Formulation Development Course - Fundamentals of Formulation Development for Small Molecules, March 3, 2011
Speaker Roster and Topics
Introduction to drug-like properties and selection of drug-like leads during lead selection and lead optimization
Michael Hageman, Ph.D., Group Director, Discovery Pharmaceutics, Bristol-Myers Squibb
BCS and the influence of the BCS classification on formulation development
Alice Loper, Ph.D., Head, Preclinical Development, Alternative Development Program, GlaxoSmithKline
Solid-state properties and formulation strategies
Örn Almarsson, Ph.D., Vice President, Pharmaceutical Research and Development, Alkermes
Early DMPK and bioanalytical method development
Mark Rose, Ph.D., Scientific Director, DMPK, Amgen
Lipid-based formulations and absorption mechanisms
Vincent Jannin, Pharm.D., Ph.D., Hab., Pharmaceutical Research and Development Project Director, Gattefossé
Enabling formulations for poorly soluble compounds
Michael Frid, Ph.D., Principal Scientist, Wolfe Laboratories
Course Description
Small drug candidates (MW <1,000) are becoming ever more complex, often possessing low water solubility and poor chemical and/or physical stability. These physico-chemical properties present significant challenges to those involved in the product development of new molecular entities. Each molecule has unique characteristics that must be understood and addressed during the formulation development process, and rigorous preformulation studies are the cornerstone of successful drug product development. Fundamentals of Formulation Development for Small Molecules is designed to impart the tools and knowledge necessary to ensure that you can position these molecules to move rapidly and seamlessly from discovery through the various stages of product development to commercial manufacturing.
The course will provide an overview of the Biopharmaceutics Classification System and the impact of physico-chemical properties on formulation strategies at each stage of development. Methods of solid state characterization and preformulation studies needed to select the most appropriate physical form and lay the foundation for formulation development will be discussed in detail. The influence of the pharmacokinetic and metabolic properties on the formulation strategy will be addressed. Strategies for rapid development of first in human formulations will encompass approaches that utilize a range of enabling technologies. Case studies will be used to illustrate the importance of physico-chemical properties in the selection of the most suitable physical forms (polymorph, salt, etc.) and proper dosage form selection to allow development of a stable, bioavailable and manufacturable drug products.
Session Overviews and Speaker Bios
Session 1. Introduction to drug-like properties and selection of drug-like leads during lead selection and lead optimization
Overview: In an effort to reduce attrition rates of potential drug candidates progressing through development, increasing attention is being paid to the drug candidate selection process. Awareness around selecting the pharmacological target, selecting the lead template, and enhancing the rigor of the molecular optimization process is becoming a standard protocol. Molecular attributes consistent with drug-like properties are being used to better understand the level of uncertainty surrounding a drug candidate, thus enabling a more confident assessment of risk and a better understanding of the drug candidate’s potential value. Molecular properties of a molecule, whether inherent to the lead template, or introduced during the structural optimization phase, dictate the “intrinsic” properties that define the drug-like nature of the molecule. The highly interdependent properties of solubility, stability, permeability, metabolism, clearance, distribution, toxicology and pharmacology make it extremely difficult to selectively modulate one property without influencing another. The ability to efficiently influence the optimization process is predicated on the ability to generate the desired information at a time which coincides with decisions around molecule selection and evolution of development plans. This presentation will discuss the interactive nature of what we consider to be drug-like properties and the importance of mechanistic understanding of molecular performance to appreciate the risks for progression and the potential for mitigating those risks while accepting other trade-offs.
