Impurities in new drug substances are addressed from two perspectives:
Chemistry Aspects includes classification and identification of impurities, report generation, setting specifications and a brief discussion of analytical procedures and
Safety Aspects includes specific guidance for qualifying impurities which were not present in batches of new drug substance use din safety and clinical studies and /or impurity levels substantially higher than in those batches. Threshold limits are defined below which, qualification is not need
Classification of Impurities
Impurities may be classified into the following categories:
• Organic impurities (Processes and Drug Related)
• Inorganic impurities
• Residual solvents
Organic impurities may arise during the manufacturing process and/or storage of the new drug substance. They may be identified or unidentified, volatile or non-volatile and include:
• Starting Materials
• Degradation Products
• Reagents, Ligands and Catalysts
Inorganic impurities may derive from the manufacturing process. They are normally known and identified and include:
• Reagents, Ligands and Catalysts
• Heavy Metals
• Inorganic Salts
• Other materials (e.g. Filter Aids, Charcoal etc.)
Rationale for the Reporting and Control of Impurities
The applicant should summaries those 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 which could contributed to the impurity profile of the new drug substance, and possible degradation products.
In addition, the applicant should summaries 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 form the proposed commercial process, as well as results of intentional degradation studies used to identify potential impurities arising during storage.
The studies conducted to characterize the structure of actual impurities present in the new drug substance at or above apparent level of 0.1% (e.g. Calculated using the response factor of the drug substance) should be described.
Degradation products observed in stability studies at recommended storage conditions should be similarly 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 impurities below the 0.1% level, it is useful to also report the results of these studies.
In organic impurities
In organic impurities are normally detected and quantitated using pharmacopeial or other appropriate procedures. Carry-over of catalysts to the new drug substance should be evaluated during development.
Any solvents which may appear in the drug substance should be quantified using analytical procedures with an appropriate level of sensitivity pharmacopoeial or other appropriate procedures should be utilized. Limits should be base on pharmacopoeial standards or known safety data taking into consideration dose, duration of treatment and route of administration. Particular attention should be given to quantitation of toxic solvents used in the manufacturing process.
Reporting impurity content of batches
Analytical results should be provided for all batches of the new drug substance used of clinical, safety testing as well as for batches representative of the proposed commercial process. The content of individual identified and unidentified and total impurities, observed in these batches of the new drug substances, should be reported with the analytical procedures indicated. Tabulation (e.g. spreadsheet) of the data is recommended. Impurities should be designated by code number or by an appropriate descriptor, e.g. retention time. When analytical procedures change during development, reported results should be linked with the procedure used, with appropriate validation information provided. Representative chromatograms should be provided. Chromatograms of such representative batches from methods validation studies showing separation and detectability of impurities (e.g. on spiked samples) along with any other impurity tests routinely performed, can serve as the representative impurity profiles. The applicant should ensure that complete impurity profiles (i.e. chromatograms) of individual batches are available if requested.
Tabulation should be provided which links the specific new drug substance batch to each safetystudy and each clinical study in which it has been used.
For each batch of the new drug substance, the report should include:
• Batch Identity and Size
• Date of Manufacture
• Site of Manufacture
• Manufacturing Process
• Impurity Content, Individual and Total
• Use of Batches
• Reference to analytical procedure used
• Specification limits for impurities
The specification for new drug substances should include limits for impurities. Stability studies, chemical development studies and routine batch analyses can be used to predict those impurities likely to occur in the commercial product. The selection of impurities to include in the new drug substances specifications should be based on the impurities found in batches manufactured by the proposed commercial process. Those impurities selected for inclusion in the specifications for the new drug substance are referred to as “specified impurities”. Specified impurities may be identified or unidentified and should be individually listed in the new drug substance specification.
Specific identified impurities should be included along with recurring unidentified impurities estimated to be at or above 0.1%. For impurities known to be unusually potent or to produce toxic or unexpected pharmacological effects, the quantitation / detection limit of the analytical methods should be commensurate with the level at which the impurities must be controlled. For unidentified impurities, the procedure used and assumptions made in establishing the level of the impurity should be clearly stated. Unidentified impurities included in the specifications should be referred to by some appropriate qualitative analytical descriptive label (e.g. Unidentified A “unidentified with relative retention of 0.9” etc.
Limits should be set no higher than the level which can be justified by safety data, and, unless safety data indicate otherwise, no lower than the level achievable by the manufacturing process and the analytical capability. In other words, where there is no safety concern impurity specifications should be based on data generated on actual batches of the new drug substance allowing sufficient latitude to deal with normal manufacturing and analytical variation and the stability characteristics of the new drug substances. Although normal manufacturing variations are expected, significant variation in batch to batch impurity levels may indicate that the manufacturing process of the new drug substance is not adequately controlled and validated.
In summary, the new drug substance specifications should include, where applicable limits for:
Each specified identified impurity
Each specified unidentified impurity at or above 0.1%
Any unspecified impurity, with a limit of not more than 0.1%
During the course of a drug development program, the qualitative impurity profile of the new drug substance may change, or anew impurity may appear as a result of synthetic route changes, process optimization, scale-up, etc. New impurities may be identified or unidentified. Such changes call for consideration of the need of qualification of the level of the impurity unless it is below the threshold values as noted above. When a new impurity exceeds the threshold the “Decision Tree for Safety studies” should be consulted. Safety studies should compare the new drug substance containing a representative level of the new impurity with previously qualified material, although studies using the isolated impurity are also acceptable (these studies may not always have clinical relevance