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| 2. |
- Druedahl, Louise C., et al.
(författare)
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Evolving Biosimilar Clinical Requirements : A Qualitative Interview Study with Industry Experts and European National Medicines Agency Regulators
- 2021
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Ingår i: BioDrugs. - : ADIS INT LTD. - 1173-8804 .- 1179-190X. ; 35:3, s. 351-361
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Tidskriftsartikel (refereegranskat)abstract
- Background A biosimilar is a biological medicine highly similar to another already approved biological medicine (reference product). The availability of biosimilars promotes competition and subsequently lower prices. Changing the current biosimilar clinical comparability trial requirements may lead to lower biosimilar development costs that potentially could increase patients' access to biologics. Objective The aim was to determine the perceptions of industry and medicines agency regulators regarding the value, necessity, and future developments of the European biosimilar clinical comparability trial requirements for establishing biosimilarity. Methods Semi-structured interviews were conducted with eight European national medicines agency regulators and 17 pharmaceutical company employees or consultants with experience in biologics between September 2018 and August 2019. Data were subjected to content analysis. Results In general, the participants expected that clinical comparability trial requirements will continue to be reduced, in particular based on advancements in analytical testing and knowledge generated from prior biosimilar approvals. However, there are also competing issues at play, such as competition, physician's trust, and ethical considerations. Participants also reported that any new initiative to reduce or waive biosimilar clinical requirements needs to be scientifically sound and could potentially lower biosimilar development costs. Conclusion The main findings are that biosimilar clinical comparability trial requirements are likely to change in the near future. Clarity is needed on how to ensure adequate correlation between physicochemical data, pharmacokinetic/pharmacodynamic studies, and the drugs' performance in the clinic, as well as how to continue sufficient immunogenicity assessment. Obtaining this clarity can facilitate regulatory assessment of the next biosimilars.
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| 3. |
- Druedahl, Louise C., et al.
(författare)
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Interchangeability of biosimilars : A study of expert views and visions regarding the science and substitution
- 2022
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Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 17:1
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Tidskriftsartikel (refereegranskat)abstract
- Healthcare systems have reached a critical point regarding the question of whether biosimilar substitution should become common practice. To move the discussion forward, the study objective was to investigate the views of experts from medicines agencies and the pharmaceutical industry on the science underpinning interchangeability of biosimilars. We conducted an empirical qualitative study using semi-structured interviews informed by a cross-disciplinary approach encompassing regulatory science, law, and pharmaceutical policy. In total 25 individuals with experience within biologics participated during September 2018-August 2019. Eight participants were EU national medicines authority regulators, and 17 had pharmaceutical industry background: five from two originator-only companies, four from two companies with both biosimilar and originator products, and eight from seven biosimilar-only companies. Two analysts independently conducted inductive content analysis, resulting in data-driven themes capturing the meaning of the data. The participants reported that interchangeability was more than a scientific question of likeness between biosimilar and reference products: it also pertained to regulatory practices and trust. Participants were overall confident in the science behind exchanging biosimilar products for the reference products via switching, i.e., with physician involvement. However, their opinions differed regarding the scientific risk associated with biosimilar substitution, i.e., without physician involvement. Almost all participants saw no need for additional scientific data to support substitution. Moreover, the participants did not believe that switching studies, as required in the US, were appropriate for obtaining scientific certainty due to their small size. It is unclear why biosimilar switching is viewed as scientifically safer than substitution; therefore, we expect greater policy debate on biosimilar substitution in the near future. We urge European and UK policymakers and regulators to clarify their visions for biosimilar substitution; the positions of these two frontrunners are likely to influence other jurisdictions on the future of biosimilar use.
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| 4. |
- Anderot, Maria, et al.
