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This workshop report summarizes the proceedings of Day 2 of a three-day workshop on “Current State and Future Expectations of Translational Modeling Strategies to Support Drug Product Development, Manufacturing Changes and Controls”. From a drug product quality perspective, physiologically based biopharmaceutics modeling (PBBM) is a tool to link variations in the drug product quality attributes to in vivo outcomes enabling the establishment of clinically relevant drug product specifications (CRDPS). Day 2 of the workshop focused on best practices in developing, verifying and validating PBBM. This manuscript gives an overview of podium presentations and summarizes breakout (BO) session discussions related to (1) challenges and opportunities for using PBBM to assess the clinical impact of formulation and manufacturing changes on the in vivo performance of a drug product, (2) best practices to account for parameter uncertainty and variability during model development, (3) best practices in the development, verification and validation of PBBM and (4) opportunities and knowledge gaps related to leveraging PBBM for virtual bioequivalence simulations.

Elucidating the impact of excipient variability on oral product performance in a biopharmaceutical perspective would be beneficial and allow excipient implementation on Quality by Design (QbD) approaches. The current study investigated the impact of varying viscosity of binders (hypromellose (HPMC)) and superdisintegrants (sodium starch glycolate (SSG)) and particle size distribution of lubricants (magnesium stearate (MgSt)) on the in vitro dissolution of a highly and a poorly soluble drug from immediate release formulations. Compendial (pharmacopoeia buffers) and biorelevant (media simulating the gastrointestinal fluids) media and the USP 2 and USP 4 apparatuses were used to assess the exerted excipient effects on drug dissolution. Real-time dissolution UV imaging provided mechanistic insights into disintegration and dissolution of the immediate release formulations. Varying the viscosity type of HPMC or SSG did not significantly affect drug dissolution irrespective of the compound used. Faster drug dissolution was observed when decreasing the particle size of MgSt for the highly soluble drug. The use of real-time dissolution UV Imaging revealed the influential role of excipient variability on tablet disintegration, as for the highly soluble drug, tablets containing high viscosity HPMC or low particle size MgSt disintegrated faster as compared to the control tablets while for the poorly soluble drug, slower tablet disintegration was observed when increasing the viscosity of the HPMC as compared to the control tablets. Changes in drug dissolution when varying excipients may be anticipated if the excipient change has previously affected drug solubility. The use of multivariate data analysis revealed the influential biopharmaceutical factors such as critical excipient types/properties, drug aqueous solubility, medium/hydrodynamic characteristics affecting the impact of excipient variability on in vitro drug dissolution.

Food and drinks are commonly used to facilitate administration of paediatric medicines to improve palatability and enhance patient compliance. However, the impact of this practice on drug solubility and on oral drug bioavailability is not usually studied. Based on recommended strategies for oral administration of paediatric medicines with food and drink vehicles, the aims of this study were (i) to measure the physicochemical properties of (soft) food and drink vehicles, commonly mixed with paediatric medicines prior to administration, and (ii) to assess the impact of the co-administered vehicles on the solubility of two poorly soluble paediatric drugs. Montelukast (sodium) and mesalazine were selected as the model compounds. Distinct differences were observed between the physicochemical properties (i.e. pH, surface tension, osmolality, viscosity and buffer capacity) and macronutrient composition (i.e. fat, sugar and protein content) of the different soft foods and drinks, not only among vehicle type but also within vehicles of the same subtype. Solubility studies of the two model compounds in selected drinks and soft foods resulted in considerably different drug solubility values in each vehicle. The solubility of the drugs was significantly affected by the vehicle physicochemical properties and macronutrient composition, with the solubility of montelukast being driven by the pH, fat and protein content of the vehicles and the solubility of mesalazine by vehicle osmolality, viscosity and sugar content. This vehicle-dependent impact on drug solubility could compromise its bioavailability, and ultimately affect the safety and/or efficacy of the drug and should be taken into consideration during paediatric product development.

