The Case for Apex Vessels

Apex vessels are an important element of the dissolution scientist’s toolbox and are frequently used in pharmaceutical drug product development settings. However, their use in development has not translated widely into use in the final approved QC method. This article aims to demonstrate the significant benefit of the apex vessel relative to the standard vessel in overcoming coning for formulations which contain dense insoluble excipients. Industrial case studies outline the benefits imparted by the apex vessel such as improved clinical relevance, more robust and discriminatory methods, and streamlined in vitro bridging strategies. Furthermore, to understand the impact of apex vessels produced by different dissolution bath manufacturers, an interlaboratory study was performed across 11 partners which demonstrated minimal differences in dissolution performance between partners when a controlled protocol was executed

White Paper - Biopharmaceutics Modelling as a Fundamental Tool to Support Accelerated Access

Using a combination of advanced bio-relevant in-vitro systems and in-silico Physiologically Based Pharmacokinetic (PBPK) models, in combination with agile and information-rich clinical study designs will enable rapid development and change management of drug products with optimal performance

In vivo release of peptide-loaded PLGA microspheres assessed through deconvolution coupled with mechanistic approach

International audienceIn this study, a reevaluation of the in vivo release phases from long-release PLGA-based microspheres is presented, leading to a better characterization of the plasma concentrations/time profile. Microspheres were designed for intramuscular injection releasing a cyclic somatostatin analog over 70 days. Clinical study was performed in 64 healthy subjects receiving a subcutaneous dose of an immediate release solution as reference formulation and an intramuscular injection of microspheres as test formulation. The in vivo input curve was obtained by numerical deconvolution. Results showed that double Weibull function could not fit correctly the tri-phasic (burst, lag, and erosion) in vivo input profile typical for PLGA-based formulations, due to a change in the drug release trend in the terminal phase. Triple Weibull showed a significant improvement in the curve fitting, each term being assigned to one of the following phases: initial (burst/lag), erosion, and terminal phase of drug release. The existence of the additional terminal phase was confirmed by a mechanistic approach as well, which denoted that this phase was, most probably, a consequence of the release mechanism change from erosion to diffusion controlled. The same model demonstrated that the burst release was as well influenced by the polymer swelling, while currently existing theories state that the burst phase is mainly determined by the dissolution of immediately available drug substance and diffusion through surface related pores

Setting accelerated dissolution test for PLGA microspheres containing peptide, investigation of critical parameters affecting drug release rate and mechanism

The objective of this study was development of accelerated in vitro release method for peptide loaded PLGA microspheres using flow-through apparatus and assessment of the effect of dissolution parameters (pH, temperature, medium composition) on drug release rate and mechanism. Accelerated release conditions were set as pH 2 and 45°C, in phosphate buffer saline (PBS) 0.02M. When the pH was changed from 2 to 4, diffusion controlled phases (burst and lag) were not affected, while release rate during erosion phase decreased two-fold due to slower ester bonds hydrolyses. Decreasing temperature from 45°C to 40°C, release rate showed three-fold deceleration without significant change in release mechanism. Effect of medium composition on drug release was tested in PBS 0.01M (200 mOsm/kg) and PBS 0.01M with glucose (380 mOsm/kg). Buffer concentration significantly affected drug release rate and mechanism due to the change in osmotic pressure, while ionic strength did not have any effect on peptide release. Furthermore, dialysis sac and sample-and-separate techniques were used, in order to evaluate significance of dissolution technique choice on the release process. After fitting obtained data to different mathematical models, flow-through method was confirmed as the most appropriate for accelerated in vitro dissolution testing for a given formulation

Establishing the Bioequivalence Safe Space for Immediate-Release Oral Dosage Forms using Physiologically Based Biopharmaceutics Modeling (PBBM): Case Studies.

For oral drug products, in vitro dissolution is the most used surrogate of in vivo dissolution and absorption. In the context of drug product quality, safe space is defined as the boundaries of in vitro dissolution, and relevant quality attributes, within which drug product variants are expected to be bioequivalent to each other. It would be highly desirable if the safe space could be established via a direct link between available in vitro data and in vivo pharmacokinetics. In response to the challenges with establishing in vitro-in vivo correlations (IVIVC) with traditional modeling approaches, physiologically based biopharmaceutics modeling (PBBM) has been gaining increased attention. In this manuscript we report five case studies on using PBBM to establish a safe space for BCS Class 2 and 4 across different companies, including applications in an industrial setting for both internal decision making or regulatory applications. The case studies provide an opportunity to reflect on practical vs. ideal datasets for safe space development, the methodologies for incorporating dissolution data in the model and the criteria used for model validation and application. PBBM and safe space, still represent an evolving field and more examples are needed to drive development of best practices

