Analytical Challenges Assessing Protein Aggregation and Fragmentation Under Physiologic Conditions.

Therapeutic proteins are administered by injection or infusion. After administration, the physiologic environment in the desired body compartment - fluid or tissue - can impact protein stability and lead to changes in the safety and/or efficacy profile. For example, protein aggregation and fragmentation are critical quality attributes of the drug product and can occur after administration to patients.

Stability of monoclonal antibodies after simulated subcutaneous administration.

Changes in the environment from the drug product to the human physiology might lead to physical and/or chemical modifications of the protein drug, such as in vivo aggregation and fragmentation. Although subcutaneous (SC) injection is a common route of administration for therapeutic proteins, knowledge on in vivo stability in the SC tissue is limited. In this study, we developed a physiologic in vitro model simulating the SC environment in patients.

Assessing Particle Formation of Biotherapeutics in Biological Fluids.

The stability of therapeutic proteins can be impacted in vivo after administration, which may affect patient safety or treatment efficacy, or both. Stability testing of therapeutic proteins using models representing physiologic conditions may guide preclinical development strategy; however, to date only a few studies assessing the physical stability are available in the public domain. In this manuscript, the stability of seven fluorescently labeled monoclonal antibodies (mAbs) was evaluated in human serum and phosphate-buffered saline, two models often discussed to be representative of the situation in humans after intravenous administration.

Role of Formulation Parameters on Intravitreal Dosing Accuracy Using 1 mL Hypodermic Syringes.

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.

Determining Maximum Allowable Rubber Stopper Displacement for Container Closure Integrity (CCI).

Sterile pharmaceuticals require they be developed and manufactured using suitable container closure systems to maintain sterility until product opening. Characterizing container closure integrity (CCI) in relation to rubber stopper displacement was controversially discussed during the Annex 1 revision process. An automated inspection system can reject units with displaced rubber stoppers, and the related acceptance criteria for such in-process testing can be established by adequate studies.

Characterization of Polymeric Syringes Used for Intravitreal Injection.

Intravitreal (IVT) injection is currently the state of the art for drug delivery to the back of the eye. Drug Products (DP) intended for IVT injections usually pose challenges such as a very low injection volume (e.g.

Tracking the physical stability of fluorescent-labeled mAbs under physiologic in vitro conditions in human serum and PBS.

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.

Evaluation of Different Quality-Relevant Aspects of Closed System Transfer Devices (CSTDs).

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 <800> monograph was issued.

Method to Predict Glass Vial Fogging in Lyophilized Drug Products.

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.

Subcutaneous Injection Volume of Biopharmaceuticals-Pushing the Boundaries.

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.

Understanding the freezing of biopharmaceuticals: first-principle modeling of the process and evaluation of its effect on product quality.

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.