(författare)
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Determination of dissociation constants between polyelectrolytes and proteins by affinity capillary electrophoresis
- 2009
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Ingår i: Journal of chromatography. B. - : Elsevier BV. - 1570-0232 .- 1873-376X. ; 877:10, s. 892-896
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Tidskriftsartikel (refereegranskat)abstract
- In this manuscript we report the binding affinity between two model proteins, human serum albumin (HSA) and ribonuclease A (RNase A), and negatively charged polyelectrolytes, two different heparin fractions and dextran sulfate, by means of partial filling and affinity capillary electrophoresis. The apparent dissociation constants, K-d, obtained by use of the partial-filling method, between HSA and heparin (17 kDa), heparin (3 kDa) and dextran sulfate (8 kDa) were 33 and 307 mu M, respectively. A new method was developed to determine affinities that take in account different migration directions between the protein and the polyelectrolyte, which was required to study RNase A. By use of this affinity capillary electrophoresis two K-d values were observed for the interaction between RNase A and heparin 17 kDa, yielding a high affinity binding with K-d1 0.0075 mu M, and a lower affinity binding with K-d2 8.7 mu M. For dextran sulfate 8 kDa these K-d values were 0.027 and 10.4 mu M, respectively. Heparin 3 kDa only showed a single K-d value of 0.52 mu M. The results show that the magnitude of the binding affinity depends on the type of polyelectrolyte and its molecular weight. (C) 2009 Elsevier B.V. All rights reserved.
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| 5. |
- Andersen, Anders J., et al.
(författare)
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Characterization of salmon calcitonin in spray-dried powder for inhalation : effect of formulation and process variables
- 2006
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Ingår i: 2006 AAPS Annual Meeting and Exposition. - : American Association of Pharmaceutical Scientists.
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Konferensbidrag (refereegranskat)abstract
- To characterize physicochemical properties of salmon calcitonin in spray-dried powder for inhalation and understand the interplay between stability, formulation and process parametersSalmon calcitonin (sCT) was spray-dried together with mannitol and chitosan that acts as stabiliser and absorption enhancer, respectively. Two process variables, i.e. inlet temperature and atomizing air volumetric flow rate, were investigated. Solid state properties of the spray-dried powders were characterized using SEM, TGA, XRPD and DSC. The physicochemical stability of salmon calcitonin in the dry powder was investigated by FTIR, HPLC and LC-MS techniques.A high yield of up to 80 % spray-dried powder was obtained with an improved cyclone assembled with B-290 Mini Spray Drier. Nevertheless, the yield was markedly reduced when addition of chitosan exceeded a certain proportion in spray drying formulation. XRPD and DSC results indicated that crystallinity of mannitol was inhibited with an increase of chitosan in the formulation. Residual moisture levels in the spray dried powders were 1-2%. As indicated by FTIR analysis, sCT retained its structural integrity under the spray drying conditions studied, i.e. 100-180 ºC inlet temperature and 357-742 L/h atomizing air volumetric flow rate. Addition of mannitol and chitosan in the spray drying formulation did not improve stabilization of sCT, in which around 7 % degraded impurities were found at a condition of 180 ºC inlet temperature. Yet no obvious degraded impurities were found in plain sCT spray-dried powder under the conditions studied. The LC-MS analysis showed that oxidation was the main degradation pathway at high inlet temperature. Other minor impurities originated from deamidation of Asn26, N-O acyl migration on Ser29 and dimerization by cross-linkage of the disulfide bonds. Two fragments, i.e. H-(Cys1-Gly28)-OH and H-(Ser29-Pro32)-NH2, could also be found when the degraded ester bond between Gly28 and Ser29 was further hydrolysed in phosphate buffer.Salmon calcitonin can be spray-dried into dry powders with good physical integrity under certain conditions. Chemical stability of sCT in spray-dried powder could be improved by the optimization of formulation and process variables.
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| 6. |
- Hedegaard, Sofie, et al.
