Post on 03-Dec-2014
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
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
1. Introduction1. Introduction
Nandkumar
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
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
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
Who are Who are Affected? Affected?
Manufacturer
Regulators
Compendia
Consumers
BusinessBusinessSegmentsSegments
Nandkumar
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
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
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
Regulators
Identification & Control of Identification & Control of ImpuritiesImpurities
Chiral Biochemical Isomeric
Polymorphic
New
Microbial TSC
Current Current RequirementsRequirements
Nandkumar
2. Classification of Impurities2. Classification of Impurities
Nandkumar
Regulators
Control & Qualification of Impurities (for APIs Manufactured by Chemical Synthesis)
Two Perspectives / Aspects of the guideline
Chemical Aspect Safety Aspects
Nandkumar
RegulatorsChemical Aspect
Classification
Identification
Report Generation
Listing of impurities in specification
Discussion of Analytical ProcedureNandkumar
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
Manufacturer
Manufacturing
Storage
By-products
Intermediates
DegradationImpuritiesReagents
Catalyst
Legands
Heavy MetalsResidual MetalsInorganic SaltsOther MaterialsFilter aids, Carbon
&
INORGANIC
ORGANIC
StartingMaterial
ClassificationClassification
Nandkumar
Rationale for The Reporting Rationale for The Reporting & &
Control of ImpuritiesControl of Impurities
Impurity Profiling in Drug Substance
Nandkumar
Reporting for the Reporting & Control Impurities
Organic In-organic Residual solvent
Volatile Non-volatile
Identified Unidentified
Nandkumar
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
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
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
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
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
Analytical ProceduresAnalytical Procedures
Nandkumar
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
Reporting impurity Content in Reporting impurity Content in The Batches The Batches
Nandkumar
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
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
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
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
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
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
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
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
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
Total impurities
Residual solvent
Inorganic impurities
Extend the same concept for the Drug Products
Nandkumar
Qualification of ImpuritiesQualification of ImpuritiesHow to carry out Qualification of impurities?Qualification of impurities-Use “Decision Tree”
Nandkumar
Decision Tree-Upside down
Nandkumar
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
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
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
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
Nandkumar Chodankar (Ph D. Tech)President
Watson (Formerly Sekhsaria Chemicals Ltd.)nkc@bom7.vsnl.net.in