Masterarbeit

Quality of APIs and Starting Materials used for the Manufacture of Medicinal Products in the EU Including Risks for Genotoxic Impurities

Dr. Claudia Osterhage (2013)

Summary
Language: English
In a time of globalisation and in particular in a time of Asian APIs representing the majority of the APIs contained in European medicinal products, an appraisal of the current quality situation of APIs and starting materials used for the manufacture of a medicinal product for the European market has been done.
This involves a presentation of publicly available EDQM findings with respect to evaluation of API quality documentation as well as EDQM findings obtained during inspections of API manufacturers. Considering some of the top deficiencies found during the CEP procedure, it becomes apparent that a comprehensive overall discussion on impurities is the basis for adequate quality control. Furthermore this depends on the completeness of specifications for starting materials, intermediates, raw materials and solvents used in the API manufacture. Additionally, the point which defines the starting material in the RoS of API is essential for the comprehensiveness of the impurity discussion with respect to possible carry-over of impurities to the final API.
By definition, starting materials used for the manufacture of APIs do not have to be manufactured according to ICH Q7 GMP rules. Therefore these imply the risk for containing additional impurities that are not process-related, e.g., introduced by cross-contamination. These extraneous impurities pose special risks as nothing is known about their existence. As a consequence, they cannot be controlled. Any information including their potential to impact the patient’s health is confined to a big "black box".
Some impurities, such as genotoxic impurities, may be expected to be unusually potent already at low levels. A case study describes how recently a European originator pharmaceutical company found a potentially genotoxic impurity in the starting material of a newly synthesised API and how this impurity brought the project for a new API on a knife’s edge. As today many APIs and starting materials for APIs for the European market are sourced in Asian countries the starting material concerned originated from China.
In the following, this thesis focuses on genotoxic impurities. First, genotoxic impurities rank as a top finding in EDQM evaluations of API quality documentation. Although regulatory guidance for this topic has been in place in Europe since 2007 it has obviously not been implemented by pharmaceutical industry. Second, particular attention should be paid to this topic as guideline ICH M7 "Assessment and Control of DNA reactive (mutagenic) Impurities in Pharmaceuticals to limit potential Carcinogenic Risk" currently follows the formal ICH procedure and has recently reached Step 3. This means that the topic of genotoxic impurities will not only be dealt by regional guidance documents but will soon be harmonised for the most relevant pharmaceutical markets in the world. This is a milestone for both regulatory HAs and for the pharmaceutical industry in Europe, US and Japan.
Pages: 75