Stability of Abuse-deterrent properties of PEO-based Abuse-deterrent formulation.

Abuse of opioid drug products is a national health crisis in the US. To deter abuse, a number of drug products with abuse-deterrent (AD) properties have been approved by the US Food and Drug Administration (FDA). For abuse deterrence, it is critical to maintain the AD properties during the product shelf life. However, no information on the stability of AD properties during product shelf life is publicly available. In this study, stability of AD properties of surrogate AD formulation (ADF) of opioid active pharmaceutical ingredients (APIs) were studied. Surrogate extended release (ER) AD tablets were prepared by direct compression using Diltiazem HCl (model drug), polyethylene oxide (PEO WSR 301) polymer and magnesium stearate followed by curing at 70 °C for 30 mins. The stability studies were conducted at 25 °C/60 % RH and 40 °C/75 % RH storage conditions for 12 months (M) and 6 months (M), respectively. In vitro characterization and evaluation of AD properties of tablets were performed. As anticipated, the curing process increased the crushing strength of the tablets. However, the tablets could still be manipulated and compromised leading to an enhancement in the amount of drug extracted in solvents (e.g., water, alcohol), regardless of extraction temperature as well as tablet storage condition and time. Furthermore, the granule particle size as well as viscosity in water of manipulated samples were found to be lower for tablets stored at 25 °C/60 % RH or 40 °C/75 % RH for 12 M or 3 M/6M, respectively. The changes in AD properties eased the syringeability of hydrated samples and ultimately led to the withdrawal of higher amounts of drug into the syringe, thereby, impacting the abuse deterrence potential of the formulation by an IV route. These data demonstrated that the stability of AD properties (i.e., granule particle size, viscosity and syringeability-injectability) of PEO-based tablets was dependent on the storage condition. In conclusion, the design of AD formulation and setting of product quality profile should take into consideration the stability of AD properties during the product shelf life.

Effect of formulation and peptide folding on the fibrillar aggregation, gelation, and oxidation of a therapeutic peptide.

The physical and chemical stability of therapeutic peptides presents challenges in developing robust formulations. The stability of the formulation affects product safety, efficacy and quality. Therefore, an understanding of the effects of formulation variables on the peptide's conformational structure and on its possible physical and chemical degradation is vital. To this end, computational and experimental analysis were employed to investigate the impact of formulation, peptide folding and product handling on oxidation, fibrillar aggregation and gelation of teriparatide. Teriparatide was used as a model drug due to the correlation of its conformation in solution with its pharmacological activity. Fibrillar aggregation and gelation were monitored using four orthogonal techniques. An innovative, automated platform coupled with ion mobility mass spectrometry was used for profiling chemical degradants. Increases in teriparatide concentration, pH, and ionic strength were found to increase the rate of fibrillar aggregation and gelation. Conversely, an increase in peptide folding and stabilization of the folded structures was found to decrease the rate of fibrillar aggregation and gelation. Moreover, the rate of oxidation was found to be inversely related to its solution concentration and extent of peptide folding. The present study provides an insight into formulation strategies designed to reduce the potential risk of physical and chemical degradation of peptides with a defined conformation.

Zinc supplementation improves the harvest purity of ß-glucuronidase from CHO cell culture by suppressing apoptosis.

The variability of trace metals in cell culture media is a potential manufacturing concern because it may significantly affect the production and quality of therapeutic proteins. Variability in trace metals in CHO cell culture has been shown to impact critical production metrics such as cell growth, viability, nutrient consumption, and production of recombinant proteins. To better understand the influence of excess supplementation, zinc and copper were initially supplemented with 50-µM concentrations to determine the impact on the production and quality of ß-glucuronidase, a lysosomal enzyme, in a parallel bioreactor system. Ethylenediaminetetraacetic acid (EDTA), a metal chelator, was included as another treatment to induce a depletion of trace metal bioavailability to examine deficiency. Samples were drawn daily to monitor cell growth and viability, nutrient levels, ß-glucuronidase activity, and trace zinc flux. Cell cycle analysis revealed the inhibition of sub-G0/G1 species in zinc supplemented cultures, maintaining higher viability compared to the control, EDTA-, and copper-supplemented cultures. Enzyme activity analysis in the harvests revealed higher specific activity of ß-glucuronidase in reactors supplemented with zinc. A confirmation run was conducted with supplementations of zinc at concentrations of 50, 100, and 150 µM. Further cell cycle analysis and caspase-3 analysis demonstrated the role of zinc as an apoptosis suppressor responsible for the enhanced harvest purity of ß-glucuronidase from zinc-supplemented bioreactors.

Quality attributes and evaluation of pharmaceutical glass containers for parenterals.

Pharmaceutical containers for parenterals have been predominantly manufactured using glass as a packaging material of choice, especially Type-I glass, since it has been regarded as a chemically inert and an effective container closure system (CCS). Nevertheless, there have been reports and recalls related to glass quality issues, such as breakage, flakes, and particles observed in marketed products. The novelty of this research is based on the knowledge gathered from our previously conducted risk assessments and establishing a comprehensive testing platform focused on risk factors for glass container failure modes and applicability to other types of pharmaceutical containers. The evaluation of container quality attributes was performed for three model glass vials using a mechanical and chemical durability testing platform: freeze-thaw, lyophilization, compression, scratch tests; visual inspection, pH, particle size analyses, extractable, leachable and imaging studies that were conducted under normal (4 and 25 °C), and stress condition (60 °C), respectively. The performance between the glass containers tested under certain stress conditions (failure modes) were variable and differentiated. The systematic platform testing approach shows the importance of lab-based risk evaluation in assessing common failure modes of pharmaceutical containers, since the quality attributes for injectable products are complex and can impact final product quality.