Patientenpartizipation in der pädiatrischen Versorgungsforschung am Universitätsklinikum Freiburg: von der Projektbeteiligung zum Patientenbeirat.

Participation of patients and relatives in research means that those affected are involved in the research process in a partnership role. Despite the growing importance of participatory approaches and the large number of available concepts, many researchers and patients are faced with the question of how participatory research can be realized and organized in concrete terms. Here we report on our experiences with two different forms of patient participation in research in the context of pediatric health care research at a university hospital: (1) In a project for the development and evaluation of a case management for patients with spinal muscular atrophy, patient representatives have an consultative role. (2) In the patient advisory board, which is to accompany the research activities of the research group at the site continuously and systematically, i.e. in all phases, the participation currently corresponds to a contributory role (involvement) which, in the future, could be moved onto the collaborative stage. In both forms of participation, the essential questions include the selection of the participating patients, the type and extent of participation, and the evaluation of the effect of participation on the research that is carried out. In our experience, both forms of participation add value to research from the perspective of all participants. At the same time, they bring different opportunities and challenges. While in project-based participation the sphere of influence is already delineated by researchers, the context of the patient advisory board provides more room and openness to develop, for example, a research agenda and thus identify new research topics. In our experience, however, sufficient resources (in terms of time and money) are required from all participants, as well as good, trusting cooperation with jointly developed processes to realize both forms of participation.

Influence of particle shedding from silicone tubing on antibody stability.

OBJECTIVES: Peristaltic pumps are increasingly employed during fill & finish operations of a biopharmaceutical drug, due to sensitivity of many biological products to rotary piston pump-related stresses. Yet, possibly also unit operations using peristaltic pumps may shed particulates into the final product due to abrasion from the employed tubing. It was the aim of this study to elucidate the potential influence of particles shed from peristaltic pump tubing on the stability of a drug product. METHODS: Spiking solutions containing shed silicone particles were prepared via peristaltic pumping of placebo under recirculating conditions and subsequently characterized. Two formulated antibodies were spiked with two realistic, but worst-case levels of particles and a 6-month accelerated stability study with storage at 2-8, 25 and 40°C were conducted. KEY FINDINGS: Regarding the formation of aggregates and fragments, both mAbs degraded at their typically expected rates and no additional impact of spiked particles was observed. No changes were discerned however in turbidity, subvisible and visible particle assessments. Flow imaging data for one of the mAb formulations with spiked particles suggested limited colloidal stability of shed particles as indicated by a similar increase in spiked placebo. CONCLUSIONS: Shed silicone particles from peristaltic pump tubing are assumed to not impair drug product stability.

Preservative loss from silicone tubing during filling processes.

Significant loss of preservative was observed during filling of drug products during filling line stops. This study evaluated the losses of three commonly used preservatives in protein drugs, i.e. benzyl alcohol, phenol, and m-cresol. Concentration losses during static incubation were quantified and interpreted with regard to the potential driving forces for the underlying sorption, diffusion, and desorption steps. Partitioning from the solution into the silicone polymer was identified as the most decisive parameter for the extent of preservative loss. Additionally, the influence of tubing inner diameter, starting concentration as well as silicone tubing type was evaluated. Theoretical calculations assuming equilibrium between solution and tubing inner surface and one-directional diffusion following Fick's first law were used to approximate experimental data. Since significant losses were found already after few minutes, adequate measures must be taken to avoid deviations during filling of preservative-containing protein solutions that may impact product quality or antimicrobial efficacy. As a possible alternative to the highly permeable silicone tubing, a specific make of fluoropolymer tubing was identified being suitable for peristaltic pumps and not showing any preservative losses.

Silicone Migration From Baked-on Silicone Layers. Particle Characterization in Placebo and Protein Solutions.

A significant number of therapeutic proteins are marketed as pre-filled syringes or other drug/device combination products and have been safely used in these formats for years. Silicone oil, which is used as lubricant, can migrate into the drug product and may interact with therapeutic proteins. In this study, particles in the size range of 0.2-5 µm and ≥1 µm as determined by resonant mass measurement and micro-flow imaging/light obscuration, respectively, resulted from silicone sloughing off the container barrel after agitation. The degree of droplet formation correlated well with the applied baked-on silicone levels of 13 µg and 94 µg per cartridge. Silicone migration was comparable in placebo, 2 mg/mL and 33 mg/mL IgG1 formulations containing 0.04% (w/v) polysorbate 20. Headspace substantially increased the formation of silicone droplets during agitation. The highest particle concentrations reached, however, were still very low compared to numbers described for spray-on siliconized containers. When applying adequate baked-on silicone levels below 100 µg, bake-on siliconization efficiently limits silicone migration into the drug product without compromising device functionality.

Optimization of the bake-on siliconization of cartridges. Part II: Investigations into burn-in time and temperature.