Identification of the biopharmaceutical risks of excipients and excipient variability on oral drug performance can be beneficial for the development of robust oral drug formulations. The current study investigated the impact of Hypromellose (HPMC) presence and varying viscosity type, when used as a binder in immediate release formulations, on the apparent solubility of drugs with wide range of physicochemical properties (drug ionization, drug lipophilicity, drug aqueous solubility). The role of physiological conditions on the impact of excipients on drug apparent solubility was assessed with the use of pharmacopoeia (compendial) and biorelevant media. Presence of HPMC affected drug solubility according to the physicochemical properties of studied compounds. The possible combined effects of polymer adsorption (drug shielding effect) or the formation of a polymeric viscous layer around drug particles may have retarded drug dissolution leading to reduced apparent solubility of highly soluble and/or highly ionized compounds and were pronounced mainly at early time points. Increase in the apparent solubility of poorly soluble low ionized drugs containing a neutral amine group was observed which may relate to enhanced drug solubilization or reduced drug precipitation. The use of multivariate data analysis confirmed the importance of drug physicochemical properties on the impact of excipients on drug apparent solubility and revealed that changes in HPMC material properties or amount may not be critical for oral drug performance when HPMC is used as a binder. The construction of a roadmap combining drug, excipient, and medium characteristics allowed the identification of the cases where HPMC presence may present risks in oral drug performance and bioavailability. Electronic supplementary material The online version of this article (10.1208/s12248-019-0411-1) contains supplementary material, which is available to authorized users.

The release and absorption profile of an oral medication is influenced by the physicochemical properties of the drug and its formulation, as well as by the anatomy and physiology of the gastrointestinal (GI) tract. During drug development the bioavailability of a new drug is typically assessed in early clinical studies in a healthy adult population. However, many disease conditions are associated with an alteration of the anatomy and/or physiology of the GI tract. The same holds true for some subpopulations, such as paediatric or elderly patients, or populations with different ethnicity. The variation in GI tract conditions compared to healthy adults can directly affect the kinetics of drug absorption, and thus, safety and efficacy of an oral medication. This review provides an overview of GI tract properties in special populations compared to healthy adults and discusses how drug absorption is affected by these conditions. Particular focus is directed towards non-disease dependent conditions (age, sex, ethnicity, genetic factors, obesity, pregnancy), GI diseases (ulcerative colitis and Crohn's disease, celiac disease, cancer in the GI tract, Roux-en-Y gastric bypass, lactose intolerance, Helicobacter pylori infection, and infectious diseases of the GI tract), as well as systemic diseases that change the GI tract conditions (cystic fibrosis, diabetes, Parkinson's disease, HIV enteropathy, and critical illness). The current knowledge about GI conditions in special populations and their impact on drug absorption is still limited. Further research is required to improve confidence in pharmacokinetic predictions and dosing recommendations in the targeted patient population, and thus to ensure safe and effective drug therapies. ispartof: EUROPEAN JOURNAL OF PHARMACEUTICAL SCIENCES vol:147 ispartof: location:Netherlands status: published

The aim of Biopharmaceutics Risk Assessment Roadmap (BioRAM) and the BioRAM Scoring Grid is to facilitate optimization of clinical performance of drug products. BioRAM strategy relies on therapy-driven drug delivery and follows an integrated systems approach for formulating and addressing critical questions and decision-making (J Pharm Sci. 2014,103(11): 3777-97). In BioRAM, risk is defined as not achieving the intended in vivo drug product performance, and success is assessed by time to decision-making and action. Emphasis on time to decision-making and time to action highlights the value of well-formulated critical questions and well-designed and conducted integrated studies. This commentary describes and illustrates application of the BioRAM Scoring Grid, a companion to the BioRAM strategy, which guides implementation of such an integrated strategy encompassing 12 critical areas and 6 assessment stages. Application of the BioRAM Scoring Grid is illustrated using published literature. Organizational considerations for implementing BioRAM strategy, including the interactions, function, and skillsets of the BioRAM group members, are also reviewed. As a creative and innovative systems approach, we believe that BioRAM is going to have a broad-reaching impact, influencing drug development and leading to unique collaborations influencing how we learn, and leverage and share knowledge.

The aim of this research survey was to understand current global thinking around the need for and development of a paediatric biopharmaceutics classification system (pBCS) to be used for the development of paediatric medicines and regulatory purposes (e.g. Biowaivers). A literature review highlighted the paucity of data in this area and therefore a survey was developed to better understand this topic to identify areas of common thinking and highlight future research needs. Global experts in paediatric biopharmaceutics were identified from existing networks and public forums. An online survey was developed and circulated broadly to maximise participation. Sixty individuals (including academics, health care professionals, pharmaceutical industry scientists and regulators) completed the survey, bringing together their views on the need for a pBCS. The results highlighted that the area of greatest concern was the definition of BCS II and IV drugs within this population and additional research is required to generate evidence to underpin this issue. In questions relating to permeability and dissolution consensus was generally reached within the expert population suggesting that little additional research is required to define suitable criteria. More than 90% of those experts who participated agreed that a pBCS would be useful for paediatric populations with a greater need identified for the younger populations (newborn and infants compared to adolescents). The results presented will facilitate further discussion and research into the evidence to underpin a relevant pBCS. These results highlight the need for additional evidence and guidance in this area.