 Michael J. Hageman, Ph.D., Group Director of Discovery Pharmaceuticals at Bristol-Myers Squibb (Princeton, NJ). As part of Candidate Optimization, Dr. Hageman’s work is directed toward the design, optimization and selection of new drugs possessing adequate drug-like properties for transition into development. Previously, he worked on preformulation, drug delivery and parenteral formulation of proteins at Upjohn. He then moved to early evaluation of small molecules, supporting drug candidate selection and formulation for early phase clinical studies and was also engaged in the technology development for poorly soluble drugs to support the discovery interface and product life-cycle management for Pharmacia and Pfizer. Dr. Hageman has more than 25 years of experience in preformulation and early evaluation of small molecules, and has held adjunct faculty positions at the University of Kansas, Purdue University and the University of Utah. Elected a Fellow of AAPS, he was previously chair of the Drug Discovery & Delivery Interface (D3I) Task Force for AAPS and the AAPS Physical Pharmacy and Biopharmaceutics Section. He received a B.S. in Pharmacy and doctorate in Pharmaceutical Chemistry from the University of Kansas.
Session 2. BCS and the influence of the BCS classification on formulation development
Overview: Coming soon.
 Alice Loper, Ph.D., Head of Preclinical Development, Alternative Development Program (ADP), GlaxoSmithKline (Philadelphia, PA). Within the ADP biotech model, Dr. Loper is responsible for preclinical and CMC development for select late-stage programs, which focus on type 2 diabetes. Prior to joining GSK, she headed Pharmaceutical Technologies at Adolor Corporation. She was Vice President, Pharmaceutical Development at Schering Plough Research Institute, and prior to that was Director of Biopharmaceutical Chemistry in Pharmaceutical Research and Development at Merck Research Laboratories. She received her Ph.D. degree in Pharmaceutics and B.S. in Pharmacy from the University of Texas at Austin. Dr. Loper’s product development experience spans early discovery support through late stage development of products for oral, parenteral and inhalation therapy. Her publications, patents and invited lectures have focused on understanding the interaction of drug properties, drug delivery systems and biological systems through the application of appropriate pharmaceutics and biopharmaceutics models. Dr. Loper is a member of the American Association of Pharmaceutical Scientists, the American Chemical Society and the Controlled Release Society.
Session 3. Solid-state properties and formulation strategies
Overview: Formulation design of small molecule drugs relies on understanding and exploitation of solid-state and thermodynamic properties of the materials used to produce the drug product. With few exceptions, drug substances (APIs) are solids at room temperature and ambient pressure, and, in many instances, the process of formulating the drug product retains the API in an ordered solid state. Accordingly, the lecture will begin with focus on solid-state properties of small-molecule APIs and characterization of these materials and resulting formulated products. The various types of single-component and multi-component API types will be compared. Fundamentals of preformulation evaluation of the API will be linked with the formulation design activities to illustrate continuity of learning and the evolutionary nature of formulation strategies as a program matures in development. Several examples will be used throughout to illustrate challenges and opportunities to build stability of performance into a drug product. Connections with discovery research will be highlighted to showcase the option of early intervention to enhance early evaluation of promising compound classes. Additionally, the translation to clinical evaluation is described, focusing on how formulation design adapts to progress and learning during initial toxicology studies and in the clinic. Examples of disordered systems will also be shown to demonstrate the viability of amorphous drugs in those cases where the amorphous nature of the API and drug product is warranted, required or unavoidable. The key take-away message is that understanding of the solid-state and materials properties is essential to successful development of drug products.
 Örn Almarsson, Ph.D., Vice President of Pharmaceutical Research and Development at Alkermes (Waltham, MA). He leads the pharmaceutical research and development group which covers formulation, analytical development and pharmaceutical chemistry. He joined Alkermes from TransForm Pharmaceuticals, a J&J company, where he led product generation based on high-throughput materials platforms. He previously served in a cross-site capacity as Head of Early Development Drug Products in the US in Chemical and Pharmaceutical Development for J&J PRD, including responsibility for early-stage API generation and drug product to support US-based programs from pre-clinical through Phase II candidate evaluation. Following post-doctoral work, he joined Pharmaceutical R&D at Merck Research Laboratories in 1995. From 1999 he was responsible for the pharmaceutical chemistry group at Merck West Point, supporting both discovery and development programs. Dr. Almarsson has more than 15 years of experience in pharmaceutical R&D. He received a B.S. in Chemistry from the University of Iceland and doctorate in Physical-Organic Chemistry from the University of California at Santa Barbara. Dr. Almarsson has published widely in areas of pharmaceutical chemistry, materials discovery, solid-state characterization, formulation and biopharmaceutical optimization.
