Towards New Challenges in Global Regulatory Perspectives

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1 Towards New Challenges in Global Regulatory Impurities Characterization and Controls Genotoxic, Catalyst and Heavy Metals, and Residual Solvents January 28 th,2010 Bhanu M Narayan API R & D - VP Watson Pharma Pvt Ltd

2 Topics of Discussion General Principles Specification of Impurities Residual Solvents Metal Catalyst and Heavy Metals Genotoxic Impurities Additional Reading

3 Definition Impurity (1) Any Component of the New Drug Substance which is not the Chemical Entity defined as the New Drug Substance. (2) Any Component of the Drug Product which is not the Chemical Entity defined as the drug Substance or an Excipient in the Drug Product. (ICH Q6: Specifications)

4 Identified Impurity: Definition of Impurities An impurity for which a structural characterization has been achieved Unidentified Impurity: An impurity for which a structural characterization has not been achieved and that is defined solely by Qualitative analytical properties (e.g. Chromatographic retention time) Specified Impurity: An impurity that is individually listed and limited with a specific acceptance criterion in the specification. Can be either identified or unidentified Unspecified Impurity: An impurity that is limited by a general acceptance criterion but not individually listed with its own specific acceptance criterion in the specification Qualification: Process of acquiring and evaluating data that establishes the biological safety of an individual impurity or a given impurity profile at the level(s) specified

5 Classification of Impurities Organic Impurities ( Process- and Drug Related) Inorganic Impurities Residual Solvents Polymorphic Forms Enantiomeric Impurities

6 Classification of Impurities Organic Impurities ( Process- and Drug Related) e.g.: Organic Impurities can arise during the manufacturing process or storage of the API. They can be Identified or unidentified, volatile or nonvolatile. Starting materials By-Products Intermediates Degradation Products Reagents, ligands and catalyst

7 Inorganic Impurities e.g.: Classification of Impurities Inorganic impurities can result from the manufacturing process, they are normally known and identified and include Reagents, Ligands, Catalyst Heavy Metals or other residual metals Inorganic Salts Other material e.g. Filter aids, charcoal

8 Specification of Impurities in the API Impurities Testing Guideline: Impurities in New Drug Substances (ICH Q3A (R2)) Specific Pharmacopoeial Monograph and General Monograph Substance for Pharmaceutical Use

9 Based on Daily dose Maximum Daily Dose Threshold Limits for Impurities Reporting Threshold Identification Threshold 2 g/day > 0.05% >0.10% or 1.0 mg/day (which ever is lower) Qualification Threshold >0.15% or 1.0mg/day (which ever is Lower > 2g/day >0.03% > 0.05% >0.05% Application of Conventional rounding rules Total impurities >0.05%

10 Topics of Discussion General Principles Specification of Impurities Residual Solvents Metal Catalyst and Heavy Metals Genotoxic Impurities Additional Reading

11 Residual Solvents Classification, limits and Specification Class I Benzene, Carbontetrachloride,1,2,dichloroethane etc. Known human carcinogens, and environmental hazards Solvents to be Avoided Class II Acetonitrile, Chloroform, methanol, toluene etc. Non- Genotoxic animal carcinogens, Solvents suspected of significant but reversible toxicities Solvents to be limited Class III- Acetone, Butanol, Ethyl acetate, Isopropanol etc. Solvents with Low toxic potential to humans, no health based exposure limit needed Solvents with Low toxic Potential

12 Topics of Discussion General Principles Specification of Impurities Residual Solvents Metal Catalyst and Heavy Metals Genotoxic Impurities Additional Reading

13 Impurities of Heavy Metals and Metal Catalyst USP Chapter <231> Heavy Metals Background of Regulations USP Chapter <730> Plasma Spectrochemistry USP-NF 29 <730>, p. 2700, 2006, 2007 EP 01/2008:20408 Heavy Metals European Pharmacopoeia 6.0, EP 01/2008:20257, 58 Inductively Coupled Plasma European Pharmacopoeia 6.0, , ICP-AES European Pharmacopoeia 6.0, , ICP-MS USP Chapter <1225> Validation of Compendial Methods USP-NF 30 <1225>, 2007, 680 Draft EU Guideline on the specification Limits of Residues of Metal Catalysts, scope: Metal catalyst in API and Excipients

14 Concerns of Compendial Methods for Heavy Metals USP Heavy Metals Chapter <231> has been problematic for many years Difficulties in achieving anticipated results (monitor solutions, standards, etc.) Difficulties with reagents (moved from use of H2S to other sulfide sources) With the increased use of instrumental techniques for metals analysis, some investigators began to compare instrumental methods vs. USP Heavy Metals Chapter <231>

16 Guidance of Specification Limits for Residues of Metal Catalyst

17 EMEA Guidance--Classification of Metals Class 1 - Metals metals of significant safety concern known/suspected human carcinogens, other significant toxicity Class 2 - Metals metals of low safety concern generally well tolerated at typical pharmaceutical exposure, may be nutritional trace metals Class 3 - Metals metals of minimal safety concern well established safety profile, no significant toxicity, well tolerated even at levels above the typical pharmaceutical exposure, typically ubiquitous in nature

