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January 28th ,2010Bhanu M Narayan
API R & D - VPWatson Pharma Pvt Ltd
Impurities Characterization and Controls –Genotoxic, Catalyst and Heavy Metals, and Residual Solvents
Towards New Challenges in Global Regulatory Perspectives
IPA / EDQM / IPC,TECHNICAL CONFERENCE - 2010
Topics of Discussion
General Principles
Specification of Impurities
Residual Solvents
Metal Catalyst and Heavy Metals
Genotoxic Impurities
Additional Reading
IPA / EDQM / IPC,TECHNICAL CONFERENCE - 2010
Towards New Challenges in Global Regulatory Perspectives
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)
IPA / EDQM / IPC,TECHNICAL CONFERENCE - 2010
Towards New Challenges in Global Regulatory Perspectives
Definition of ImpuritiesIdentified Impurity:An impurity for which a structural characterization has been achievedUnidentified 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 unidentifiedUnspecified Impurity: An impurity that is limited by a general acceptance criterion but not individually listed with its own specific acceptance criterion in the specificationQualification: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
IPA / EDQM / IPC,TECHNICAL CONFERENCE - 2010
Towards New Challenges in Global Regulatory Perspectives
Classification of Impurities
• Organic Impurities ( Process- and Drug Related)
• Inorganic Impurities
• Residual Solvents
• Polymorphic Forms
• Enantiomeric Impurities
IPA / EDQM / IPC,TECHNICAL CONFERENCE - 2010
Towards New Challenges in Global Regulatory Perspectives
Classification of Impurities
Organic Impurities ( Process- and Drug Related)
Organic Impurities can arise during the manufacturing process or storage of the API. They can be Identified or unidentified, volatile or nonvolatile.
e.g.:Starting materialsBy-ProductsIntermediatesDegradation ProductsReagents, ligands and catalyst
IPA / EDQM / IPC,TECHNICAL CONFERENCE - 2010
Towards New Challenges in Global Regulatory Perspectives
Classification of Impurities
Inorganic Impurities
Inorganic impurities can result from the manufacturing process, they are normally known and identified and include
e.g.:Reagents, Ligands, CatalystHeavy Metals or other residual metalsInorganic SaltsOther material e.g. Filter aids, charcoal…
IPA / EDQM / IPC,TECHNICAL CONFERENCE - 2010
Towards New Challenges in Global Regulatory Perspectives
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”
IPA / EDQM / IPC,TECHNICAL CONFERENCE - 2010
Towards New Challenges in Global Regulatory Perspectives
Threshold Limits for Impurities• Based on Daily dose
• Application of Conventional rounding rules• Total impurities >0.05%
Maximum Daily Dose
Reporting Threshold
Identification Threshold
Qualification Threshold
≤ 2 g/day > 0.05% >0.10% or 1.0 mg/day(which ever is lower)
>0.15% or 1.0mg/day(which ever is Lower
> 2g/day >0.03% > 0.05% >0.05%
IPA / EDQM / IPC,TECHNICAL CONFERENCE - 2010
Towards New Challenges in Global Regulatory Perspectives
Topics of Discussion
General Principles
Specification of Impurities
Residual Solvents
Metal Catalyst and Heavy Metals
Genotoxic Impurities
Additional Reading
IPA / EDQM / IPC,TECHNICAL CONFERENCE - 2010
Towards New Challenges in Global Regulatory Perspectives
Residual SolventsClassification, 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
IPA / EDQM / IPC,TECHNICAL CONFERENCE - 2010
Towards New Challenges in Global Regulatory Perspectives
Topics of Discussion
General Principles
Specification of Impurities
Residual Solvents
Metal Catalyst and Heavy Metals
Genotoxic Impurities
Additional Reading
IPA / EDQM / IPC,TECHNICAL CONFERENCE - 2010
Towards New Challenges in Global Regulatory Perspectives
Impurities of Heavy Metals and Metal CatalystBackground of Regulations
USP Chapter <231> “Heavy Metals”USP Chapter <730> “Plasma Spectrochemistry”
–USP-NF 29 <730>, p. 2700, 2006, 2007EP 01/2008:20408 “Heavy Metals”
–European Pharmacopoeia 6.0, §2.4.8EP 01/2008:20257, 58 “Inductively Coupled Plasma”
–European Pharmacopoeia 6.0, §2.2.57, ICP-AES– European Pharmacopoeia 6.0, §2.2.58, 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
IPA / EDQM / IPC,TECHNICAL CONFERENCE - 2010
Towards New Challenges in Global Regulatory Perspectives
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>
IPA / EDQM / IPC,TECHNICAL CONFERENCE - 2010
Towards New Challenges in Global Regulatory Perspectives
Concerns of Compendial Methods for Heavy Metals
IPA / EDQM / IPC,TECHNICAL CONFERENCE - 2010
Towards New Challenges in Global Regulatory Perspectives
