ICH Q3D Drug Product Elemental Risk Assessment: The Use of An Elemental Impurities Excipients Database.

The purpose of this publication is to show how an elemental impurities excipient database can be used in assisting the execution of a drug product elemental impurities risk assessment as required by the ICH Q3D guidelines. As a result of this exercise, we have demonstrated that the database, used in conjugation with other sources of information, is a credible source of elemental impurity levels in excipients therefore, a valuable source of information in completion of drug product risk assessments. This useful collection of data helps to reduce the burden of analytical testing for elemental impurities in excipients.

Photostability testing using online reactor HPLC hyphenation and mass spectrometric compound identification illustrated by ketoprofen as model compound.

Investigations on the photochemical stability of pharmaceutical substances are mandatory in drug development and licensing as photo-induced degradation of an active pharmaceutical ingredient (API) may not only lead to decreased API concentrations but also to toxic or reactive products. Thus, the US Food and Drug Administration (FDA) and the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) issued Guidance for Industry Q1B "Photostability Testing of New Drug Substances and Products" for testing of pure but also packed drugs. However, photoproducts are also known to be generated in vivo under sunlight exposure of the skin and lead to considerable amounts of adverse drug effects. Herein we present an alternative system that may be used for photostability testing mimicking both situations. It combines a tailored photoreactor with an exchangeable pen light source and a modified HPLC system with online-SPE. Identification of photoproducts may be performed using mass spectrometry. The potential of accurate mass spectrometry as a tool for identification of photoproducts was demonstrated as well. A comparison of the online photoreactor system and the traditional photochamber irradiation was performed using ketoprofen for proof of concept. In both designs acetylbenzophenone and ethylbenzophenone were detected as main photoproducts. The new device allows for fast and easy photostability studies that may help to reduce time consuming in vitro experiments and animal trials. Using state of the art instruments kinetic studies could also easily be performed with qualitative and quantitative perspectives combined into one experimental design with only very low amounts of API needed. This may be useful in early drug development, where only small amounts of API are available. Scale-up may also be easily realized for the generation of reference material for quantification and quality control (QC) processes as well as for toxicity testing.