Issues in regard to quality and safety. Impurities. Preclinical Safety EU. Novartis Pharma AG. Lutz Müller

Transcription

1 Impurities Issues in regard to quality and safety Lutz Müller Novartis Pharma AG Preclinical Safety EU Investigational and in silico Safety & Metabolism (ISIS)

2 Relevant guidelines ICH Guidelines ICH Q3A(R) Impurities in New Drug Substances ICH Q3B(R) Impurities in New Drug Products ICH Q3C Residual Solvents (including maintencance) CPMP draft NfG (2002) Specification limits for residues of metal catalysts (on hold) CPMP draft position paper (2002) Limits for genotoxic impurities (on hold)

3 General approach for identification and qualification of impurities Impurities are normally qualified in appropriate toxicological studies as part of a drug substance or drug product It is assumed that their structure is normally close to that of the drug substance The toxicological qualification threshold for drug substance impurities is 0.15% (0.5% for daily dose of more than 2g) = 1500ppm (or 500ppm) The (structure) identification threshold is 0.1% (or 1mg/day, whichever is lower) (0.5% for daily dose of more than 2g) = 1000ppm (or 500ppm) Essential qualification studies are Genotoxicity in vitro A (sub) chronic toxicity study (in rodents) Specifications/levels in clinical batches should be covered by tox investigations Either in acutal percentage or with appropriate safety factors

4 What about highly toxic impurities? Identification of impurities present at an apparent level of not more than ( ) the identification threshold is generally not considered necessary. However, analytical procedures should be developed for those potential impurities that are expected to be unusually potent, producing toxic or pharmacological effects at a level not more than ( ) the identification threshold. All impurities should be qualified as described later in this guideline. For impurities known to be unusually potent or to produce toxic or unexpected pharmacological effects, the quantitation/detection limit of the analytical procedures should be commensurate with the level at which the impurities should be controlled. Issue: How to control, if you do not know the structure?

5 Potential presence of reactive impurities in drug substances Process-related Starting materials e.g. alkylating agents and similar reactive species Intermediates / by-products e.g. strong acid/alcohol interactions Catalysts, ligands Long-term storage Degradation products (by oxidation?) Complete elimination of such impurities is often not feasible

6 Why to address the concern regarding high toxicity/non-reversible toxicity of impurities? We do not want to put patients at undue risk of exposure to toxic agents if this is avoidable according to best technical procedures The presence of a genotoxic/carcinogenic impurity may falsely stigmatize an otherwise safe drug substance if there are no efficient means to eliminate influences of genotoxic impurities on the test results obtained with batches of poor purity e.g. testing of such batches would be a risk for two year carcinogenicity studies in rodents ICH guidances on impurities in new drug substances and new drug products state that: analytical procedures should be developed for those potential impurities that are expected to be unusually potent, producing toxic or pharmacological effects at a level of not more than the identification threshold. It is agreed that compounds of high acute or potentially non-reversible toxicity would fall into this category. Genotoxic compounds are generally believed to have the potential to exert nonreversible changes in the genetic material

7 Genotoxic impurities how to detect? The structure of impurities present at levels above the identification threshold is known, their impact on safety of the drug substance can be appropriately assessed But: the ICH guidance on drug substance impurities does not stipulate identification of the structure of impurities below a level of 0.1% =1000 ppm (0.05% or 500 ppm if daily dose is above 2 g) ppm (500 ppm) may be unacceptably high for an impurity if it is genotoxic. A 2 g daily dose of a pharmaceutical may contain 2 mg of a potential toxin E.g. 2 mg residues of an alkylating starting material would not be desired What would happen if you spike drug substance X with 1000ppm of an alkylating agent? Genotoxicity tests may not be sensitive enough to detect the effect of genotoxic impurities in a batch if the impurity is present at the 0.1% level In other words: few genotoxic compounds have a potency e.g. in the Ames that would enable their detection at or below 0.1% (the same is true for rodent carcinogenicity studies) Without a structure, we do not have an idea whether we have a genotoxic impurity problem unless we start to approach the problem from the synthesis side

