Extractables and leachables, (E&L), are chemical impurities that migrate from delivery devices, packaging, and manufacturing systems into pharmaceutical products. Extractables are compounds that can be released from materials under exaggerated lab conditions, such as exposure to solvents, heat, or extended contact time. Leachables, are compounds that enter the drug product under normal manufacturing, storage, or use conditions over time.
Key differences between extractables and leachables lie in the conditions under which the compounds are identified. Extractables are compounds that can be released from materials such as plastics, elastomers, or adhesives under exaggerated laboratory conditions, such as elevated temperatures, aggressive solvents, or extended exposure times). These studies are designed as simulation or worst-case scenario assessments to help identify compounds that could potentially enter a pharmaceutical product. Leachables, are the compounds that are present in the drug product under normal manufacturing, storage, or use conditions, making controlled leachables studies critical for evaluating real-world patient risk.
Extractables and leachables testing is immensely important and subsequently a mandated process in the medical device and pharmaceutical industries. This testing identifies and quantifies chemical compounds migrating from manufacturing, packaging, and delivery systems. The primary role of testing is to eliminate the toxicological risks to patients and ensure a drug’s efficacy, quality, and safety. This mandatory testing involves specific documentation that satisfies global regulatory requirements.
Defining Extractables and Leachables
Extractables can be released from device materials that occur in forced laboratory conditions. Leachable impurities can migrate into the drug formulation over time. Leachables are considered a subset of extractables. Common sources and drivers of migration include rubber stoppers or plastics, lubricants, and labels and adhesives. The migration process is often the result of the following situations:
- Passive Diffusion and Migration: Monomers, additives, and residual chemicals move from high areas of concentration in the packaging into the drug product itself, which is low concentration, and is considered a molecular diffusion. They can also be absorbed directly from the packaging, especially when oil-based formulations, water, or organic solvents are involved and act as carriers for additives. Surface erosion is also possible and occurs when the drug product erodes the surface of a container, releasing pigments and fillers.
- Physical and Chemical Interactions: Materials that are soluble, and match polarity are more likely to leach into drug products. For example, non-polar additives from rubber can easily migrate into high-surfactant or oily drug formations. Basic or acidic drug products can also alter the ionic balance of packaging materials, a process called pH-induced leaching.
- Physical State and Environmental Factors: Temperature effects, surface area to volume ratio, permeation through closures, and headspace migration or outgassing can also either cause or accelerate the mobility of molecules and rate or migration.
In simple terms, extractables and leachables are impurities that can migrate into products from materials they come into contact with. The idea behind testing and regulations overseeing this issue is to predict and then be able to rectify issues that could ultimately impact the safety and efficacy of a pharmaceutical product.
Importance of Testing for Extractables and Leachables
E&L testing, including safety assessment, toxicology studies, chemical safety testing protocols, and risk assessments, is a critical part of a mandated process that is vital to both the medical device and pharmaceutical industries. The primary role of testing is to eliminate toxicological risks to patients and promote drug efficacy, quality, and safety. Testing is a preventive measure utilized to identify potential chemical contaminants that could mitigate into products from various sources, making it a key part of pharmaceutical development. Following testing guidelines ensures that manufacturers can safeguard patient safety and maintain product efficacy, as well as meet stringent regulatory standards set forth by the EMA and FDA.
E&L can pose a significant safety risk in the pharmaceutical industry. For example, many leachables are either toxic or carcinogenic, such as plasticizers, stabilizers, and antioxidants from rubber and plastics. In addition, certain leachables can react with drug substances and induce genetic damage or even immune responses in a patient. Some compounds can also cause endocrine disruption that can cause long-term health concerns, and high levels of contaminants can also cause immediate systemic toxicity or irritation, which are all types of key risks that can impact patients. Consequently, testing is the cornerstone in pharmaceutical and medical device development and is the foremost protection ensuring patient safety.
In addition to patient safety or the way the drug interacts with patients, other risks that occur from E&L include drug efficacy, negatively impacting the product itself or the way it is perceived. This can include API (Active Pharmaceutical Ingredient) Degradation that occurs when chemical interactions occur between leachables and an active ingredient, causing the drug to break down. E&L interference can also trigger product degradation that can shorten a product’s shelf life or stability. Regulatory Guidelines and Compliance Standards
The main regulatory guidelines and compliance standards for extractables and leachables in pharmaceutical packaging encompass risk assessment and patient safety. The emerging global standards include ICH Q3E, FDA guidance as well as USP <661.1>, USP <661.2> <665>, <1663>, <1664>, and ISO 10933-18. Following is a more in-depth breakdown regarding these regulatory guidelines:
- ICH Q3E Guideline: This was developed by the International Council for Harmonisation. It is made up of a risk-based framework that is designed to control E&L and promote quality and safety. It is a stricter guideline and framework created to harmonize global efforts towards safer pharmaceutical products.
