Specified and Unspecified Impurities In APIs: How To Set Limits

The specified and unspecified Impurities play a vital role in the related substance or impurities profile specification of any pharmaceutical. Both specified and unspecified Impurities refer to the identification, control, and regulation of these impurities during drug development and manufacturing.

In pharmaceuticals, impurities are unwanted substances that may be present in drug products. They can affect the safety, efficacy, and quality of the product. Impurities are generally classified into specified and unspecified impurities based on their identification and control requirements.

Specified and Unspecified Impurities

Specified Impurities:

• These are impurities that have been identified and characterised during the pharmaceutical development using different analytical techniques like FTIR, NMR, Mass, HPLC, GC and KF/LOD
• Their chemical structure, origin, and potency are known.
• They are typically listed and quantified in the drug’s specification.
• Regulatory guidelines often set limits for these impurities to ensure that they are present within safe, acceptable levels.
• Examples include process-related impurities, degradation products, residual solvents, or by-products from synthesis, which are well-characterised.

Unspecified Impurities:

• These are impurities that are not identified or characterised during pharmaceutical development.
• Their chemical structure and origin are unknown.
• They may be detected during testing, but their structure is not known.
• These impurities come under the related substances or impurities profile tests.
• Regulatory agencies may set limits on unspecified impurities, typically based on safety concerns or the potential for these substances to impact the drug’s quality, safety, and efficacy.

Related topic: How To Control Impurities in Pharmaceuticals: Get Mastery In …

Types of Specified Impurities:

The following are the different types of the specified impurities:

1. Known Impurities: Impurities whose structure is known (e.g., degradation products, by-products, residual solvents).
2. Process-Related Impurities: Result from the manufacturing process (e.g., catalysts, reagents).
3. Degradation Products: Formed due to chemical degradation during storage or processing.

Examples:

• Paracetamol: Acetanilide (a known impurity).
• Antibiotics: Degradation products like penicilloic acid.

Types of Unspecified Impurities:

• Unknown Degradation Products: Arise from unexpected reactions during storage.
• Trace Contaminants: From raw materials, equipment, or the environment.
• Miscellaneous By-products: Not fully characterised yet.

Specified vs. Unspecified Impurities

1. Identification:
   • Specified impurities are identified and known.
   • Unspecified impurities are unknown and not characterised.
2. Regulation:
   • Specified impurities have known limits and are monitored during production.
   • Unspecified impurities are controlled with a limit of NMT (not more than 0.10%)
3. Safety:
   • Specified impurities are typically controlled based on known toxicological data.
   • Unspecified impurities may pose unknown risks, which is why limits for these are often set conservatively.

Key Differences

Specified and Unspecified Impurities In APIs: How To Set Limits

Setting limits for specified and unspecified impurities in APIs (Active Pharmaceutical Ingredients (APIs) is a critical part of drug development and regulatory compliance. These limits are established based on regulatory guidelines, toxicological data, process understanding, and analytical capabilities.

The following ICH Q3A(R2) Guidelines approaches are considered while setting the limit:

1. Reporting Threshold
2. Identification Threshold
3. Qualification Threshold
4. Specified Impurity Limit
5. Unspecified Impurity Limit

Reporting Threshold

• Minimum level at which an impurity must be reported.
• Typically based on the maximum daily dose (MDD) of the drug substance.

Identification Threshold

The level above which an impurity should be identified (i.e., structurally characterised).

Qualification Threshold

• The level above which the impurity must be qualified for safety (toxicology testing)

Specified Impurity Limit

The limit should be set based on:

• Expected process-related or degradation pathways.
• Toxicological qualification data.
• Must be ≤ qualification threshold, unless justified.

Note: The following Common practices are widely used in the industries:

• Individual specified impurity: typically 0.10–0.15%
• Total impurities: ≤ 1.0–1.5%, unless otherwise justified

Unspecified Impurity Limit

• Generally limited to 0.10% (for MDD ≤ 2 g/day)
• Controlled under a generic limit (e.g., “Any other impurity: NMT 0.10%”)
• Total of all impurities (specified + unspecified): NMT 1.0–1.5%, depending on the drug.

How to Decide the Limits?

The following approaches are considered while deciding the impurity limit:

• Assess the Process: List all known process-related and degradation impurities.
• Toxicological Evaluation: Conduct safety studies for recurring impurities above the qualification threshold.
• Regulatory References: Use ICH Q3A(R2), Ph. Eur, USP, and regional guidelines.
• Set Specification: Propose individual limits for specified impurities (justified via synthesis route, stability, and safety data), and apply general limits for unspecified ones.
• Justify Any Exceedance: If limits exceed thresholds, provide safety justification or risk assessment data.

Case study: An API with MDD (max. daily dose) = 500 mg/day)

Specified, unspecified and total impurities can be kept as:

• Imp-A ≤ 0.10%
• Imp-B ≤ 0.15%
• Any unknown impurity: ≤ 0.10%
• Total impurities: ≤ 0.50%

Conclusion

In summary, the control of specified and unspecified impurities is a critical aspect of pharmaceutical quality assurance. These impurities can significantly impact the safety, efficacy, and overall quality of drug products. By understanding their nature, sources, and regulatory requirements, pharmaceutical professionals can ensure robust impurity profiling during drug development and manufacturing. This not only meets stringent regulatory standards but also upholds patient safety and product reliability. We hope this article has provided a clear and comprehensive understanding of specified and unspecified impurities, addressing your key queries effectively.

FAQs

What is the difference between specified and unspecified impurities?

Specified impurity comes under known impurity in the specification, whereas unspecified impurity comes under unknown impurity in the specification

How to decidethe unknown impurity limit?

The limit of unknown impurity is not more than 0.10%

What is the ICH limit for unspecified impurities?

The ICH limit for unspecified impurity is not more than 0.10%

Reference:

• ⟨1086⟩ IMPURITIES IN DRUG SUBSTANCES AND