Evaluation of a novel silicone oil free primary packaging system with PTFE-based barrier stopper for biologics.

In order to overcome silicone oil related problems for biopharmaceuticals, novel container systems are of interest with a focus on the reduction, fixation or complete avoidance of silicone oil in the primary container. Ultimately, silicone oil free (SOF) container systems made from cyclic olefin (co-)polymer or glass combined with the respective silicone-oil free plungers were developed. In the following study we evaluated the potential of a SOF container system based on a glass barrel in combination with a fluoropolymer coated syringe plunger. In a long-term stability study, the system was compared to other alternative container systems in terms of functionality and particle formation when filled with placebo buffers. The system proved to be a valuable alternative to marketed siliconized container systems with acceptable and consistent break-loose gliding forces and it was clearly superior in terms of particle formation over storage time. Additionally, we evaluated the importance of the glass barrel surface for functionality. The interaction of the fill medium with the glass surface significantly impacted friction forces. Consequently, storage conditions and production processes like washing and sterilization, which can easily alter the surface properties, should be carefully evaluated, and controlled. The novel combination of non-lubricated glass barrel and fluoropolymer coated plunger provides a highly valuable SOF packaging alternative for biopharmaceuticals.

Impact of autoclavation on baked-on siliconized containers for biologics.

Many pharmaceutical manufacturing units utilize pre-sterilized ready-to fill primary containers for parenterals. The containers may have been sterilized by the supplier via autoclavation. This process can change the physicochemical properties of the material and the subsequent product stability. We studied the impact of autoclavation on baked on siliconized glass containers for biopharmaceuticals. We characterized the container layers of different thickness before and after autoclavation for 15 min at 121 °C and 130 °C. Furthermore, we analyzed the adsorption of a mAb to the silicone layer and subjected filled containers to 12 weeks storage at 40 °C monitoring functionality and subvisible particle formation of the product. Autoclavation turned the initially homogenous silicone coating into an incoherent surface with uneven microstructure, changed surface roughness and energy, and increased protein adsorption. The effect was more pronounced at higher sterilization temperatures. We did not observe an effect of autoclavation on stability. Our results did not indicate any concerns for autoclavation at 121 °C for safety and stability of drug/device combination products using baked-on siliconized glass containers.

Safety and Feasibility of Robot-assisted Gait Training in Adults with Cerebral Palsy in an Inpatient Setting - an Observational Study.

BACKGROUND: To investigate the safety and feasibility of six sessions of Hybrid Assistive Limb (HAL) robot-assisted gait training (RAGT) integrated into an inpatient therapy concept and their influence on walking speed and gait parameters in adult CP patients. METHODS: Eleven subjects (male = 8, female = 3, mean age: 23 years and 2 months, ± 4.5 years) with spastic CP underwent six 20-minute RAGT sessions with the HAL during an 11-day hospital stay. Additionally, physiotherapy, physician-performed manual medicine, massage and exercise therapy were provided. Pre- (T1) and post- (T2) intervention assessments were: 10-metre walking test (10MWT), 6-minute walking test (6MWT), Gross Motor Function Measure (GMFM-88) and lower extremities passive range of motion (pROM). RESULTS: All subjects completed the study. No adverse events were noted. Walking speed in the 10MWT test increased from 32.5 s (± 24.5 s) at T1 to 27.5 s (± 21.4 s) at T2, without significance. Slight, but non-significant improvements were detected in the 6MWT, GMFM and pROM. Confounding factors did not significantly affect the results. Conclusion: Intensive therapy including HAL training leads to non-significant improvements. Further studies with more patients and longer intervention time could provide further insights into the RAGT therapy of adult patients with CP. Registration DRKS-ID: DRKS00020275.

Pre-manipulative cervical spine testing and sustained rotation do not influence intracranial hemodynamics: an observational study with transcranial Doppler ultrasound.

INTRODUCTION: Manual joint mobilization and manipulation are recommended therapeutic interventions for people with neck pain. High-velocity thrust and sustained techniques have an uncertain association with serious arterial trauma. The validity of pre-manipulative tests of the cervical spine is often questioned, and the understanding of the effect of head/neck position on blood flow is still incomplete. Most of the evidence concerning hemodynamics in this area relates to extracranial flow (vertebral and carotid artery). Less is understood about the effects on intracranial flow while performing pre-manipulative tests and sustained positions like end of range cervical rotation mobilization. The aim of the study was to assess the influence of commonly used evaluation and treatment positions on intracranial hemodynamic parameters. METHOD: A randomized, cross-over observational study using ultrasonography on healthy subjects (n = 19) was conducted to measure hemodynamic parameters (peak systolic velocity and end diastolic maximum) of intracranial arterial systems. Two test positions (sustained pre-manipulative thrust C0-1 and sustained cervical end of range rotation) were compared with a sham position for each test position. RESULTS: :Neither the sequence of tests performed nor an independent variable (the two positions) had a significant effect (p < 0.05) on peak systolic velocity (PSV) or end diastolic maximum (EDM). DISCUSSION: No effects from commonly used assessment and treatment of neck positions on hemodynamic parameters were found. This is consistent with previous studies. Further study is indicated on people with symptoms and known pathologies.

