Effect of Antioxidants in Medicinal Products on Intestinal Drug Transporters.

The presence of mutagenic and carcinogenic N-nitrosamine impurities in medicinal products poses a safety risk. While incorporating antioxidants in formulations is a potential mitigation strategy, concerns arise regarding their interference with drug absorption by inhibiting intestinal drug transporters. Our study screened thirty antioxidants for inhibitory effects on key intestinal transporters-OATP2B1, P-gp, and BCRP in HEK-293 cells (OATP2B1) or membrane vesicles (P-gp, BCRP) using 3H-estrone sulfate, 3H-N-methyl quinidine, and 3H-CCK8 as substrates, respectively. The screen identified that butylated hydroxyanisole (BHA) and carnosic acid inhibited all three transporters (OATP2B1, P-gp, and BCRP), while ascorbyl palmitate (AP) inhibited OATP2B1 by more than 50%. BHA had IC50 values of 71 ± 20 µM, 206 ± 14 µM, and 182 ± 49 µM for OATP2B1, BCRP, and P-gp, respectively. AP exhibited IC50 values of 23 ± 10 µM for OATP2B1. The potency of AP and BHA was tested with valsartan, an OATP2B1 substrate, and revealed IC50 values of 26 ± 17 µM and 19 ± 11 µM, respectively, in HEK-293-OATP2B1 cells. Comparing IC50 values of AP and BHA with estimated intestinal concentrations suggests an unlikely inhibition of intestinal transporters at clinical concentrations of drugs formulated with antioxidants.

Innovation for Generic Drugs: Science and Research Under the Generic Drug User Fee Amendments of 2012.

Regulatory science is science and research intended to improve decision making in a regulatory framework. Improvements in decision making can be in both accuracy (making better decisions) and in efficiency (making faster decisions). Science and research supported by the Generic Drug User Fee Amendments of 2012 (GDUFA) have focused on two innovative methodologies that work together to enable new approaches to development and review of generic drugs: quantitative models and advanced in vitro product characterization. Quantitative models faithfully represent current scientific understanding. They are tools pharmaceutical scientists and clinical pharmacologists use for making better and faster product development decisions. Advances in the in vitro product comparisons provide the measurements of product differences that are the critical input into the models. This paper outlines four areas where science and research funded by GDUFA support synergistic use of models and characterization at critical decision points during generic drug product development and review.

Impact of Vehicle Physicochemical Properties on Modeling-Based Predictions of Cyclosporine Ophthalmic Emulsion Bioavailability and Tear Film Breakup Time.

Several physicochemical parameters are thought to affect in vivo performance of cyclosporine ophthalmic emulsion, including globule size distribution, viscosity profile as a function of applied shear, pH, zeta potential, osmolality, and surface tension. Using a modeling approach, this study predicts cyclosporine ophthalmic emulsion drug bioavailability to the cornea and conjunctiva and tear film breakup time for human subjects as a function of the vehicle physicochemical properties viscosity, surface tension, and osmolality for products that are qualitatively (Q1) and quantitatively (Q2) the same. The change in tear film breakup time from baseline, a potential indirect measure of therapeutic benefit, was predicted to characterize the direct effect of the vehicle on efficacy. Bioavailability predictions showed that while individual predictions were sensitive to variations in corneal and conjunctival permeabilities, geometric mean ratios of the test-to-reference comparisons for formulations that are Q1 and Q2 the same showed little sensitivity. Parameter sensitivity analysis showed that bioavailability and change in tear film breakup time from baseline values were both very sensitive to viscosity, slightly sensitive to surface tension, and insensitive to osmolality. With further improvements, the modeling framework developed for this study may be useful for informing future recommendations of cyclosporine ophthalmic emulsion bioequivalence for potential generic drug products.

Clinical, Pharmacokinetic, and In Vitro Studies to Support Bioequivalence of Ophthalmic Drug Products.

For ophthalmic drug products, the determination of bioequivalence can be challenging, as drug concentrations at the site of action cannot always be measured. The FDA has recommended a variety of studies that can be used to demonstrate bioequivalence for different ophthalmic drug products. Product-specific bioequivalence recommendations for 28 ophthalmic products have been posted on FDA's website as of May 2016, outlining the specific tests which should be performed to demonstrate bioequivalence. The type of study that can be used to demonstrate bioequivalence depends on the drug product's active pharmaceutical ingredient(s), dosage form, indication, site of action, mechanism of action, and scientific understanding of drug release/drug availability and drug product characteristics. This article outlines the FDA's current guidance on studies to demonstrate bioequivalence through clinical endpoint studies, pharmacokinetic studies, and in vitro studies for generic ophthalmic drug products.

