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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
Volatile

Identified Organic Impurities Inorganic Residual solvents


Non-Volatile

Unidentified

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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 salts

Inorganic salts

Other materials (filter aids, charcoal)

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control organic impurity


Control of organic impurities

API Synthesis

API Purification

Packaging and storage

Raw materials, by-products, related intermediates

Solvents, reagents, ligands and catalysts

Carbon Related? Polymorph or chiral or solvents

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

Packaging and storage

Starting Material

Reaction Byproducts

Unreacted Intermediates

Reagents, Ligands and catalysts

Degradation Products

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Impurities in specification

Organic Impurities
Each specified identified impurity
Each specified unidentified impurity Any 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 > 1.0% < 1.0% Listing in specification 1.3 %( one digit after decimal place) 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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Thresholds
Max daily Dose Reporting threshold Identification Threshold Qualification Threshold

2 g / day

0.05%

0.10% or 1.0 mg per day whichever is lower 0.05%

0.15% or 1.0 mg per day intake, whichever is lower 0.05%

> 2 g / day

0.03%

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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

or Reaction products of the drug substance with an excipient and/or Immediate 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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Defs
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 thresholds
Max Daily Dose *
< 1mg

Threshold
1.0% or 5 g TDI, whichever is lower 0.5% or 20 g TDI, whichever is lower 0.2 % or 2mg TDI, whichever is lower 0.10%

1mg-10 mg

> 10 mg

>2g

* Per Day
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