Use of Robot-Assisted Gait Training in Pediatric Patients with Cerebral Palsy in an Inpatient Setting-A Randomized Controlled Trial.

Robot-assisted gait training (RAGT) provides a task-based support of walking using exoskeletons. Evidence shows moderate, but positive effects in the therapy of patients with cerebral palsy (CP). This study investigates the impact of RAGT on walking speed and gait parameters in pediatric CP patients. Thirty subjects (male = 23; female = 7), with a mean age of 13.0 ± 2.5 (9-17) years, and with spastic CP, were recruited. The intervention group (n = 15) underwent six 20-minute RAGT sessions with the Hybrid Assistive Limb (HAL) during an 11-day hospital stay. Additionally, a therapy concept including physiotherapy, physician-performed manual medicine, massage and exercise therapy was provided. The control group (n = 15) was treated with the therapy concept only. The outcome was based on a 10-Metre Walking Test (10MWT), 6-Minute Walking Test (6MWT), Gross Motor Function Measure (GMFM-88) and lower extremities passive range of motion. The intervention group achieved a mean increase in walking speed in the 10MWT (self-selected walking speed SSW) of 5.5 s (p = 0.378). There were no significant differences between the groups in the 10MWT (max) (p = 0.123) and the 6MWT (p = 0.8). Changes in the GMFM (total) and in the dimension standing and walking, running and jumping (D + E) showed clinically relevant significant results (p = 0.002 and p = 0.046). RAGT as a supplement to an inpatient therapy stay appears to have a positive, yet not significant impact on the gait parameters of pediatric CP patients as well as motivating them to practice walking. Further studies with adapted study designs are needed to evaluate different influencing factors.

Replacing the Emulsion for Bake-on Siliconization of Containers-Comparison of Emulsion Stability and Container Performance in the Context of Protein Formulations.

Pre-filled syringes have simplified parenteral administration of protein drugs. To ensure an easy and consistent movement of the plunger, the inner glass container surface is typically siliconized. For bake-on siliconization, emulsions are sprayed on and heat treated. Due to the European Union regulation REACh (Regulation concerning theRegistration,Evaluation,Authorisation and Restriction ofChemicals) the use of certain emulsion components, partially constituting the gold standard LiveoTM 365 35% Dimethicone NF Emulsion (LiveoTM 365), becomes restricted and LiveoTM 366 35% Dimethicone NF Emulsion (LiveoTM 366) has been introduced as an alternative. This change may affect the handling properties as well as the silicone layer formed. The purpose of these studies was to identify any differences that may influence the stability and safety of the final drug/device combination product to enable the use of the new emulsion. We compared silicone emulsions LiveoTM 365 and LiveoTM 366 and dilutions focusing on 1) their general physical stability, 2) the thermal degradation process of the emulsions and their components, and 3) the resulting silicone layer concerning chemistry, morphology, and functionality. The results were linked to the assessment of the final product regarding particle formation and short-term stability. A comparison of the emulsions LiveoTM 365 and LiveoTM 366 for bake-on siliconization is presented to support the transition of the latter as it becomes mandatory with REACh. Our studies show that the two emulsions do not significantly differ with respect to handling and stability, the resultant silicone layer characteristics as well as its functionality. We conclude that the transition to the new emulsion will not significantly impact the final product or the layer performance upon storage and with respect to particle formation.

Replacing the emulsion for bake-on siliconization of containers - comparison of emulsion stability and container performance in the context of protein formulations.

Pre-filled syringes have simplified parenteral administration of protein drugs. To ensure an easy and consistent movement of the plunger, the inner glass container surface is typically siliconized. For bake-on siliconization emulsions are sprayed on and heat treated. Due to the European Union regulation REACh (Regulation concerning the Registration, Evaluation, Authorisation and Restriction of Chemicals) the use of certain emulsion components, partially constituting the gold standard Liveo™ 365 35% Dimethicone NF Emulsion (Liveo™ 365), becomes restricted and Liveo™ 366 35% Dimethicone NF Emulsion (Liveo™ 366) has been introduced as an alternative. This change may affect the handling properties as well as the silicone layer formed. The purpose of these studies was to identify any differences that may influence the stability and safety of the final drug/device combination product to enable the use of the new emulsion. We compared silicone emulsions Liveo™ 365 and Liveo™ 366 and dilutions focusing on I) their general physical stability, II) the thermal degradation process of the emulsions and their components, and III) the resulting silicone layer concerning chemistry, morphology, and functionality. The results were linked to the assessment of the final product regarding particle formation and long-term stability. A comparison of the emulsions Liveo™ 365 and Liveo™ 366 for bake-on siliconization is presented to support the transition of the latter as it becomes mandatory with REACh. Our studies show that the two emulsions do not significantly differ with respect to handling and stability, the resultant silicone layer characteristics as well as its functionality. We conclude that the transition to the new emulsion will not significantly impact the final product or the layer performance upon storage and with respect to particle formation.