USP 6th Annual Scientific Meeting, India

Impurities in Drug Substance & Products

Compendial & Regulatory Perspectives in Impurity Characterization & Control

A Global Perspective
Nandkumar Chodankar (Ph D) President API Watson Pharmaceuticals India

Impurities in Drug Substance & Products

Introduction & Definition Why Control ? Who are Affected? Classification of Impurities Rational for Reporting & Control of Impurities Analytical Procedures Reporting impurity content of Batches Arriving at Threshold Listing of impurities in specifications Qualification of Impurities Decision tree for Identification & Qualification Summary Examples Thresholds, Identification & Qualification Additional Data 3 6 12 15 24 26 30 34 37 38 42 44 48
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1. Introduction

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As a result of EU Mutual Recognition Procedure and US FDA collaboration with ICH, the Drug Product standards are getting harmonized. As a result of this, the Global Health Authoritys requirement for
Classification of impurities, Rational for reporting and control of Organic, Inorganic, Solvents and other impurities (Chiral, Polymorphs, Microbial, and Qualification of New Impurities is becoming almost uniform)

Summary

Analytical procedures Reporting impurity content of batches Listing of impurities in specifications, Identification & Qualification of impurities in the drug substance & product is getting harmonized.

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Definition: Impurity
Any extraneous material present in the drug substance requiring it to be controlled even if it is totally inert or has superior pharmacological properties
Other 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 impurity Any 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 is not the chemical entity defined as a new drug substance
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Why Control?
Different reasons for different Segments of Pharmaceutical business (Regulators, Manufacturers, Pharmacopeias) Can have
Different Efficacy Different Bioavailability Adverse or Toxic effect
Guidelines on Impurities: ICH Q3A(R1), Q3A(R2), Q3B (R2), Q3C and Q6A, CPMP guidance, US FDA Guidelines, Recent Changes, Future Expectation

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Who are Affected?

Regulators

Business Segments

Consumers

Compendia

Manufacturer
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General Chapters & Guideline Impurity Specifications (Binding to all,

generally submitted by Innovator)

Analytical Techniques for the determination of Impurities Reporting Impurities in Regulatory Submission Reference Substances Different Pharmacopoeia
USP vs. EP/BP/JP/IP Availability of Reference Standards Analytical methods to Control Inorganic Impurities

Compendia

Continual updates
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<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

Compendia

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Provide Guidelines, Advise Specification,

Qualification, Quantitation, Threshold Safety

Regulators

Complaint Handling

Filings NDAs, ANDAs, DMFs, Sampling, Inspections

Regulate Industry

Regulatory perspectives on Impurity Characterization and Control Control of Impurities in Drug Substance Control of Impurities in Drug Products Control of Impurities in Excipients Residual solvents in marketed Products Impurity Qualification (Actual & Potential) Impurity Specifications & Reporting Limits Degradation study & Shelf life, Safety

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Current Regulators Requirements

Identification & Control of Impurities

Chiral Microbial

Biochemical Isomeric Polymorphic

New TSC
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2. Classification of Impurities

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Regulators

Control & Qualification of Impurities (for APIs Manufactured by Chemical Synthesis) Two Perspectives / Aspects of the guideline

Chemical Aspect

Safety Aspects
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Chemical Aspect
Regulators Classification Identification Report Generation Listing of impurities in specification Discussion of Analytical Procedure
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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 for safety & clinical studies.
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Classification
Catalyst
I N O R G A N I C

Starting Material By-products

Manufacturing
O R G A N I C

Legands

Storage

&

Intermediates

Heavy Metals Residual Metals Inorganic Salts Other Materials

Filter aids, Carbon

Reagents

Degradation Manufacturer Impurities

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Rationale for The Reporting & Control of Impurities

Impurity Profiling in Drug Substance

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Reporting for the Reporting & Control Impurities

Organic

In-organic

Residual solvent

Identified

Unidentified

Volatile

Non-volatile
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Where does the Organic Impurities come from? API & Drug Product, Excipient.

Drug Substance Drug Product

Manufacturing
Unit Excipients Operations Compatibility

Packaging & Storage

Starting Reaction Material Byproducts

Un-reacted Intermediates

Reagents Ligands Catalysts

Degradation Products

Control Impurity at Every Stage

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In what form the Inorganic Impurity can be present?

Inorganic: Drug Substance, Excipient or Product

Reagents Ligands Catalysts

Heavy Metals Other Residual Salts

Inorganic Salts

Other Materials (Filter aids Carbon, etc.)

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Solvent as an Impurity & its Limit

How does the Solvent remain as an Impurity?

Used as vehicle during

Dissolution during

Synthesis
may remain as residue

Purification or Crystallization
may remain as residue

Used During Granulation, Coating or any other Unit Operation

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Rationale to Report & Control Organic Impurities

Summarize the actual and potential impurities that are most likely to arise during:
API Synthesis Raw Materials By-products Related Intermediates Solvents API Purification Carbon? Related Polymorph Chiral Solvates Solvents Packaging & Storage Drug Product Unit Operations Processes

Degradation products
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Reagents, ligands, catalyst

Additional Information on Reporting & Control

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
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Analytical Procedures

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What should Analytical Procedures include? Analytical Procedure

Identification

Qualification

Quantitation

Analytical Procedure should be validated

[Refer ICH Q2A & Q2B]

Read Additional slides included in this Presentation

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Reporting impurity Content in The Batches

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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

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How to Report Impurity content of the batches?

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.
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How to Report Impurity content of the batches? 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.
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How to arrive at Thresholds?

Maximum Reporting Identification Daily Threshold Threshold Dose < 2g/day 0.05% 0.10% or 1.0mg/day intake (whichever is lower) 0.05% Qualification Threshold 0.15% or 1.0mg/day intake (whichever is lower) 0.05%

> 2g/day
1:

0.03%

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

How to Report Impurity content of the batches? 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.
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How to Report Impurity content of the batches? 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:

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Batch identity and size Date of manufacture Site of manufacture Manufacturing process Impurity content (individual & total) Use of Batches (distribution) Reference to analytical procedure used
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Listing of Impurities in Specifications

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

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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.
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Total impurities Residual solvent Inorganic impurities Extend the same concept for the Drug Products

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Qualification of Impurities
How to carry out Qualification of impurities? Qualification of impurities-Use Decision Tree

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Decision Tree-Upside down

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Decision Tree-Qualification
Structure Identified? No Yes Yes Is impurity greater No than identification Threshold? No Action

Reduce to Yes No further Not More action Than (<) No Identification Yes Threshold? Reduce to Not Yes No No More Than (<) Greater than Qualification Qualification No Action Threshold Threshold? No
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Any known Yes Reduce to human relevant Safe level risk?

Decision Tree- Continued

NMT Identification Threshold No NMT Qualification Threshold No

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
Yes Any clinically relevant adverse Effects? No

Reduce Safe level

Qualified
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Notes to the Decision Tree

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

As a result of EU Mutual Recognition Procedure and US FDA collaboration with ICH, the Drug Product standards are getting harmonized. As a result of this, the Global Health Authoritys requirement for
Classification of impurities, Rational for reporting and control of Organic, Inorganic, Solvents and other impurities (chiral, polymorphs, microbial, and Qualification of New Impurities is becoming almost uniform

Summary

Analytical procedures Reporting impurity content of batches Listing of impurities in specifications, Identification & Qualification of impurities in the drug substance & product is getting harmonized.

Nandkumar

Nandkumar Chodankar (Ph D. Tech) President Watson (Formerly Sekhsaria Chemicals Ltd.) nkc@bom7.vsnl.net.in