Masterstudiengang "Drug Regulatory Affairs"

Master-Thesis

Impact of the genotoxic requirements on the generic industry

Angela Röder (Abschlußjahr: 2009)

Language: English

The intention of this Master Thesis is to outline the impact the genotoxic requirements have primarily on the generic industry. They are developed from the knowledge that a mutagenic substance carries the risk of inducing germ line mutations. Consequences of such changes may be inherited disorders and the risk of somatic mutations including those leading to cancer.
Studying the mutagenic and clastogenic potential of substances therefore is of special importance to disclose the changes they may induce into the genetic material of cells or individuals. Additional in general applies that the risk that any impurity or any impurity profile would give raise to adverse reaction is clearly to minimize. The focus on drug substance impurities is necessary to guarantee the quality and safety standard in the generic industry. Generic products inter alia are determined by their impurity profile measured on the reference product they claim to refer to. Based on the long term of experience in the medical use of the active substance, in general without reporting of serious events by the reference product, the generic products normally do not pose a question about genotoxicity or carcinogenicity. This should have been dealt with at a former stage during the non clinical development of the related product.

However, the authorisation holder of the generic medicinal product has the duty to prove that his medicinal product throughout its lifecycle as well as the manufacturing process has to be conform to the requirements of quality and therefore to the Pharmacopoeia if covered here and the Guideline on limits of genotoxic impurities, too. This applies for new applications or variations to existing Marketing Authorisations e.g. particularly use including a higher daily dose, the change of the manufacturing process due to an add of or a change of the manufacturer. Outsourcing of the manufacturing is today increasingly necessary for the generic industry to withstand the price pressure evoked inter alia by the invitation to tender.

In the course of variations finding a structural alert the Agency requests the control of specified substances to the TTC limit or the submission of toxicity assays for safety precautions although these active ingredient are on market up for years with many years medical experience. Because the TTC limit depends on the maximum daily dose of the active substance an impurity far below the reporting threshold could be a cause for concern. An additional burden for the generic industry is to comply with the TTC limit, because it needs the knowledge in and the application of innovative analytical tools like trace analytic. Furthermore a specific cause for concern may arise in case of lacking tests on known genotoxic substances covered by the European Pharmacopoeia. Consequently a delayed processing of the application of national or European approval on request for additional specifications may decrease the opportunity to place well the medicinal product on market inter alia determined by the speed the generic medicinal product gets an approval.

Regarding global marketing there are still different points of view between EMEA and FDA because in USA drug substance and related genotoxic impurities seem to be more flexible controlled than these regulated according the EMEA equivalent. In contrast to USA in Europe the guideline will leave the generic applicant no alternative than the TTC limit of 1.5ìg/day for nonthresholded substances. In USA the Draft Guidance on` Genotoxic and Carcinogenic Impurities in Drug Substances and Products` admits always a pharmaceutical assessment.
The aim of this Master Thesis is to show the generic industry needs a rethinking in regulatory affairs because of the changed regulatory requirements, triggered from the Viracept® incident happened in the `ethical industry`. Caution should be applied on positive results in retrospective tests of marketed drugs. The process chemistry and quality assurance should consider how to avoid genotoxic impurities. Therefore it is indispensible to use the available tools for test strategy like computational systems to detect structural alerts of potential genotoxic impurities in starting materials or intermediates of synthesis of API. The generic regulatory affairs should specify in all stages of development a consensus on acceptance criteria including regulatory clarification for successfully detecting, assessing, reporting and managing genotoxic impurities. In the process a risk communication and follow up measures should be established between industry and regulatory bodies.

Thus already during the development time of a generic product the key factors incorporate the application of innovative analytical tools, appropriate controls at key process steps based on up-to date scientific findings and risk assessment. Although outsourcing is a common process in the generic industry teamwork among the groups in Toxicology, Analytical Development, Organic Chemistry and Regulatory Affairs is indispensible because of the aggressive timelines the generic industry has to fulfill in order to do well on the market.

Pages: 52, Annexes: 14 pages