Toxicological studies of impurities and degradation products: in silico Methodologies as a safety assessment tool

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2 Toxicological studies of impurities and degradation products: in silico Methodologies as a safety assessment tool Azeddine Elhajouji, Novartis Institutes for Biomedical Research, Basel, Switzerland 22-Jun-2016

3 Impurities, solvents and heavy metals in drugs Definitions (according to ICH) Impurity Accompanying substance that is not identical with the structure of the active ingredient (by-products, degradation products, residual solvents, etc.) By-product Starting materials, intermediates, reagents, products of side reactions Degradation product Substance formed by chemical reactions of drug substance or by-products during processing and/or storage Impurity profile Description of identified/unidentified impurities in the drug substance Qualification of impurities The process of acquiring & evaluating data that establishes the biological safety of an impurity or an impurity profile at the level(s) specified 3 V Simpósio SINDUSFARMA - IPS/FIP - ANVISA Azeddine Elhajouji 22-Jun-2016 Impurities and degradation products

4 Impurities in General Impurities in drug substances and drug products give no benefit to patients and if not tightly controlled, may be hazardous Impurities must be reduced to levels As Low As Reasonably Practicable (ALARP) Limits should be based on toxicological reasoning in congruence with analytical and technical capabilities 4 V Simpósio SINDUSFARMA - IPS/FIP - ANVISA Azeddine Elhajouji 22-Jun-2016 Impurities and degradation products

5 Genotoxic Impurities (GTIs) Genotoxic impurities (i.e., potentially carcinogenic impurities with a genotoxic mechanism of action) deserve special attention in pharmaceuticals Impurities in pharmaceuticals require higher safety margins and lower limits than most other types of impurities Accepted modern toxicological risk assessment implies that the risk stemming from exposure to genotoxic carcinogens is a function of dose and length of exposure 5 V Simpósio SINDUSFARMA - IPS/FIP - ANVISA Azeddine Elhajouji 22-Jun-2016 Impurities and degradation products

6 Impurities, solvents and heavy metals in drugs Which guidance to follow? ICH Q 3 A (R2) Impurities in New Drug Substances CPMP/ICH/2737/99 Rev. 2 Aug 2002 ICH Q 3 B (R2) Impurities in New Drug Products CPMP/ICH/2738/99 Aug 2003 ICH Q 3 C (R3) Impurities: Residual Solvents CPMP/ICH/283/95 Sep 1997, Mar 1998 ICH Q 3 D Guideline for Elemental Impurities EMA/CHMP/ICH/353369/2013, Aug 2015 Guideline on the limits of genotoxic impurities CPMP/SWP/5199/02, CHMP/QWP/251344/ Jan 2007 Genotoxic and Carcinogenic Impurities in Drug Substances & Products: Recommended Approaches US FDA, CDER, guideline, Dec 2008 ICH M7 Assessment and Control of DNA Reactive (Mutagenic) Impurities in Pharmaceuticals to Limit Potential Carcinogenic Risk, Jun V Simpósio SINDUSFARMA - IPS/FIP - ANVISA Azeddine Elhajouji 22-Jun-2016 Impurities and degradation products

7 The good old days are over.. Analytical capabilities are continuously improving Example: DS containing a GTI at ppm 1990 not detectable with available method (LoD 50 ppm): no toxicological assessment requested 2016 easily quantifiable: Is this level acceptable? Toxicological assessment imperative New: detailed process analysis for potential GTIs! 7 V Simpósio SINDUSFARMA - IPS/FIP - ANVISA Azeddine Elhajouji 22-Jun-2016 Impurities and degradation products

8 Why a guideline for genotoxic impurities? ICH Q3A does indicate that lower thresholds for reporting, identification & qualification can be appropriate if the impurity is unusually toxic but no guidance is given on what unusual toxicity is & how to handle it Guideline emphasizes the No-threshold-dogma for genotoxicants... for genotoxic carcinogens... there is no discernable threshold and any level of exposure carries a risk. NOEL + Uncertainty Factors = Safe Dose NO OPTION! 8 V Simpósio SINDUSFARMA - IPS/FIP - ANVISA Azeddine Elhajouji 22-Jun-2016 Impurities and degradation products

9 Exceptions from the dogma? Threshold effects for genotoxins increasingly acknowledged, particularly for those acting on non-dna targets For threshold impurities Permitted Daily Exposure (PDE) can be calculated according to ICH Q3C ( Residual Solvents ) using N(L)OEL/UF approach However: in practice data providing sufficient evidence for a threshold will be rarely available 9 V Simpósio SINDUSFARMA - IPS/FIP - ANVISA Azeddine Elhajouji 22-Jun-2016 Impurities and degradation products