International Guidelines for Bioequivalence of Locally Acting Orally Inhaled Drug Products: Similarities and Differences.

International regulatory agencies have developed recommendations and guidances for bioequivalence approaches of orally inhaled drug products (OIDPs) for local action. The objective of this article is to discuss the similarities and differences among these approaches used by international regulatory authorities when applications of generic and/or subsequent entry locally acting OIDPs are evaluated. We focused on four jurisdictions that currently have published related guidances for generic and/or subsequent entry OIDPs. They are Therapeutic Goods Administration (TGA) in Australia, Health Canada (HC) in Canada, European Medicines Association (EMA) of European Union (EU), and the Food and Drug Administration (FDA) in the United States of America (USA). The comparisons of these bioequivalence (BE) recommendations are based on selection of reference products, formulation and inhaler device comparisons, and in vitro tests and in vivo studies, including pharmacokinetic (PK), pharmacodynamics (PD), and clinical studies. For the in vivo studies, the study design, choices of dose, subject inclusion/ exclusion criteria, study period, study endpoint, and equivalence criteria are elaborated in details. The bioequivalence on multiple-strength products and waiver options are also discussed.

Completeness assessment of type II active pharmaceutical ingredient drug master files under generic drug user fee amendment: review metrics and common incomplete items.

Under the Generic Drug User Fee Amendments (GDUFA) of 2012, Type II active pharmaceutical ingredient (API) drug master files (DMFs) must pay a user fee and pass a Completeness Assessment (CA) before they can be referenced in an Abbreviated New Drug Application (ANDA), ANDA amendment, or ANDA prior approval supplement (PAS). During the first year of GDUFA implementation, from October 1, 2012 to September 30, 2013, approximately 1,500 Type II API DMFs received at least one cycle of CA review and more than 1,100 Type II DMFs were deemed complete and published on FDA's "Available for Reference List". The data from CA reviews were analyzed for factors that influenced the CA review process and metrics, as well as the areas of DMF submissions which most frequently led to an incomplete CA status. The metrics analysis revealed that electronic DMFs appear to improve the completeness of submission and shorten both the review and response times. Utilizing the CA checklist to compile and proactively update the DMFs improves the chance for the DMFs to pass the CA in the first cycle. However, given that the majority of DMFs require at least two cycles of CA before being deemed complete, it is recommended that DMF fees are paid 6 months in advance of the ANDA submissions in order to avoid negatively impacting the filling status of the ANDAs.

Innovative approaches for demonstration of bioequivalence: the US FDA perspective.

In this article, the authors will briefly introduce the general concepts and background of bioavailability and bioequivalence (BE), discuss the conventional method for BE demonstration, and present case examples where novel approaches have been adopted by the US FDA for BE demonstration. Here, 'novel approaches' include unconventional BE studies, as well as statistical criteria for comparison. More specifically, biowaivers, methods to demonstrate BE for highly variable drugs and drug products, and narrow therapeutic index drugs, partial AUCs as additional metrics for some modified-release drug products, methods to demonstrate BE for locally acting gastrointestinal, dermatological, nasal and inhalation products, and non-biological complex drug products, and future perspectives in the field of BE assessment will be discussed. Methods adopted by other agencies, such as European Medicines Agency and Health Canada will be compared with the FDA approaches when appropriate.

Implementation of a reference-scaled average bioequivalence approach for highly variable generic drug products by the US Food and Drug Administration.

Highly variable (HV) drugs are defined as those for which within-subject variability (%CV) in bioequivalence (BE) measures is 30% or greater. Because of this high variability, studies designed to show whether generic HV drugs are bioequivalent to their corresponding HV reference drugs may need to enroll large numbers of subjects even when the products have no significant mean differences. To avoid unnecessary human testing, the US Food and Drug Administration's Office of Generic Drugs developed a reference-scaled average bioequivalence (RSABE) approach, whereby the BE acceptance limits are scaled to the variability of the reference product. For an acceptable RSABE study, an HV generic drug product must meet the scaled BE limit and a point estimate constraint. The approach has been implemented successfully. To date, the RSABE approach has supported four full approvals and one tentative approval of HV generic drug products.

Effects of device and formulation on in vitro performance of dry powder inhalers.

The study examined the sensitivity of DPI in vitro performance to formulation and device changes. Rotahaler/Rotacaps was selected as the reference DPI drug product, and Aerolizer was selected as the test device. Since the test device was recognized to have much greater efficiency of dispersion, simple modifications to both formulation and device were made in an effort to provide a closer match to the in vitro performance of the reference product. The modifications included varying the drug and lactose particle sizes and/or lactose fine particle content in the test formulations, as well as lowering the specific resistance of the test device. These modifications were intended to address variables important for drug product performance for a defined experimental design and were not intended to mimic the extensive formulation and device design strategies that are employed in an industrial setting. Formulation and device modifications resulted in a modified test product that approached the reference product in the in vitro performance.

