Prolonged In-use Stability of Reconstituted Herceptin in Commercial Intravenous Bags.

Herceptin is a humanized monoclonal antibody that selectively binds to the extracellular domain of human epidermal growth factor receptor 2 (HER2). Herceptin has an important role in the treatment of HER2-positive breast cancer when used in the neoadjuvant, adjuvant, and metastatic settings, and in the treatment of HER2-positive metastatic gastric cancer, and gastroesophageal junction adenocarcinoma. Prior to intravenous infusion, Herceptin must be reconstituted with sterile water for injection and then diluted in intravenous bags with normal saline. The objective of this study was to test the in-use physicochemical stability of the Herceptin drug product after dilution in 0.9% sodium chloride in commercial polyvinylchloride, and polyolefin/ polyethylene/polypropylene infusion bags over the course of a 7-day storage at 2°C to 8°C followed by 24 hours of storage at 30°C with ambient light exposure. Three batches of Herceptin were reconstituted to yield a 21-mg/mL solution that was stored for 48 hours at 2°C to 8°C prior to dilution with 0.9% sodium chloride to create low (0.24-mg/mL) and high (3.84-mg/mL) concentration solutions that were then tested in simulated infusions with a polyvinylchloride or polyolefin/polyethylene/polypropylene infusion bag. Samples for analysis were obtained immediately after dilution of the reconstituted solution (T0), after 7 days of storage at 5°C (T7), after 1 further day of storage at 30°C (T7+1), and after administration through intravenous tubing (Tend). Control samples were obtained from bags containing only 0.9% sodium chloride at each time point. For experiments with both infusion bags, all samples were practically free from particles, were colorless, and had low numbers of subvisible particles with no differences between control and experimental samples. No change in turbidity was detected between T0 and Tend for low and high-concentration samples for each batch. The pH values remained consistent between T0 and T7+1, and osmolality values were consistent across low-concentration and high-concentration samples. Protein content, size, and potency remained consistent throughout storage and simulated infusion. In conclusion, Herceptin remains physicochemically stable for 7 days when stored at 2°C to 8°C, followed by an additional 24 hours at 30°C when diluted in 0.9% sodium chloride and stored in commercially available polyvinylchloride or polyolefin/polyethylene/polypropylene infusion bags.

Physico-chemical Stability of MabThera Drug-product Solution for Subcutaneous Injection under in-use Conditions with Different Administration Materials.

MabThera is an essential component of the standard-of-care regimens in the treatment of non-Hodgkin lymphoma and Chronic Lymphatic Leukemia. MabThera for subcutaneous injection is a novel line extension that has been approved by the European Medicines Agency for the treatment of patients with follicular lymphoma and diffuse large B-cell lymphoma. This study aimed to evaluate in-use stability data of MabThera subcutaneous drug-product solution in single-use syringes for subcutaneous administration according to the European Medicines Agency guideline. The drug-product solution was exposed to material contact surfaces of five different administration setups commonly used in subcutaneous drug delivery. MabThera subcutaneous was transferred under aseptic conditions into polypropylene and polycarbonate syringes and stored for 1, 2, and 4 weeks at 2°C to 8°C followed by 24 hours at 30°C. After storage, subcutaneous administration was simulated and MabThera subcutaneous drug-product solution quality attributes were evaluated by using compendial physico-chemical tests, as well as suitable and validated molecule- and formulation-specific analytical methods. MabThera subcutaneous vials were treated and analyzed in parallel. The physico-chemical results of MabThera subcutaneous in the different setups were comparable to the control for all timepoints. No change in drug-product quality after storage and simulated administration was found compared to the control. However, since single-dose products do not contain preservatives, microbial contamination and growth needs to be avoided and product sterility needs to be ensured. The results showed that MabThera subcutaneous remains compatible and stable, from a physico-chemical perspective, for up to 4 weeks at 2°C to 8°C followed by 24 hours at 30°C with the contact materials tested in this study. In order to avoid and minimize microbial growth, MabThera subcutaneous should be used immediately after removal from the original packaging container and strict aseptic handling conditions need to be followed.

Modulating charge-transfer interactions in topologically different porphyrin-C60 dyads.

Control over the interchromophore separation, their angular relationship, and the spatial overlap of their electronic clouds in several ZnP-C(60) dyads (ZnP=zinc porphyrin) is used to modulate the rates of intramolecular electron transfer. For the first time, a detailed analysis of the charge transfer absorption and emission spectra, time-dependent spectroscopic measurements, and molecular dynamics simulations prove quantitatively that the same two moieties can produce widely different electron-transfer regimes. This investigation also shows that the combination of ZnP and C(60) consistently produces charge recombination in the inverted Marcus region, with reorganization energies that are remarkably low, regardless of the solvent polarity. The time constants of electron transfer range from the mus to the ps regime, the electronic couplings from a few tens to several hundreds of cm(-1), and the reorganization energies remain below 0.54 eV and can be as low as 0.16 eV.

Isolation, structural characterization, and antiviral activity of positional isomers of monopegylated interferon alpha-2a (PEGASYS).

Interferon alpha-2a plays an essential role in the treatment of chronic hepatitis C, but it is limited in its efficacy by the short in vivo half-life. To improve the half-life and efficacy, interferon alpha-2a is conjugated with a 40-kDa branched polyethylene glycol moiety (PEG-IFN, PEGASYS). From this preparation the positional PEG-IFN isomers were isolated and characterized by different analytical methods and antiviral assay. Two chromatographic steps were used to separate and purify nine isomers. The analytical methods IE-HPLC, RP-HPLC, SE-HPLC, SDS-PAGE, and MALDI-TOF MS indicated that each of these nine isomers is conjugated to the branched polyethylene glycol chain at a specific lysine. No isomer with a modification at the amino terminus was observed. All positional isomers induced viral protection of MDBK cells in the antiviral assay. When comparing the quantitative potency of the individual isomers with the whole mixture of PEG-IFN, significant differences in the specific activities were observed: PEG-Lys(31) and PEG-Lys(134) showed higher activities than the mixture, PEG-Lys(164) was equal to the mixture, whereas the activities of PEG-Lys(49), PEG-Lys(70), PEG-Lys(83), PEG-Lys(112), PEG-Lys(121), and PEG-Lys(131) were lower.