Guidance of Specification Limits for Residues of Metal Catalyst
IPA / EDQM / IPC,TECHNICAL CONFERENCE - 2010
Towards New Challenges in Global Regulatory Perspectives
EMEA Guidance--Classification of Metals
Class 1 - Metals –metals of significant safety concernknown/suspected human carcinogens, other significant toxicity
Class 2 - Metals –metals of low safety concerngenerally well tolerated at typical pharmaceutical exposure, may be nutritional trace metals
Class 3 - Metals –metals of minimal safety concernwell established safety profile, no significant toxicity, well tolerated even at levels above the typical pharmaceutical exposure, typically ubiquitous in nature
IPA / EDQM / IPC,TECHNICAL CONFERENCE - 2010
Towards New Challenges in Global Regulatory Perspectives
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
IPA / EDQM / IPC,TECHNICAL CONFERENCE - 2010
Towards New Challenges in Global Regulatory Perspectives
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)
IPA / EDQM / IPC,TECHNICAL CONFERENCE - 2010
Towards New Challenges in Global Regulatory Perspectives
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)
IPA / EDQM / IPC,TECHNICAL CONFERENCE - 2010
Towards New Challenges in Global Regulatory Perspectives
Different Metals used in Manufacture of API
Important Characteristics of an Analytical Method for Metal Detection
IPA / EDQM / IPC,TECHNICAL CONFERENCE - 2010
Towards New Challenges in Global Regulatory Perspectives
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
Modern Methods of Analytical Instrumentation
Graphite furnace (electrothermal vaporization) atomic absorptionspectrophotometer (GFAAS)Inductively coupled plasma atomic emission spectrometry (ICP-AES)Inductively coupled plasma mass spectrometry
Most sensitive techniqueTypical detection limits 0.01 –1 μg/L (ppb) in solutionFast (2 minutes)Multi-element(> 60 elements)Definitive, multiple isotope identification
IPA / EDQM / IPC,TECHNICAL CONFERENCE - 2010
Towards New Challenges in Global Regulatory Perspectives
IPA / EDQM / IPC,TECHNICAL CONFERENCE - 2010
Towards New Challenges in Global Regulatory Perspectives
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
IPA / EDQM / IPC,TECHNICAL CONFERENCE - 2010
Towards New Challenges in Global Regulatory Perspectives
Topics of Discussion
General Principles
Specification of Impurities
Residual Solvents
Metal Catalyst and Heavy Metals
Genotoxic Impurities
Additional Reading
IPA / EDQM / IPC,TECHNICAL CONFERENCE - 2010
Towards New Challenges in Global Regulatory Perspectives
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
IPA / EDQM / IPC,TECHNICAL CONFERENCE - 2010
Towards New Challenges in Global Regulatory Perspectives
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.
IPA / EDQM / IPC,TECHNICAL CONFERENCE - 2010
Towards New Challenges in Global Regulatory Perspectives
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
IPA / EDQM / IPC,TECHNICAL CONFERENCE - 2010
Towards New Challenges in Global Regulatory Perspectives
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 carcinogenicriskConsideration of Flexibility in Approach
Decision Tree
IPA / EDQM / IPC,TECHNICAL CONFERENCE - 2010
Towards New Challenges in Global Regulatory Perspectives
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.
Towards New Challenges in Global Regulatory Perspectives
Genotoxic ImpuritiesEstablishment of Two classes
1. Class 1Genotoxic substances with sufficient evidence for a threshold – related mechanismE.g. topoisomerase inhibition, Inhibition of DNA synthesis
Interaction with the spindle apparatus of cell divisionEstablishment 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
IPA / EDQM / IPC,TECHNICAL CONFERENCE - 2010
Towards New Challenges in Global Regulatory Perspectives
Genotoxic Impurities2.Class 2
Genotoxic compounds without sufficient evidence for a threshold – related mechanisme.g. alkylating agents
ALARP – As Low As Possible Principle to be followed
Case by Case Decision with an Overall Risk – Benefit evaluation criteria
IPA / EDQM / IPC,TECHNICAL CONFERENCE - 2010
Towards New Challenges in Global Regulatory Perspectives
Towards New Challenges in Global Regulatory Perspectives
IPA / EDQM / IPC,TECHNICAL CONFERENCE - 2010
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
Genotoxic ImpuritiesTTC Concept (Threshold of Toxicological Concern)
Definition of a common exposure level for any Unstudied chemicalthat 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!!