Use of partial AUC to demonstrate bioequivalence of Zolpidem Tartrate Extended Release formulations.

PURPOSE: FDA's bioequivalence recommendation for Zolpidem Tartrate Extended Release Tablets is the first to use partial AUC (pAUC) metrics for determining bioequivalence of modified-release dosage forms. Modeling and simulation studies were performed to aid in understanding the need for pAUC measures and also the proper pAUC truncation times. METHODS: Deconvolution techniques, In Vitro/In Vivo Correlations, and the CAT (Compartmental Absorption and Transit) model were used to predict the PK profiles for zolpidem. Models were validated using in-house data submitted to the FDA. Using dissolution profiles expressed by the Weibull model as input for the CAT model, dissolution spaces were derived for simulated test formulations. RESULTS: The AUC(0-1.5) parameter was indicative of IR characteristics of early exposure and effectively distinguished among formulations that produced different pharmacodynamic effects. The AUC(1.5-t) parameter ensured equivalence with respect to the sustained release phase of Ambien CR. The variability of AUC(0-1.5) is higher than other PK parameters, but is reasonable for use in an equivalence test. CONCLUSIONS: In addition to the traditional PK parameters of AUCinf and Cmax, AUC(0-1.5) and AUC(1.5-t) are recommended to provide bioequivalence measures with respect to label indications for Ambien CR: onset of sleep and sleep maintenance.

The role of predictive biopharmaceutical modeling and simulation in drug development and regulatory evaluation.

Advances in predicting in vivo performance of drug products has the potential to change how drug products are developed and reviewed. Modeling and simulation methods are now more commonly used in drug product development and regulatory drug review. These applications include, but are not limited to: the development of biorelevant specifications, the determination of bioequivalence metrics for modified release products with rapid therapeutic onset, the design of in vitro-in vivo correlations in a mechanistic framework, and prediction of food effect. As new regulatory concepts such as quality by design require better application of biopharmaceutical modeling in drug product development, regulatory challenges in bioequivalence demonstration of complex drug products also present exciting opportunities for creative modeling and simulation approaches. A collaborative effort among academia, government and industry in modeling and simulation will result in improved safe and effective new/generic drugs to the American public.

Utility of physiologically based absorption modeling in implementing Quality by Design in drug development.

To implement Quality by Design (QbD) in drug development, scientists need tools that link drug products properties to in vivo performance. Physiologically based absorption models are potentially useful tools; yet, their utility of QbD implementation has not been discussed or explored much in the literature. We simulated pharmacokinetics (PK) of carbamazepine (CBZ) after administration of four oral formulations, immediate-release (IR) suspension, IR tablet, extended-release (XR) tablet and capsule, under fasted and fed conditions and presented a general diagram of a modeling and simulation strategy integrated with pharmaceutical development. We obtained PK parameters and absorption scale factors (ASFs) by deconvolution of the PK data for IR suspension under fasted condition. The model was validated for other PK profiles of IR formulations and used to predict PK for XR formulations. We explored three key areas where a modeling and simulation approach impacts QbD. First, the model was used to help identify optimal in vitro dissolution conditions for XR formulations. Second, identification of critical formulations variables was illustrated by a parameter sensitivity analysis of mean particle radius for the IR tablet that showed a PK shift with decreased particle radius, C (max) was increased and T (max) was decreased. Finally, virtual trial simulations allowed incorporation of inter-subject variability in the model. Virtual bioequivalence studies performed for two test formulations suggested that an in vitro dissolution test may be a more sensitive discriminative method than in vivo PK studies. In summary, a well-validated predictive model is a potentially useful tool for QbD implementation in drug development.

Analysis of bead sizes for MR capsules labeled for sprinkle.

The bead sizes used in approved modified release capsules labeled for sprinkling on food was investigated to generate bead size guidelines for generic products labeled for sprinkling. The conclusions from a survey of FDA databases were corroborated with experimental data obtained by measuring the bead sizes of several reference-listed drugs on the market labeled for administration by sprinkling on food. The experimental data show that majority of the marketed products were found to have bead sizes of less than 1,500 microm (1.5 mm). Based on this information, a bead size of less than 1,500 microm should generally be considered acceptable for use in generic products labeled for sprinkling.

FDA critical path initiatives: opportunities for generic drug development.