10 Assessment of acceptable limits for genotoxic impurities without evidence for thresholded MoA Proposal: Generic threshold below which hazard to human health is considered negligible! Threshold of Toxicological Concern (TTC): Based on an analysis of the potencies (TD 50 ) of over 700 chemical carcinogens from the Gold et al. carcinogenic potency database (CPDB) it is estimated that for most carcinogens an intake level of less than 1.5 µg/day (=TTC) would give rise to less than 10-5 risk of cancer ( virtually safe dose ) 10 V Simpósio SINDUSFARMA - IPS/FIP - ANVISA Azeddine Elhajouji 22-Jun-2016 Impurities and degradation products

11 Limit of Impurity [ppm] TTC translates into ppm impurity in drug Limit of Impurity [ppm] = 1.5 µg Daily Dose of Drug [g] Analytical control: readily achievable 10 1 technically challenging impractical? 10 ppm 1 ppm ppm Daily Dose of Drug [g] 11 V Simpósio SINDUSFARMA - IPS/FIP - ANVISA Azeddine Elhajouji 22-Jun-2016 Impurities and degradation products

12 Classification of mutagenic impurities ICH M7 classes Class Definition Proposed action for control 1 Known mutagenic Known carcinogens 2 Known mutagens (Ames positive) Unknown carcinogenic potential (no rodent carcinogenicity data) 3 Alerting structure (in-silico), unrelated to the structure of the drug substance; No mutagenicity data 4 Alerting structure (in-silico), same alert in the drug substance or related Ames negative intermediate, No mutagenicity data 5 No structural alert or alerting structure with sufficient data to demonstrate lack of mutagenicity Cohort of concern Control at or below compound specific acceptable limit Control at or below acceptable limit (LTL / TTC) Control at or below acceptable limit (appropriate TTC) or conduct bacterial mutagenicity assay If mutagenic: class 2 If not mutagenic: class 5 Treat as non-mutagenic impurity according to ICH Q3A/B Treat as non-mutagenic impurity according to ICH Q3A/B Individual control strategy 12 V Simpósio SINDUSFARMA - IPS/FIP - ANVISA Azeddine Elhajouji 22-Jun-2016 Impurities and degradation products

13 The Salmonella mutagenicity ( Ames ) test 0.1 ml Bacteria (10 8 cells) Overnight culture of bacteria +/- 0,5 ml S9 mix 0.1 ml test compound 2 ml minimal agar (0.05 mm histidine) +/- Pre-incubation Histidine-free bottom agar Incubate for about 72 hours Count colonies Determine ratio treatment group/solvent control 13 V Simpósio SINDUSFARMA - IPS/FIP - ANVISA Azeddine Elhajouji 22-Jun-2016 Impurities and degradation products

14 Evaluation of drug substance synthetic route First step of identifying GTIs In silico tox evaluation of synthetic route, raw materials and intermediates Class 1 and 2: Known mutagens/ carcinogens Class 3: Intermediates with structural alerts Class 4 and 5: Intermediates API related or without structural alerts Ames test: 5 strains Positive Negative Class 1: Calculate PDE Class 2: Limit according to TTC Limit according to ICHQ3A 14 V Simpósio SINDUSFARMA - IPS/FIP - ANVISA Azeddine Elhajouji 22-Jun-2016 Impurities and degradation products

15 Compound-specific risk assessment Mutagenic carcinogens (ICH M7 Class 1) Compound-specific risk assessments to derive acceptable intakes (AI) should be applied instead of TTC-based acceptable intakes where sufficient carcinogenicity data exists For known mutagenic carcinogen, a compound-specific acceptable intake can be calculated based on carcinogenic potency and linear extrapolation as default approach 15 V Simpósio SINDUSFARMA - IPS/FIP - ANVISA Azeddine Elhajouji 22-Jun-2016 Impurities and degradation products

16 Compound-specific risk assessment Methods Linear mode of action and calculation of acceptable intake (AI) (standard method) Selection of studies (consider quality), usually from CPDB Selection of tumor and site, route of administration, human relevance of tumor AI = TD 50 / x 50 kg Published regulatory limits Non-linear (threshold) mode of action and calculation of permissible daily exposure (PDE) Clear evidence for thresholded mechanism of action Acceptable limit based on exposure in the environment, e.g. intake from food 16 V Simpósio SINDUSFARMA - IPS/FIP - ANVISA Azeddine Elhajouji 22-Jun-2016 Impurities and degradation products

