Bristol-Myers Squibb (Ireland)

Among many operating parameters that control cell culture environment, appropriate mixing and aeration are crucial for cells to meet oxygen demand in aerobic microbial and mammalian production processes. A model-based manufacturing facility fit approach was applied to define agitation and air flow rates during cell culture process scale-up from laboratory to manufacturing, of which computational fluid dynamics (CFD) was the core modeling tool. The realizable k-ε turbulent dispersed Eulerian two-fluid model was used to simulate gas-liquid flow in the bioreactor and predict volumetric oxygen transfer coefficients ( ka), where the simulation was performed in the basal medium and the resulting ka was adjusted using modification factors for surfactants such as Pluronic F68 and Antifoam C. The CFD prediction of ka resulted in adequate agreement with the empirical values in 15,000-L and 25,000-L bioreactors. The model was then applied to define a range of agitation and bottom air flow rates for meeting cellular oxygen demand and mitigating risks of cell damage and safety hazards. The recommended operating conditions led to the completion of five manufacturing runs with a 100% success rate. The model-based approach reduced the required number of at scale development batches and hence enabled seamless scale-up, shortened timelines, and cost savings in cell culture process technology transfer.

We present a hypothetical case study to examine the use of a next‐generation framework developed by the Genetic Toxicology Technical Committee of the Health and Environmental Sciences Institute for assessing the potential risk of genetic damage from a pharmaceutical perspective. We used etoposide, a genotoxic carcinogen, as a representative pharmaceutical for the purposes of this case study. Using the framework as guidance, we formulated a hypothetical scenario for the use of etoposide to illustrate the application of the framework to pharmaceuticals. We collected available data on etoposide considered relevant for assessment of genetic toxicity risk. From the data collected, we conducted a quantitative analysis to estimate margins of exposure (MOEs) to characterize the risk of genetic damage that could be used for decision‐making regarding the predefined hypothetical use. We found the framework useful for guiding the selection of appropriate tests and selecting relevant endpoints that reflected the potential for genetic damage in patients. The risk characterization, presented as MOEs, allows decision makers to discern how much benefit is critical to balance any adverse effect(s) that may be induced by the pharmaceutical. Interestingly, pharmaceutical development already incorporates several aspects of the framework per regulations and health authority expectations. Moreover, we observed that quality dose response data can be obtained with carefully planned but routinely conducted genetic toxicity testing. This case study demonstrates the utility of the next‐generation framework to quantitatively model human risk based on genetic damage, as applicable to pharmaceuticals.

Small-molecule inhibitors of transforming growth factor beta receptor 1 (TGFβRI) have a history of significant class-based toxicities (eg, cardiac valvulopathy) in preclinical species that have limited their development as new medicines. Nevertheless, some TGFβRI inhibitors have entered into clinical trials using intermittent-dosing schedules and exposure limits in an attempt to avoid these toxicities. This report describes the toxicity profile of the small-molecule TGFβRI inhibitor, BMS-986260, in rats and dogs. Daily oral dosing for 10 days resulted in valvulopathy and/or aortic pathology at systemic exposures that would have been targeted clinically, preventing further development with this dosing schedule. These toxicities were not observed in either species in 1-month studies using the same doses on an intermittent-dosing schedule of 3 days on and 4 days off (QDx3 once weekly). Subsequently, 3-month studies were conducted (QDx3 once weekly), and while there were no cardiovascular findings in dogs, valvulopathy and mortality occurred early in rats. The only difference compared to the 1-month study was that the rats in the 3-month study were 2 weeks younger at the start of dosing. Therefore, a follow-up 1-month study was conducted to evaluate whether the age of rats influences sensitivity to target-mediated toxicity. Using the same dosing schedule and similar doses as in the 3-month study, there was no difference in the toxicity of BMS-986260 in young (8 weeks) or adult (8 months) rats. In summary, an intermittent-dosing schedule mitigated target-based cardiovascular toxicity in dogs but did not prevent valvulopathy in rats, and thus the development of BMS-986260 was terminated.

