impurities slideshow

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



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)



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



Classification of Impurities

• Organic Impurities ( Process- and Drug Related)

• Inorganic Impurities

• Residual Solvents

• Polymorphic Forms

• Enantiomeric 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




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…



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”



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%




General Principles


Residual Solvents



Additional Reading



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




General Principles


Residual Solvents



Additional Reading



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



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>



Concerns of Compendial Methods for Heavy Metals

Guidance of Specification Limits for Residues of Metal Catalyst



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



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



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)



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)



Different Metals used in Manufacture of API

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

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



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




General Principles


Residual Solvents



Additional Reading



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




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.



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



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



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.


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



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





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!!



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




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




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)



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

+



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



• Genotoxic Impurities – Toxicology Assessment and Classification.



Genotoxic Impurities – Toxicology Assessment and Classification. – Qualification Strategy



EMEA 2006 guidelines for Assessment of Acceptability of GTI’s





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



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



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



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.


General Principles


Residual Solvents



Additional Reading





Additional Information

impurities slideshow

Documents