impurity tree

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Impurities in Drug Impurities in Drug Substance & Products Substance & Products Nandkumar Chodankar (Ph D) Nandkumar Chodankar (Ph D) President API President API Watson Pharmaceuticals Watson Pharmaceuticals India India Compendial & Regulatory Perspectives in Compendial & Regulatory Perspectives in Impurity Characterization & Control Impurity Characterization & Control USP 6 USP 6 th th Annual Scientific Meeting, Annual Scientific Meeting, India India A Global Perspective A Global Perspective

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Page 1: Impurity Tree

Impurities in Drug Impurities in Drug Substance & ProductsSubstance & Products

Nandkumar Chodankar (Ph D)Nandkumar Chodankar (Ph D)President APIPresident API

Watson Pharmaceuticals Watson Pharmaceuticals IndiaIndia

Compendial & Regulatory Perspectives in Compendial & Regulatory Perspectives in

Impurity Characterization & ControlImpurity Characterization & Control

USP 6USP 6thth Annual Scientific Meeting,Annual Scientific Meeting,India India

A Global PerspectiveA Global Perspective

Page 2: Impurity Tree

Impurities in Drug Substance & ProductsImpurities in Drug Substance & ProductsIntroduction & Definition Introduction & Definition 33Why Control ? Who are Affected?Why Control ? Who are Affected? 66Classification of ImpuritiesClassification of Impurities 1212Rational for Reporting & Control of ImpuritiesRational for Reporting & Control of Impurities 1515

Analytical ProceduresAnalytical Procedures 2424

Reporting impurity content of Batches Reporting impurity content of Batches 2626

Arriving at ThresholdArriving at Threshold 3030

Listing of impurities in specificationsListing of impurities in specifications 3434

Examples Thresholds, Identification & QualificationExamples Thresholds, Identification & Qualification 4444

Additional Data Additional Data 4848

Qualification of ImpuritiesQualification of Impurities 3737

Decision tree for Identification & QualificationDecision tree for Identification & Qualification 3838

SummarySummary 4242

Nandkumar

Page 3: Impurity Tree

1. Introduction1. Introduction

Nandkumar

Page 4: Impurity Tree

As a result of EU Mutual Recognition Procedure As a result of EU Mutual Recognition Procedure and US FDA collaboration with ICH, the Drug and US FDA collaboration with ICH, the Drug Product standards are getting harmonized. Product standards are getting harmonized. As a result of this, the Global Health Authority’s As a result of this, the Global Health Authority’s requirement forrequirement for

Classification of impurities,Classification of impurities,Rational for reporting and control of Organic, Rational for reporting and control of Organic, Inorganic, Solvents and other impurities (Chiral, Inorganic, Solvents and other impurities (Chiral, Polymorphs, Microbial, and Qualification of New Polymorphs, Microbial, and Qualification of New Impurities is becoming almost uniform)Impurities is becoming almost uniform)

Analytical proceduresAnalytical proceduresReporting impurity content of batchesReporting impurity content of batchesListing of impurities in specifications, Listing of impurities in specifications, Identification &Identification &Qualification of impurities in the drug substance & Qualification of impurities in the drug substance & product is getting harmonized.product is getting harmonized.

SummarySummary

Nandkumar

Page 5: Impurity Tree

Definition: Impurity Definition: Impurity

Any extraneous material present in the Any extraneous material present in the drug substance …requiring it to be drug substance …requiring it to be controlled even if it is totally inert or controlled even if it is totally inert or has superior pharmacological propertieshas superior pharmacological propertiesOther DefinitionsOther Definitions

As per the US Federal Register Vol. 65, No. 251 Any Component of the New Drug Substance (New Active Pharmaceutical Ingredient-API) that is not the chemical entity defined as the new drug substance (New API) is an impurityAny component of the Drug Product (Finished dose) that is not the chemical entity defined as drug substance (API) or an excipients in the drug product is an impurity.According to EMEA: Any component of the new drug substance that According to EMEA: Any component of the new drug substance that is not the chemical entity defined as a new drug substance is not the chemical entity defined as a new drug substance

Nandkumar

Page 6: Impurity Tree

Why Control? Why Control? Different reasons for different Segments of Different reasons for different Segments of Pharmaceutical business Pharmaceutical business ((Regulators, Manufacturers, PharmacopeiasRegulators, Manufacturers, Pharmacopeias) ) Can haveCan have

Different EfficacyDifferent EfficacyDifferent BioavailabilityDifferent BioavailabilityAdverse or Adverse or Toxic effect Toxic effect

Guidelines on Impurities: ICH Q3A(R1), Q3A(R2), Q3B (R2), Q3C Guidelines on Impurities: ICH Q3A(R1), Q3A(R2), Q3B (R2), Q3C and Q6A, CPMP guidance, US FDA Guidelines, Recent Changes, and Q6A, CPMP guidance, US FDA Guidelines, Recent Changes, Future Expectation Future Expectation

Nandkumar

Page 7: Impurity Tree

Who are Who are Affected? Affected?