8 Genotoxic impurities - the limit of detection issue Take EMS (ethylmethane sulfonate) and MMS (methylmethane sulfonate) as model mutagenic impurities LOEC for EMS in Ames test is: 1500 µg/plate (TA 100) LOEC for MMS in Ames test is: 15 µg/plate (TA 100) Question: at which level can you detect these as mutagenic in an Ames test of drug substance X Answer: assume that drug substance x is tested up to 5 mg/plate EMS can be detected at 33.3% only (= ppm) MMS can be detected at 0.33 % (15 µg in 5 mg =3 300 ppm) A batch of drug substance X can be qualified as non genotoxic in an Ames test although it may contain e.g ppm MMS Nevertheless, the presence of ppm MMS is not acceptable Few genotoxic carcinogens have a detection limit in the Ames test below 5 µg/plate, which would correspond to 1000 ppm if expressed as impurity level in 5 mg drug substance

9 LOEL in genotoxicity assays by structural alert class Salmonella Reverse Mutation Assay Anthraquinones (12) N-Oxides (Aromatic) (5) Azirine/Aziridine (5) Aromatic Nitro (45) Aromatic Amines (48) Chromium (10) Vic Dihalides (6) Quinolines (18) PAHs (K-, Bay-Region) (7) Alkylating Agents (15) Nitrosamines/N-Nitroso (32) Isocyanate (4) Aliphatic Epoxides (21) Hydroxamates (13) Heterocyclic Nitro (3) Halogenated Methane (3) Hydrazo/Hydrazine (9) Rodent Micronucleus Assay Azirine/ Aziridine (6) N-Nitroso (4) Alkylating Agent (15) Triazene (6) Aromatic Amine (9) Hydrazine (4) mg/kg µg/ml Theoretical detection limit 1 ppm % of drug substance if drug substance is 1mg/ml

10 CPMP draft position paper on genotoxic impurities (as of December 2002) Issue of non-consistent regulatory action and deficits in the existing ICH guidances regarding genotoxic impurities was realized by the CPMP: In the case of impurities with a genotoxic potential, determination of acceptable dose levels is generally considered as a particularly critical issue, which is not specifically covered by the existing guidelines. (from the introductory paragraph of the position paper) While regulatory action appears to be executed preferentially in late stages of the development process, it is better for us to implement a process of continuous data exchange between TRD and PCS to improve step-wise our syntheses with regard to a potential carry over of toxic impurities at unacceptably high levels into the DS To avoid regulatory surprises To minimise risks for volunteers and patients

11 Our Novartis policy regarding (geno)toxic impurities We have introduced a new policy regarding the detection, testing, elimination and risk assessment of potentially (geno)toxic impurities in drug substances or drug products In general, the procedure starts with a Computational toxicology assessment of every drug substance synthesis scheme Why?: focus on toxicological knowledge and informed decision making Product of this assessment and the interaction between chemistry and toxicology is a Notification on the presence of unacceptable substances in synthesis before Phase I trials. This Notification is constantly updated throughout the development process The Notification includes actions and measures regarding purity, limits based on toxicity and scientific rationales on these limits The new policy is described in a new world-wide SOP: GENERATION OF THE SYNTHESIS SCHEME AND COMPLETION OF THE SYNTHESIS CONTROL FORM AND NOTIFICATION FORM FOR KNOWN AND POTENTIAL IMPURITIES

12 What is the role of toxicology as described in this new SOP? PCS assesses raw materials & intermediates for toxicity. If not listed in a general list of potential carcinogens, a structureactivity (in-silico) analysis for the presence of toxicological alerts is performed Are alerting structural elements present (primary focus on genotoxicity / carcinogenicity)? Our present in silico systems give us about 80% accuracy for genotoxicity The in silico systems are continuously improved with experimental data If no, then no special limits, normally no special testing needed. Qualification according to existing ICH guidance procedures, i.e. appropriate ( dirty ) batches are tested If yes, a bacterial mutagenicity assay (Ames test) is normally initiated

13 Verification/falsification of structural alerts Toxicology will perform Ames test (or other suitable test as indicated by structural alert) Why primarily the Ames test?: it detects with greatest reliability DNA reactive compounds (or metabolites of them) Most DNA reactive compounds are multi-organ carcinogens Few false positives in the Ames test (Ames positive non-carcinogens) Few toxins are known that are DNA reactive in mammalian cells but not in bacteria ( Test(s) confirm in-silico hypothesis? If no, then no special limits, no special testing If yes, acceptable limits proposed adapted to the phase of the clinical program! Important: chemical expert reasonning can be an alternative to testing (and limit setting) especially in early phases of development!