17 Addendum to ICH M7 guideline Compound specific AIs (lifelong, all patient populations, all administration routes; with exceptions) Acrylonitrile: 6 μg/day Aniline: 720 μg/day Benzyl chloride: 41 ug/day Bis(chloromethyl)ether: 4 ng/day p-chloroaniline: 34 μg/day 1-Chloro-4-nitrobenzene: 117 μg/day p-cresidine: 45 μg/day Dimethylcarbamyl chloride: 5 μg/day; inhalation: 0.6 μg/day Dimethyl sulfate: 1.5 μg/day Ethyl chloride: μg/day Glycidol: 4 μg/day Hydrazine: 42 μg/day; inhalation: 0.2 μg/day Hydrogen peroxide: μg/day Hydroxylamine: 2 μg/day Methyl chloride: μg/day 17 V Simpósio SINDUSFARMA - IPS/FIP - ANVISA Azeddine Elhajouji 22-Jun-2016 Impurities and degradation products

18 Evaluation of DS byproducts, degradants... Continuous step of identifying GTIs During whole development process for all drug substances or product related impurities this basic process is applied: Evaluate for structural alerts/ literature data Evaluate a molecule as GTI or carcinogen (genotoxic or non-genotoxic carcinogen) or conventional impurity Apply limits (TTC, PDE) or qualify (following ICH Q3C guideline for limits of impurities in new drug substances) if necessary 18 V Simpósio SINDUSFARMA - IPS/FIP - ANVISA Azeddine Elhajouji 22-Jun-2016 Impurities and degradation products

19 In silico systems QSAR approaches Why use Quantitative Structure Activity Relationship (QSAR) approaches for safety evaluation? Mining of knowledge stored in huge public and proprietary data bases allows to profit from experiences of thousands of laboratories Possibility to predict safety issues without before test material synthesis and wet lab experiments Various commercial software packages available that allow to add proprietary databases and which considerably improves predictions 19 V Simpósio SINDUSFARMA - IPS/FIP - ANVISA Azeddine Elhajouji 22-Jun-2016 Impurities and degradation products

20 (Q)SAR systems: Overview Commercial systems MCase DEREK TOPKAT OncoLogic etc Company specific systems Software packages to develop QSAR packages OASIS etc 20 V Simpósio SINDUSFARMA - IPS/FIP - ANVISA Azeddine Elhajouji 22-Jun-2016 Impurities and degradation products

21 (Q)SAR systems DEREK (Lhasa Ltd.) Computer expert systems for the prediction of toxicological hazard - Rule based, reflecting the current state of knowledge of the relationship between chemical structure and biological activity - Every rule covers one endpoint (carcinogenicity, mutagenicity, skin sensitisation and more) - Toxophores of a compound are identified, highlighted and explained - Brief statement about the hazard is given DEREK v : List of all alerts detected Description of alerting substructure References Comment (explanations, mechanism of action) 21 V Simpósio SINDUSFARMA - IPS/FIP - ANVISA Azeddine Elhajouji 22-Jun-2016 Impurities and degradation products

22 QSAR systems MCASE (MultiCASE Inc.) Predicts toxicity on the basis of discrete structural fragments found to be statistically relevant for a specific biological activity (biophores) Presence of biophores previously found in a number of active compounds (represent in the database) is indicative of potential activity Generates also information on deactivating fragments (biophobes) and unknown functionalities (coverage of the molecule) Super-mutagen Prominent structural alerts 2-10 atom fragmentation N N O H 2 N O N N O O. and many more O CH 2 Alerting fragments for rat tumorigenicity Databases used - Rodent carcinogenicity (FDA + non-proprietary) - Ames mutagenicity a) - Skin sensitization a) - Human liver toxicity (FDA modules) - herg channel interaction a) a) in-house data 22 V Simpósio SINDUSFARMA - IPS/FIP - ANVISA Azeddine Elhajouji 22-Jun-2016 Impurities and degradation products

23 Synthesis scheme evaluation A snapshot from a computational toxicology report Structural alert and MCASE biophore Compound has a high likelihood to show genotoxicity Synthesize the impurity Test the impurity in an Ames test to verify or reject the in silico prediction 23 V Simpósio SINDUSFARMA - IPS/FIP - ANVISA Azeddine Elhajouji 22-Jun-2016 Impurities and degradation products

24 Summary Pharmaceutical industries have to optimize the synthesis of the drugs to minimize and/or eliminate the impurities Limits for impurities and degradation products are regulated in the respective ICH guidelines. Specification and qualification needs input from Expert Toxicologists Genotoxic impurities are limited according to the TTC concept (Guideline for genotoxic impurities: ICH M7) (Q)SAR methods are highly sensitive tools to identify genotoxic impurities via determination of structural alerts The careful control of the levels of impurities in drugs is very important, because impurities may be hazardous to patients without giving them any benefit GMP principles must be followed for the production of drug substance to ensure the tight control of potential impurities 24 V Simpósio SINDUSFARMA - IPS/FIP - ANVISA Azeddine Elhajouji 22-Jun-2016 Impurities and degradation products

25 Thank you!