Active pharmaceutical ingredients are the main part of every pharmaceutical product because these are the active content in any drug formulation. The presence of impurities in any active pharmaceutical ingredient during product development always remains a concern for product safety and regulatory compliance. Identification and control of these impurities are not only required for regulatory compliance but are also important for patient safety. In this article, we will explore different sources and types of impurities and strategies to resolve the challenges during product development.
1. Organic Impurities: Organic impurities are generated from organic compounds used in the manufacturing process including intermediates, by-products or degradation products. They have similarities with the original active pharmaceutical ingredient.
2. Inorganic Impurities: These impurities are basically residues of inorganic compounds used in manufacturing processes like catalysts, reagents, inorganic salts or sometimes heavy metals. These are always different from active pharmaceutical ingredients.
3. Residual Solvents: Residual solvents are the traces of solvents used in the manufacturing process; those are not completely removed during the final product.
1. Raw Material: Sometimes impurities remain in starting materials used for API manufacturing.
2. Manufacturing Process: Some impurities are generated during the manufacturing process due to side reactions or alterations in reaction conditions like temperature and pH.
3. Reaction Issues: Incomplete reactions during the manufacturing process can also lead to the generation of impurities.
4. Solvents and Reagents: The use of impure solvents or reagents in chemical reactions in the manufacturing process may also leave the impurities behind.
5. Storage Conditions: If APIs are restored in any inappropriate environmental condition, they can degrade forming different impurities.
6. Packaging Materials: Interaction between packaging material and API can lead to the formation of new impurities.
It is required to have a proper root cause analysis to identify the real cause of the presence of the impurity. By finding the root cause we can implement a robust strategy to mitigate these issues completely.
1. High-Performance Liquid Chromatography (HPLC): HPLC is the most commonly used technique to identify and quantify organic impurities in any drug product.
2. Gas Chromatography (GC): Guess chromatography is used to determine the residual solvents and volatile impurities.
3. Mass Spectroscopy (MS): Mass spectroscopy is used to determine the molecular structure of any unknown impurity.
4. Nuclear Magnetic Resonance (NMR): NMR is used to identify unknown compounds on the basis of their molecular structure.
5. Fourier Transform Infrared Spectroscopy (FTIR): FTIR is also widely used in pharmaceutical manufacturing companies to identify the material by comparing it with the standard. It identifies the material by analyzing the functional groups of the compounds.
Each of the above methods must be validated according to the ICH Q2R1 to ensure its reliability, specificity, and sensitivity.
2. Modification in Reaction Conditions: A small change in manufacturing reaction conditions like pH, temperature or change in solvents can reduce the formation of byproducts during manufacturing.
3. Change in Manufacturing Path: Sometimes any specific API manufacturing pathway produces more byproducts. Any change in the reaction pathway can help to control the formation of impurities.
2. Crystallization: APIs can be purified by use of selective crystallization of the desired impurity of the compound.
3. Distillation: Distillation is widely used to separate the volatile solvents. This method can be used to separate volatile compounds, especially residual solvents from API products.
2. Stress Study: Testing of products in extreme conditions like heat, light, humidity and oxidation can help to identify the instability of the product formulations in the development stage.
It is essential to document the above activities according to the ICH guidelines.
Types of Impurities
According to the ICH guidelines ICH Q3A and ICH Q3B, impurities can be classified into three types.1. Organic Impurities: Organic impurities are generated from organic compounds used in the manufacturing process including intermediates, by-products or degradation products. They have similarities with the original active pharmaceutical ingredient.
2. Inorganic Impurities: These impurities are basically residues of inorganic compounds used in manufacturing processes like catalysts, reagents, inorganic salts or sometimes heavy metals. These are always different from active pharmaceutical ingredients.
3. Residual Solvents: Residual solvents are the traces of solvents used in the manufacturing process; those are not completely removed during the final product.
Sources of Impurities
Finding the source of impurity is important in the process of resolving the problem effectively. It is easy to track the source if you have an idea of the possible sources. The following are the common sources of impurities in pharmaceutical products.1. Raw Material: Sometimes impurities remain in starting materials used for API manufacturing.
2. Manufacturing Process: Some impurities are generated during the manufacturing process due to side reactions or alterations in reaction conditions like temperature and pH.
3. Reaction Issues: Incomplete reactions during the manufacturing process can also lead to the generation of impurities.
4. Solvents and Reagents: The use of impure solvents or reagents in chemical reactions in the manufacturing process may also leave the impurities behind.
5. Storage Conditions: If APIs are restored in any inappropriate environmental condition, they can degrade forming different impurities.
6. Packaging Materials: Interaction between packaging material and API can lead to the formation of new impurities.
It is required to have a proper root cause analysis to identify the real cause of the presence of the impurity. By finding the root cause we can implement a robust strategy to mitigate these issues completely.
Analytical Methods for Impurity Detection
The foundation of impurity control is the effective identification and quantification of all contaminants in API. Modern analytical methods are able to detect the impurities very precisely even at trace levels. Key detection methods include:1. High-Performance Liquid Chromatography (HPLC): HPLC is the most commonly used technique to identify and quantify organic impurities in any drug product.
2. Gas Chromatography (GC): Guess chromatography is used to determine the residual solvents and volatile impurities.
3. Mass Spectroscopy (MS): Mass spectroscopy is used to determine the molecular structure of any unknown impurity.
4. Nuclear Magnetic Resonance (NMR): NMR is used to identify unknown compounds on the basis of their molecular structure.
5. Fourier Transform Infrared Spectroscopy (FTIR): FTIR is also widely used in pharmaceutical manufacturing companies to identify the material by comparing it with the standard. It identifies the material by analyzing the functional groups of the compounds.
Each of the above methods must be validated according to the ICH Q2R1 to ensure its reliability, specificity, and sensitivity.
Strategies to Resolve API Impurity Issues
Once impurity is identified and its source is stretched then strategies are implemented to eliminate the occurrence by the pharmaceutical developers. Following actions could be taken to minimize the impurity formation.A. Process Optimization
1. Improve Raw Material Quality: High-quality raw materials can be used to overcome the impurity issues from raw materials. Best quality raw materials are the key to successful production of high quality products.2. Modification in Reaction Conditions: A small change in manufacturing reaction conditions like pH, temperature or change in solvents can reduce the formation of byproducts during manufacturing.
3. Change in Manufacturing Path: Sometimes any specific API manufacturing pathway produces more byproducts. Any change in the reaction pathway can help to control the formation of impurities.
B. Use of Specific Purification Techniques
1. Filtration: Filtration removes insoluble impurities from the API in solution form. Centrifugation and vacuum filtration speed up the filtration of material.2. Crystallization: APIs can be purified by use of selective crystallization of the desired impurity of the compound.
3. Distillation: Distillation is widely used to separate the volatile solvents. This method can be used to separate volatile compounds, especially residual solvents from API products.
C. Stability Studies:
1. Accelerated Stability Study: Accelerated stability testing can help to identify the formation of degradation products in early development stages.2. Stress Study: Testing of products in extreme conditions like heat, light, humidity and oxidation can help to identify the instability of the product formulations in the development stage.
It is essential to document the above activities according to the ICH guidelines.
Regulatory Guidelines and Compliance
Regulatory agencies take the presence of impurities in pharmaceutical products very seriously. Regulatory agencies like USFDA, EMA and ICH have issued guidelines on impurity testing and control.- ICH Q3A (R2): Impurities in New Drug Substances
- ICH Q3B (R2): Impurities in New Drug Substances
- USP and EP Monographs: Provides the limits and analytical methods for impurities
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