Vrednotenje z DNA regirajočih nečistot v učinkovinah in silico v skladu s smernico ICH M7

Soklič, Karina (author), Peterlin Mašič, Lucija (mentor)

Prisotnost DNA regirajočih nečistot v zdravilnih učinkovinah in posledično tudi v končnih zdravilih predstavlja tveganje za zdravje ljudi. Te snovi že v nizkih koncentracijah predstavljajo tveganje za razvoj rakavih obolenj, saj so reaktivne in lahko delujejo neposredno na genetski material posameznika. Raven nečistot v učinkovini je treba zmanjšati na sprejemljiv nivo, da ne predstavljajo tveganja za zdravje ljudi. Pri tem se moramo zavedati, da nečistot nikoli ne moremo popolnoma odstraniti. Področje nečistot urejajo smernice ICH, EMA in FDA. V okviru magistrske naloge smo ugotovili, da se najpomembnejši izzivi za farmacevtsko industrijo nanašajo na implementacijo smernice. Pregledali smo EMA in FDA smernice in razlike med njima. Najbolj pa smo se osredotočili na novo smernico ICH M7, ki se uporablja od leta 2016 dalje. Smernica dopolnjuje ICH Q3A in ICH Q3B smernici in prinaša nov pristop vrednotenja nečistot, ki temelji na kombinaciji dveh komplementarnih računalniških metod. V skladu z ICH M7 se nečistote razdelijo v pet razredov glede na njihov mutageni in karcinogeni potencial. V nalogi smo se osredotočili na DNA regirajoče nečistote, ki smo jih vrednotili in silico v skladu z novo smernico ICH M7 in prikazali implementacijo smernice na dveh modelnih primerih učinkovin.

• Language: Slovenian
• Keywords: DNA regirajoče nečistote, ICH M7, in silico vrednotenje, Amesov test
• Work type: Master's thesis/paper
• Organization: FFA - Faculty of Pharmacy
• Year: 2019
• PID: 20.500.12556/RUL-112652
• Publication date in RUL: 30.10.2019

Secondary language

• Language: English
• Title: In silico evaluation od DNA reactive impurities in the active pharmaceutical ingredients in line with the ICH M7 guideline

Abstract

The presence of genotoxic impurities in drug substances and consequently in the final drug products represents a potential risk for users. These substances at low concentrations pose a risk of developing cancer, as they are reactive and can act directly on the genetic material of the individual. Concentrations of impurities in the active substance must be reduced to an acceptable level so that they do not represent a risk to human health. The field of impurities is regulated by the ICH, EMA and FDA guidelines. As part of the master thesis, we found out that the implementation of the guideline represents important challenges for the pharmaceutical company. We reviewed EMA and FDA guidelines and the differences between them. We focused mainly on the new ICH M7 guideline, which has been used since 2016. The guideline complements the ICH Q3A and ICH Q3B guidelines and introduces a new approach to the evaluation of genotoxic impurities based on a combination of two complementary computational methods. According to ICH M7, genotoxic impurities are divided into five classes based on their mutagenic and carcinogenic potential. The purpose of the task was to evaluate the DNA reactive impurities in silico in accordance with the new ICH M7 guideline and to demonstrate the guideline implementation on two model compounds.

• Keywords: DNA reactive impurities, ICH M7, in silico evaluation, Ames test