What is Impurity?
Any part of the new drug substance that is not the chemical entity defined as the new drug substance or any part that is not drug substance or an excipient.
Classification of Impurities
Impurities can be classified into the following categories:
1.Organic Impurities
2.Inorganic Impurities
3.Residual solvents
Organic Impurities:
Organic impurities can occur during the manufacturing process and/or storage of the new drug substance.They can be identified or unidentified, volatile or non-volatile and include
• Starting materials
• By Products:
• Intermediates
• Degradation products
• Reagents,ligand and catalysts
Inorganic Impurities:
Inorganic impurities can result from the manufacturing process.They are normally known and identified
and include:
Residual Solvents:
Solvents are inorganic or organic liquids utilized as vehicles for the formation of solutions or suspensions in the assembly of a new drug substance.
Residual solvents in pharmaceuticals are described as organic volatile chemicals that are used or produced in manufacture of drug substances.
Rationale for the reporting and control of impurities.
Organic Impurity
The actual and potential impurities most likely to occur during the synthesis, purification and storage of a new drug substance should be summarized.
Inorganic Impurity:
Inorganic impurities are usually identified and quantified using pharmacopoeial or other appropriate procedures.Carry over of catalysts to the new drug substance should be assessed during development.
Residual Solvent:
The control of residues of the solvents used in the manufacturing process for the new drug substance should be addressed and presented according to the ICH Q3C guideline for Residual Solvent.
Analytical Procedure:
Analytical procedures should be validated and demonstrate that it is suitable for the identification and quantification of the impurities.
Reference standards used in the analytical methods for control of impurities should be assessed and characterized according to their intended uses.
Classification, Reporting and qualification of Impurities.
Quantitative results should be presented numerically ,and not in general terms such as “complies”,”meets limits”etc.
Below 1.0%,the results should be recorded to two decimal places (e.g. 0.06%,0.13%);at and above 1.0%,the results should be recorded to one decimal place.(e.g.,1.3%).
Results should be rounded using standard rules.
Thresholds:
|
Maximum Daily Dose |
Reporting Threshold |
Identification Thershold |
Qualification thershold |
|
<= 2g/day |
0.05% |
0.10% or 1.0 mg per day intake (whichever is lower) |
0.15% or 1.0 mg per day Intake (whichever is lower) |
|
0.03% |
0.05% |
0.05% |
Any impurity at a level higher than the identification threshold should be classified.
Any impurity at a level higher than the recording threshold and total impurities observed in these batches of the new drug substance should be recorded.
All impurities at a level higher than the reporting threshold should be summed and reported as total impurities.
All impurities at a level higher than the qualification threshold should be suited.
Listing of Impurities in specification:
The specification in a new drug substance should include a list of impurities.
The choice of impurities in the new drug substance specification should be based upon the impurities found in batches produced by the stated commercial process.
Specific impurities can be identified or unidentified.
In brief,the new drug substance specification should incorporate ,where applicable ,the following list of impurities.
Organic Impurities
• Every specified identified impurity
• Every specified unidentified impurity
• Any unspecified impurity with the approval criterion of not more than the identification threshold.
• Total impurities
Residual Solvents
Inorganic Impurities
Definition
Impurity Profile:
A report of the identified and unidentified impurities present in a new drug substance.
Potential Impurity:
An impurity that theoretically can occur during manufacture or storage.It may or may not really materialize in the new drug substance.
Identified Impurity:
An impurity concerning which a structural characterization has been achieved.
Unidentified Impurity
An impurity concerning which a structural characterization has not been achieved and that is defined solely by qualitative analytical properties.
Specified Impurity
An impurity that is individually registered and limited with a specific acceptance criterion in the fresh drug substance specification.A specified impurity can be each identified or unidentified.
Unspecified Impurity:
An impurity that is restricted by a general acceptance criterion,but not individually listed with its own specific acceptance criterion ,in the fresh drug substance specification.
Enantiomeric Impurity:
A compound with the equivalent molecular formula as the drug substance that differs in the spatial arrangement of atoms with in the molecule and is a non-superimposable mirror image
More on Residual solvents
ICH Q3C,recommends acceptable amounts of residual solvents in pharmaceuticals for the safety of patients.
It recommends adoption of less toxic solvents and describes levels considered to be toxicologically acceptable for a few residual solvents.
Suitable selection of the solvent for the synthesis of drug substance may improve the yield, or determine characteristics as crystal form, purity and solubility.
Since there is no therapeutic gain from residual solvents, all residual solvents should be discarded to the extent possible to meet product specifications, good manufacturing practices or different quality-based requirements.
Conclusion:
Identification of impurities is very important task during the synthesis of drug substance and manufacture of dosage forms.It can provide critical data regarding the toxicity,safety,various limits of detection and limits of quantitation of various organic and inorganic impurities,usually accompany with API’s and finished products.