Masterarbeit

Characterization of Impurities during Development of Chemically Synthesized Compounds Regulatory Requirements ***

Dr. Thomas Lauterbach (2004)

Summary
The ICH impurity guidelines Q3A, Q3B and Q3C provide guidance on how to characterize impurities and degradation products in new drug substances and new products. Although they formally only define requirements for new active substances at the registration stage, they may also be applied during development and most of the principles are also valid for existing compounds.
This master thesis summarizes the ICH threshold concept for the reporting, identification and qualification of impurities. The decision tree on how to react if these thresholds are exceeded is discussed for impurities with a known and an unknown structure and for different levels of safety information available for the impurities concerned.
ICH guideline Q3C defines clear individual specification limits for known residual solvents. Such limits do not exist for other - non compendial - impurities. The risk qualification system and the Permitted Daily Exposure concept used for solvents can however often be applied to other identified impurities, if safety data exist. Special requirements exist for unidentified impurities, enantiomeric impurities, impurities also occurring as metabolites and for impurities in existing compounds.
The major sources for safety information and a guide how this information can help to define specification limits for impurities are addressed in a separate chapter. This chapter also discusses to which extent (Quantitative) Structure Activity Relationship programs can be used to assess the safety of impurities, if the structure of an impurity is known, but no data can be found in the scientific literature. The acceptance of such assessments by regulatory agencies, esp. the FDA, is presented.
Much attention is paid to impurities with a known genotoxic potential and the actual status of discussion on the introduction of thresholds for these kinds of impurities. The text mainly refers to the recently published EMEA Position Paper on Genotoxic impurities in medicinal products and the Threshold of Toxicological Concern concept which is used by the FDA to define thresholds for chemicals in the diet. Examples for very toxic compounds, which should be avoided under all circumstances, are mentioned.
The last chapter is dedicated to new impurities occurring during the research and development phase and after the launch of a product. This refers to the synthesis of the active drug substance, the formulation development and the development of analytical methods used to detect impurities. The chapter defines the situations which require additional preclinical safety studies. The type and the design of these studies are presented taking into consideration the stage of development and the type of impurity which is observed.
Finally the importance of the impurity profile of clinical trial batches and the handling of impurities in the Common Technical document are summarized.
Pages: 56