From Start to Finish: Managing Impurities and Degradants Throughout Drug Product Development

As pharmaceutical companies continue to develop innovative drugs, it is imperative to consider the impact of impurities and degradants on drug product safety and efficacy. Impurities are defined as any component that is not the drug substance, while degradants refer to chemical entities that result from degradation of the drug substance or impurities. In this article, we will explore the impact of impurities and degradants on drug product quality and safety, as well as regulatory CMC considerations to control these factors.

The Impact of Impurities and Degradants on Drug Product Quality and Safety

Impurities and degradants can have a significant impact on drug product quality and safety. These impurities can be present at various stages of drug development, including raw materials, intermediates, and the final drug product. Impurities can be introduced through a variety of sources such as starting materials, reagents, solvents, catalysts, or even from the environment.

Impurities can affect drug product quality and safety in several ways. First, they can have a direct impact on the efficacy of the drug product. For example, impurities can reduce the potency of the drug or cause unwanted side effects. Second, impurities can impact the stability of the drug product, leading to degradation of the drug over time. Finally, impurities can also impact the safety of the drug product, potentially causing toxicity or other adverse effects.

Degradants, on the other hand, are formed due to chemical or physical changes to the drug substance. Degradation can occur through a variety of mechanisms, such as oxidation, hydrolysis, or photolysis. These degradation products can be toxic, and if not controlled, can significantly impact the safety and efficacy of the drug product.

Regulatory CMC Considerations to Control Impurities and Degradants

Controlling impurities and degradants in drug products is crucial for ensuring drug product safety and efficacy. Regulatory agencies such as the FDA and EMA have established guidelines and regulations for impurities and degradants in drug products. These guidelines help ensure that drug products are safe and effective for patient use.
The following are some regulatory CMC considerations to control impurities and degradants:

1.    Identification and Quantification of Impurities and Degradants: It is essential to identify and quantify impurities and degradants in drug products. This can be done through various analytical techniques such as HPLC, GC, or MS. By identifying and quantifying impurities and degradants, it is possible to establish acceptable limits for these impurities.

2.    Setting Acceptable Limits: Once impurities and degradants are identified and quantified, it is necessary to set acceptable limits for these impurities. These limits are established based on safety and efficacy considerations and can be different for different drug products.

3.    Control Strategies: Control strategies are developed to prevent the introduction of impurities and degradants during drug product manufacturing. These control strategies can include process changes, changes in raw materials, and improvements in manufacturing equipment.

4.    Stability Testing: Stability testing is performed to evaluate the impact of impurities and degradants on drug product stability over time. This testing can help establish the shelf-life of the drug product and ensure that impurities and degradants are controlled within acceptable limits.

The Best time during development to start to look for and control Impurities and Degradants

Controlling impurities and degradants in drug products is crucial for ensuring drug product safety and efficacy. It is recommended that drug developers start looking for and controlling impurities and degradants early in the drug development process.

The identification and control of impurities and degradants should be considered as part of the overall drug development strategy. This includes the selection of appropriate starting materials, development of the manufacturing process, and establishment of analytical methods to monitor impurities and degradants.

During the early stages of drug development, the focus should be on identifying potential impurities and degradants that could arise during the manufacturing process. This includes evaluating the stability of the drug substance and potential impurities under various conditions, such as temperature, humidity, and light.

As the drug development process progresses, analytical methods should be developed and validated to identify and quantify impurities and degradants in the drug product. Acceptable limits for impurities and degradants should be established based on safety and efficacy considerations.

It is also essential to consider the impact of impurities and degradants on drug product stability. Stability testing should be performed to evaluate the impact of impurities and degradants on drug product stability over time. This testing can help establish the shelf-life of the drug product and ensure that impurities and degradants are controlled within acceptable limits.

In summary, the best time to start looking for and controlling impurities and degradants in your drug product is early in the drug development process. This allows for the identification of potential impurities and degradants and the development of appropriate control strategies to ensure drug product safety and efficacy.

An Example of an Impurity that was hard to control and how that was Handled.

During the development of a recent drug product, a new impurity was identified that was difficult to control during the manufacturing process. This impurity was a result of a chemical reaction that occurred during the manufacturing process, and it was causing a decrease in the potency of the drug product.

The development team first attempted to modify the manufacturing process to prevent the formation of the impurity. However, these modifications were not successful in reducing the level of the impurity to an acceptable level.

Next, the development team investigated alternative starting materials and reaction conditions to reduce the formation of the impurity. This approach was successful in reducing the level of impurity but did not eliminate it.

Finally, the development team decided to develop a new purification process to remove the impurity from the drug product. This involved the use of a new chromatography step that was effective in removing the impurity while maintaining the potency of the drug product.

The new purification process was validated, and the drug product was able to meet the acceptable level of impurities for regulatory approval. The development team was able to successfully control the impurity by implementing a new purification process, which was critical for ensuring the safety and efficacy of the drug product.

Conclusion

Impurities and degradants can have a significant impact on drug product quality and safety. It is crucial to control these factors during drug development and manufacturing to ensure the drug product is safe and effective for patient use. Regulatory agencies have established guidelines and regulations for impurities and degradants in drug products, and it is essential to consider these factors during drug development and manufacturing. By implementing appropriate control strategies and performing stability testing, it is possible to ensure that impurities and degradants are under control.

This article discusses the impact of impurities and degradants on drug product safety and efficacy, as well as regulatory considerations for controlling these factors. Impurities and degradants can affect drug product quality and safety in various ways, and it is important to identify, quantify, and set acceptable limits for these impurities. Control strategies should be developed to prevent the introduction of impurities and degradants during drug product manufacturing, and stability testing should be performed to evaluate their impact on drug product stability. It is recommended to start looking for and controlling impurities and degradants early in the drug development process, including the selection of appropriate starting materials and the development of analytical methods.