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A Global Perspective
Nandkumar Chodankar (Ph D) President API Watson Pharmaceuticals India
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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Regulators
Business Segments
Consumers
Compendia
Manufacturer
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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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Compendia
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Regulators
Complaint Handling
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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Chiral Microbial
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
Classification
Catalyst
I N O R G A N I C
Legands
Storage
&
Intermediates
Reagents
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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.
Un-reacted Intermediates
Degradation Products
Inorganic Salts
Dissolution during
Synthesis
may remain as residue
Purification or Crystallization
may remain as residue
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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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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Identification
Qualification
Quantitation
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Report analytical results of all batches used for Clinical Study Safety Study Stability Study Proposed commercial process
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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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> 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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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-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
For Further action see the Next Page Nandkumar
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
Qualified
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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