Karen M. Alsante

Can light absorption and photostability data be used to assess the photosafety risks in patients for a new drug molecule

Photosafety assessments are recommended for all new drug candidates intended for clinical use. In 2002, Testing guidances were issued by the regulatory authorities in the USA (2003) and Europe (2002). A key requirement is to measure the absorption of UV-visible light by a compound in the 290-700 nm range and to assess photostability. Further photosafety evaluation is recommended for molecules which absorb light energy in this region and may be unstable in light. Consequently, the current guidances do not specify what constitutes a significant level of light absorbance or photoinstability. The current study was undertaken to determine the level of light absorption by measuring the molar extinction coefficients (MEC) of a wide range of compounds reported in the literature to have known photosafety issues in humans. The results have shown that all compounds tested have absorbance intensities significantly above an MEC threshold of 1000 L mol(-1)cm(-1) and also display a wide range of photoinstability. The measurement of light absorption is a contributing part of an overall pre-clinical photosafety risk assessment process, whereas photostability assessments have proven to have limited value. Molecules with an MEC less than 1000 L mol(-1)cm(-1)are deemed less of a photosafety risk since this low level of light absorption is unlikely to prove harmful.

Stabilization of Pharmaceuticals to Oxidative Degradation

A guide for stabilization of pharmaceuticals to oxidation is presented. Literature is presented with an attempt to be a ready source for data and recommendations for formulators. Liquid and solid dosage forms are discussed with options including formulation changes, additives, and packaging documented. In particular, selection of and methods for use of antioxidants are discussed including recommended levels.

Hydrolysis in pharmaceutical formulations.

This literature review presents hydrolysis of active pharmaceutical ingredients as well as the effects on dosage form stability due to hydrolysis of excipients. Mechanisms and measurement methods are discussed and recommendations for formulation stabilization are listed.

A Critical Assessment of the ICH Guideline on Photostability Testing of New Drug Substances and Products (Q1B): Recommendation for Revision

The ICH guideline on photostability (ICH Topic Q1B) was published in November 1996 and has been implemented in all three regions (US, EU, and Japan). The guideline describes a useful basic protocol for testing of new drug substances and associated drug products for manufacturing, storage, and distribution, but it does not cover the photostability of drugs under conditions of patient use. The pharmaceutical industry now has considerable experience in designing and carrying out photostability studies within the context of this guideline, and issues have been identified that would benefit from the revision process. The purpose of this commentary is to accomplish the following: (i) highlight issues proposed for consideration in the ICH revision process, (ii) offer a rationale for why these issues may compromise the design of a testing protocol and/or the results of the testing program, and (iii) provide recommendations for clarification of the guideline.

Degradation and Impurity Analysis for Pharmaceutical Drug Candidates

Abstract The objective of this chapter is to give guidance with degradation and impurity structure elucidation for pharmaceutical drug candidates. Stress testing knowledge is provided as guidance in developing and executing forced degradation experiments. Impurity and degradant structure elucidation is a collaborative effort involving the degradation chemist, analytical chemist, process chemist, and/or formulator, as well as the isolation chemist, mass spectrometry and NMR experts. Updates in this second addition include: (1) the use of quality by design (QbD) model as applied to stress testing practices, expanded oxidative experimental analysis, and expanded information on predictive programs. (2) The impact of supercritical fluid chromatography as a tool for impurity isolations, along with expanded information on process workflow. (3) Mass spectrometry: additional examples and a section on the use of accurate mass information in the role of structure elucidation. (4) Expansion on the use of NMR as applied to structure characterization and elucidation. (5) In‐depth case studies that illustrate collaborative efforts made between disciplines, as well as the impact that new technologies have on the structure elucidation process.

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

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 13–14 October 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 without compromising quality. The workshop comprised four different sessions. Each session focused on separate fundamental issues to build a comprehensive understanding of the physical and chemical processes that affect drug impurities and drug degradation products, 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 approach 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 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 and addresses issues of safety considerations of impurities in pharmaceutical products and surveying the impurity landscape. 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 are summarized in 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 published separately.

In Silico Prediction of Pharmaceutical Degradation Pathways: A Benchmarking Study

Zeneth is a new software application capable of predicting degradation products derived from small molecule active pharmaceutical ingredients. This study was aimed at understanding the current status of Zeneths predictive capabilities and assessing gaps in predictivity. Using data from 27 small molecule drug substances from five pharmaceutical companies, the evolution of Zeneth predictions through knowledge base development since 2009 was evaluated. The experimentally observed degradation products from forced degradation, accelerated, and long-term stability studies were compared to Zeneth predictions. Steady progress in predictive performance was observed as the knowledge bases grew and were refined. Over the course of the development covered within this evaluation, the ability of Zeneth to predict experimentally observed degradants increased from 31% to 54%. In particular, gaps in predictivity were noted in the areas of epimerizations, N-dealkylation of N-alkylheteroaromatic compounds, photochemical decarboxylations, and electrocyclic reactions. The results of this study show that knowledge base development efforts have increased the ability of Zeneth to predict relevant degradation products and aid pharmaceutical research. This study has also provided valuable information to help guide further improvements to Zeneth and its knowledge base.

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.

Solving impurity/degradation problems: Case studies

Publisher Summary The chapter presents case studies related to solving impurity/degradation problems. The chapter presents guidance for isolating and identifying process-related impurities and degradation products from pharmaceutical drug candidates using actual case studies. Impurity and degradant structure elucidation is a collaborative effort involving the analytical chemist, process chemist and/or formulator, as well as the degradation, mass spectrometry, and nuclear magnetic resonance (NMR) experts. The process described in this chapter uses a designed approach for the impurity and/or degradant identification, which focuses on efficiency so that the success of data collection is maximized and project time lines are met. There are a number of activities other than collecting experimental data, even though the experiments are central to the process. Some of these key activities include collecting project background information prior to pursuing experimental work, asking the right questions, and meeting with project analysts and structure elucidation experts. The activities associated with the overall process are captured in the process flowchart presented. One of the most important aspects of the project that determines approach is where the pharmaceutical drug candidate is in the drug development time line. NMR spectroscopy is used as a complementary technique to liquid chromatography/mass spectrometry (LC/MS). The chapter presents several case studies related to scaled-up oxidative degradation and isolation using solid-phase extraction and preparative high-performance liquid chromatography (HPLC), scaled-up oxidative degradation, preparative HPLC, and characterization by LC/MS and NMR, scaled-up light degradation and LC/MS and NMR characterization, and others.