FDA's critical path initiative documents have focused on the challenges involved in the development of new drugs. Some of the focus areas identified apply equally to the production of generic drugs. However, there are scientific challenges unique to the development of generic drugs as well. In May 2007, FDA released a document "Critical Path Opportunities for Generic Drugs" that identified some of the specific challenges in the development of generic drugs. The key steps in generic product development are usually characterization of the reference product, design of a pharmaceutically equivalent and bioequivalent product, design of a consistent manufacturing process and conduct of the pivotal bioequivalence study. There are several areas of opportunity where scientific progress could accelerate the development and approval of generic products and expand the range of products for which generic versions are available, while maintaining high standards for quality, safety, and efficacy. These areas include the use of quality by design to develop bioequivalent products, more efficient bioequivalence methods for systemically acting drugs (expansion of BCS waivers, highly variable drugs), and development of new bioequivalence methods for locally acting drugs.

Quality by design: concepts for ANDAs.

Quality by design is an essential part of the modern approach to pharmaceutical quality. There is much confusion among pharmaceutical scientists in generic drug industry about the appropriate element and terminology of quality by design. This paper discusses quality by design for generic drugs and presents a summary of the key terminology. The elements of quality by design are examined and a consistent nomenclature for quality by design, critical quality attribute, critical process parameter, critical material attribute, and control strategy is proposed. Agreement on these key concepts will allow discussion of the application of these concepts to abbreviated new drug applications to progress.

Applications of process analytical technology to crystallization processes.

Crystallizations of pharmaceutical active ingredients, particularly those that posses multiple polymorphic forms, are among the most critical and least understood pharmaceutical manufacturing processes. Many process and product failures can be traced to a poor understanding and control of crystallization processes. The Food and Drug Administration's process analytical technology (PAT) initiative is a collaborative effort with industry to introduce new and efficient manufacturing technologies into the pharmaceutical industry. PAT's are systems for design, analysis, and control of manufacturing processes. They aim to assure high quality through timely measurements of critical quality and performance attributes of raw materials, in-process materials, and final products. Implementation of PAT involves scientifically based process design and optimization, appropriate sensor technologies, statistical and information tools (chemometrics), and feedback process control strategies working together to produce quality products. This review introduces the concept of PAT and discusses its application to crystallization processes through review of several case studies. A variety of in situ analytical methods combined with chemometric tools for analysis of multivariate process information provide a basis for future improvements in modeling, simulation, and control of crystallization processes.

Impact of P-glycoprotein-mediated intestinal efflux kinetics on oral bioavailability of P-glycoprotein substrates.

Studies of many P-glycoprotein (Pgp) substrates have demonstrated a significant effect of Pgp-mediated efflux on intestinal drug transport. However, most of these studies were designed to detect whether a particular drug is a Pgp substrate and thus were conducted at very low concentrations. We performed two simulations to evaluate the effect of Pgp-mediated efflux on oral drug absorption at various concentrations. In the first simulation, a steady-state model allowed us to predict whether the contribution of Pgp to oral drug absorption would be significant at clinically relevant concentrations. Our second simulation investigated the role of Pgp-mediated efflux in oral absorption with a dynamic compartmental absorption and transit model linked to a pharmacokinetic model. For high-solubility drugs, Pgp-mediated efflux altered the bioavailability only at drug concentrations corresponding to doses much lower than the usual clinical dose. The ratio of transporter-mediated transport to passive transport determined whether intestinal Pgp transporters would reduce the bioavailability of high-solubility drugs.

Viscosity of bimodal and polydisperse colloidal suspensions.

We present a theoretical framework for the viscosity of bimodal and polydisperse colloidal suspensions. For colloidal dispersions both interparticle forces between pairs of particles and many-particle effects such as depletion forces can have a significant effect on rheology. As hydrodynamic interactions are also important for colloidal systems, a theoretical description that includes hydrodynamic and thermodynamic interactions is required. An integral equation theory for multicomponent systems accounts for the contribution of thermodynamic interactions to the viscosity of dispersions. Introduction of small particles into a system of larger particles causes depletion forces between the large particles that increase the viscosity, while replacing large particles with an equal volume fraction of small particles increases the free volume in the system and decreases the viscosity. The integral equations model both of these effects in concentrated suspensions and provide a microscopic interpretation of free volume changes as changes in radial distribution functions. For a bimodal mixture they predict a dependence of the viscosity on size ratio, composition, and total volume fraction. Polydispersity is modeled by a small number of components whose sizes and weights are chosen to match the moments of the size distribution. This theory predicts a reduction in viscosity due to polydispersity and explains conflicting experimental measurement of the viscosity of hard-sphere colloids. Existing theoretical approaches that neglect the multiparticle correlations, included through the integral equations, yield qualitatively incorrect results for the change in the viscosity relative to monodisperse systems.