1. Impurities in Drugs author: srikanth N
Drug Substance and Drug Product
Impurities in Drugs author: srikanth N

2.
Impurity
Any component of the new drug substance that is not the chemical entity defined as the new drug substance

3. Type of Impurities http://stabilitystudies.blogspot.in Impurity
Process
Degradation
Contamination
Enantiomeric
Polymorphic

4. Types of Impurities
Each type of Impurity can be classified as follows.

5. Types of impurities Volatile Non-Volatile
Organic
Identified
Un-identified
Inorganic
Residual solvents
Volatile
Non-Volatile

6. Reagents, catalysts and Ligands
Organic Impurities
Organic Impurities
Starting Materials
By-Products
Intermediates
Degradation Products
Reagents, catalysts and Ligands

7. Inorganic impurities Inorganic Impurities
Reagents,ligands and catalysts
Heavy Metals or Other residual salts
Inorganic salts
Other materials (filter aids, charcoal)

8. control organic impurity
Control 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

9. 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

10. 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

11. Drug substance Drug Substance Manufacturing Starting Material
Reaction By-products
Unreacted Intermediates
Reagents, Ligands and catalysts
Packaging and storage
Degradation Products

12. 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

13. Listing in specification
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)

14. 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.

15. 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.

16. 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.

17. 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
0.15% or 1.0 mg per day intake, whichever is lower
> 2 g / day
0.03%

18. 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

19. 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

20. 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.

21. 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.

22. 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.

23. Identification thresholds
Identification thresholds
Max 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