IPA / EDQM / IPC,TECHNICAL CONFERENCE - 2010
Towards New Challenges in Global Regulatory Perspectives
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, by-
products, degradation products residual solvents and the
final Purity of the API
IPA / EDQM / IPC,TECHNICAL CONFERENCE - 2010
Towards New Challenges in Global Regulatory Perspectives
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
IPA / EDQM / IPC,TECHNICAL CONFERENCE - 2010
Towards New Challenges in Global Regulatory Perspectives
Evaluating Genotoxic Impurities – Challenges and Concerns
Understanding whether the Impurities come from
Key Starting MaterialsReagents ( Methane sulfonic acid, 2-methoxy ethanol)Side reactions/byproducts ( N-oxides, alkenes etc)Catalyst/solventsFunctional isomers, geometrical isomers etc ( Eg –Terbinafine)
IPA / EDQM / IPC,TECHNICAL CONFERENCE - 2010
Towards New Challenges in Global Regulatory Perspectives
Evaluating Genotoxic Impurities – Challenges and Concerns
IPA / EDQM / IPC,TECHNICAL CONFERENCE - 2010
Towards New Challenges in Global Regulatory Perspectives
Evaluating Genotoxic Impurities – Challenges and Concerns
IPA / EDQM / IPC,TECHNICAL CONFERENCE - 2010
Towards New Challenges in Global Regulatory Perspectives
NO
S
O
O
N
C l
N
C l
N H 2
C l
O
NH 2
(R )-In d a n -1 -y l-p ro p -2 -y n y l-a m in e ;s a lt w ith m e th a n e s u lfo n ic a c id
((E )-3 -C h lo ro -a lly l)- (R )- in d a n -1 -y l-a m in e
(2 -C h lo ro -a lly l) - (R )- in d a n -1 -y l-a m in e
R a s a g ilin e M e s y la te , is a m e d ic a tio n o fte n p re s c r ib e d fo r th e tre a tm e n t o f P a rk in s o n 's d is e a s e (A z ile c t--T e va )
+B a s e
+
IPA / EDQM / IPC,TECHNICAL CONFERENCE - 2010
Towards New Challenges in Global Regulatory Perspectives
Evaluating Genotoxic Impurities – Challenges and ConcernsApproaches to Assess the genotoxicity
Ames TestEvaluation with known structurally similar compoundComputational Toxicology
OSIRIS property explorerTOPKAT
Suitable Analytical MethodsDetection in ppm/ppb levelsAppropriate 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
IPA / EDQM / IPC,TECHNICAL CONFERENCE - 2010
Towards New Challenges in Global Regulatory Perspectives
• Genotoxic Impurities – Toxicology Assessment and Classification.
IPA / EDQM / IPC,TECHNICAL CONFERENCE - 2010
Towards New Challenges in Global Regulatory Perspectives
IPA / EDQM / IPC,TECHNICAL CONFERENCE - 2010
Towards New Challenges in Global Regulatory Perspectives
IPA / EDQM / IPC,TECHNICAL CONFERENCE - 2010
Towards New Challenges in Global Regulatory Perspectives
IPA / EDQM / IPC,TECHNICAL CONFERENCE - 2010
Towards New Challenges in Global Regulatory Perspectives
Genotoxic Impurities – Toxicology Assessment and Classification. – Qualification Strategy
IPA / EDQM / IPC,TECHNICAL CONFERENCE - 2010
Towards New Challenges in Global Regulatory Perspectives
IPA / EDQM / IPC,TECHNICAL CONFERENCE - 2010
Towards New Challenges in Global Regulatory Perspectives
EMEA 2006 guidelines for Assessment of Acceptability of GTI’s
IPA / EDQM / IPC,TECHNICAL CONFERENCE - 2010
Towards New Challenges in Global Regulatory Perspectives
Towards New Challenges in Global Regulatory Perspectives
IPA / EDQM / IPC,TECHNICAL CONFERENCE - 2010
Major Points in EMEA’s June 2008 Q & AGuidelines 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
Towards New Challenges in Global Regulatory Perspectives
IPA / EDQM / IPC,TECHNICAL CONFERENCE - 2010
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
Towards New Challenges in Global Regulatory Perspectives
IPA / EDQM / IPC,TECHNICAL CONFERENCE - 2010
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)
120 60 30 10 5
Towards New Challenges in Global Regulatory Perspectives
IPA / EDQM / IPC,TECHNICAL CONFERENCE - 2010
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.
Topics of Discussion
General Principles
Specification of Impurities
Residual Solvents
Metal Catalyst and Heavy Metals
Genotoxic Impurities
Additional Reading
IPA / EDQM / IPC,TECHNICAL CONFERENCE - 2010
Towards New Challenges in Global Regulatory Perspectives
IPA / EDQM / IPC,TECHNICAL CONFERENCE - 2010
Towards New Challenges in Global Regulatory Perspectives
Additional Information
IPA / EDQM / IPC,TECHNICAL CONFERENCE - 2010
Towards New Challenges in Global Regulatory Perspectives
Additional Information
IPA / EDQM / IPC,TECHNICAL CONFERENCE - 2010
Towards New Challenges in Global Regulatory Perspectives
Additional Information
IPA / EDQM / IPC,TECHNICAL CONFERENCE - 2010
Towards New Challenges in Global Regulatory Perspectives
Additional Information
IPA / EDQM / IPC,TECHNICAL CONFERENCE - 2010
Towards New Challenges in Global Regulatory Perspectives
IPA / EDQM / IPC,TECHNICAL CONFERENCE - 2010
Towards New Challenges in Global Regulatory Perspectives
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