Laboratory capacities are often limited by time-consuming manual repetitive procedures rather than analysis time itself. While modern instruments are typically equipped with an autosampler, sample preparation often follows manual procedures including many labor-intensive, monotonous tasks. Particularly, for a high number of samples, well plates, and low microliter pipetting, manual preparation is error-prone often requiring repeated experiments.
View Article and Find Full Text PDFRegulatory authorities and the scientific community have identified the need to monitor the in vivo stability of therapeutic proteins (TPs). Due to the unique physiologic conditions in patients, the stability of TPs after administration can deviate largely from their stability under drug product (DP) conditions. TPs can degrade at substantial rates once immersed in the in vivo milieu.
View Article and Find Full Text PDFEur J Pharm Biopharm
February 2022
Monoclonal antibodies (mAbs) and excipients can degrade owing to different stress factors they encounter during their life cycle or after administration in human body. This can result in the formation of aggregates and particulates. As particles can evoke an immune response in patients, it becomes increasingly important to monitor their fate after administration.
View Article and Find Full Text PDFPDA J Pharm Sci Technol
June 2022
All products labeled as sterile are required to be free of microbial contamination throughout their shelf life (obligatory critical quality attribute). Container closure integrity (CCI) needs to be addressed with a holistic life cycle strategy comprising adequate primary packaging components selection and the assessment of critical unit operations and critical process parameters (CPPs) according to quality by design (QbD) principles. The helium leak method is currently the most sensitive CCI test method and preferably used for the initial container closure system (CCS) qualification and characterization studies.
View Article and Find Full Text PDFTherapeutic proteins can degrade upon administration as they are subjected to a variety of stresses in human body compartments. In vivo degradation may cause undesirable pharmacokinetic/pharmacodynamic profiles. Pre-clinical in vitro models have gained scientific interest as they enable one to evaluate the in vivo stability of monoclonal antibodies (mAbs) and ultimately can improve patient safety.
View Article and Find Full Text PDFTherapeutic 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.
View Article and Find Full Text PDFChanges 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.
View Article and Find Full Text PDFThe 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.
View Article and Find Full Text PDFPurpose: 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.
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.
View Article and Find Full Text PDFIntravitreal (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.
View Article and Find Full Text PDFIn 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.
View Article and Find Full Text PDFPurpose: 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.
View Article and Find Full Text PDFA manuscript version without peer-review revisions was mistakenly processed and published.
View Article and Find Full Text PDFSignificant efforts are made to characterize molecular liabilities and degradation of the drug substance (DS) and drug product (DP) during various product life-cycle stages. The in vivo fate of a therapeutic protein is usually only considered in terms of pharmacokinetics (PKs) and pharmacodynamics (PDs). However, the environment in the human body differs substantially from that of the matrix (formulation) of the DP and may impact on the stability of an injected therapeutic protein.
View Article and Find Full Text PDFThe phase-appropriate application of analytical methods to characterize, monitor, and control particles is an important aspect of the development of safe and efficacious biotherapeutics. The AAPS Product Attribute and Biological Consequences (PABC) focus group (which has since transformed into an AAPS community) conducted a survey where participating labs rated their method of choice to analyze protein aggregation/particle formation during the different stages of the product life cycle. The survey confirmed that pharmacopeial methods and SEC are the primary methods currently applied in earlier phases of the development to ensure that a product entering clinical trials is safe and efficacious.
View Article and Find Full Text PDFCell therapy products represent an exciting new class of medicinal products, which must be parenterally administered. Thus, compliance with parenteral preparation guidelines is required. One requirement for parenteral products is the characterization of particle contaminations.
View Article and Find Full Text PDFProtein aggregates and subvisible particles (SbvP), inherently present in all marketed protein drug products, have received increasing attention by health authorities. Dynamic imaging analysis was introduced to visualize SbvP and facilitate understanding of their origin. The educational United States Pharmacopeia chapter <1787> emphasizes that dynamic imaging analysis could be used for morphology measurements in the size range of 4-100 μm.
View Article and Find Full Text PDFGlass 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.
View Article and Find Full Text PDFSubvisible particles (SVPs) are an obligatory critical quality attribute of the product, and yet, they are found in all biopharmaceutical products intended for infusion or injection. Light obscuration (LO) is the primary pharmacopeial method used to quantify SVPs. However, the method may not be equally sensitive toward all particles that can possibly occur.
View Article and Find Full Text PDFThe sterility of drug products intended for parenteral administration is a critical quality attribute (CQA) because it serves to ensure patient safety and is thus a key requirement by health authorities. While sterility testing is a probabilistic test, the assurance of sterility is a holistic concept including adequate design of manufacturing facilities, process performance, and product design. Container closure integrity testing (CCIT) is necessary to confirm the integrity of a container closure system (CCS), until the end of a product's shelf life.
View Article and Find Full Text PDFTherapeutic proteins show a rapid market growth. The relatively young biotech industry already represents 20 % of the total global pharma market. The biotech industry environment has traditionally been fast-pasted and intellectually stimulated.
View Article and Find Full Text PDFPrefilled syringes (PFSs) are increasingly preferred over vials as container closure systems (CCSs) for injectable drug products when facilitated or self-administration is required. However, PFSs are more complex compared to CCSs consisting of vial, rubber stopper, and crimp cap. Container closure integrity (CCI) assurance and verification has been a specific challenge for PFSs as they feature several sealing areas.
View Article and Find Full Text PDFThe assurance of sterility of a parenteral drug product, prior to any human use, is a regulatory requirement. Hence, all strategies related to container closure integrity (CCI) must demonstrate absence of microbial contamination through leaks as part of the container closure system (CCS) qualification, during manufacturing, for quality control purposes and to ensure microbiological integrity (sterility) during storage and shipment up to the end of product shelf life. Current regulatory guidances, which differ between countries and regions, provide limited detail on how to assess CCI.
View Article and Find Full Text PDF