Impurities in Drugs

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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


Types of impurities

Impurities

OrganicIdentified

Un-identified

Inorganic

Residual solvents

Volatile

Non-Volatile


Organic Impurities

Organic Impurities

Starting Materials By-Products Intermediates Degradation

Products

Reagents, catalysts and

Ligands


Inorganic impurities

Inorganic Impurities

Reagents,ligands and catalysts

Heavy Metals or Other residual

saltsInorganic salts

Other materials (filter aids, charcoal)


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


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


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


Drug substance

Drug Substance

Manufacturing

Starting Material

Reaction By-products

Unreacted Intermediates

Reagents, Ligands and

catalysts

Packaging and storage

Degradation Products


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


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)


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.


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.


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.


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%


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


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


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.


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.


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.


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