Institute for International Research

Monday, January 22nd, 2007

AM Workshop: The Fundamentals of Forced Degradation in Small Molecules

8:30 Registration and Morning Coffee
9:00 Workshop Begins
10:30 30 Minute Networking and Refreshment Break
12:30 Luncheon for Morning Workshop Leaders and Participants

This pre-conference workshop was first offered in 2005, and has received rave reviews every year. Now in its 3rd year, our fundamentals workshop is a must-attend for all those who are new to stability science and forced degradation, or who want a refresher course on the topic.

Part I: Understand the Chemistry behind Chemical Degradations in Drugs

Chemical degradation is one of the most important stability issues that impacts the quality and safety of a drug. One of the main goals of forced degradation studies is to assess chemical stability by using various stress conditions to predict the potential degradation products and degradation pathways. Understanding the chemical reactivity of various functional groups and the conditions required for these functional groups to be reactive is the key to understanding the chemical degradation and chemical stability of drugs.

• Why do drugs degrade?
• What are the function groups that can cause and the conditions that can facilitate drug degradation?
• What are the most important types of drug degradation?

Part II: Intro to Test Methods and Setting up a Forced Degradation Experiment

Equipment, stress storage protocols for API and drug product, and appropriate sample analyses will be presented. Experimental conditions including temperatures and durations, reagent and API concentrations, sample workup, reaction glassware, oxidative conditions, solid state stress conditions, photolysis conditions, and degradation product isolation/characterization will be discussed. Peak purity and mass balance will be included. A tablet formulation case study will be examined. Learn:

• Appropriate stress conditions for API and drug products
• What tests to perform on stressed samples
• Strategies for determination of mass balance, peak purity, and stereochemical stability
• Strategies for preparation, isolation, and characterization of degradation products
• A novel approach for distinguishing API related peaks in stressed drug product
• How results of stress testing can help solve stability problems through a case study

Part III: Intro to Oxidative Stress Testing

Oxidative testing can be a useful tool for predicting and rapidly generating the potential oxidative degradation products of a drug substance. Oxidative stress testing can be performed using a variety of reagents, and under a variety of conditions. This session will provide an overview of setting up oxidative testing strategies. Explore:

• Different variations of oxidative stress for optimal performance
• Optimal filter setup strategies for successful oxidative stress testing
• Oxidation examples to improve testing efficiencies

Part IV: Stability Science: An Introduction to Regulatory Expectations for Optimal Success

This talk provides an overview of regulatory and scientific purposes, timings, and requirements for stress testing of new drug substances and products. Topics discussed in the context of stress testing include:

• GMP Requirements for stress testing
• What conditions does the FDA consider acceptable for stress testing?
• When to perform forced degradation, and on what?
• Drive your processes to meet regulatory expectations more efficiently
• Optimize success in a changing regulatory climate

Workshop Leaders
Fengue Qiu, PhD, Principal Scientist, BOEHRINGER INGELHEIM PHARMACEUTICAL, INC.

Dan W. Reynolds, PhD, Team Manager, GLAXOSMITHKLINE

12:30  Workshop Registration Begins
1:30  Workshop Begins
2:30  30 Minute Networking Break
4:15  Workshop Concludes

Part I: BASIC INSTRUMENTATION: Instrumentation Considerations

The photostability workshop kicks off with an overview of ICH photostability requirements and the equipment light source options which are available to meet them. This session also provides detailed information with regards to spectral power distributions and light measurement techniques.

• Understand Option 1 and Option 2 light sources and how they differ
• Caveats of actinometry and light measurement
• Understand issues regarding sample presentation in testing

Part II: Practical Considerations for Effectively Conducting Pharmaceutical Photostability Testing

The Q1B guideline on photostability testing provides some degree of clarity on the type and extent of testing required by pharmaceutical applicants to support the successful regulatory filing of pharmaceutical products. Like many guidelines, the practical interpretations of how to actually conduct the studies properly are left to the hands of practicing scientists and wide variability in approaches have consequently developed. This session will focus on:

• Practical considerations in performing photostability testing
  
• "Best" practices learned for a number of important aspects of photostability testing such as: sample presentation, use of appropriate controls, properly conducting a study that meets ICH Q1B requirements
  
• Differences in data resulting from selection of Option 1 or Option 2

Part III: Fundamental Photophysics and Photochemistry: A Mechanistic View of Pharmaceutical Photoinduced Degradation

One of the key benefits of forced degradation studies is that the study enables the scientist to predict potential degradants in drug substance and drug product in formal photostability trials. However, in many cases, prediction of degradant structures arising from photochemical reactions is less straightforward than for their thermal counterparts. This presentation focuses on the light-induced aspects of the journey that an active pharmaceutical ingredient takes from light absorption to degradation. Along the way, we will uncover energy-wasting mechanisms (such as vibrational energy or luminescent pathways), the formation of reactive oxygen species and mechanisms of photodegradation.

• Develop your understanding of photochemistry and photophysics
• Improve your understanding of how degradants form via light-induced pathways
  
• Gain insight into your photochemical predictions by considering known photoinduced degradation mechanisms

Workshop Leaders
Mark H. Kleinman, PhD, Manager, Degradation Chemistry, GLAXOSMITHKLINE

Allen C. Templeton, PhD, Associate Director, Pharmaceutical Analytical Chemistry, MERCK & COMPANY

Allen F. Zielnik, Senior Consultant, Weathering Science, ATLAS MATERIAL TESTING TECHNOLOGY LLC