Manufacturer

Regulators

Compendia

Consumers

BusinessBusinessSegmentsSegments

Nandkumar

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General Chapters & GuidelineGeneral Chapters & GuidelineImpurity Specifications Impurity Specifications (Binding to all, (Binding to all, generally submitted by Innovator)generally submitted by Innovator)

Analytical Techniques for the Analytical Techniques for the determination of Impuritiesdetermination of ImpuritiesReporting Impurities in Regulatory Reporting Impurities in Regulatory SubmissionSubmissionReference SubstancesReference SubstancesDifferent Pharmacopoeia Different Pharmacopoeia

USP vs. EP/BP/JP/IPUSP vs. EP/BP/JP/IPAvailability of Reference StandardsAvailability of Reference StandardsAnalytical methods to Control Inorganic Analytical methods to Control Inorganic ImpuritiesImpurities

Continual updates Continual updates Compendia

Nandkumar

Page 9: Impurity Tree

Compendia

<1086> USP 30 “Impurities in Official Articles”“Concepts about impurities change with time are inseparable from developments in analytical chemistry.”“If a material previously considered to be pure, can be resolved into more than one component, that material can be redefined into new terms of purity & impurity.”“Inorganic, organic, biochemical, isomeric or polymeric component can all be considered impurities.” This is the continuous improvement.”Inorganic organic, biochemical, isomeric, or polymeric components can all be considered impurities

Nandkumar

Page 10: Impurity Tree

Control of Impurities in Drug SubstanceControl of Impurities in Drug SubstanceControl of Impurities in Drug ProductsControl of Impurities in Drug ProductsControl of Impurities in ExcipientsControl of Impurities in ExcipientsResidual solvents in marketed ProductsResidual solvents in marketed ProductsImpurity Qualification (Actual & Potential)Impurity Qualification (Actual & Potential)Impurity Specifications & Reporting LimitsImpurity Specifications & Reporting LimitsDegradation study & Shelf life, SafetyDegradation study & Shelf life, Safety

Regulators

Regulatory perspectives on Regulatory perspectives on Impurity Characterization and ControlImpurity Characterization and Control

Regulate IndustryFilings NDAs, ANDAs,

DMFs, Sampling, Inspections

Complaint Handling

Provide Guidelines,Advise Specification, Qualification, Quantitation,ThresholdSafety

Nandkumar

Page 11: Impurity Tree

Regulators

Identification & Control of Identification & Control of ImpuritiesImpurities

Chiral Biochemical Isomeric

Polymorphic

New

Microbial TSC

Current Current RequirementsRequirements

Nandkumar

Page 12: Impurity Tree

2. Classification of Impurities2. Classification of Impurities

Nandkumar

Page 13: Impurity Tree

Regulators

Control & Qualification of Impurities (for APIs Manufactured by Chemical Synthesis)

Two Perspectives / Aspects of the guideline

Chemical Aspect Safety Aspects

Nandkumar

Page 14: Impurity Tree

RegulatorsChemical Aspect

Classification

Identification

Report Generation

Listing of impurities in specification

Discussion of Analytical ProcedureNandkumar

Page 15: Impurity Tree

Regulators

Safety Aspect: Toxic vs. Non-toxic

How to qualify the impurities which Were not present or Were present at substantially lower levels, (almost negligible), in batches of a new drug substances (i.e., New API) used forsafety & clinical studies.

Nandkumar

Page 16: Impurity Tree

Manufacturer

Manufacturing

Storage

By-products

Intermediates

DegradationImpuritiesReagents

Catalyst

Legands

Heavy MetalsResidual MetalsInorganic SaltsOther MaterialsFilter aids, Carbon

&

INORGANIC

ORGANIC

StartingMaterial

ClassificationClassification

Nandkumar

Page 17: Impurity Tree

Rationale for The Reporting Rationale for The Reporting & &

Control of ImpuritiesControl of Impurities

Impurity Profiling in Drug Substance

Nandkumar

Page 18: Impurity Tree

Reporting for the Reporting & Control Impurities

Organic In-organic Residual solvent

Volatile Non-volatile

Identified Unidentified

Nandkumar

Page 19: Impurity Tree

Manufacturing Packaging & Storage

StartingMaterial

ReactionByproducts

Un-reactedIntermediates

DegradationProducts

ReagentsLigandsCatalysts

Drug Substance

Where does the Organic Impurities come Where does the Organic Impurities come from? API & Drug Product, from? API & Drug Product, ExcipientExcipient..

