Andreas Abend

Development and validation of an automated extraction method (accelerated solvent extraction®) and a reverse-phase HPLC analysis method for assay of ivermectin in a meat-based chewable formulation

A new method for monitoring ivermectin content in HEARTGARD CHEWABLES has been developed and validated. The method consists of the automated extraction of ivermectin from the meat-based formulation under conditions of elevated temperature and pressure (accelerated solvent extraction, ASE, and determination of the active by reverse-phase high performance liquid chromatography (HPLC). The method resolves both active species of ivermectin (components H(2)B(1a) and H(2)B(1b)) from the formulation matrix.

Recent Trends in Product Development and Regulatory Issues on Impurities in Active Pharmaceutical Ingredient (API) and Drug Products. Part 1: Predicting Degradation Related Impurities and Impurity Considerations for Pharmaceutical Dosage Forms

The American Association for Pharmaceutical Scientists (AAPS) Workshop on Predicting and Monitoring Impurities in API and Drug Products: Product Development and Regulatory Issues was held on October 13–14, 2012 at the McCormick Place in Chicago, IL, USA. The goal of the workshop was to discuss control strategies of chemical and physical changes of active pharmaceutical ingredients (API) and drug products in the drug development process. These changes can affect both the safety and efficacy of drugs; therefore, the ability to rapidly predict and assess the potential for drug product performance changes for impurity formation and the associated safety concerns are important parts of speeding the development of innovative drug therapies. The workshop consisted of four different sessions. Each session focused on separate fundamental issues to build a comprehensive understanding of the physical and chemical processes that impact drug degradation, the control of impurities and the impact of these factors on safety and regulatory areas. Taken together, this comprehensive understanding is used to achieve a more robust development process that enables predictability with a concomitant assurance of safety and efficacy. Innovative methodologies for development of effective stability control strategies were also presented. This article summarizes Sessions 1 and 2 of the American Association for Pharmaceutical Scientists (AAPS) Workshop on Predicting and Monitoring Impurities in API and Drug Products: Product Development and Regulatory Issues and addresses of predicting degradation related impurities and impurity considerations for pharmaceutical dosage forms. Sessions 3 and 4 of the American Association for Pharmaceutical Scientists (AAPS) Workshop on Predicting and Monitoring Impurities in API and Drug Products: Product Development and Regulatory Issues are summarized in Recent Trends in Product Development and Regulatory Issues on Impurities in Active Pharmaceutical Ingredient (API) and Drug Products Part 2: Safety Considerations of Impurities in Pharmaceutical Products and Surveying the Impurity Landscape published separately.

Approaches for Establishing Clinically Relevant Dissolution Specifications for Immediate Release Solid Oral Dosage Forms

This manuscript represents the perspective of the Dissolution Analytical Working Group of the IQ Consortium. The intent of this manuscript is to highlight the challenges of, and to provide a recommendation on, the development of clinically relevant dissolution specifications (CRS) for immediate release (IR) solid oral dosage forms. A roadmap toward the development of CRS for IR products containing active ingredients with a non-narrow therapeutic window is discussed, within the context of mechanistic dissolution understanding, supported by in-human pharmacokinetic (PK) data. Two case studies present potential outcomes of following the CRS roadmap and setting dissolution specifications. These cases reveal some benefits and challenges of pursuing CRS with additional PK data, in light of current regulatory positions, including that of the US Food and Drug Administration (FDA), who generally favor this approach, but with the understanding that both industry and regulatory agency perspectives are still evolving in this relatively new field. The CRS roadmap discussed in this manuscript also describes a way to develop clinically relevant dissolution specifications based primarily on dissolution data for batches used in pivotal clinical studies, acknowledging that not all IR product development efforts need to be supported by additional PK studies, albeit with the associated risk of potentially unnecessarily tight manufacturing controls. Recommendations are provided on what stages during the life cycle investment into in vivo studies may be valuable. Finally, the opportunities for CRS within the context of post-approval changes, Modeling and Simulation (M&S), and the application of biowaivers, are briefly discussed.

