Silicone-Oil-Based Subvisible Particles: Their Detection, Interactions, and Regulation in Prefilled Container Closure Systems for Biopharmaceuticals

Felsovalyi, Flora; Janvier, Sébastien; Jouffray, Sébastien; Soukiassian, Herve; Mangiagalli, P.

doi:10.1002/jps.23328

Cited by 56 publications

(56 citation statements)

References 20 publications

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“…Considering the surface-active properties of PS-20, the observed increase of silicone-oil droplets generated in PS-20 samples (Figure 3) was consistent with previous reports (Felsovalyi et al, 2012).…”

Section: Agitation In Siliconized Pfs Increases Aggregation Formationsupporting

confidence: 91%

“…However, the focus has been the larger sub-visible size range of particulates i.e. > 0.5 m (Felsovalyi et al;Krayukhina et al, 2015;Teska et al); due to the current lack of available technologies that are sensitive to the detection of smaller particles, whilst capable of differentiating between proteinaceous and foreign particulates (e.g. silicone-oil).…”

Section: Common Termsmentioning

confidence: 99%

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Evaluation of aggregate and silicone-oil counts in pre-filled siliconized syringes: An orthogonal study characterising the entire subvisible size range

Shah

Rattray

Day³

et al. 2017

International Journal of Pharmaceutics

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Characterisation of particulates in therapeutic monoclonal antibody (mAb) formulations is routinely extended to the sub-visible size-range (0.1-, with the increased use of prefilled syringes (PFS), particle differentiation is required between proteinaceous and non-proteinaceous particles such as silicone-oil droplets. Here, three orthogonal techniques: Raster Image Correlation Spectroscopy (RICS), Resonance Mass Measurements (RMM) and Micro-Flow Imaging (MFI), were evaluated with respect to their sub-visible particle measurement and characterisation capabilities. Particle formation in mAb PFS solutions was evaluated with increasing polysorbate-20 (PS-20) concentrations. All three techniques provided complementary but distinct information on protein aggregate and silicone-oil droplet presence. PS-20 limited the generation of mAb aggregates during agitation, while increasing the number of silicone-oil droplets (PS-20 concentration dependent). MFI and RMM revealed PS-20 lead to the formation of larger micron-sized droplets, with RICS revealing an increase in smaller submicron droplets. Subtle differences in data sets complicate the apparent correlation between silicone-oil sloughing and mAb aggregates' generation. RICS (though the use of a specific dye) demonstrates an improved selectivity for mAb aggregates, a broader measurement size-range and smaller sample volume requirement. Thus, RICS is proposed to add value to the currently available particle measurement techniques and enable informed decisions during mAb formulation development. ABSTRACTCharacterisation of particulates in therapeutic monoclonal antibody (mAb) formulations is routinely extended to the sub-visible size-range (0.1-10 m). Additionally, with the increased use of pre-filled syringes (PFS), particle differentiation is required between proteinaceous and non-proteinaceous particles such as silicone-oil droplets. Here, three orthogonal techniques: Raster Image Correlation Spectroscopy (RICS), Resonance Mass Measurements (RMM) and Micro-Flow Imaging (MFI), were evaluated with respect to their sub-visible particle measurement and characterisation capabilities. Particle formation in mAb PFS solutions was evaluated with increasing polysorbate-20 (PS-20) concentrations. All three techniques provided complementary but distinct information on protein aggregate and silicone-oil droplet presence. PS-20 limited the generation of mAb aggregates during agitation, while increasing the number of silicone-oil droplets (PS-20 concentration dependant). MFI and RMM revealed PS-20 lead to the formation of larger micron-sized droplets, with RICS revealing an increase in smaller sub-micron droplets. Subtle differences in data sets complicate the apparent correlation between silicone-oil sloughing and mAb aggregates' generation. RICS (though the use of a specific dye) demonstrates an improved selectivity for mAb aggregates, a broader measurement size-range and smaller sample volume requirement. Thus, RICS is proposed to add value to the currently available pa...

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Section: Agitation In Siliconized Pfs Increases Aggregation Formationsupporting

confidence: 91%

Section: Common Termsmentioning

confidence: 99%

Evaluation of aggregate and silicone-oil counts in pre-filled siliconized syringes: An orthogonal study characterising the entire subvisible size range

Shah

Rattray

Day³

et al. 2017

International Journal of Pharmaceutics

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“…Several recent studies have focused on how proteins may be affected by exposure to these interfaces. In particular, protein adsorption to both air–water and silicone oil–water interfaces has been shown to promote protein aggregation and particle formation …”

Section: Introductionmentioning

confidence: 99%

“…In addition, there is a growing concern about the number of particles between 0.1 and 10 μm in protein formulations, as particles in this size range may be the most immunogenic and are considered a critical quality attribute . With new technologies, the ability to quantify and characterize particles in the 0.1–10 μm size range has significantly improved, and as a result, several recent studies have focused on identifying the extent to which these particles arise in protein therapeutic products and their impact on product quality, safety, and immunogenicity . For example, Barnard et al suggest a link between the presence of aggregates and particles in interferon‐β products and the production of neutralizing antibodies in patients.…”

Section: Introductionmentioning

confidence: 99%

Protein Aggregation and Particle Formation in Prefilled Glass Syringes

Gerhardt

Mcgraw

Schwartz

et al. 2014

Journal of Pharmaceutical Sciences

156

124

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“…To this end, lubricity in glass syringes is generally achieved using medical grade silicone oil, typically a polydimethylsiloxane (PDMS, Me 3 Si(OSiMe 2 ) n OSiMe 3 ), n∼ 380, 1000 cSt viscosity). This material provides the correct viscosity and shear-thinning properties [6, 7, 8, 9] while forming an excellent, biocompatible seal for the aqueous solution [10].…”

Section: Introductionmentioning

confidence: 99%

The stability of insulin solutions in syringes is improved by ensuring lower molecular weight silicone lubricants are absent

Nayef

Khan

Brook

2017

Heliyon

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Protein drugs such as insulin are almost universally delivered via glass syringes lubricated with silicone oil. It is not uncommon for prefilled syringes (PFS) to become cloudy, which may affect bioavailability or total drug dose. To examine the role, if any, of the silicone oil lubricant in this process, a systematic evaluation of the degree of insulin denaturation and aggregation as a function of silicone oils of different molecular weights was undertaken. The former was measured using fluorescence changes of aqueous insulin/silicone dispersions, while the latter examined changes in turbidity as a function of mixing and silicone oil type; the results were confirmed at two different insulin concentrations and agitation speeds. Lower molecular weight silicones led to the most rapid denaturation and aggregation, and when examined in blends of silicones at a fixed viscosity of 1000 cSt, commonly used for syringe lubrication, more rapid denaturation/aggregation was noted in blends of silicones containing the largest fractions of low molecular weight materials. As a consequence, the molecular weight profile of silicone lubricants should be established prior to the preparation of prefilled syringes.

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Silicone-Oil-Based Subvisible Particles: Their Detection, Interactions, and Regulation in Prefilled Container Closure Systems for Biopharmaceuticals

Cited by 56 publications

References 20 publications

Evaluation of aggregate and silicone-oil counts in pre-filled siliconized syringes: An orthogonal study characterising the entire subvisible size range

Evaluation of aggregate and silicone-oil counts in pre-filled siliconized syringes: An orthogonal study characterising the entire subvisible size range

Protein Aggregation and Particle Formation in Prefilled Glass Syringes

The stability of insulin solutions in syringes is improved by ensuring lower molecular weight silicone lubricants are absent

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