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There is a concern that low atmospheric pressure typically encountered during shipment could result in plunger-stopper displacement in prefilled syringes impacting sterility and container closure integrity (CCI) of drug product.

A drug delivery system is designed to administer a therapeutic dose according to its label claim. Upon delivery of a parenteral drug product, the volume remaining inside the container that cannot be extracted at the end of drug administration is called the hold-up volume (HUV) and is primarily considered product wastage. To meet the label claim, every drug product container is filled with a slight excess volume. For early-stage products in clinical phase, for which material availability is often a limitation, excess volume in drug product containers has to be determined experimentally using several grams of product. In such scenarios, established models that can predict HUV in primary drug product containers would be valuable for product development. The objective of this study was to determine HUV with 95% confidence intervals across various container closures and drug delivery systems by using aqueous PEG 400 solution mimicking the viscosity of biologic drug products. ISO 2R, 6R, and 10R vials and single-use hypodermic syringes attached to a Luer lock needle (25 gauge, 1½ in.) were used to mimic parenteral drug product container and delivery systems for determination of HUV. Glass prefilled syringes in 1 mL and 2.25 mL configurations were also used to determine HUV with 95% confidence intervals. A linear regression model was developed for determination of HUV as a function of viscosity and as a function of container closure and a needle-based delivery system. This model predicting HUV was confirmed by using monoclonal antibodies of varying formulations and viscosities for container closure and delivery systems tested in this study. The model provided here can be used to determine HUV for a particular container closure for a drug solution with known viscosity that can subsequently be used to evaluate fill volume specifications and label claim for a dosage form.

Monoclonal antibodies (mAbs) may be prone to self-association leading to formation of dimers, trimers, or other high molecular weight species during bio-processing. In order to implement appropriate manufacturing control strategies during bio-processing, it is important to understand various real life bio-processing conditions where such self-associations may manifest. One such case study is presented here of increase in dimer content for an mAb during scale-up bio-processing and the approach taken to understand the under-lying mechanism. In this example, a therapeutic mAb demonstrated a consistently higher dimer values (~0.5% higher) in the drug product (DP) during release when compared to the same value measured in the corresponding drug substance (DS) lot. This observation was interesting since the DS was supplied frozen, and the DS and DP share the same formulation composition and therefore investigation of this dimer change was the scope of the characterization study. Variable path length spectroscopy and size exclusion chromatography was used for protein quantification and to monitor %dimer respectively during characterization of fill-finish unit operations. At the start of DP manufacturing process, immediately after thaw of bulk DS, a protein concentration gradient was observed and the concentration ranged from 90 mg/mL (top of container) to 210 mg/mL (bottom of container). The dimerization kinetics in the same DS container was dependent on concentration with higher concentrations demonstrating higher rates of dimerization. After the bulk DS was mixed for further processing, %dimer in purified bulk DS was quantitated to be approximately 1.4% which is identical to levels observed during scale-up manufacturing of DP. After each unit operation, the in-process samples tested for %dimer showed a gradual increase in dimer as a function of time over the next 7 days accumulating to 1.8% dimer at the end of DP manufacturing process. Samples subjected to static incubation at 2-8°C and room temperature (RT; 15-25°C) showed a gradual increase in dimer over the same time frame; however, the rate of increase in dimer at RT was higher compared to samples stored at 2-8°C. The results from this demonstrate two important key findings: self-association kinetics of mAbs could be exacerbated by protein cryoconcentration and temperature conditions during bioprocessing. Since these two parameters are commonly encountered during manufacturing, the proposed mitigation strategy is to ensure homogeneity of the bulk DP during processing. The temperature dependent self-association kinetics of mAb could be mitigated by processing at lower temperature (e.g., 2-8°C) and by storing the finished DP at lower temperature after manufacturing. The results from this study also highlight the criticality of setting slightly wider specifications for DP compared to DS following ICH Q6B guidelines.