Impurity Standards

IMPURITY STANDARDS

• 'Impurities' refers to synthetic impurity standards and known metabolites of APIs that have been resynthesized to the highest purity, and are supplied with full analytical data, allowing precise identification and quantification of extraneous molecules that may be present in a drug.

• Drug Impurities are unwanted chemicals that remain with the active pharmaceutical ingredients (APIs) or develop during formulation or upon aging of both API and formulation.

• The presence of these unwanted chemicals even in trace amount may influence the efficacy and safety of pharmaceutical product. The control of impurities is an important task pharmaceutical impurities as per the regulatory norms.

High Pure and Well characterized impurity Standards are used for Related Substances, Organic impurities and Validation of Analytical Methods.

ORGANIC IMPURITIES

• The applicant should summarize the actual and potential impurities most likely to arise during the synthesis, purification, and storage of a 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.

• In addition, the applicant should summarize 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.

• Identification of impurities present at an apparent level of not more than (?) the 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. All impurities should be qualified as described later in this guidance.

INORGANIC IMPURITIES

• Inorganic impurities are normally detected and quantified using Pharmacopoeial or other appropriate procedures. Carry-over of catalysts to a new drug substance should be evaluated during development. The need for inclusion or exclusion of inorganic impurities in a 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 a new drug substance

QUALIFICATION OF IMPURITIES

• Qualification is 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.

• The applicant should provide a rationale for establishing impurity acceptance criteria that includes safety considerations. The level of any impurity present in a new drug substance that has been adequately tested in safety and/or clinical studies would be considered qualified. Impurities that are also significant metabolites present in animal and/or human studies are generally considered qualified.

• A level of a qualified impurity higher than that present in a new drug substance can also be justified based on an analysis of the actual amount of impurity administered in previous relevant safety studies.

• Higher or lower thresholds for qualification of impurities can be appropriate for some individual drugs based on scientific rationale and level of concern, including drug class effects and clinical experience. For example, qualification can be especially important when there is evidence that such impurities in certain drugs or therapeutic classes have previously been associated with adverse reactions in patients. In these instances, a lower qualification threshold can be appropriate. Conversely, a higher qualification threshold can be appropriate for individual drugs when the level of concern for safety is less than usual based on similar considerations (e.g., patient population, drug class effects, clinical considerations). Proposals for alternative thresholds would be considered on a case-by-case basis

• Although this guidance is not intended to apply during the clinical research stage of development, in the later stages of development, the thresholds in this guidance can be useful in evaluating new impurities observed in drug substance batches prepared by the proposed commercial process. Any new impurity observed in later stages of development should be identified if its level is greater than (>) the identification threshold.

Similarly, the qualification of the impurity should be considered if its level is greater than (>) the qualification threshold .Safety assessment studies to qualify an impurity should compare the new drug substance containing a representative amount of the new impurity with previously qualified material. Safety assessment studies using a sample of the isolated impurity can also be considered.