Session 4. Early DMPK and bioanalytical method development
Overview: Many of the characteristics that make a molecule a good potential drug candidate fall into the DMPK (drug metabolism and pharmacokinetics) category. These characteristics can include high oral bioavailability, an adequate half-life and a balanced clearance profile. Early experiments in DMPK are fundamental to identifying compounds with favorable properties for development as potential drugs. DMPK covers all aspects of a drug’s adsorption, distribution, metabolism and excretion (ADME), and a fundamental goal of early DMPK is to build an understanding of the effect of structural features on drug ADME. DMPK consists of a mix of both in vivo and in vitro experiments. In vitro tests include screens for metabolic stability, determination of plasma protein binding, permeability, transporter susceptibility and the identification of metabolites using liver isolates. In vivo tests consist primarily of oral and intravenous dosing to preclinical species to determine pharmacokinetic properties like bioavailability, half-life, clearance and exposure, as well as the identification of metabolites and routes of drug elimination.
Almost every experiment in DMPK has an instrumental analysis component, which requires bioanalytical method development. The primary method of bioanalysis is a combination of high performance liquid chromatography and tandem mass spectrometry detection (LC-MS/MS). LC-MS/MS has allowed access to many more experiments than were previously possible using UV, fluorescence or radiochemical detection. Unfortunately, the effective application of LC-MS/MS to DMPK requires money, time and significant scientific skill. Scientists who use LC-MS/MS must have expertise in biological sample preparation, HPLC, mass spectrometry, and data interpretation.
This course module will survey some of the more important experiments run in early DMPK, as well as summarize important issues in supporting these experiments using LC-MS/MS.
 Mark J. Rose, Ph.D., Scientific Director, DMPK, Amgen (Thousand Oaks, CA). Dr. Rose currently leads a bioanalytical group in the Pharmacokinetics and Drug Metabolism department at Amgen Inc., where he is responsible for the support of discovery, preclinical, toxicology, and clinical studies for small and large molecules. Previously, he worked in the Drug Metabolism department at Merck Research Laboratories, and was an analytical scientist in the Pharmaceutics department with Glaxo Inc. Dr. Rose has been involved in the bioanalytical community for 20 years, contributing to the areas of ultra trace detection, new technology, high-throughput techniques, metabolite analysis and method validation. He is currently Chair-Elect of the Analysis and Pharmaceutical Quality Section of the AAPS, and is past chairman of the AAPS Bioanalytical Focus Group. Dr. Rose was a co-chair, speaker and panel expert at the AAPS/FDA Third Bioanalytical Workshop, “Quantitative Bioanalytical Methods Validation and Implementation: Best Practices for Chromatographic and Ligand Binding Assays” and is a co-author on the resulting conference summary report. He is co-author on over 65 publications and presented abstracts in the areas of analytical chemistry, bioanalysis and drug discovery. He received a B.S. in Chemistry from Pennsylvania State University and doctorate in Pharmaceutical Chemistry from the University of Kansas.
Session 5. Lipid-based formulations and absorption mechanisms
Overview: Interest in lipid-based formulations is largely driven by the growing need for novel drug delivery systems to deal with the new chemical entities that have poor solubility and/or permeability. The increasing use of lipid-based excipients in bioavailability enhancement is due to their functional properties which include:
- Improvement of the solubility of the drug in the dosage form.
- Spontaneous or easy formation of finely dispersed systems with aqueous media.
- Maintenance of the drug in a dissolved state and protection against drug precipitation after
dispersion into gastrointestinal milieu.
- Working in synergy with in-vivo processes to improve drug absorption.