Combination products have become popular formats for the delivery of parenteral medications. Bake-on siliconization of glass syringes or cartridges allows good piston break-loose and gliding during injection at low silicone levels. Although widely implemented in industry, still little is known and published on the effect of the bake-on process on the silicone level, layer thickness and chemical composition. In this study, cartridges were bake-on siliconized in a heat-tunnel by varying both temperature from 200 to 350°C for 12min and time from 5min to 3h at 316°C. Furthermore, a heat-oven with air-exchange was established as an experimental model. Heat treatment led to a time- and temperature-dependent decrease in the silicone level and layer thickness. After 1h at 316°C lubrication was insufficient. The silicone levels substantially decreased between 250 and 316°C after 12min. After bake-on, the peak molecular weight of the silicone remained unchanged while fractions below 5000g/mol were removed at 316 and 350°C. Cyclic low molecular weight siloxanes below 500g/mol were volatilized under all conditions. Despite most of the baked-on silicone was solvent-extractable, contact angle analysis indicated a strong binding of a remaining, thin silicone film to the glass surface.

Optimization of the bake-on siliconization of cartridges. Part I: Optimization of the spray-on parameters.

Biopharmaceutical products are increasingly commercialized as drug/device combinations to enable self-administration. Siliconization of the inner syringe/cartridge glass barrel for adequate functionality is either performed at the supplier or drug product manufacturing site. Yet, siliconization processes are often insufficiently investigated. In this study, an optimized bake-on siliconization process for cartridges using a pilot-scale siliconization unit was developed. The following process parameters were investigated: spray quantity, nozzle position, spray pressure, time for pump dosing and the silicone emulsion concentration. A spray quantity of 4mg emulsion showed best, immediate atomization into a fine spray. 16 and 29mg of emulsion, hence 4-7-times the spray volume, first generated an emulsion jet before atomization was achieved. Poor atomization of higher quantities correlated with an increased spray loss and inhomogeneous silicone distribution, e.g., due to runlets forming build-ups at the cartridge lower edge and depositing on the star wheel. A prolonged time for pump dosing of 175ms led to a more intensive, long-lasting spray compared to 60ms as anticipated from a higher air-to-liquid ratio. A higher spray pressure of 2.5bar did not improve atomization but led to an increased spray loss. At a 20mm nozzle-to-flange distance the spray cone exactly reached the cartridge flange, which was optimal for thicker silicone layers at the flange to ease piston break-loose. Initially, 10µg silicone was sufficient for adequate extrusion in filled cartridges. However, both maximum break-loose and gliding forces in filled cartridges gradually increased from 5-8N to 21-22N upon 80weeks storage at room temperature. The increase for a 30µg silicone level from 3-6N to 10-12N was moderate. Overall, the study provides a comprehensive insight into critical process parameters during the initial spray-on process and the impact of these parameters on the characteristics of the silicone layer, also in context of long-term product storage. The presented experimental toolbox may be utilized for development or evaluation of siliconization processes.

Analysis of thin baked-on silicone layers by FTIR and 3D-Laser Scanning Microscopy.

Pre-filled syringes (PFS) and auto-injection devices with cartridges are increasingly used for parenteral administration. To assure functionality, silicone oil is applied to the inner surface of the glass barrel. Silicone oil migration into the product can be minimized by applying a thin but sufficient layer of silicone oil emulsion followed by thermal bake-on versus spraying-on silicone oil. Silicone layers thicker than 100nm resulting from regular spray-on siliconization can be characterized using interferometric profilometers. However, the analysis of thin silicone layers generated by bake-on siliconization is more challenging. In this paper, we have evaluated Fourier transform infrared (FTIR) spectroscopy after solvent extraction and a new 3D-Laser Scanning Microscopy (3D-LSM) to overcome this challenge. A multi-step solvent extraction and subsequent FTIR spectroscopy enabled to quantify baked-on silicone levels as low as 21-325µg per 5mL cartridge. 3D-LSM was successfully established to visualize and measure baked-on silicone layers as thin as 10nm. 3D-LSM was additionally used to analyze the silicone oil distribution within cartridges at such low levels. Both methods provided new, highly valuable insights to characterize the siliconization after processing, in order to achieve functionality.

Particle shedding from peristaltic pump tubing in biopharmaceutical drug product manufacturing.

In a typical manufacturing setup for biopharmaceutical drug products, the fill and dosing pump is placed after the final sterile filtration unit in order to ensure adequate dispensing accuracy and avoid backpressure peaks. Given the sensitivity of protein molecules, peristaltic pumps are often preferred over piston pumps. However, particles may be shed from the silicone tubing employed. In this study, particle shedding and a potential turbidity increase during peristaltic pumping of water and buffer were investigated using three types of commercially available silicone tubing. In the recirculates, mainly particles of around 200 nm next to a very small fraction of particles in the lower micrometer range were found. Using 3D laser scanning microscopy, surface roughness of the inner tubing surface was found to be a determining factor for particle shedding from silicone tubing. As the propensity toward particle shedding varied between tubing types and also cannot be concluded from manufacturer's specifications, individual testing with the presented methods is recommended during tubing qualification. Choosing low abrasive tubing can help to further minimize the very low particle counts to be expected in pharmaceutical drug products.