Physiologically Based Pharmacokinetic Modeling of Oral Absorption, pH, and Food Effect in Healthy Volunteers to Drive Alpelisib Formulation Selection

A physiologically based pharmacokinetic (PBPK) human model for alpelisib, an oral α-specific class I phosphatidylinositol-3-kinase (PI3K) inhibitor, was established to simulate oral absorption and plasma pharmacokinetics of healthy subjects to allow model-informed drug development. The GastroPlus™ model consisted of an advanced absorption gut model, which was linked to a 2-compartmental model. Systemic clearance and volume of distribution were estimated using population pharmacokinetics (popPK). Various food effect and pH-mediated absorption drug–drug interaction (DDI) scenarios were modeled. In fasted healthy subjects, simulated absorption was lower (ca. 70% for a 300-mg dose) due to pH and bile acid concentration-dependent solubility. Ranitidine showed a significant pH-mediated DDI effect only in the fasted but not fed state. The PBPK model identified that more drug is absorbed in the fed state, and alpelisib intestinal permeability is rate limiting to systemic exposure. Simulations for healthy subject showed a positive food effect with ca. 2-fold increase in plasma Cmax and 1.5-fold increase in AUC0-inf with a meal compared with fasted conditions. The PBPK model was verified using clinical food effect data with pivotal clinical formulation (PCF) and then applied to predict the performance of a commercial formulation (CF) in healthy volunteers. The model successfully predicted the outcome of a clinical bioequivalence study for PCF and CF with included in vitro dissolution data, both fasted and fed state. Estimated predictive errors (based on plasma Cmax, AUC0-t) were equal or below 30%. The alpelisib model for healthy subjects enables future bioequivalence formulation assessments, in fasted, fed, or altered pH conditions. [Figure not available: see fulltext.

Establishing the clinical bioequivalence safe space via physiologically-based population pharmacokinetics absorption modeling. Case study: Fevipiprant/QAW039

Physiologically based pharmacokinetics (PBPK) and absorption modeling has increasingly been implemented for biopharmaceutics applications to define the bioequivalence safe space for drug product quality attributes such as dissolution. For fevipiprant/QAW039, PBPK analyses were performed to assess the impact of in vitro dissolution on the in vivo PK performance of immediate release (IR) film coated tablets during development and scaling-up to commercial scale. A fevipiprant dissolution safe space was established using observed clinical intravenous and oral PK data from bioequivalent and non-bioequivalent formulations. Quality control tablet dissolution profiles were used as GastroPlusTM model inputs to estimate the in vivo dissolution in the GI tract, and to predict human exposure. The model was used to evaluate the intraluminal performance of the dosage forms and to determine the absorption rate limits for the 450 mg dose. The predictive model performance was demonstrated for various oral dosage forms (150‒500 mg), including the non-bioequivalent batches in fasted healthy adults. To define the dissolution safe space boundaries at 450 mg, simulations were performed using theoretical dissolution profiles. A specification of Q=80% dissolved after 60 min for an IR oral solid dosage form reflected the limitations of the safe space. The dissolution profile of the 450 mg commercial-scale batch was within a dissolution region where bioequivalence is anticipated, not near an edge of failure for dissolution, providing additional confidence to the proposed acceptance criteria. Thus, the PBPK dissolution safe space allowed for a wider than 10% dissolution difference for bioequivalent batches, superseding f2 similarity analyses

Dissolution Method Troubleshooting: An Industry Perspective

Quality control dissolution testing represents a key product performance test for solid oral dosage forms and is the most likely QC test to result in laboratory investigations because of the relatively complex relationship between the dissolution performance, the drug product properties, and the systems necessary to measure the quality attribute. The Dissolution Working Group of the International Consortium for Innovation and Quality in Pharmaceutical Development (IQ) has pooled our collective knowledge to outline some common ways that dissolution methods can fail. Examples and case studies have been highlighted focusing on errors of equipment, method, materials, measurement, people, and the environment, while providing best practices for building method understanding and avoiding the exemplified issues. The case studies have highlighted the importance of buffer preparation, potential impact of contamination of the dissolution medium, additive-induced degradation, risks in the use of automation, differences between dissolution systems, and the effect of filter selection. By applying the learnings in this article and investing in analyst training programs, understanding the capabilities of your equipment portfolio, and well-designed robustness and ruggedness studies will reduce dissolution method investigations and improve compliance and productivity during the method lifecycle