IMPURITIES IN NEW DRUG SUBSTANCES
To provide guidance for registration applications on the content and qualification of impurities in new drug substances produced by chemical syntheses and not previously registered in a region or member state
Impurities in new drug substances are addressed from two perspectives:
Chemistry Aspects include classification and identification of impurities, report generation, listing of impurities in specifications, and a brief discussion of analytical procedures; and
Safety Aspects include specific guidance for qualifying those impurities that were not present, or were present at substantially lower levels, in batches of a new drug substance used in safety and clinical studies.
CLASSIFICATION OF IMPURITIES
Impurities can be classified into the following categories:
- Organic impurities (process- and drug-related)
- Inorganic impurities
- Residual solvents
Organic impurities can arise 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, ligands and catalysts
Inorganic impurities can result from the manufacturing process. They are normally known and identified and include:
- Reagents, ligands and catalysts
- Heavy metals or other residual metals
- Inorganic salts
- Other materials (e.g., filter aids, charcoal)
Solvents are inorganic or organic liquids used as vehicles for the preparation of solutions or suspensions in the synthesis of a new drug substance. Since these are generally of known toxicity, the selection of appropriate controls is easily accomplished
Following Impurities Not Included here that is
(1) Extraneous contaminants that should not occur in new drug substances and are more appropriately addressed as Good Manufacturing Practice (GMP) issues,
(2) Polymorphic forms, and (3) enantiomeric impurities.
RATIONALE FOR THE REPORTING AND CONTROL OF IMPURITIES
Organic Impurities
To summarized the actual and potential impurities most likely to arise during the synthesis, purification, and storage of the new drug substance.
This summary should be based on sound scientific appraisal of the chemical reactions involved in the synthesis, impurities associated with raw materials that could contribute to the impurity profile of the new drug substance, and possible degradation products.
This discussion can be limited to those impurities that might reasonably be expected based on knowledge of the chemical reactions and conditions involved.
Also summarized the laboratory studies conducted to detect impurities in the new drug substance.
This summary should include test results of batches manufactured during the development process and batches from the proposed commercial process, as well as the results of stress testing used to identify potential impurities arising during storage.
The impurity profile of the drug substance batches intended for marketing should be compared with those used in development, and any differences discussed.
The studies conducted to characterise the structure of actual impurities present in the new drug substance at a level greater than (>) the identification threshold given in Attachment 1 (e.g., calculated using the response factor of the drug substance) should be described.
Note that any impurity at a level greater than (>) the identification threshold in any batch manufactured by the proposed commercial process should be identified. In addition, any degradation product observed in stability studies at recommended storage conditions at a level greater than (>) the identification threshold should be identified.
When identification of an impurity is not feasible, a summary of the laboratory studies demonstrating the unsuccessful effort should be included in the application. Where attempts have been made to identify) the identification thresholds, it is £ impurities present at levels of not more than (useful also to report the results of these studies.
Identification of impurities present at an apparent level of not more than (identification threshold is generally not considered necessary.
However, analytical procedures should be developed for those potential impurities that are expected to be unusually potent, producing toxic or pharmacological effects at a level not more than ) the identification threshold.
Inorganic Impurities
Inorganic impurities are normally detected and quantified using pharmacopoeial or other appropriate procedures.
Carry-over of catalysts to the new drug substance should be evaluated during development.
The need for inclusion or exclusion of inorganic impurities in the new drug substance specification should be discussed.
Acceptance criteria should be based on pharmacopoeial standards or known safety data.
Solvents
The control of residues of the solvents used in the manufacturing process for the new drug substance should be discussed and presented according to the ICH Q3C Guideline for Residual Solvents.
ANALYTICAL PROCEDURES
The registration application should include documented evidence that the analytical procedures are validated and suitable for the detection and quantification of impurities.
Technical factors (e.g., manufacturing capability and control methodology) can be considered as part of the justification for selection of alternative thresholds based on manufacturing experience with the proposed commercial process.
The use of two decimal places for thresholds does not necessarily reflect the precision of the analytical procedure used for routine quality control purposes.
Thus, the use of lower precision techniques (e.g., thin-layer chromatography) can be acceptable where justified and appropriately validated.
Differences in the analytical procedures used during development and those proposed for the commercial product should be discussed in the registration application.
The quantitation limit for the analytical procedure should be not more than (£) the reporting threshold.
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