Administration into the subcutaneous (SC) tissue is a typical route of delivery for therapeutic proteins, especially for frequent treatments, long-term regimens, or self-administration. It is ...currently believed that the maximum volume for SC injections is approximately 1.5 mL. Larger SC injection volumes are considered to be associated with injection pain and adverse events at the injection site. However, no controlled clinical studies and actual evidence exist to support this assumption. In this review, we discuss current and publically available data related to SC administration volumes. We conclude that injection volumes higher than 3.5 mL are worth exploring if required for the development of efficacious drug treatments. Studying tissue back pressure, injection site leakage, local tolerability, and injection-related adverse events, such as injection pain, should be considered for the development of higher SC injection volumes.
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In recent years, the stability of biotherapeutics in vivo has received increasing attention. Assessing the stability of biotherapeutics in serum may support the selection of adequate ...molecule candidates. In our study, we compared the physical stability of 8 different monoclonal antibodies (mAbs) in phosphate-buffered saline (PBS) and human serum. mAbs were Alexa Fluor 488-labeled and characterized with respect to fragmentation, aggregation, and proteinaceous particle formation. Samples were analyzed using size-exclusion chromatography, light obscuration, and flow imaging. In addition, novel methods such as flow cytometry and fluorescence microscopy were applied. mAbs were selected based on their hydrophobicity and isoelectric point. All mAbs studied were inherently less stable in human serum as compared to PBS. Particle size and particle counts increased in serum over time. Interestingly, certain mAbs showed significant levels of fragmentation in serum but not in PBS. We conclude that PBS cannot replicate the physical stability measured in serum. The stability of labeled mAbs in human serum did not correlate with their hydrophobicity and isoelectric point . Serum stability significantly differed amongst the tested mAbs.
Freezing and thawing are important process steps in the manufacture of numerous biopharmaceuticals. It is well established that these process steps can significantly influence product quality ...attributes (PQA). Herein, we describe a physico-mathematical model to predict product temperature profiles based on the freezing program as input parameter in a commercial freeze–thaw module. Applying this model, the time from first nucleation until the last point to freeze (LPF) reaching −5°C and the time from −5°C at LPF to −30°C at LPF was varied to study the effect on PQA in a full factorial design. Effects of process parameter settings on a typical fully formulated, highly concentrated monoclonal antibody (mAb) solution as well as highly concentrated mAb solution formulated with buffer only were investigated. We found that both process phases affected PQA, such as aggregates by size-exclusion chromatography, polydispersity index by dynamic light scattering, and number of subvisible particles and turbidity in a complex way. In general, intermediate cooling and freezing times resulted in overall optimized PQA. Fully formulated mAb solution containing cryoprotectant and nonionic surfactant was significantly less affected by freezing–thawing than mAb solution formulated in buffer only.
Glass fogging is a phenomenon occurring in lyophilized drug products and can be described as a thin product layer deposited on the inner surface of the glass container, in the area not covered by the ...lyo cake itself. It is often considered a cosmetic defect; however, the loss of container closure integrity is a potential consequence of the fogging's expansion to the vial neck region, making this a potential critical defect. Thus, a method for predicting the extent of vial fogging before the actual freeze-drying is of particular interest for the pharmaceutical industry. For that reason, we evaluated a simple method ("simulated fogging") applicable to drug product formulations in a specific container closure system. Two different vial types with different surface hydrophilicity were tested using 3 model protein formulations, comparing the simulated fogging test and the degree of fogging after actual lyophilization. The simulated fogging method could predict fogging and showed a correlation to fogging in lyophilized drug product glass vials. We observed that all formulations showed fogging in the hydrophilic vials. By contrast, hydrophobic vials prevented fogging, however, interestingly with remaining defects of so-called droplet formation. Other than extent of fogging, no additional differences of lyophilized cake properties or other product quality attributes were observed between products using the different glass vial types tested.
Purpose
Health care professionals can be exposed to hazardous drugs such as cytostatics during preparation of drugs for administration. Closed sytem transfer devices (CSTDs) were introduced to ...provide protection for healthcare professional against unintended exposure to hazardous drugs. The interest in CSTDs has significantly increased after USP monograph was issued. The majority of the studies published so far on CSTDs have focused on their “containment” function. However, other important attributes for CSTDs with potential importance for product quality impact are not yet fully evaluated.
Methods
In the current study, we evaluated four sytems from different suppliers, in combination with different container closure systems (CCS), using solutions of different viscosity and surface tension. The different CSTD / CCS combinations were tested for (a) containment (integrity) using a highly sensitive helium leak test, (b) the force required for mounting the vial adaptor, (c) contribution to visible and subvisible particles as well as (d) the hold-up volume.
Results
Results show that the majority of CSTDs may have leaks varying in size, and that some of them generated visible particles due to stopper coring and subvisible particles, both due to silicon oil and particulate contaminations of the Devices. Finally, the holdup volume was up to 1 mL depending on the CSTD type, vial size and solution viscosity.
Conclusion
These results show that there is a need to evaluate the compatibility of CSTD systems to select the best system for the intended use and that CSTDs may adversely impact product quality and delivered dose.
ABSTRACT
Purpose
Evaluation of product viscosity, density and aeration on the dose delivery and accuracy for intravitreal injections with commonly used commercially available hypodermic 1 mL ...syringes.
Methods
Six commercially available hypodermic 1 mL syringes with different specifications were used for the study. Syringes were filled with the test solutions with different densities and viscosities. Syringes were also subjected to shaking stress to introduce aeration in the test solutions in the presence of different surfactant concentrations with and without high antibody concentration. Target intravitreal volumes of 100 μL, 50 μL and 30 μL were tested to assess dosing accuracy in a controlled simulated administration setup using DIN ISO 11040-4 guidelines and Zwick/Roell Z010 TN instrument.
Results
With increasing product viscosity, higher volumes and hence doses were delivered especially for very low volumes like 50 μL and 30 μL. No impact of increasing product density was found on the delivered dose. The presence of surfactants or high protein concentration can lead to aeration, which also negatively affects the dose accuracy and precision.
Conclusion
Formulation parameters like viscosity can have an impact on dose delivery using hypodermic syringes for intravitreal injections and on the resulting glide force.
Grammar and Dialogism Susanne Günthner, Wolfgang Imo, Jörg Bücker / Susanne Günthner, Wolfgang Imo, Jörg Bücker
2014
eBook
Die Buchreihe Linguistik – Impulse & Tendenzen (LIT) ist ein attraktives Forum für hochwertige Arbeiten zur Sprachwissenschaft – insbesondere zur germanistischen Linguistik. Sie sucht aktuelle ...Tendenzen aufzunehmen und widerzuspiegeln, gleichzeitig aber wegweisende Impulse für das Fach und seine weitere Entwicklung zu geben. Ihr Fokus ist die synchrone Sprachwissenschaft mit all ihren Facetten. Die Reihe versammelt ebenso Arbeiten zur Pragmatik, Computerlinguistik und Grammatiktheorie wie zur Soziolinguistik, Fachsprachenforschung oder Textlinguistik. Ihre Leitlinien sind Innovativität, Transdisziplinarität und qualitative Exzellenz. Sie steht Monographien ebenso offen wie systematisch angelegten Sammel- und Tagungsbänden.
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