BPOG model solvent comparison for extractables testing for single use systems

Regulatory guidance requires an extractables based evaluation for drug manufacturing processes. Concerns about the increasing use of hyrbrid and fully single use systems in manufacturing processes and what they may contribute the bulk drug substance and final drug product has highlighted the need for thorough risk assessments and safety evaluations. Awareness of the risk each unit operation represents a strategy to deal with the risk is crucial. An outline of a manufacturing process will be presented along with each unit operations potential risk. This discussion will define an extractables testing strategy based upon the Biophorum Operations Group (BPOG) Extractables Protocol for the highest risk process step - sterilizing filtration in a point of use filling line application that is in direct contact with drug product. Analytical results from multiple methods for six model solvent streams will be shown: water, 0.5N NaOH, 0.1 M Phosphoric Acid, 50% Denatured Ethanol/ 50% Water mixture, 1% Polysorbate 80 and 5M NaCL; using time points of \u3c30 \u3eminutes, 24 hours and 7 days. A comparison of the compounds identified by each method, solvent and time point will presented. The extractables data from the sterilizing grade filter will be used to perform a patient safety evaluation for a typical process and a representative drug product. The calculated extractables concentration per dose will be compared to the Permissible Daily Exposure (PDE) level for individual compounds

Estimated potential water needs for the eastern Grand Prairie region by irrigation scheduling

Prepare maps showing the annual, monthly and peak weekly volume of irrigation water required in each 3 mile by 3 mile cell of the study area for the selected cropping pattern. Maps are presented for average and dry climatological conditions

Optimal regional potentiometric surface design: least cost water supply/sustained groundwater yield

A distributed parameter groundwater management model utilizing quadratic programming to develop an optimal regional steady-state potentiometric surface and its sustained groundwater withdrawal strategy is presented. It minimizes the regional cost of attempting to satisfy the water needs of each finite-difference cell (a) from groundwater and diverted surface water or (b) from groundwater and reduction of water needs achieved by reducing production acreages. Groundwater elevations, withdrawal and recharge are constrained, satisfying legal and hydrologic constraints. The technique is applicable for assuring a regional sustained yield of groundwater in a conjunctive water management setting. It represents the first application of optimization in the target objective approach to regional groundwater management

Interactive modification of quadratic multiobjective water resources planning strategies

An interactive method is presented for modifying a mtltiobjective water resources planning strategy by changing constraining conditions on regional objectives and local variables. The method is illustrated by modifying a conjunctive use. sustained groundwater withdrawal strategy for minimizing the cost of meeting regional water demand on the Arkansas Grand Prairie. The strategy was developed using a model in which the finite difference form of the two-dimensional groundwater flow equation is embedded in an optimization process. The quadratic optimization is accomplished by utilizing the General Differential Algorithm to obtain values of drawdown. pumping. and recharge in each finite difference cell. Results from the formal cpt1mizetion process are submitted to a separate program for interactive evaluation and modification. The interactive algorithm applies the constraint method and constrained derivatives of the objective function to develop the noninferior solution and tradeoff functions. The modification procedure is extended to determining the influence on the regional objectives for repeated changes in several local decision variables

The practical application of BPOG E&L protocols to viral clearance filters

Regulatory guidance advocates virus control at various stages of the drug manufacturing process and directs that you test the capacity of the process to remove or inactivate virus. Patient safety concerns require you to determine what impurities may be added by the virus control steps you implement. While the application of a standardized approach to identifying and quantifying the extractables from these steps has benefits when making comparisons, choices have to be made when developing the protocol that take into account the characteristics of the clearance device and use conditions This presentation will illustrate the practical implementation of standardized extractables method on an industry leading viral clearance technology by explaining the rational for the selection of extraction solvents; extraction conditions and sampling points. Data generated during the study will be presented as well as lessons learned in implementing the new protocol

Mass scaling and non-adiabatic effects in photoassociation spectroscopy of ultracold strontium atoms

