Every product should have a sufficient level of quality to ensure its efficacy and safety. The impurities/degradation products are the ones that arise during different stages of synthesis, manufacture and storage. They should be controlled at certain level to maintain the required quality of the drug substance/product.
The potential impurities are most likely to arise during the synthesis of drug substance, purification, manufacturing and storage of the drug substance/drug product. The degradation products may arise from drug substances or reaction products of the drug substance with the environment, with an excipient, or an immediate container closure system.
Classification of Impurities:
Majorly the impurities can be classified in to five categories.
- Organic Impurities
- Inorganic Impurities
- Residual Solvents
- Elemental Impurities
- Nitrosamine Impurities
Organic Impurities –
The organic impurities can arise during manufacturing process/ storage of drug substance. The probable impurities may include
- Starting materials
- Reagents, ligands and catalysts
- Intermediates
- By-products
- Degradation products
- Geometric and Stereoisomers
Inorganic Impurities – They arise during manufacturing process.
- Reagents, ligands and catalysts
- Heavy metals
- Inorganic salts
- Inert materials
Residual Solvents –
The organic liquids that are in volatile in nature and used as vehicles in the preparation of solutions or suspensions in the synthesis of a drug substance or in the manufacture of the excipients, or in the preparation of drug products. They are classified into three types:
Elemental Impurities –
Elemental impurities are the catalysts and environmental contaminants that may be present in drug substances, excipients, or drug products. These impurities may occur naturally, be added intentionally, or be introduced inadvertently (e.g., by interactions with processing equipment and the container closure system).
When elemental impurities are known to be present, have been added, or have the potential for introduction, assurance of compliance to the specified levels is required. They are classified into three types:
Nitrosamines Impurities –
Nitrosamine – a class of compounds having the chemical structure of a nitroso group bonded to an amine (R1N(-R2)-N=O). Nitrosamines are a family of carcinogens impurities which are formed by the reaction of secondary amines, amides, carbamates, derivatives of urea with nitrite or other nitrogenous agents with the nitrogen in the +3 state. These are the chemical compounds classified as probable human carcinogens on the basis of animal studies.
The major nitrosamines impurities are listed below.
The evaluation of impurities/degradation products 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 drug substance, and manufacture and/or stability studies of the drug product. The potential degradation pathways in the drug product and impurities arising from the interaction with excipients and/or the immediate container closure system.
What is a Threshold and its Significance?
Threshold is a cut-off limit above which an action to be performed.
There are 03 types of thresholds to differentiate the significance of impurity whether to list or not in the specification.
- Reporting Threshold: A limit above (>) which an impurity should be reported.
- Identification Threshold: A limit above (>) which an impurity should be identified.
- Qualification Threshold: A limit above (>) which an impurity should be qualified.
Any degradation product at a level greater than (>) the reporting threshold, total degradation products observed in the relevant batches of the drug product, should be reported with the analytical procedures indicated.
What is Identification and Qualification?
Identification: The process establishing complete structural evidence of an impurity.
Identification of impurities present at an apparent level of not more than (≤) the identification threshold is generally not considered necessary.
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.
A Rationale for establishing impurity acceptance criteria that includes safety considerations should be provided.
- Any impurity that is higher than the reporting threshold to be reported in the specification.
- Any impurity that is higher than the identification threshold to be identified in the specification.
- Any impurity that is higher than the qualification threshold in the specification to be qualified.
What are Thresholds for Drug Substances and Drug Products?
The ICH guidelines Q3A and Q3B provides the threshold limits for the drug substances and drug products above which the impurities to be reported, identified and qualified.
What is a Specification and when to list an impurity in a Specification?
Every product should have a sufficient level of quality to ensure its efficacy and safety. The impurities/degradation products are the ones that arise during different stages of synthesis, manufacture and storage. They should be controlled at certain level to maintain the required quality of the drug substance/product. Hence, these impurities/degradation products to be listed as part of a specification with acceptance criteria.
The specification for a drug substance/drug product includes a list of impurities/degradation products. An appropriate rationale for the inclusion or exclusion of impurities/degradation products in the drug substance/drug product specification to be included as part of the dossier.
The inclusion or exclusion criteria of impurities/degradation products in the specification should be set based on a rationale derived from the observed levels in the safety, clinical, development and routine release data.
The impurity/degradation profile of the substance/product can be predicted analysing the routine activities/operations such as chemical development studies, product development studies, stress testing, batch analysis and stability studies of the developmental and commercial batches.
For drug products the concept for setting degradation product limits is based on sound scientific judgment as applied to available data on the safety and stability of the drug product, data that may include the degradation pathways of the drug substance, the manufacturing process, known excipient interactions, any safety assessment studies, stability studies conducted under the recommended storage conditions, and ancillary studies that may provide additional information on the stability profile of the drug product.
For degradation products known to be unusually potent or to produce toxic or unexpected pharmacological effects, the quantitation and/or detection limit of the analytical procedures correspond to the level at which the degradation products are expected to be controlled.
The acceptance criteria for an impurity/degradation product should be established by taking into account its acceptance criterion in the drug substance (if applicable), its qualified level (safety data), its increase during stability studies, and the proposed shelf life and recommended storage conditions for the drug product and be consistent with the level achievable by the manufacturing process and the analytical capability.
Impurities that are not degradation products (e.g., process impurities from the drug substance) are often not controlled in the drug product, as they are typically controlled in the drug substance and these impurities are not expected to be reported as part of drug product specification.
A rationale should be provided for exclusion of those impurities that are not degradation products.
What are the types of impurities/degradation products?
