An Industry Perspective on the use of Forced Degradation Studies to Assess Comparability of Biopharmaceuticals.

Forced degradation, also known as stress testing, is used throughout pharmaceutical development for many purposes including assessing the comparability of biopharmaceutical products according to ICH Guideline Q5E. These formal comparability studies, the results of which are submitted to health authorities, investigate potential impacts of manufacturing process changes on the quality, safety, and efficacy of the drug. Despite the wide use of forced degradation in comparability assessments, detailed guidance on the design and interpretation of such studies is scarce.

An Intercompany Perspective on Practical Experiences of Predicting, Optimizing and Analyzing High Concentration Biologic Therapeutic Formulations.

Developing high-dose biologic drugs for subcutaneous injection often requires high-concentration formulations and optimizing viscosity, solubility, and stability while overcoming analytical, manufacturing, and administration challenges. To understand industry approaches for developing high-concentration formulations, the Formulation Workstream of the BioPhorum Development Group, an industry-wide consortium, conducted an inter-company collaborative exercise which included several surveys. This collaboration provided an industry perspective, experience, and insight into the practicalities for developing high-concentration biologics.

An Intercompany Perspective on Compatibility and In-use Stability Studies to Enable Administration Of Biopharmaceutical Drug Products.

In-use stability and compatibility studies are often used in biotherapeutic development to assess stability and compatibility of biologic drugs with diluents and/or administration components at relevant conditions for the target route of administration (commonly intravenous, subcutaneous or intramuscular), to assure that patient safety and product efficacy are maintained during clinical use. To gain an understanding of current industry approaches for in-use stability and compatibility studies, the Formulation Workstream of the BioPhorum Development Group (BPDG), an industry-wide consortium, conducted an inter-company collaboration exercise, which included five bench-marking surveys around in-use stability and compatibility studies of biologic drugs. The results of this industry collaboration provide insights into the practicalities of these studies and how they are being used to support administration of biologics from early clinical programs to marketed products.

An Industry Perspective on Compatibility Assessment of Closed System Drug-Transfer Devices for Biologics.

The Formulation Workstream of the BioPhorum Development Group (BPDG), an industry-wide consortium, has identified the increased use of closed system drug-transfer devices (CSTDs) with biologics, without an associated compatibility assessment, to be of significant concern. The use of CSTDs has increased significantly in recent years due to the recommendations by NIOSH and USP that they be used during preparation and administration of hazardous drugs. While CSTDs are valuable in the healthcare setting to reduce occupational exposure to hazardous compounds, these devices may present particular risks that must be adequately assessed prior to use to ensure their compatibility with specific types of drug products, such as biologic drugs, which may be sensitive.

An Industry Perspective on Forced Degradation Studies of Biopharmaceuticals: Survey Outcome and Recommendations.

The BioPhorum Development Group is an industry-wide consortium enabling networking and sharing of common practices for the development of biopharmaceuticals. Forced degradation studies (FDSs) are often used in biotherapeutic development to assess criticality of quality attributes and in comparability studies to ensure product manufacturing process consistency. To gain an understanding of current industry approaches for FDS, the BioPhorum Development Group-Forced Degradation Point Share group conducted an intercompany collaboration exercise, which included a benchmarking survey and group discussions around FDS of monoclonal antibodies.

An Intercompany Perspective on Biopharmaceutical Drug Product Robustness Studies.

The Biophorum Development Group (BPDG) is an industry-wide consortium enabling networking and sharing of best practices for the development of biopharmaceuticals. To gain a better understanding of current industry approaches for establishing biopharmaceutical drug product (DP) robustness, the BPDG-Formulation Point Share group conducted an intercompany collaboration exercise, which included a bench-marking survey and extensive group discussions around the scope, design, and execution of robustness studies. The results of this industry collaboration revealed several key common themes: (1) overall DP robustness is defined by both the formulation and the manufacturing process robustness; (2) robustness integrates the principles of quality by design (QbD); (3) DP robustness is an important factor in setting critical quality attribute control strategies and commercial specifications; (4) most companies employ robustness studies, along with prior knowledge, risk assessments, and statistics, to develop the DP design space; (5) studies are tailored to commercial development needs and the practices of each company.

Design and campaign synthesis of pyridine-based histone deacetylase inhibitors.

A lead benzamide, bearing a cyanopyridyl moiety (3), was identified as a potent and low molecular weight histone deacetylase (HDAC) inhibitor. Various replacements of the cyano group were explored at the C3-position, along with the exploration of solubility-enhancing groups at the C5-position. It was determined that cyano substitution at the C3-position of the pyridyl core, along with a methylazetidinyl substituent at the C5-position yielded optimal HDAC1 inhibition and anti-proliferative activity in HCT-116 cells.

Design and campaign synthesis of piperidine- and thiazole-based histone deacetylase inhibitors.

A lead benzamide, 3, was identified as a potent and low molecular weight histone deacetylase (HDAC) inhibitor. Optimization led to 16d, demonstrating an excellent balance of efficacy and non-efficacy properties, along with very desirable in vivo DMPK. The final compounds presented are >1000-fold more potent than the initial screen hit, an improvement in potency which was achieved with a concomitant significant improvement in all the main non-efficacy properties.

The stereochemical course of bromoetherification of enynes.

Enynes undergo stereoselective syn intramolecular bromoetherification; the stereochemical course of the reaction was elucidated by X-ray crystallographic studies and by stereospecific synthesis of authentic bromoallenes.

A biosynthetically-inspired synthesis of the tetrahydrofuran core of obtusallenes II and IV.

[reaction: see text] Sharpless asymmetric dihydroxylation was regioselective for the trans olefin in an E vs Z vs terminal triene substrate. To test a biosynthetic hypothesis, the resulting diol underwent diastereoselective bromoetherification to provide the des-chloro core of marine natural products obtusallenes II and IV. Alternatively, anionic chloride ring-opening of a Z-beta,gamma-unsaturated epoxide gave separable regioisomeric halohydrins.

ZD6474 inhibits vascular endothelial growth factor signaling, angiogenesis, and tumor growth following oral administration.

ZD6474 [N-(4-bromo-2-fluorophenyl)-6-methoxy-7-[(1-methylpiperidin-4-yl)methoxy]quinazolin-4-amine]is a potent, p.o. active, low molecular weight inhibitor of kinase insert domain-containing receptor [KDR/vascular endothelial growth factor receptor (VEGFR) 2] tyrosine kinase activity (IC(50) = 40 nM).

Novel 4-anilinoquinazolines with C-7 basic side chains: design and structure activity relationship of a series of potent, orally active, VEGF receptor tyrosine kinase inhibitors.

We have previously shown that 4-anilinoquinazolines can be potent inhibitors of vascular endothelial growth factor (VEGF) receptor (Flt-1 and KDR) tyrosine kinase activity. A novel subseries of 4-anilinoquinazolines that possess basic side chains at the C-7 position of the quinazoline nucleus have been synthesized. This subseries contains potent, nanomolar inhibitors of KDR (median IC(50) 0.