Automated multifactorial design of experiment and Bayesian optimisation algorithm approaches to method development for the green analysis by supercritical fluid chromatography of a pharmaceutical ingredient.

During drug development, chromatography is frequently used for purity and stability testing of both drug substance and drug product. Reversed phase liquid chromatography (RPLC) is one of the most widely used methodologies due to its wide scope of application. In the later stages of drug development, the specified impurities and degradation products that define the critical quality attribute of the final API, also known as Key Predictive Sample Set (KPSS), are usually well defined and controlled. At this point, a method review enables selecting the most appropriate technique which should be the one providing optimal robustness (ICH-Q14[1]), with the support of Quality by Design (QbD) approaches. Supercritical Fluid Chromatography (SFC) is a preferred technique for its proven diversity in selectivity. The adoption of a technique which presents the most favourable environmental impact, such as, but not limited to, SFC, is also becoming increasingly important as laboratories strive to reduce carbon footprint. Re-developing a method requires high resource-demands in terms of staff, materials, and time. Any step of the process that can be automated can facilitate this approach, speeding up the delivery of the method whilst preserving robustness. In this article we describe how an SFC method was developed for the purity profiling of a late-stage oncology candidate, taking advantage of the superior selectivity of SFC towards structurally similar analytes, owed to the high orthogonality with R2 as low as 0.014 towards the KPSS. We describe two approaches to automate the method development. Firstly, a multifactorial design of experiments (DoE) and secondly, an optimization via a Bayesian algorithm, which was completed in one night, highlighting the potential and limitations, with an insight into the robustness. Both methods achieved baseline separation with varying levels of automation embedded into the process and a large reduction of the resource demands when compared to traditional optimisation methods. Finally, we describe the beneficial environmental impact that implementing SFC methods can yield, with a calculated green score reduced to a value between 17 and 30 % compared to RPLC, depending on the number of runs per sequence.

Transoral Parotidectomy.

Transoral parotidectomy allows for the management of parapharyngeal space tumors and accessory parotid gland tumors without the need for a transfacial/transparotid or mandible splitting procedure. It is a minimally invasive approach that permits a faster recovery and with a lesser risk of facial palsy.

Adjuvant external-beam radiotherapy in patients with high-risk well-differentiated thyroid cancer.

The role of adjuvant external-beam radiation therapy (EBRT) in well-differentiated thyroid cancer is not well delineated. Many clinicians rely solely on iodine 131 (131I) to destroy thyroid remnants following thyroidectomy. However, the lesser uptake of isotope in tumor cells suggests that 131I alone may not be sufficient to eradicate microscopic residual disease when no gross thyroid tissue remains. We conducted a retrospective study to examine the potential benefit of adjuvant EBRT in patients at high risk for microscopic residual disease following thyroidectomy. Between 1973 and 2001, 44 patients with well-differentiated papillary or follicular thyroid cancer were found to have extracapsular extension following thyroidectomy. These patients were divided into 2 groups based on the type of treatment; 11 patients had received adjuvant EBRT (with or without 131I) and 33 patients had not received EBRT (i.e., they received adjuvant 131I only). We reviewed their medical records and compiled data on local recurrence and overall survival (Kaplan-Meier analysis). Despite having a less favorable prognosis, the EBRT group experienced no local recurrences during a mean follow-up of 7.8 years; in contrast, 9 local recurrences were seen in the no-EBRT group. Also, the median survival for patients without a local recurrence was longer than that for those who had failed locally (425 vs. 317 mo). Although our population was not large enough for these differences to achieve statistical significance, our study did show that adjuvant EBRT provided excellent results. We hypothesize that a reciprocal irradiation effect between cancer cells and normal cells may be necessary in order for 131I to be tumoricidal. If so, a patient with microscopic residual disease would not have enough cancer cells to sufficiently concentrate 131I. Because EBRT does not depend on such a mechanism, it may be more effective than 131I in controlling disease in the setting of microscopic disease. Larger studies are needed to validate our results. In the meantime, we believe that adjuvant EBRT should play an important role in the treatment of patients with high-risk well-differentiated thyroid cancer.