14 different elements with Acceptable Limits PDE- Maximum patient exposure- tabulation of recommendation on Oral and Parenteral PDEs, taking oral

18 14 different elements with Acceptable Limits PDE- Maximum patient exposure- tabulation of recommendation on Oral and Parenteral PDEs, taking oral bioavailability into account Routine control, based on suitable validated method. Exception: Validated reduction for a specific catalyst established

19 Different Metals used in Manufacture of API Aluminum (Al) Antimony (Sb) Arsenic (As) Beryllium (Be) Boron (B) Cadmium (Cd) Chromium (Cr) Copper (Cu) Indium (In) Iron (Fe) Lead (Pb) Lithium (Li) Magnesium (Mg) Manganese (Mn) Mercury (Hg) Molybdenum (Mo) Nickel (Ni) Osmium (Os) Palladium (Pd) Platinum (Pt) Rhodium (Rh) Rubidium (Rb) Selenium (Se) Strontium (Sr) Thallium (Tl) Tin (Sn) Tungsten (W) Zinc (Zn)

20 Different Metals used in Manufacture of API Barium (Ba) Bismuth (Bi) Bromine (Br) Cobalt (Co) Germanium (Ge) Gold (Au) Iodine (I) Ruthenium (Ru) Silver (Ag) Sulfur (S, δ34s) Tellurium (Te) Thorium (Th) Vanadium (V) Uranium (U) Radionuclides Cesium (137Cs) Polonium (210Po) Plutonium (239,240Pu) Rare Earth Elements Gadolinium (Gd)

21 Important Characteristics of an Analytical Method for Metal Detection Sensitivity Limit of detection Selectivity Measurement uncertainty Repeatability, systematic effects Matrix effects Contamination Spectroscopic interferences Sample size Sample preparation Cost Ease of use Analysis time

22 Modern Methods of Analytical Instrumentation Graphite furnace (electrothermal vaporization) atomic absorption spectrophotometer (GFAAS) Inductively coupled plasma atomic emission spectrometry (ICP-AES) Inductively coupled plasma mass spectrometry Most sensitive technique Typical detection limits μg/l (ppb) in solution Fast (2 minutes) Multi-element(> 60 elements) Definitive, multiple isotope identification

24 Control of Metal Impurities - Challenge to Meet Safe levels of heavy metals are controversial Heavy metals are not typically present but there is a possibility of contamination with significant negative consequences Typically have chronic toxicological impact (difficult to detect) Compendial general tests for heavy metals are lacking Not all toxic metals are detected Lack of harmonization between compendia

25 Topics of Discussion General Principles Specification of Impurities Residual Solvents Metal Catalyst and Heavy Metals Genotoxic Impurities Additional Reading

26 History of Chemical Carcinogens 1761 Dr John Hill first suggested that snuff caused cancer in the nose 1975 Benzo Pyrene is a carcinogen causing scrotal cancer 1980 Thalidomide tragedy 2008 Melamine tragedy

27 Genotoxic Impurities Definition: Chemical Substances capable of causing direct to indirect damage to DNA or Chromosome and lead to change in the expression of Gene thereby leading to Mutated Gene. Formation of defective Protein Create Disorder in Metabolic processes Affect the DNA repair Mechanism Examples: Alkylating agents, nitoso groups, lead, arsenic etc.

28 Guidelines on Genotoxic Impurities Changing Scenario ICH Q3A Impurities in New Drug Substances 2002, ICH Q3B(R) Impurities in New Drug Products 2003 ICH Q3C Impurities: Guidelines for Residual Solvents 1997 Establishment of Allowable Concentration o f Genotoxic Impurities in Drug Substance and Product 2005,PhRMA Position Paper EMEA, Guideline on the limit of Genotoxic Impurities 2006 FDA Draft: Genotoxic and Carcinogenic Impurities in Drug Substance and Products: Recommended Approaches and Acceptable Limits

29 Recommendation of these Guidelines Initial toxicological assessment of GTI s - Standard Battery of tests Handling of GTI s and Carcinogenic Impurities - Prevention of their Formation - Reduction to Acceptable Levels Additional characterization of Genotoxic and carcinogenic risk Consideration of Flexibility in Approach Decision Tree

30 Genotoxic Impurities - Scope: NCE s New Application for existing active substances where assessment of the route of synthesis process control and impurity profile does not provide reasonable assurance that no new or higher levels of GTI s are introduced Known Genotoxic activity Normally based on positive finding in vivo mammalian test.