Drug Product

UnitOperations

ExcipientsCompatibility

Control Impurity at Every Stage Nandkumar

Page 20: Impurity Tree

Inorganic: Drug Substance, Excipient or Product

ReagentsLigandsCatalysts

Heavy MetalsOther

ResidualSalts

InorganicSalts

Other Materials

(Filter aidsCarbon, etc.)

In what form the Inorganic Impurity can be In what form the Inorganic Impurity can be present?present?

Nandkumar

Page 21: Impurity Tree

How does the Solvent remain as an Impurity?

Dissolution during Purification or Crystallization may remain as residue

Used as vehicle during Synthesismay remain as residue

Used DuringGranulation,Coating or any other Unit Operation

Solvent as an Impurity & its Limit

Nandkumar

Page 22: Impurity Tree

Summarize the actual and potential impurities that are most likely to arise during:

Rationale to Report & Control Organic Impurities

API Synthesis

APIPurification

Packaging& Storage

Raw Materials

Intermediates

By-productsRelated

Related

SolventsDegradation

products

Reagents, ligands, catalyst

Solvents

Drug Product

Unit OperationsProcesses

Carbon?

PolymorphChiral

Solvates

Nandkumar

Page 23: Impurity Tree

What additional Data should be included? Lab Data

How to present Development history report

What is the recourse when Identification is not possible

Rationale for reporting & Controlling Inorganic Impurities. Pharmacopoeial Methods

Solvent Considered as Residual Impurity

Additional Information on Reporting & Control

Nandkumar

Page 24: Impurity Tree

Analytical ProceduresAnalytical Procedures

Nandkumar

Page 25: Impurity Tree

What should Analytical Procedures include?

Analytical Procedure should be validated [Refer ICH Q2A & Q2B]

Analytical Procedure

Identification Qualification Quantitation

Read Additional slides included in this PresentationNandkumar

Page 26: Impurity Tree

Reporting impurity Content in Reporting impurity Content in The Batches The Batches

Nandkumar

Page 27: Impurity Tree

How to Report Impurity content of the batches?

Report analytical results of all batches used for

Clinical Study

Safety Study

Stability Study

Proposed commercial process

Nandkumar

Page 28: Impurity Tree

Quantitative results should be presented “Numerically”, and not in general terms. Terms like “complies”, “meets the limit” etc. are no more accepted by Authorities. Any impurity at a level greater than (>) the reporting threshold and the total impurities observed in these batches of the NDS ( New API) should be reported indicating the analytical procedure.

How to Report Impurity content of the batches?

Nandkumar

Page 29: Impurity Tree

Below 1.0% the results should be reported to two decimal places (e.g., 0.06%, 0.13%). Results should be rounded using conventional rules. A Tabulation (spreadsheet), of the data is recommended. Impurities should be designated by code number or by appropriate descriptor, e.g., retention time.If a higher reporting threshold is proposed, it should be fully justified.All impurities reported greater than (>) the reporting threshold should be summed and reported as total impurities.

How to Report Impurity content of the batches?

Nandkumar

Page 30: Impurity Tree

How to arrive at Thresholds?

MaximumDaily Dose¹

Reporting Threshold

IdentificationThreshold

Qualification Threshold

< 2g/day 0.05% 0.10% or 1.0mg/dayintake (whichever is lower)

0.15% or 1.0mg/dayintake (whichever is lower)

> 2g/day 0.03% 0.05% 0.05%

1: The amount of drug substance administered per day.Higher reporting thresholds should be scientifically justified.Lower threshold can be appropriate if the impurity is unusually toxic. Nandkumar

Page 31: Impurity Tree

When analytical procedures change during development, reported results should be linked to the procedure used, with appropriate analytical method validation information.Chromatograms of the representative batches from analytical validation studies showing appropriate separation and detectability of impurities (spiked samples), along with any other impurity test routinely performed, can serve as the representative impurity profile.The applicant should ensure that complete impurity profile (e.g., chromatograms) of individual batches are available, if and when requested.

How to Report Impurity content of the batches?

Nandkumar

Page 32: Impurity Tree

A Table should be provided that links the specific new drug substance of batch to each safety study and each clinical study in which the new drug substance has been tested.For each batch of the new drug substance, the report should include:

How to Report Impurity content of the batches?

Nandkumar

Page 33: Impurity Tree

Batch identity and size

Date of manufacture

Site of manufacture

Manufacturing process

Impurity content (individual & total)

Use of Batches (distribution)

Reference to analytical procedure usedNandkumar

Page 34: Impurity Tree

Listing of Impurities in SpecificationsListing of Impurities in SpecificationsHow to List Impurities in Specifications?