Hydroxypropylmethylcellulose (HPMC) acetyl succinate (HPMC-AS) is a key polymer used for the enablement of amorphous solid dispersions (ASDs) in oral solid dosage forms. Choice of the appropriate grade within the material is often made empirically by the manufacturer of small-scale formulations, followed by extensive real time stability. A key factor in understanding and predicting the performance of an ASD is related to the presence of hydrogen (or other) bonds between the polymer and active pharmaceutical ingredient (API), which will increase stability over the parameters captured by miscibility and predicted by the Gordon-Taylor equation. Solid state nuclear magnetic resonance (NMR) is particularly well equipped to probe spatial proximities, for example, between polymer and API; however, in the case of HPMC-AS, these interactions have been sometimes difficult to identity as the carbon-13 NMR spectra assignment is yet to be firmly established. Using feedstock, selectively substituted HPMC polymers, and NMR editing experiments, we propose here a comprehensive understanding of the chemical structure of HPMC-AS and a definitive spectral assignment of the 13 C NMR spectra of this polymer. The NMR data also capture the molar ratios of the acetate and succinate moieties present in HPMC-AS of various grades without the need for post treatment required by chromatography methods commonly use in pharmacopoeia. This knowledge will allow the prediction and measurement of interactions between polymers and APIs and therefore a rational choice of polymer grade to enhance the solid state stability of ASDs.

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During exploration of the nickel(0)-catalyzed reaction of isocyanates and isatoic anhydrides, it was found that changes in the substitution pattern of the isocyanate led to constitutionally isomeric quinazolinediones [quinazoline-2,4(1H,3H)-diones] or benzoxazinone imines [2-imino-1,2-dihydro-4H-3,1-benzoxazin-4-ones]. Ligand and solvent screening experiments allowed for identification of conditions that could lead to each constitutional isomer in good to excellent levels of selectivity and yield. Comprehensive characterization of the previously poorly characterized benzoxazinone imines is also provided.

Bulk density can be a key indicator of performance, and may influence choice of formulation route of materials in pharmaceutical development. During early development, the cost of API's can be expensive and the availability of material for powder property analysis is limited. The aim of this work was to investigate a suitable small-scale, low material requirement, bulk density test which would provide comparable data to the recommended large volume USP test. Materials with a range of morphological characteristics typically seen in the pharmaceutical industry were assessed to ensure that methods were suitably robust. It was found that the USP II "low volume" test does not give equivalent results to other tests in the USP, across the range of materials. An alternative test based on the FT4 powder rheometer at a scale of 25 mL gave results equivalent to the large volume USP I standard test. The use of smaller 10-mL methods was also found to give acceptable results for materials that were considered well-behaved but were more variable with difficult to handle materials with low bulk density.

Objective: The objective of this study was to determine the impact that the micro-environment, as measured by PyroButton data loggers, experienced by tablets during the pan coating unit operation had on the layer adhesion of bilayer tablets in open storage conditions.Materials and methods: A full factorial design of experiments (DOE) with three center points was conducted to study the impact of final tablet hardness, film coating spray rate and film coating exhaust temperature on the delamination tendencies of bilayer tablets. PyroButton data loggers were placed (fixed) at various locations in a pan coater and were also allowed to freely move with the tablet bed to measure the micro-environmental temperature and humidity conditions of the tablet bed.Results: The variance in the measured micro-environment via PyroButton data loggers accounted for 75% of the variance in the delamination tendencies of bilayer tablets on storage (R2 = 0.75). A survival analysis suggested that tablet hardness and coating spray rate significantly impacted the delamination tendencies of the bilayer tablets under open storage conditions. The coating exhaust temperature did not show good correlation with the tablets’ propensity to crack indicating that it was not representative of the coating micro-environment. Models created using data obtained from the PyroButton data loggers outperformed models created using primary DOE factors in the prediction of bilayer tablet strength, especially upon equipment or scale transfers.Conclusion: The coating micro-environment experienced by tablets during the pan coating unit operation significantly impacts the strength of the bilayer interface of tablets on storage.

This review presents nine case studies where physiologically based pharmacokinetic modeling has been used in the design and development of extended-release formulations. While the approaches for creating the models were similar, in each case a product-development or drug-delivery problem unique to each compound was solved so that the drug-release rate could be optimized to achieve the best clinical performance. Examples presented include understanding the relationship between colonic absorption and efflux, effect of drug release and gastric emptying on maximum achieved drug concentration in plasma and area under the plasma concentration-time curve for a Biopharmaceutics Classification System class 3 compound, feasibility of an extended-release product for a prodrug, feasibility of an extended-release product for a biopharmaceutics classification system class 4 compound and predicting the pharmacokinetics in humans based on a primate model and coupling the physiologically-based pharmacokinetic model with a pharmacodynamic model so that the clinical efficacy of the formulations could be predicted based on the simulated plasma concentrations. The use of physiologically based pharmacokinetic models in the development of extended-release formulations is rapidly becoming an acceptable part of the knowledge management and design space components of a quality by design approach to product development. As the use of these in silico tools increase and examples become available through scientific presentations and literature, the inclusion of this approach will become a necessary part of the development process rather than the exception.