This topic will first describe the four types of formulations as reported in the Lipid Formulations Classification Systems (LFCS). Then formulation and characterization strategies for all four types will be discussed, including ternary phase diagram, self-emulsifying properties and in vitro lipolysis with its consequences on drug solubilization & precipitation. Finally the impact of lipid excipients on absorption mechanisms by the modulation of enterocytes-based drug transport and disposition (targeted lymphatic transport, P-glycoprotein and cytochrome P 3A4 inhibition) will be addressed.
Vincent Jannin, Pharm.D., Ph.D., Hab., Pharmaceutical Research and Development Project Director, Gattefossé (France). Vincent Jannin received his Pharm.D. and Ph.D. degrees from the University of Bourgogne (France) in 1999 and 2004, respectively, and his Habilitation (HDR) from the University Claude Bernard Lyon 1 in 2010. He joined Gattefossé in 1999 as manager of the Pharmaceutical Formulation Laboratory and moved to the R&D division of the group in 2002 both as manager of the Pharmaceutical R&D Laboratory and project director. His research is centered on the characterization of physical-chemical properties of lipid-based excipients and their behavior in gastro-intestinal fluids. He has published more than 20 papers and was awarded five patents on lipid-based systems.
Session 6. Enabling formulations for poorly soluble compounds
Overview: The concepts of formulation and excipients will be defined, and conventional approaches will be introduced and illustrated through a case study. The need for enabled formulation approaches then will be discussed, highlighting the growing percentage of molecules for which traditional formulation techniques are inadequate. The utility of enabling formulations for solving the problems presented by poorly-soluble compounds will be illustrated through case studies. The lecture will conclude with a brief perspective on the relationship between conventional and enabling formulations.
 Michael Frid, Ph.D., Principal Scientist, Wolfe Laboratories (Watertown, MA). His work is the CMC area, focusing on determining, understanding, and utilizing the physicochemical properties of compounds for effective lead selection and translation of a candidate through IND-enabling studies. He plays an active role in designing the CMC sections of custom programs for lead selection, lead optimization, formulation development, and IND-enabling studies. Dr. Frid leads the solid state characterization, salt form development and selection, and polymorph screening efforts at Wolfe. He previously held senior chemistry positions at Minerva Biotechnologies, where he established the chemistry laboratories to support the company’s research programs. He led or participated in development of proprietary in vitro assays and in design, synthesis, and testing of new chemical entities for use with Minerva’s self-assembled monolayer technology. Dr. Frid has 10 years of experience in biotechnology and pharmaceutical basic research and R&D. An author of several publications and co-inventor on patents, he obtained his B.S. cum laude with Honors from New York University and doctoral degree in Organic Chemistry from the Massachusetts Institute of Technology.
Time
Registration and breakfast is from 8:00-8:30am – we ask that you please arrive by 8:00am and highly encourage speakers to stay the duration of the day to network with attendees. The course will start promptly at 8:30am and will conclude at 5:00pm. Complimentary breakfast and lunch will be provided, along with two facility tours during morning and afternoon breaks.
Location and Parking
Wolfe Laboratories Facility
134 Coolidge Avenue
Watertown, MA 02472
Free parking is located in the back of Wolfe Laboratories' facility. The parking lot can be accessed to the left of the building – the gate will be open. Once parked, please walk to the front of the building. We are located on the second floor.
Registration
Registration fees are $50. The course will be limited to 20 attendees to ensure that we have a small and intimate group to facilitate learning and provide attendees with ample opportunities for one-on-one interaction with the course instructors.
Who Should Attend?
This course is designed for Pharmaceutical Industry personnel involved in the design and development of formulations for therapeutic proteins.
- Pharmaceutical Chemists
- Protein Chemists
- Bioanalytical Chemists
- Biochemists
- Regulatory Affairs
- Project Management
- Manufacturing
- Quality Control
Contact
Wolfe Laboratories
events@wolfelabs.com
617-923-7600
Click here to return to Events |
