pH-Dependent solubility and permeability criteria for provisional biopharmaceutics classification (BCS and BDDCS) in early drug discovery.

The Biopharmaceutics Classification System (BCS) is a scientific framework that provides a basis for predicting the oral absorption of drugs. These concepts have been extended in the Biopharmaceutics Drug Disposition Classification System (BDDCS) to explain the potential mechanism of drug clearance and understand the effects of uptake and efflux transporters on absorption, distribution, metabolism, and elimination. The objective of present work is to establish criteria for provisional biopharmaceutics classification using pH-dependent passive permeability and aqueous solubility data generated from high throughput screening methodologies in drug discovery settings. The apparent permeability across monolayers of clonal cell line of Madin-Darby canine kidney cells, selected for low endogenous efflux transporter expression, was measured for a set of 105 drugs, with known BCS and BDDCS class. The permeability at apical pH 6.5 for acidic drugs and at pH 7.4 for nonacidic drugs showed a good correlation with the fraction absorbed in human (Fa). Receiver operating characteristic (ROC) curve analysis was utilized to define the permeability class boundary. At permeability ≥ 5 × 10(-6) cm/s, the accuracy of predicting Fa of ≥ 0.90 was 87%. Also, this cutoff showed more than 80% sensitivity and specificity in predicting the literature permeability classes (BCS), and the metabolism classes (BDDCS). The equilibrium solubility of a subset of 49 drugs was measured in pH 1.2 medium, pH 6.5 phosphate buffer, and in FaSSIF medium (pH 6.5). Although dose was not considered, good concordance of the measured solubility with BCS and BDDCS solubility class was achieved, when solubility at pH 1.2 was used for acidic compounds and FaSSIF solubility was used for basic, neutral, and zwitterionic compounds. Using a cutoff of 200 µg/mL, the data set suggested a 93% sensitivity and 86% specificity in predicting both the BCS and BDDCS solubility classes. In conclusion, this study identified pH-dependent permeability and solubility criteria that can be used to assign provisional biopharmaceutics class at early stage of the drug discovery process. Additionally, such a classification system will enable discovery scientists to assess the potential limiting factors to oral absorption, as well as help predict the drug disposition mechanisms and potential drug-drug interactions.

Challenges of Using Closed System Transfer Devices With Biological Drug Products: An Industry Perspective.

Hazardous drug is a common term used by the National Institute of Occupational Health and Safety (NIOSH) to classify medications that may induce adverse mutagenic and reproductive responses in health care personnel. NIOSH publishes a list of drugs it defines as hazardous where it may be appropriate for health care workers to take protective measures to reduce the potential for occupational exposure. Recent updates and proposed updates to this list have included large molecule biological products with oncology indications. Both NIOSH and USP <800> recommend the use of closed system transfer devices (CSTDs) during compounding. CSTDs are required for administration of prepared solution in NIOSH. However, USP has suggested that the principles of <800> are broadly applicable to hazardous drug handling activities across all facility types. USP encourages the widespread adoption and use of <800> across all health care settings, which many health care workers have interpreted beyond compounding to include administration and preparation of conventionally manufactured sterile products per approved labeling. Although the use of CSTDs may reduce exposure of health care personnel to chemotherapy agents in health care setting, the impact of CSTDs on quality of biologic drug products, including monoclonal antibodies and other proteins, is not fully understood. To complicate this issue further, there are several commercially available CSTDs in the market which have different fluid paths and material of construction that comes in contact with the drug. Testing every combination of CSTD and drug product for potential incompatibilities can be a labor intensive and impractical approach and cause delay in getting essential drugs to patients. A panel discussion was held at a recent American Association of Pharmaceutical Scientists 2018 PharmSci 360 conference to discuss the impact of CSTDs on biologics. Impact on subvisible and visible particulates and impact to other product quality attributes such as high molecular weight species formation upon contact with CSTDs were reported in American Association of Pharmaceutical Scientists meeting. Impact to deliverable dose, holdup volumes of various CSTDs, and stopper coring were also reported that has significant impact to patient safety. Given the fact that USP chapter <800> will be implemented in December 2019, feedback from health authorities regarding the use of CSTDs for biological drug products is needed to provide an appropriate risk/benefit balance to ensure patient safety and quality of the biologic drug product while also protecting the health care worker and the environment. The purpose of this commentary is to provide an industry perspective on the challenges during the use of CSTDs for biologic drug products and is intended to raise caution and awareness on the benefits and shortcomings of these devices.