14 The new SOP applied to Novartis projects in 2002 Evaluation period: syntheses evaluated for the presence of alerting structures: in silico prediction plus published/in house data on genotoxicity or carcinogenicity 6 syntheses were clean, i.e. no alerting structures were present Recommendations for limitations or genotoxicity testing given for 139 intermediates 65 intermediates tested for genotoxicity (usually Ames screen in two strains, using less than 100mg substance) 38 tested negative: no limits given 27 tested positive: limits discussed 20 syntheses out of 46 (43%) involve a mutagenic intermediate, which is potentially present as impurity

15 Setting limits based on toxicity data? Toxic residual solvents/heavy metal catalysts limits are described in ICH or CPMP guidances (or draft guidance) However, there are extensive discussions in the quality and safety community on what are suitable/acceptable limits e.g. for genotoxins Few compounds are sufficiently experimentally characterized (e.g. in rodent carcinogenicity studies) to do a reliable risk assessment The draft position paper from the CPMP Safety Working Party is not very clear on this issue Extensive comments via EFPIA and PhRMA have been submitted It appears that the EFPIA proposal to adopt the concept of a Threshold of Toxicological Concern (TTC) as applied in the food contact substances area may be acceptable to the CPMP TTC lies at 1.5ug/day for lifetime exposure (exceptions: very potent carcinogens such as a few nitrosamines) Proposed ICH topic?

16 Normally used formula for calculating permitted daily exposure (PDE) based on toxicology data PDE (mg/day) = NOEL or LOEL (mg / kg) x human bodyweight (50 kg) F1 x F2 x F3 x F4 x F5 Uncertainty factors F1 - F5 to account for: F1: Interspecies differences (surface area : body weight ratio for man compared to testing species; rat = 5, mouse = 12) F2: Inter-individual differences (10) F3: Duration of exposure (1-10) F4: Severity of toxicity (1-10) (is this sufficient for genotoxicity/carcinogenicity?) F5: Quality of data (1-10) / LOEL = 10

17 The dilemma of lacking data is a majorhindranceforusing NOEL s and uncertainty factors! In vitro + in vivo genotoxicity assays are hazard identification tests, and thus do not provide data suitable for use in quantitative risk assessment Approach proposed (use of NOEL + UF) is unlikely to be feasible in most circumstances (no adequate data)! Pragmatic approach is needed (amount of impurity in µg/day considered as generally acceptable intake level) The NOEL / UF approach can be used for toxicologically well characterized compounds, a condition, which is normally not met for impurities

18 Alternative to PDE calculation: the Threshold of Toxicological Concern (TTC) This concept acknowledges a human exposure threshold value for chemicals (including those of unknown toxicity) below which there is no significant risk to human health. Established by the FDA ( Threshold of Regulation ) as a level low enough to ensure that public health is protected, even in the event that a substance exempted from regulation... is later found to be carcinogenic. Examined for broader applications by ILSI Europe Task Group Based on an analysis of over 700 chemical carcinogens from the Gold et al. carcinogenic potency database estimate of a human exposure threshold value for a high probability of not exceeding a 1x10-6 cancer lifetime risk : 1.5 µg/person/day (= no safety concern!) both, genotoxic and non-genotoxic carcinogens are covered in the database!

19 Translate Threshold of Toxicological Concern (TTC) in ppm? Maximum levels of impurity in a chronic use drug (scenario for PDE s between 0.05 and 50 ug/day) PDE* for impurity (µg/day) Max. content (in ppm) of impurity in drug substance if daily dose of drug (g/day) is: * Denotes Permitted Daily Exposure To be used if Threshold of Toxicological Concern will be generally accepted

20 Deviations from TTC possible (if justified) route of administration target population / proposed indication toxicology of the impurity in relation to the active substance high potency carcinogens excluded from TTC ( the dirty four ) aflatoxin-like compounds azoxy compounds N-nitrosamines tetrasubstituted dibenzodioxins and dibenzofurans

21 Advantages of Using the TTC Concept scientifically (databases) derived threshold (in contrast to the arbitrary use of uncertainty factors) conservative approach resulting in low ppm values can be applied even without preclinical data! will provide more consistency in controlling genotoxic impurities than case-by-case use of NOEL+UF-derived limits already accepted for regulatory purposes

22 Regulatory Applications of the TTC Concept FDA ( Threshold of Regulation ): for indirect food additives = food contact material Joint FAO/WHO Expert Committee on Food Additives (JECFA): for flavouring substances Could this concept be applied more widely than just to food toxicology?