What is the rational for Impurities inclusion/exclusion? How do you arrive at Acceptance Criteria?

Nandkumar

Page 35: Impurity Tree

In short consider following

In API include, where applicable, the following list of impurities

Organic Impurities

1. Each specified Identified

2. Each specified Unidentified

3. Any unspecified impurity with an acceptance criteria of not more than (<) the identified threshold.

Nandkumar

Page 36: Impurity Tree

Total impurities

Residual solvent

Inorganic impurities

Extend the same concept for the Drug Products

Nandkumar

Page 37: Impurity Tree

Qualification of ImpuritiesQualification of ImpuritiesHow to carry out Qualification of impurities?Qualification of impurities-Use “Decision Tree”

Nandkumar

Page 38: Impurity Tree

Decision Tree-Upside down

Nandkumar

Page 39: Impurity Tree

Is impurity greaterthan identification

Threshold?

No ActionStructure Identified?

Any knownhuman relevant

risk?

Reduce toSafe level

Reduce to Not More Than (<)IdentificationThreshold?

No further action

Reduce to Not More Than (<)Qualification

Threshold

Greater thanQualificationThreshold?

Yes

Yes

Yes

Yes

Yes

No

Yes

No

No

No Action

No

No

No

Decision Tree-Qualification

For Further action see the Next Page Nandkumar

Page 40: Impurity Tree

Reduce Safe level

Any clinicallyrelevant adverseEffects?

Qualified

Consider patients population and duration of use and consider conducting:• Genotoxicity studies (point mutation, chromosomal

aberration)• General toxicity studies (one species, usually

14 –90 days)• Other specific toxicity end points, as appropriate

No No

Yes No

Decision Tree- ContinuedNMT Identification Threshold NMT Qualification Threshold

Nandkumar

Page 41: Impurity Tree

Notes to the Decision TreeNotes to the Decision Tree

If considered desirable a minimum screen (e.g.., genotoxic If considered desirable a minimum screen (e.g.., genotoxic potential), should be conducted. A study to detect point potential), should be conducted. A study to detect point mutations and one to detect chromosomal aberrations, both in mutations and one to detect chromosomal aberrations, both in vitro, are considered an appropriate minimum screen.vitro, are considered an appropriate minimum screen.If general toxicity studies are desirable, one or more studies If general toxicity studies are desirable, one or more studies should be designed to allow compensation of unqualified to should be designed to allow compensation of unqualified to qualified material. The study duration should be based on qualified material. The study duration should be based on relevant information and performed in the species most likely torelevant information and performed in the species most likely tomaximize the potential to detect the toxicity of an impurity. Onmaximize the potential to detect the toxicity of an impurity. Ona casea case--byby--case basis, single dose studies can be appropriate, case basis, single dose studies can be appropriate, especially for single dose drugs. In general a minimum duration especially for single dose drugs. In general a minimum duration of 14 days and a maximum duration of 90 days would be of 14 days and a maximum duration of 90 days would be considered appropriate.considered appropriate.Lower threshold can be appropriate if the impurity is unusually Lower threshold can be appropriate if the impurity is unusually toxic.toxic.Foe example, do known data for this impurity or its structure Foe example, do known data for this impurity or its structure class preclude human exposure at concentration present?class preclude human exposure at concentration present?Nandkumar

Page 42: Impurity Tree

As a result of EU Mutual Recognition Procedure As a result of EU Mutual Recognition Procedure and US FDA collaboration with ICH, the Drug and US FDA collaboration with ICH, the Drug Product standards are getting harmonized. Product standards are getting harmonized. As a result of this, the Global Health Authority’s As a result of this, the Global Health Authority’s requirement forrequirement for

Classification of impurities,Classification of impurities,Rational for reporting and control of Organic, Rational for reporting and control of Organic, Inorganic, Solvents and other impurities (chiral, Inorganic, Solvents and other impurities (chiral, polymorphs, microbial, and Qualification of New polymorphs, microbial, and Qualification of New Impurities is becoming almost uniformImpurities is becoming almost uniform

Analytical proceduresAnalytical proceduresReporting impurity content of batchesReporting impurity content of batchesListing of impurities in specifications, Listing of impurities in specifications, Identification &Identification &Qualification of impurities in the drug substance & Qualification of impurities in the drug substance & product is getting harmonized.product is getting harmonized.

SummarySummary

Nandkumar

Page 43: Impurity Tree

Nandkumar Chodankar (Ph D. Tech)President

Watson (Formerly Sekhsaria Chemicals Ltd.)[email protected]