Navigating the Complexities of Impurities in Pharmaceuticals

Impurities in pharmaceuticals are a major concern for drug manufacturers, as they can significantly impact the quality, safety and effectiveness of the final product. Even a single unknown impurity discovered late in production can lead to the rejection of entire batches. The International Council for Harmonisation (ICH) defines an impurity as any substance in a drug product that is not the active pharmaceutical ingredient or the excipients.

Impurities are categorized into organic impurities, inorganic impurities, other materials and residual solvents. They can originate at various stages – from manufacturing to transportation and storage. During production, impurities may arise from interactions between the active pharmaceutical ingredient (API) and excipients, or from contact with packaging materials. Understanding these sources is crucial for maintaining the purity and safety of pharmaceuticals throughout their lifecycle.

Impact of impurities on product approvals and regulatory actions

The presence of impurities can delay product approvals during manufacturing and prompt recalls once products are on the market, triggering regulatory actions. Recent incidents involving substances like N-nitrosodimethylamine (NDMA) in medications such as ranitidine and valsartan have resulted in widespread recalls, highlighting the ongoing challenges in effectively managing pharmaceutical impurities.

Naiffer Romero, USP Principal Scientist and Community Manager of the Nitrosamines Exchange says, “Since nitrosamines were first found in drug products in 2018, there has been a coordinated effort among international regulatory and health agencies to advance the development of guidance to mitigate their presence, collaboration with industry and manufacturers to deepen the science and understanding of identifying and testing these impurities in medicines. Although our understanding of the issue has come a long way, it continues to evolve as new challenges arise, and the problem facing industry is far from over. Regulatory agencies initially aimed to unify their approach to nitrosamines in pharmaceuticals, but global variation in testing capabilities has led to differing stages of managing and reducing these impurities. This highlights the importance of discussions and educational efforts among regulators, drug manufacturers and industry stakeholders to address the issue.”

ICH guidelines for managing impurities in drug substances and products

The quantification, qualification, identification and control of impurities are critical in drug development to ensure the safety and purity of the final drug product. International and regional guidelines play a key role in guiding drug developers and regulatory agencies in evaluating and managing impurities in both drug substances and products.

The ICH has established several key guidelines for managing impurities. The ICH Q3A focuses on impurities in new drug substances, while ICH Q3B addresses impurities in new drug products. These guidelines outline essential criteria including identification and characterization, accurate quantification, established limits and understanding the origin of impurities. They also emphasize the importance of conducting toxicological assessments, evaluating the stability of the drug in the presence of impurities, ensuring regulatory compliance, performing thorough risk assessments and implementing effective control strategies.

While reducing impurities to practical minimums is ideal, complete elimination is often not feasible, necessitating the establishment of specific impurity criteria. The ICH Q3A and Q3B guidelines provide essential thresholds for reporting, identifying and qualifying impurities in new drug substances and new drug products respectively.

Impurity investigations by phase of development

Managing impurities is crucial throughout the entire product lifecycle, from initial development to manufacturing and distribution. Yaman Abdin, research fellow at Saarland University, says, “Impurities are everywhere! This simple truth keeps colleagues in quality control, from devising guidelines to implementing strategies, very busy. Impurities are an inevitable challenge in chemistry, especially in pharmacy, and the field is dynamic and evolving.”

The level of scrutiny in impurity investigations depends on the project's development phase. In the early stages of development, it's impractical to investigate all impurities; the focus should be on the most likely potential impurities observed in the initial phases (e.g., intermediates, solvents, predictable by-products from stress studies). In the later phases of development, more detailed studies are conducted to understand impurity origins and behaviors, guiding decisions on which impurities require routine monitoring with defined limits. Stress degradation studies in later phases further identify degradation products, helping to inform formulation and storage requirements.

“We're constrained by the accuracy and precision of our analytical methods as well as the fact that we only find what we look for. To manage impurities effectively, we must focus on the purity of starting materials, controlled processing environments, and proper handling and storage. Adopting a “quality by design” approach is key to achieving better purity profiles,” explains Abdin.

