitudinal study |
| title_full_unstemmed | Formulation mitigations for particle formation induced by enzymatic hydrolysis of polysorbate 20 in protein-based drug products: insights from a full-factorial longitudinal study |
| title_short | Formulation mitigations for particle formation induced by enzymatic hydrolysis of polysorbate 20 in protein-based drug products: insights from a full-factorial longitudinal study |
| title_sort | formulation mitigations for particle formation induced by enzymatic hydrolysis of polysorbate 20 in protein based drug products insights from a full factorial longitudinal study |
| topic | Free fatty acids Formulation design Particles Polysorbate degradation Stability Statistical analysis |
| url | https://doi.org/10.1186/s41120-022-00064-3 |
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