Industry's View on Using Quality Control, Biorelevant, and Clinically Relevant Dissolution Tests for Pharmaceutical Development, Registration, and Commercialization

This article intends to summarize the current views of the IQ Consortium Dissolution Working Group, which comprises various industry companies, on the roles of dissolution testing throughout pharmaceutical product development, registration, commercialization, and beyond. Over the past 3 decades, dissolution testing has evolved from a routine and straightforward test as a component of end-product release into a comprehensive set of tools that the developer can deploy at various stages of the product life cycle. The definitions of commonly used dissolution approaches, how they relate to one another and how they may be applied in modern drug development, and life cycle management is described in this article. Specifically, this article discusses the purpose, advantages, and limitations of quality control, biorelevant, and clinically relevant dissolution methods.

Applications of Clinically Relevant Dissolution Testing: Workshop Summary Report

This publication summarizes the proceedings of day 3 of a 3-day workshop on “Dissolution and Translational Modeling Strategies Enabling Patient-Centric Product Development.” Specifically, this publication discusses the current approaches in building clinical relevance into drug product development for solid oral dosage forms, along with challenges that both industry and regulatory agencies are facing in setting clinically relevant drug product specifications (CRDPS) as presented at the workshop. The concept of clinical relevance is a multidisciplinary effort which implies an understanding of the relationship between the critical quality attributes (CQAs) and their impact on predetermined clinical outcomes. Developing this level of understanding, in many cases, requires introducing deliberate but meaningful variations into the critical material attributes (CMAs) and critical process parameters (CPPs) to establish a relationship between the resulting in vitro dissolution/release profiles and in vivo PK performance, a surrogate for clinical outcomes. Alternatively, with the intention of improving the efficiency of the drug product development process by limiting the burden of conducting in vivo studies, this understanding can be either built, or at least enhanced, through in silico efforts, such as IVIVC and physiologically based pharmacokinetic (PBPK) absorption modeling and simulation (M&S). These approaches enable dissolution testing to establish safe boundaries and reject drug product batches falling outside of the established safe range (e.g., due to inadequate in vivo performance) enabling the method to become clinically relevant. Ultimately, these efforts contribute towards patient-centric drug product development and allow regulatory flexibility throughout the lifecycle of the drug product.

Dissolution and Translational Modeling Strategies Enabling Patient-Centric Drug Product Development: the M-CERSI Workshop Summary Report

On May 15th–17th, 2017, the US FDA and the International Consortium for Innovation and Quality in Pharmaceutical Development (IQ) held a workshop at the University of Maryland’s Center of Excellence in Regulatory Science and Innovation (M-CERSI), to discuss the role of dissolution testing and translational modeling and simulation in enabling patient-centric solid oral drug product development. This 3-day event was attended by scientists from regulatory agencies, pharmaceutical companies, and academia. The workshop included podium presentations followed by breakout session discussions. The first day of the meeting focused on the challenges in dissolution method development and the role of dissolution testing throughout drug product development. On the second day, approaches to establish a link between in vitro testing and in vivo drug product performance (e.g., systemic exposure) were presented. Overall success rates and challenges in establishing IVIVCs via traditional and modern physiologically based pharmacokinetic (PBPK) modeling and simulation approaches were discussed. Day 3 provided an opportunity to discuss the expectations for establishing clinically relevant drug product specifications (CRDPS). It was recognized that understanding the impact of formulation and process variations on dissolution and in vivo performance is critical for most drug products formulated with poorly soluble drugs to ensure consistent product performance. The breakout sessions served as platforms for discussing controversial topics such as the clarification of dissolution terminology, PBPK model development and validation expectations, and approaches to set CRDPS. The meeting concluded with a commitment to continue the dialog between regulators, industry, and academia to advance overall product quality understanding.