We report photoassociation spectroscopy of ultracold $^{86}$Sr atoms near the intercombination line and provide theoretical models to describe the obtained bound state energies. We show that using only the molecular states correlating with the $^1S_0$$+$$^3P_1$ asymptote is insufficient to provide a mass scaled theoretical model that would reproduce the bound state energies for all isotopes investigated to date: $^{84}$Sr, $^{86}$Sr and $^{88}$Sr. We attribute that to the recently discovered avoided crossing between the $^1S_0$$+$$^3P_1$ $0_u^+$ ($^3\Pi_u$) and $^1S_0$$+$$^1D_2$ $0_u^+$ ($^1\Sigma^+_u$) potential curves at short range and we build a mass scaled interaction model that quantitatively reproduces the available $0_u^+$ and $1_u$ bound state energies for the three stable bosonic isotopes. We also provide isotope-specific two-channel models that incorporate the rotational (Coriolis) mixing between the $0_u^+$ and $1_u$ curves which, while not mass scaled, are capable of quantitatively describing the vibrational splittings observed in experiment. We find that the use of state-of-the-art ab initio potential curves significantly improves the quantitative description of the Coriolis mixing between the two -8 GHz bound states in $^{88}$Sr over the previously used model potentials. We show that one of the recently reported energy levels in $^{84}$Sr does not follow the long range bound state series and theorize on the possible causes. Finally, we give the Coriolis mixing angles and linear Zeeman coefficients for all of the photoassociation lines. The long range van der Waals coefficients $C_6(0_u^+)=3868(50)$~a.u. and $C_6(1_u)=4085(50)$~a.u. are reported.Comment: 14 pages, 7 tables, 5 figures. Submitted to Phys. Rev.

Risk-based qualification of X-ray sterilization for single-use systems

The urgent need for life-saving therapies as a result of the global pandemic has reinforced the criticality of flexibility in pharmaceutical manufacturing, including sterilization. The single-use bioprocess industry traditionally has employed gamma irradiation sterilization. X-ray irradiation warrants consideration as an alternate sterilization technology. X-ray irradiation offers better penetration characteristics, improved dose uniformity ratio (DUR), and less environmental impact when compared to other sterilization modalities. We will share a risk based qualification testing strategy including Extractables and data generated to support comparability of gamma irradiation and X-ray irradiation as equivalent ionizing irradiation sterilization modalities

Clinicopathological determinants of an elevated systemic inflammatory response following elective potentially curative resection for colorectal cancer

Introduction: The postoperative systemic inflammatory response (SIR) is related to both long- and short-term outcomes following surgery for colorectal cancer. However, it is not clear which clinicopathological factors are associated with the magnitude of the postoperative SIR. The present study was designed to determine the clinicopathological determinants of the postoperative systemic inflammatory response following colorectal cancer resection. Methods: Patients with a histologically proven diagnosis of colorectal cancer who underwent elective, potentially curative resection during a period from 1999 to 2013 were included in the study (n = 752). Clinicopathological data and the postoperative SIR, as evidenced by postoperative Glasgow Prognostic Score (poGPS), were recorded in a prospectively maintained database. Results: The majority of patients were aged 65 years or older, male, were overweight or obese, and had an open resection. After adjustment for year of operation, a high day 3 poGPS was independently associated with American Society of Anesthesiologists (ASA) grade (hazard ratio [HR] 1.96; confidence interval [CI] 1.25–3.09; p = 0.003), body mass index (BMI) (HR 1.60; CI 1.07–2.38; p = 0.001), mGPS (HR 2.03; CI 1.35–3.03; p = 0.001), and tumour site (HR 2.99; CI 1.56–5.71; p < 0.001). After adjustment for year of operation, a high day 4 poGPS was independently associated with ASA grade (HR 1.65; CI 1.06–2.57; p = 0.028), mGPS (HR 1.81; CI 1.22–2.68; p = 0.003), NLR (HR 0.50; CI 0.26–0.95; p = 0.034), and tumour site (HR 2.90; CI 1.49–5.65; p = 0.002). Conclusions: ASA grade, BMI, mGPS, and tumour site were consistently associated with the magnitude of the postoperative systemic inflammatory response, evidenced by a high poGPS on days 3 and 4, in patients undergoing elective potentially curative resection for colorectal cancer