Transcript
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IMPURITIES IN DRUGSAUTHOR: SRIKANTH N
Drug Substance and Drug Product
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Impurity Any component of the new drug
substance that is not the chemical entity defined as the new drug substance
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Types of impurities
Impurities
OrganicIdentified
Un-identified
Inorganic
Residual solvents
Volatile
Non-Volatile
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Organic Impurities
Organic Impurities
Starting Materials By-Products Intermediates Degradation
Products
Reagents, catalysts and
Ligands
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Inorganic impurities
Inorganic Impurities
Reagents,ligands and catalysts
Heavy Metals or Other residual
saltsInorganic salts
Other materials (filter aids, charcoal)
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control organic impurityControl of organic
impurities
API Synthesis
Raw materials, by-products,
related intermediates
Solvents, reagents,
ligands and catalysts
API Purification
Carbon Related?
Polymorph or chiral or solvents
Packaging and storage
Degradants
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Residual solvents Solvents are inorganic or organic liquids
used as vehicles for the preparation of solutions or suspensions in the synthesis of a new drug substance
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Solvent as an impurity
Solvents
Used as vehicle during synthesis may remain as
residue
Dissolution during purification/crystallization may remain as residue
Used during granulation/coating/any
other operation
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Drug substance
Drug Substance
Manufacturing
Starting Material
Reaction By-products
Unreacted Intermediates
Reagents, Ligands and
catalysts
Packaging and storage
Degradation Products
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Impurities in specification Organic Impurities
Each specified identified impurityEach specified unidentified impurityAny unspecified impurity with an acceptance
criterion of not more than () the identification threshold
Total impurities Residual Solvents Inorganic Impurities
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Listing of impurities% of Impurity Listing in specification
> 1.0% 1.3 %( one digit after decimal place)
< 1.0% 0.18% (Two digits after decimal Place)
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Others Enantiomeric Impurity: A compound with
the same molecular formula as the drug substance that differs in the spatial arrangement of atoms within the molecule and is a non-superimposable mirror image.
Polymorphic Forms: Different crystalline forms of the same drug substance. These can include solvation or hydration products (also known as pseudo-polymorphs) and amorphous forms.
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Types Potential Impurity: An impurity that
theoretically can arise during manufacture or storage. It may or may not actually appear in the new drug substance.
Actual Impurity: An impurity that is actually appear in the new drug substance.
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Qualification Qualification: The 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.
Qualification Threshold: A limit above (>) which an impurity should be qualified.
Reporting Threshold: A limit above (>) which an impurity should be reported. Reporting threshold is the same as reporting level in Q2B.
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ThresholdsMax daily Dose Reporting
thresholdIdentification Threshold
Qualification Threshold
≤ 2 g / day 0.05% 0.10% or 1.0 mg per day whichever is lower
0.15% or 1.0 mg per day intake, whichever is lower
> 2 g / day 0.03% 0.05% 0.05%
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Drug product In the Drug product specification, only
degradation products are to be incorporated as impurities.
The degradation products include Degradation products of the drug substance
orReaction products of the drug substance
with an excipient and/orImmediate container closure system
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Rationale for the reporting and control of degradation products
The applicant should summarise the degradation products observed during manufacture and/or stability studies of the new drug product.
Any degradation product observed in stability studies conducted at the recommended storage condition should be identified when present at a level greater than (>) the identification thresholds
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Analytical procedures Validated analytical procedures should be used to
analyze the impurities. As appropriate, this validation should include samples
stored under relevant stress conditions: light, heat, humidity, acid/base hydrolysis, and oxidation.
When an analytical procedure reveals the presence of other peaks in addition to those of the degradation products (e.g., the drug substance, impurities arising from the synthesis of the drug substance, excipients and impurities arising from the excipients), these peaks should be labeled in the chromatograms and their origin(s) discussed in the validation documentation.
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Listing in the specification
Each specified identified degradation product
Each specified unidentified degradation product
Any unspecified degradation product with an acceptance criterion of not more than () the identification threshold
Total Degradation products.
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Def’s Degradation Product: An impurity resulting
from a chemical change in the drug substance brought about during manufacture and/or storage of the new drug product by the effect of, for example, light, temperature, pH, water, or by reaction with an excipient and/or the immediate container closure system.
Degradation Profile: A description of the degradation products observed in the drug substance or drug product.
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Identification thresholdsMax Daily Dose * Threshold
< 1mg 1.0% or 5 µg TDI, whichever is lower
1mg-10 mg 0.5% or 20 µg TDI, whichever is lower
> 10 mg 0.2 % or 2mg TDI, whichever is lower
> 2 g 0.10%
* Per Day
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