Analytical techniques for impurity detection

A variety of analytical techniques are employed to identify and quantify impurities throughout the drug development process. Each method offers distinct advantages and is suited to specific types of analyses. Below, we explore several key analytical methods used for impurity detection in pharmaceutical products.

Table 1: Analytical methods used for the detection of impurities in drug products.

Advances in NMR‐based characterization of drug impurities

NMR facilitates the identification and confirmation of molecular structures, aiding in the detection of impurities. NMR helps elucidate the mechanisms behind the formation of process and degradation impurities, which is vital for maintaining drug quality. However, challenges remain. Gary Martin, adjunct professor at the Stevens Institute of Technology, explains, “Undoubtedly, the biggest challenge associated with the identification and characterization of drug impurities is the size of the sample that can be isolated vs. the NMR probe technology available where the research is being done. While sensitivity has never been an issue for mass spectrometric methods, quite the opposite is true for NMR spectroscopy, which is notoriously sensitivity-challenged. Obviously, higher-field NMR spectrometers are advantageous.” 

Highlighting the recent advances, Martin says “Probably one of the most significant recently developed techniques that can be used in the characterization of drug impurities was the development of the i-HMBC experiment, which allows the unequivocal differentiation of two-bond from three-bond long-range or longer-range correlations. The full potential of this experiment and the range of applications has only just begun to be realized.” 

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Nitrosamine Impurities in Medicines

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Strategies for minimizing drug impurities

To minimize drug impurities, several effective strategies can be implemented. Firstly, optimizing synthesis routes and process controls ensures efficient pathways, significantly reducing impurity formation. Additionally, using high-quality starting materials with low impurity profiles helps to limit contaminants in the final product. Strict adherence to good manufacturing practices (GMP) is essential for maintaining high production standards and minimizing impurities. Controlled storage and handling conditions, including proper temperature and humidity management, prevent degradation and the formation of impurities. Lastly, thorough validation of cleaning procedures ensures that equipment and facilities are free from cross-contamination, further safeguarding product integrity.

“In addition to the general requirements manufacturers must meet to analyze their products for impurities, to identify those that may arise during manufacturing, and to conduct stability studies – when it comes to nitrosamines specifically – there is a need for more preemptive actions to effectively head off the risks,” Romero explains.

As per Romero, pharmaceutical companies can take the following proactive actions to mitigate the risks:

• Develop and implement risk-based assessments to evaluate chemical structures, manufacturing processes, raw materials and historical data to help determine which products are more vulnerable to the formation of nitrosamines.
• Adopt a culture of continuous improvement, regularly reviewing and refining their risk management strategies, manufacturing processes and testing protocols.
• Proactively test medicines for impurities throughout a product’s life cycle for better detection, assessment and action to keep the global medicines supply chain safe.

Regardless of the source of the impurities – whether from manufacturing to transportation or storage – comprehensive risk assessment and mitigation ultimately helps determine the safety of a product in the hands of a patient, adds Romero.

Promoting collaboration and innovation in addressing drug impurities

By adopting innovative strategies and fostering partnerships across the industry, stakeholders can effectively address the emerging issues of drug impurities and prevent unforeseen product recalls.

Romero says, “Information and knowledge sharing allows for open discussions regarding recent findings and updated regulatory requirements. To facilitate collaboration and information sharing among the global network of professionals concerned with the issue, USP created the Nitrosamines Exchange, a dedicated knowledge-based community designed to allow industry subject matter experts, along with representatives from international regulatory and health agencies, to discuss recent updates and engage in active problem-solving. Members of the quickly growing community of 4,000+ share information and solutions to mitigate nitrosamines through thread conversations, questions and anecdotal experiences. By participating in these types of conversations, industry can help prevent future nitrosamine-related recalls and help ensure medicines remain safe for patients.”

Abdin adds, “Global harmonization of regulatory standards and constantly improving analytical techniques have significantly enhanced our ability to detect and control impurities. However, emerging challenges such as microplastic and nanoplastic impurities could find their way or maybe already found their way to drug products and hence represent the next frontier. Addressing these new types of contaminants will require innovative methods and continued global collaboration to ensure the safety and efficacy of pharmaceuticals.”