Current Industry Best Practice on in-use Stability and Compatibility Studies for Biological Products.

Evaluating the in-use stability of a biological product including its compatibility with administration components allows to define handling instructions and potential hold times that retain product quality during dose preparation and administration. The intended drug product usage may involve the dilution of drug formulation into admixtures for infusion and exposure to new interfaces of administration components like intravenous (iv) bags, syringes, and tubing. In-use studies assess the potential impact on product quality by simulating drug handling throughout the defined in-use period. Considering the wide range of in-use conditions and administration components available globally, only limited guidance is available from regulators on expected in-use stability data. A working group reviewed and consolidated industry approaches to assess physicochemical stability of traditional protein-based biological products during clinical development and for commercial use. The insights compiled in this review article can be leveraged across the industry and encompass topics such as representative drug product material and administration components, testing conditions, quality attributes evaluated and respective acceptance criteria, applied quality standards, and regulatory requirements. These practices may help companies in the study design, and they may inform discussions with global regulators.

Polymer coated gold nanoshells for combinational photochemotherapy of pancreatic cancer with gemcitabine.

Pancreatic cancer is one of the most lethal malignancies with limited therapeutic options and dismal prognosis. Gemcitabine is the front-line drug against pancreatic cancer however with limited improvement of therapeutic outcomes. In this study we envisaged the integration of GEM with gold nanoshells which constitute an interesting class of nanomaterials with excellent photothermal conversion properties. Nanoshells were coated with thiol-capped poly(ethylene glycol) methacrylate polymers of different molecular weight via Au-S attachment. It was found that the molecular weight of the polymers affects the in vitro performance of the formulations; more importantly we demonstrate that the EC50 of nanoshell loaded GEM can be suppressed but fully restored and even improved upon laser irradiation. Our proposed nanoformulations outperformed the cytotoxicity of the parent drug and showed confined synergism under the tested in vitro conditions.

Dual Controlled Delivery of Gemcitabine and Cisplatin Using Polymer-Modified Thermosensitive Liposomes for Pancreatic Cancer.

Although combinational anticancer chemotherapies have been proven to improve the life expectancy of patients in the clinic, their full potential is severely limited by the additive toxicities of the drug molecules. Targeted drug delivery systems could alleviate this major limitation by the design of nanocarriers that can cocarry multiple drug molecules in order to augment drug synergism at the site of interest while reducing the systemic side effects. In this study, we report on a thermoresponsive polymer-coated liposome nanocarrier that is capable to cocarry two potent anticancer drugs and release them via a thermally triggered mechanism. A synthetic polymer ([poly(diethylene glycol) methacrylate-co-poly(oligoethylene glycol) methacrylate]-b-poly(2-ethylhexyl) methacrylate) was synthesized by reversible addition-fragmentation chain transfer (RAFT) polymerization and was used as a thermoresponsive polymer coating shell on thermosensitive liposome carriers. The formulations were tested in vitro against two pancreatic cancer cell lines, MiaPaCa-2 and BxPC-3, and their cytotoxic potency was studied with respect to their targeted release properties as well as their biological interactions with cellular organelles. The polymer-modified liposomes (PMTLs) could cocarry and release Gemcitabine (Gem) and cisplatin (Cis) in a thermally controlled rate and were also found to exhibit specific hydrophobic interactions with the cell membranes above the temperature transition of the formulations. In addition, the nanocarriers were found to induce more than 10-fold improvement of the IC50 of both drugs, either as monotherapies or in combination, in both cell lines tested, in a temperature dependent manner. The proposed formulations constitute a potent nanomedicinal approach for the codelivery of multiple drug molecules and could find potential uses as thermally triggered drug delivery systems for precision medicine and oncology and also as modulators of drug efficacy at the cellular level owing to their unique interactions with the cell membranes.