23 Are there alternative concepts for acceptable limits? Acceptable level of intake of genotoxic impurities should be set in relation to daily intake of food mutagens (1g/day) no risk level for a genotoxin: µg/day ( safety margin of 4-5 orders of magnitude below the daily mutagenic burden!) Fiori & Meyerhoff (Eli Lilly): Extending the Threshold of Regulation Concept: De Minimis Limits for Carcinogens and Mutagens (Regul. Toxicol. Pharmacol. 35, 2002, ) no risk level for a genotoxin: 90 ng/day no risk level for a carcinogen: 9 ng/day These are no real alternatives!

24 Case study I 4-hydrazinobenzoic acid in a life saving oncology product Synthesis involves 4-hydrazinobenozoic acid (4-HBA) Hydrazine is IARC Group 2B, 1,2-dimethylhydrazine is in Group 2A 4-HBA is a weak Salmonella mutagen 4-HBA does not induce chromosome aberrations in vitro Limited published data indicate tumorigenic effects in rats (one dose level only tested in drinking water, low survival) but: Agaricus bisporus, the major cultivated mushroom of the Western Hemisphere (=champignon), contains 4-HBA at a level of 10 µg/g (10ppm) wet mushroom weight One champignon meal (200 g) contains 2000 µg 4-HBA Does exposure to 4-HBA really constitute a genotoxic/tumorigenic risk? Which level would be acceptable in a pharmaceutical (life saving) preparation with life-long high daily dose Would 5 or 10 ppm be too much, can we compare the risk in XYZ123 with eating champignons? 5ppm 4-HBA in XYZ123 (the current limit) translates into an exposure of 10µg/day This level is considered appropriate based on the life-threatening indication and the relatively weak genotoxic/carcinogenic potential of this hydrazine

25 Case study II epoxide degradation product in mometasone (published case) Mometasone (corticosteroid): Daily dose ~1600 µg Epoxide degradation product in aequeous systems The epoxide is a toxicological concern Limit setting approach according to TTC: 1.5 µg < 1000 ppm! Alternative: toxicological testing Limited to 1000ppm Below threshold of toxicological concern (not published with that reasoning) Apparently no specific toxicity studies Proactive limitation in the absence of detailed tox data?

26 Case study III: Imatinib (Gleevec) Maximum daily dose of Imatinib is 800 mg STID6 bears structural alerts, and is positive in several genotoxicity systems as well as yielded toxicological findings (hyperplasia, necrosis) in various organs in a 4-week study in rats Drug substance batches spiked with up to 280 ppm yielded negative genotoxicity test results (could have been predicted by calculation) Limit based on technical feasibility is 20 ppm Highest human daily uptake/exposure would be 8 and 16 µg (equivalent to 1.6 and 3.2 ng/ml blood assuming total absorption) Human exposure is clearly below in vitro genotoxic concentrations But: D6 (CGP53715) is formed as major metabolite in mice and rabbits No major pathway in rats, dogs, humans But: are analytical methods capable of excluding D6 as a minor human metabolite It does not make sense to be very strict with applying low ppm limits for impurities, but to be not able to exclude formation by metabolism at higher levels Problem not considered important for the current life saving indications of Gleevec Gleevec N D6 (507-00) N N N H NH N N N N O N N H NH 2

27 Decision tree for assessment of acceptability of genotoxic impurities (according to publication draft by Peter Kasper, the relevant drafting regulator on the CPMP side) Established carcinogenicity from long-term studies? NO YES Genotoxicant with unknown carcinogenicity Genotoxic carcinogen Threshold-related mechanism? Eliminate? YES NO NO Determine Permitted Daily Exposure (NOEL + UF) Control below Threshold of Toxicological Concern Quantitative risk assessment: Determine acceptable dose

28 Proposal by Novartis/EFPIA group for a flow chart on genotoxic impurities

29 Next Activities on genotoxic impurities Scientific fora (experts from Industry, SWP & QWP) DIA case study workshop in London on October 28-29) EFPIA/CPMP round table to discuss & judge the implications of the various suggestions (also from a pharmaceutical point of view) Finalization of the EU Position Paper in 2004? Need of international harmonization within the ICH framework?

30 Some conclusions, but not necessarily all inclusive A genotoxic (mutagenic) impurity is potentially present in ~40% of all drug substances although batch testing for genotoxicity yielded mostly negative results For most of the genotoxic structures that show up in drug substance syntheses, there is no preexisting knowledge from published literature (i.e. we would have to generate the data) Organic chemistry involves the use of reactive materials, which may be genotoxic. Of course, it would be naïve to assume that this could be totally avoidable