Understanding the Impact of Extractables and Leachables (E&L) on Drug Safety
Extractables and leachables (E&L) pose two primary risks: contamination from harmful impurities like nitrosamine or chromium, which can cause toxicity, and the reduction of drug efficacy due to destabilization or perturbation of the active pharmaceutical ingredient (API). Although the risk posed by manufacturing equipment is relatively low compared to the threat from lifetime container closure systems and material packaging of drug products, these risks remain significant. The effects of manufacturing equipment are often more immediate and easier to detect, while the chemical transformations in packaging occur more gradually, making them more challenging to identify. In this context, leachables can be understood as a subset of extractables.
The recalls of nitrosamine-contaminated drugs have highlighted the critical need for robust analytical methods and risk-based approaches for E&L and nitrosamines testing. Drug manufacturers must also ensure that toxic elemental impurities are effectively controlled in their products. Risk-based approaches for E&L testing, especially for small molecules, are increasingly being implemented, largely in response to concerns over nitrosamine contamination. These trends align with broader industry practices aimed at minimizing contamination risks.
The Role of Packaging Components
Plasticizers, stabilizers, lubricants, and colorants are common components of medication packaging systems. The degree to which these materials affect product and patient safety depends on factors such as the delivery method and the patient’s condition. For example, aerosols, sprays, and transdermal packaging systems pose higher risks compared to tablets, capsules, or topical powders. This was emphasized by Andrew Feilden, European E&L strategic director at Element Materials Technology, who noted that inhalation aerosols and sprays, due to their route of administration, have the highest likelihood of interaction with packaging components and therefore require stringent regulatory attention. The early regulatory focus on inhalation and nasal drug products, primarily driven by the International Pharmaceutical Aerosol Consortium on Regulation & Science, laid the foundation for understanding supply chain interactions and their effects on drug products.
A crucial aspect of this interaction is the interplay between the permitted concentration limit (PCL), maximum daily dosage (MDD), and product material design. The industry has advanced significantly in the use of artificial intelligence (AI) to predict E&L exposure, yet certain limitations remain. Predictive modeling continues to evolve, driven by innovations in AI and machine learning, which are increasingly being integrated into pharmaceutical development processes.
Medical Devices and Combination Products
In recent years, drug-device combination products have become increasingly prevalent. This classification introduces additional considerations, particularly when it comes to the design of E&L studies and their regulatory review. Nicholas Morley, principal scientist at Element Materials Technology, points out that regional differences in regulations can further complicate efforts to gain approval in multiple markets. While E&L studies for medicinal products generally adhere to guidelines from the Product Quality Research Institute (PQRI) and U.S. Pharmacopeia (USP), those for medical devices typically follow International Organization for Standardization (ISO) standards. The challenge for manufacturers lies in meeting multiple standards that have similar goals—assessing patient risk—but differ in their approaches.
Designing and performing E&L studies for drug-device combination products requires a deep understanding of the similarities and differences among various standards and regional expectations. Morley emphasizes that failing to account for these differences can lead to potential deficiencies and delays in regulatory approval.
Single-Use Systems in E&L Testing
The pharmaceutical industry is increasingly adopting continuous manufacturing and single-use systems (SUS) to improve efficiency. Standardized protocols can assist in setting baselines for E&L testing and allow for easier comparisons across suppliers’ SUS products and components. According to Dan Rosen, vice president and general manager of bioproduction at Thermo Fisher Scientific, such protocols enable more consistent assessments for end-users of SUS.
As leachables are a subset of extractables, extractables testing can help identify potential leachables under standard or extreme conditions. However, leachables that may form during sterilization, storage, or use should also be considered. Discussions have emerged about moving away from gamma irradiation, which has been extensively studied, in favor of the less understood X-ray sterilization methods. While current theories suggest that the E&L profile should be similar for both methods, testing is essential to verify these assumptions.
Lalit Saxena, senior director of MSAT at Samsung Biologics, highlights that regulatory requirements are becoming more stringent, especially regarding patient safety. More in-depth risk assessments are now required to implement single-use technologies in late-stage downstream unit operations. Saxena also notes the challenges posed by compliance with United States Pharmacopeia (USP) standards, particularly USP <788> for particulate matter and USP <85> for endotoxin certification. Customized single-use assemblies, which often involve components from multiple vendors, add complexity to E&L testing.
Extractables and Leachables in Drug Lifecycle Management
The potential impact of E&L on drug products is a concern throughout the product lifecycle. Extractables and leachables can introduce impurities or destabilize the API, which can compromise patient safety and product efficacy. Although the risks posed by manufacturing equipment are often immediate and easier to detect, the slow chemical transformations in packaging materials require more diligent long-term monitoring.
Nitrosamine contamination recalls underscore the importance of implementing rigorous E&L and nitrosamines testing. The pharmaceutical industry has made progress by adopting risk-based approaches for E&L testing, particularly for small molecules, a trend that has been accelerated by concerns over nitrosamine contamination.
Plasticizers, stabilizers, lubricants, and colorants are well-established components of packaging systems. Their impact on product safety depends on various factors, such as the route of administration and the type of packaging. Inhalation aerosols and sprays, for example, have been identified as high-risk delivery systems due to the potential for interaction between the packaging material and the dosage form. Understanding these interactions is critical to ensuring the safety and efficacy of the final product.
Evolving Regulations and Predictive Modeling
The interplay between the permitted concentration limit (PCL), maximum daily dosage (MDD), and product material design is a critical consideration in E&L testing. The pharmaceutical industry has made significant strides in developing predictive modeling tools, particularly with the integration of artificial intelligence (AI). However, there are limitations, particularly with the quality and availability of data sets for training AI models.
Rick Reiley, technical director at Extractus, highlights the challenges in developing AI models for E&L predictive modeling. Many extractable data sets lack corresponding leachable data sets, which are often considered proprietary by companies. Additionally, the quality of available data can be inconsistent, with issues such as poor chromatography or insufficient identification of compounds. These limitations hinder the development of reliable predictive models.
The Role of Advanced Analytics
Traditional analytical methods for identifying extractables and leachables, such as liquid or gas chromatography combined with mass spectroscopy (LC-MS or GC-MS), remain widely used. However, other techniques are emerging to complement these methods. Fran Adar, principal Raman applications scientist at Horiba Scientific, explains that Raman spectroscopy offers unique advantages, particularly in identifying inorganic materials that standard techniques struggle to detect.
Raman spectroscopy can detect minute amounts of material without generating waste products, offering a more environmentally friendly alternative to traditional methods. While the information obtained from Raman spectroscopy may differ from that provided by LC-MS or GC-MS, it provides valuable insights into the composition of intact materials.
The Future of E&L Testing
The integration of AI, advanced analytics, and improved data sets holds promise for the future of E&L testing. As the pharmaceutical industry continues to adopt new technologies, the ability to predict and identify extractables and leachables will improve, ultimately enhancing drug safety and efficacy.
E&L testing plays a critical role in ensuring that drug products meet regulatory standards and maintain their quality throughout their lifecycle. By continuing to refine testing methods and incorporating innovative technologies, the industry can better manage the risks associated with extractables and leachables, leading to safer, more effective pharmaceuticals for patients.