(författare)
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Lipidation Effect on Surface Adsorption and Associated Fibrillation of the Model Protein Insulin
- 2016
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Ingår i: Langmuir. - : American Chemical Society (ACS). - 0743-7463 .- 1520-5827. ; 32:28, s. 7241-7249
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Tidskriftsartikel (refereegranskat)abstract
- Lipidation of proteins is used in the pharma- ceutical field to increase the therapeutic efficacy of proteins. In this study, we investigate the effect of a 14-carbon fatty acid modification on the adsorption behavior of human insulin to a hydrophobic solid surface and the subsequent fibrillation development under highly acidic conditions and elevated temperature by comparing to the fibrillation of human insulin. At these stressed conditions, the lipid modification accelerates the rate of fibrillation in bulk solution. With the use of several complementary surface-sensitive techniques, including quartz crystal microbalance with dissipation monitoring (QCM-D), atomic force microscopy (AFM), and neutron reflectivity (NR), we show that there are two levels of structurally different protein organization at a hydrophobic surface for both human insulin and the lipidated analogue: a dense protein layer formed within minutes on the surface and a diffuse outer layer of fibrillar structures which took hours to form. The two layers may only be weakly connected, and proteins from both layers are able to desorb from the surface. The lipid modification increases the protein surface coverage and the thickness of both layer organizations. Upon lipidation not only the fibrillation extent but also the morphology of the fibrillar structures changes from fibril clusters on the surface to a more homogeneous network of fibrils covering the entire hydrophobic surface.
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| 7. |
- Kapp, Sebastian, et al.
(författare)
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Competitive adsorption of monoclonal antibodies and nonionic surfactants at solid hydrophobic surfaces
- 2015
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Ingår i: Journal of Pharmaceutical Sciences. - : John Wiley & Sons. - 0022-3549 .- 1520-6017. ; 104:2, s. 593-601
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Tidskriftsartikel (refereegranskat)abstract
- Two monoclonal antibodies from the IgG subclasses one and two were compared in their adsorption behavior with hydrophobic surfaces upon dilution to 10 mg/mL with 0.9% NaCl. These conditions simulate handling of the compounds at hospital pharmacies and surfaces encountered after preparation, such as infusion bags and i.v. lines. Total internal reflection fluorescence and quartz crystal microbalance with dissipation monitoring were used to follow and quantify this. Furthermore, the influence of the nonionic surfactant polysorbate 80 (PS80) on the adsorption process of these two antibodies was investigated. Despite belonging to two different IgG subclasses, both antibodies displayed comparable adsorption behavior. Both antibodies readily adsorbed in the absence of PS80, whereas adsorption was reduced in the presence of 30 mg/L surfactant. The sequence of exposure of the surfactant and protein to the surface was found to have a major influence on the extent of protein adsorption. Although only a fraction of adsorbed protein could be removed by rinsing with 30 mg/L surfactant solution, adsorption was entirely prevented when surfaces were pre-exposed to PS80
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| 8. |
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| 9. |
- Yang, Mingshi, et al.
(författare)
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Characterisation of salmon calcitonin in spray-dried powder for inhalation : effect of chitosan
- 2007
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Ingår i: International Journal of Pharmaceutics. - : Elsevier BV. - 0378-5173 .- 1873-3476. ; 331:2, s. 176-81
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Tidskriftsartikel (refereegranskat)abstract
- Salmon calcitonin (sCT) powders suitable for inhalation, containing chitosan and mannitol as absorption enhancer and protection agent, respectively, were prepared using a spray-drying process. The effect of chitosan on physicochemical stability of sCT in the dry powder was investigated by different analytical techniques. High-performance liquid chromatography (HPLC) analysis indicated that sCT was chemically stable upon spray-drying. With the proportion of chitosan in spray-drying formulation being increased, dissolution of sCT from the dry powders was decreased both in phosphate buffer and acetate buffer. The thioflavine T fluorescence assay showed that no fibrils were present in the spray-dried powder. However, sCT partly fibrillated in the phosphate buffer, but not in acetate buffer. Fourier transform infrared (FTIR) spectra showed that the secondary structure of sCT was slightly changed in the dry powder, yet no aggregate signal was observed. Circular dichroism analysis indicated that the structure of sCT in an aqueous formulation was slightly altered by addition of chitosan. Nevertheless, recovery of sCT was not influenced by chitosan in the aqueous formulation as indicated by HPLC analysis. This study suggested that sCT, in absence of any additives, was stable during the spray-drying process under certain conditions. Addition of chitosan affects recovery of sCT from spray-dried powders, which may be due to formation of a partially irreversible complex between the protein and chitosan during the spray-drying process.
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