by Ensuring the safety, efficacy, and quality of pharmaceutical products is a top priority for manufacturers, regulators, and healthcare professionals. One crucial aspect of this quality assurance process is the Related Substances Test—an analytical procedure used to detect and quantify impurities in drug substances and drug products.
What Are Related Substances?
Related substances are chemical impurities that are structurally related to the active pharmaceutical ingredient (API) or are formed during manufacturing, storage, or degradation. These can include:
- Starting materials
- Intermediates
- Degradation products
- By-products
- Residual solvents
While some of these impurities may be present in trace amounts, they can impact the drug’s safety and stability if not adequately controlled.
Why Is the Related Substances Test Important?
The primary goals of this test are to:
- Ensure patient safety by minimizing toxic or harmful impurities.
- Meet regulatory standards set by pharmacopoeias such as the USP, EP, and ICH guidelines (e.g., ICH Q3A and Q3B).
- Monitor product stability throughout the shelf life of the drug.
- Maintain batch-to-batch consistency in manufacturing.
Methods Used in Related Substances Testing
The most common technique for related substances testing is High-Performance Liquid Chromatography (HPLC). Other analytical methods may include:
- Gas Chromatography (GC)
- Thin-Layer Chromatography (TLC)
- Mass Spectrometry (MS)
- UV-Vis Spectrophotometry, in some cases
These methods are chosen based on the nature of the drug molecule and its potential impurities.
Key Steps in Conducting the Test
- Sample Preparation: Accurate and reproducible preparation of the sample and standard solutions.
- Chromatographic Separation: Using appropriate columns and mobile phases to separate the impurities from the API.
- Detection and Quantification: Sensitive detection systems (e.g., UV or MS) help quantify even trace levels of impurities.
- Result Evaluation: Comparing impurity levels against specification limits defined in regulatory documents or the drug’s monograph.
Regulatory Guidelines and Limits
According to ICH guidelines:
- Impurities above 0.05% to 0.1% typically need to be identified and qualified.
- Toxicological assessment is required if certain limits are exceeded.
- Limits may vary depending on the daily dose of the drug and route of administration.
Common Challenges
- Detecting impurities with similar properties as the API
- Managing degradation products formed under stress conditions
- Ensuring method validation (accuracy, precision, linearity, LOD/LOQ, etc.)
Conclusion
The Related Substances Test is a cornerstone of pharmaceutical quality control. By detecting and controlling impurities, manufacturers can ensure that their products are safe, effective, and compliant with global regulatory standards. With the growing complexity of modern drug formulations, robust and validated analytical methods are more important than ever.