Based on the above criteria the impurities/ degradation products are classified in to two types.
- Specified
- Unspecified
The specified impurities are further differentiated in to:
- Specified Identified
- Specified Unidentified
Specified Impurity/degradation products:
An impurity/degradation product that is individually listed and limited with a specific acceptance criterion. A specified impurity/degradation product can be either identified or unidentified.
Unspecified impurity/degradation products:
An impurity/degradation product that is limited by a general acceptance criterion, but not individually listed with its own specific acceptance criterion.
Specified Impurities
Specified identified impurity/degradation products:
An impurity/degradation product for which a structural characterization has been established.
Specified unidentified impurity/degradation products:
An impurity/degradation product for which a structural characterization has not been established and that is defined solely by qualitative analytical properties (e.g., chromatographic retention time).
The specification should include below impurities:
- Organic Impurities
- Inorganic Impurities
- Residual Solvents
- Elemental Impurities
The Organic Impurities includes the below specific types:
- Each specified identified impurity/degradation product
- Each specified unidentified impurity/degradation product
- Any unspecified impurity/degradation product with an acceptance criterion of not more than (≤) the identification threshold
- Total impurities
How to Report the impurity Content?
The limits of the impurities to be reported in quantitative in numerical terms and the general qualitative terms like complies and meets the acceptance limits is not recommended.
For the limits below <1, the reporting decimals should be two (0.05) and if the limit is above >1 then one value after the decimals to be reported (1.0).
For each batch of the testing the report should include:
- Batch Number, Batch size and Use of batches
- Date of manufacture and facility of the manufacturing
- Impurity content, individual and total limit
- Reference to analytical procedure used (must be stability indicative and validated)
What Information to be included on Reporting, Identification and Qualification of impurities
Degradation products present at a level of not more than (≤) the identification threshold generally would not need to be identified.
However, analytical procedures should be developed for those degradation products that are suspected to be unusually potent, producing toxic or significant pharmacological effects at levels not more than (≤) the identification threshold.
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.
The unidentified degradation products listed in the drug product specification with an appropriate qualitative analytical descriptive label (e.g., unidentified A, unidentified with relative retention of 0.9). and an acceptance criterion of not more than the identification threshold for any unspecified degradation product and acceptance criteria for total degradation products.
Setting Acceptance Criteria for Degradation Products
The first consideration is whether a degradation product is specified in the United States Pharmacopeia (USP). If there is a monograph in the USP that includes a limit for a specified identified degradation product, the acceptance criterion to be set no higher than the official compendial limit.
If the acceptance criterion for a specified degradation product does not exist in the USP and this degradation product can be qualified by comparison to the reference listed drug (RLD), the acceptance criterion should be similar to the level observed in the RLD.
Special Note on Unspecified Impurity:
If a product has a monograph and the limit for unspecified impurity calculated using ICH thresholds is tighter than the listed limits in the monograph, then the ICH limits to be considered irrespective of the published monograph.
What are RTR considerations for Impurity limits?
The acceptance criteria or limits for impurities plays a crucial role in the acceptance of the marketing authorization application (NDA/ANDA/MAA). The proposed limits should be in-line with the appropriate thresholds and failing to meet specific acceptance criteria leads to typical deficiencies and enroute to an RTR decision.
The criteria to arrive at the refuse to receive decision is:
- failing to provide justification for proposed limits in drug substances and drug products for specified identified impurities that are above qualification thresholds;
- failing to provide justification for proposed limits for specified unidentified impurities that are above identification thresholds; and
- proposing limits for unspecified impurities (e.g., any unknown impurity) that are above identification thresholds.
What are the options/criteria to propose the limits that are above thresholds?
There are certain provisions where the impurity limits can be greater than the threshold criteria as appropriate, the applicant should provide a rationale for establishing the acceptance criteria of the degradation product that includes the safety evaluation and data.
The supporting data to justify the proposed acceptance criteria above the limits include:
- the observed impurity levels and proposed impurity/degradation product limits do not exceed the level observed in the reference listed drug product (RLD);
- the impurity/ degradation product is a significant metabolite of the drug substance;
- the observed impurity levels and proposed impurity/ degradation product limits are adequately justified by the scientific literature; or
- the observed impurity levels and proposed impurity/ degradation product limits do not exceed the level that has been adequately evaluated in toxicity studies.
Justifying the Higher Thresholds/Qualification Procedures
Comparative Analytical Studies
The impurity/degradation product present in a drug substance/drug product can be qualified by comparing the analytical profiles of a generic drug product with those in multiple lots of an RLD (minimum 3 lots) using the same validated, stability-indicating analytical procedure. It is essential that maximum daily doses of the degradation product and routes of administration be taken into account for qualification by comparative analytical studies.
A degradation product present in the generic drug product is considered qualified if the amount of identified degradation product in the generic drug product is similar to the levels observed in the RLD.
A region specific (US/EU/CA/JP) reference product to be utilized for physico-chemical comparative studies with multiple lots of RLD comparing the essential characteristics.
Remark: This approach is generally applicable/acceptable only for specified identified and unidentified degradation products and not recommended for unspecified impurity/degradation product.
Scientific Literature and Significant Metabolites
If the level of the specified identified degradation product is adequately justified by the scientific literature, no further qualification is considered necessary.
Toxicity Studies
Toxicity tests (non-rodent and rodent toxicological studies) are the least preferred method to qualify degradation products.
These toxicity studies need to be performed in-line to ICH/OECD guidelines.
Key Notes on Setting the Impurity Limits in the Specifications