31 Genotoxic Impurities Establishment of Two classes 1. Class 1 Genotoxic substances with sufficient evidence for a threshold related mechanism E.g. topoisomerase inhibition, Inhibition of DNA synthesis Interaction with the spindle apparatus of cell division Establishment of exposure levels using ICH Q3 (R3) based on permitted Daily Exposure (PDE) which is derived using No Observed Effect Level ( NOEL) from the most relevant animal study incorporating various uncertainty factors

32 2.Class 2 Genotoxic Impurities Genotoxic compounds without sufficient evidence for a threshold related mechanism e.g. alkylating agents ALARP As Low As Possible Principle to be followed Case by Case Decision with an Overall Risk Benefit evaluation criteria

33 Calculating threshold for effects without threshold Virtually safe dosed or TTCs Concept first proposed by CFSAN as a threshold for regulation of Food Contact materials TTC refers to a dose of a material that does not pose a significant risk of cancer or other toxic effects

34 Genotoxic Impurities TTC Concept (Threshold of Toxicological Concern) Definition of a common exposure level for any Unstudied chemical that will not pose a risk or significant carcinogenicity or other toxicity TTC estimated as 1.5 microgram/day Not applicable to highly potent genotoxic carcinogens such as N Nitroso, azoxy, compounds. This group requires compound specific toxicity data!! Not applicable to carcinogens where adequate toxicity data (long term studies) are available and allow for a compound specific risk assessment!!

35 Evaluating Genotoxic Impurities Challenges and Concerns Manufacture of API s is a Blend of Synthetic Organic reactions using various chemicals, solvents and catalyst Analytical chemistry to accurately determine impurities, byproducts, degradation products residual solvents and the final Purity of the API

36 Evaluating Genotoxic Impurities Challenges and Concerns Approaches to Identification and Detection of GTI s Evaluation of the Chemical structure of the API and Various Intermediates formed during the Synthetic Pathway Evaluation of various chemicals used during the Manufacture of the Drug substance, Identification of Possible GTI s from the Molecular structure

37 Evaluating Genotoxic Impurities Challenges and Concerns Understanding whether the Impurities come from Key Starting Materials Reagents ( Methane sulfonic acid, 2-methoxy ethanol) Side reactions/byproducts ( N-oxides, alkenes etc) Catalyst/solvents Functional isomers, geometrical isomers etc ( Eg Terbinafine)

38 Evaluating Genotoxic Impurities Challenges and Concerns

39 Evaluating Genotoxic Impurities Challenges and Concerns

40 Rasagiline Mesylate, is a medication often prescribed for the treatment of Parkinson's disease (Azilect--Teva) + Cl N O S O O Base NH 2 + H 2 N (R)-Indan-1-yl-prop-2-ynyl-amine; salt with methanesulfonic acid O N N Cl Cl ((E)-3-Chloro-allyl)-(R)-indan-1-yl -am ine (2-Chloro-allyl)-(R)-indan-1-yl-ami ne

41 Evaluating Genotoxic Impurities Challenges and Concerns Approaches to Assess the genotoxicity Ames Test Evaluation with known structurally similar compound Computational Toxicology OSIRIS property explorer TOPKAT Suitable Analytical Methods Detection in ppm/ppb levels Appropriate instruments (LC-MS-MS,NMR) Validation and Reporting Limits Appropriate guidelines for calculating the reporting limits (EU, US-FDA and maintaining the commonality across the globe) Clear Understanding of the requirements for NEW API, Generic API and other well established Drugs

42 Genotoxic Impurities Toxicology Assessment and Classification.

46 Genotoxic Impurities Toxicology Assessment and Classification. Qualification Strategy

48 EMEA 2006 guidelines for Assessment of Acceptability of GTI s

49 Major Points in EMEA s June 2008 Q & A Guidelines is NOT applied retrospectively unless there is Cause for Concern e.g. Mesylate salts If the level of a mutagenic impurity is below TTC (< 1.5 µg/day) it is not necessary to apply the ALARP unless structure is of high concern e.g. N-Nitroso or azoxy compound Negative result in an Ames Assay qualifies an Impurity with a structural alert Absence of structural alerts is sufficient to regard impurity as Non Genotoxic It is sufficient to reduce impurities with structural alerts to TTC levels without an actual test

50 Major Points in EMEA s June 2008 Q & A When more than one genotoxic impurity is present in the drug substance, the TTC of 1.5 µg/day can be applied to each impurity if they are structurally unrelated. If structurally similar, MOA expected to be the same and they are summed up May not be always achievable: Maximum daily dose of API Indication Step of synthesis at which impurity arises Capability to eliminate by Purification Capability of Analytical Procedures

51 Staged TTC During Drug Development (EMEA Q & A, June 2008) Duration of Exposure Single dose 1 month 3 month 6 month 12 month Allowable Daily Intake (µg/day)

52 Major Points in EMEA s June 2008 Q & A No action is required for a new unidentified impurity found at levels below the ICH identification threshold. When an Impurity is found above the ICH identification threshold, but below the qualification threshold and has a structural alert, this can be qualified with an Ames test on the API containing the impurity as long as the impurity is tested up to 250 µg/plate.

53 Topics of Discussion General Principles Specification of Impurities Residual Solvents Metal Catalyst and Heavy Metals Genotoxic Impurities Additional Reading

54 Additional Information

55 Additional Information

56 Additional Information

57 Additional Information

CARBOWAX SENTRY Polyethylene Glycol (PEG) and Methoxypolyethylene Glycol (MPEG) Products

Effective: June 9, 2016 Supercedes: None CARBOWAX SENTRY Polyethylene Glycol (PEG) and Methoxypolyethylene Glycol (MPEG) Products Elemental Impurities / Metal Impurities USP general chapter Elemental