- FDA Guidance: The Food and Drug Administration covers the materials used, their validation, safety testing, and the closure systems used for packaging human drugs. The FDA is the primary agency that oversees pharmaceutical packaging compliance within the United States. It also enforces current Good Manufacturing Practices (cGMP).
- BPOG: BioPhorum Operations Group (BPOG) provides standardized best-practice guidelines for evaluating leachables and extractables within a single-use systems (SUS) as part of biopharmaceutical manufacturing. These important protocols are widely utilized to assess the risk of harmful chemical migration from plastic into drugs.
- USP <661> and <1665>: United States Pharmacopeia USP <661> series covers the evaluation of plastic packaging systems. Chapter USP <655> covers requirements for plastic components used in manufacturing systems within the pharmaceutical field.
- USP <1633> and <1664>: These chapters include the best practices for assessing both extractables, USP <1663> and USP <1664> leachables as it relates to pharmaceutical delivery systems and packaging.
- ISO 10993-18: The International Organization for Standardization, or ISO, is an independent body that sets global standards for manufacturing and technology. ISO 10933-18 is a specific standard that provides the framework for identifying, quantifying and then controlling chemical constituents within medical devices and assessing potential risk to patients. It is a step-by-step approach to identifying specific materials and chemical constituents.
While many of the E&L standards agree on a global basis, there are some significant differences relating to regulatory approaches. This is especially true as it relates to risk thresholds and documentation depth. The industry is currently transitioning to implement stricter mandatory standards, which are showcased in the ICH A3E guidelines to provide a more comprehensive and unified framework for manufacturing and pharmaceutical packaging. Here is a closer look at the United States guidelines as compared to a global approach and the new global guideline:
- FDA: The United States Food and Drug Administration relies on USP standards and ICH guidelines for proper E&L oversight. It also requires that drug product container closure systems do not alter the safety, strength, identity, or quality of a drug product.
- EMA: The European Medicines Agency focuses on enforcement through EU GMP Part I guidelines. It also includes ICH guidelines and frequently collaborates with the FDA on E&L standards.
- ICH: The International Council for Harmonisation has issued the ICH Q3E guideline as an approach to creating a comprehensive, harmonized framework for E&L assessment across all regions.
Analytical Methods for Extractables and Leachables Testing
E&L testing relies on a tiered analytical approach to detect both organic and inorganic compounds from packaging. The core techniques used in this type of testing include the following:
- GC-MS: Gas Chromatography (GC) – Mass Spectrometry (MS) is ideally suited for testing of volatile organic compounds. It is often utilized to detect solvents and monomers.
- LC-MS: Liquid Chromatography (LC) – Mass Spectrometry (MS) is the primary tool used to test polar, volatile, and high-molecular-weight compounds. It is used to detect solvents and monomers.
- ICP-MS: Inductively Coupled Plasma (ICP)-Mass Spectrometry (MS) is a preferred method for detecting inorganic substances, trace materials and elemental impurities due to its high sensitivity.
E&L analysis usually starts with untargeted screening using the methods outlined above to identify potential compounds. This is followed by targeted and validated studies for formal leachables identification, a process known as quantification. This validation and specificity are necessary to ensure compliance with regulatory standards and patient safety. There are several challenges that are common in E&L analytical methods and testing overall. They are outlined below:
- Complex Identification or Unknowns: In many cases, unknown leachables are difficult to identify due to their chemical structures being unknown before analysis. Consequently, high-resolution mass spectrometry is required for accurate mass measurements.
- Low Detection Thresholds: Another common issue affecting the analytical evaluation threshold AET is low detection thresholds due to high drug dosage or high risk. This demands highly-sensitive analytical techniques to detect even trace contaminants, which can be difficult at ppb levels.
- Complex Sample Matrices: Large-molecule biologics contain complex formulations that can interfere with the detection of leachables. Sample preparation and separation techniques are often utilized to overcome this difficulty.
There are many complications and difficulties surrounding E&L testing . However most issues can be remedied or at least reduced using high-resolution spectrometry, multi-detector approaches, advanced data processing, careful documentation, and robust sample preparation.
Impact of Extractables and Leachables on Drug Safety and Efficacy
As mentioned above, the impact that E&L can have on drug safety and efficacy is immense. E&L can cause significant chemical interactions and drug degradation, which ultimately impacts the stability, efficacy, and safety of pharmaceutical drug products. E&L pose significant biocompatibility and toxicological risks when releasing chemical compounds from either packaging or medical devices into the body or breaking down medicine.
Toxicological assessments are key to determining if chemicals like additives or monomers exceed safe dosage levels and biocompatibility evaluations look at how the body reacts to these substances. Toxicological implications can involve threats like direct and indirect toxicity from leachables, which is why safety thresholds and risk calculations as well as understanding key health concerns like carcinogenicity, genotoxicity, and reproductive toxicity are so important.
Best Practices for Ensuring Safety and Compliance
While the risk from E&L should not be minimized, there are actionable ways that pharmaceutical companies can reduce these risks. For example, following specific strategies for safe packaging materials and then conducting thorough testing is key toward creating safe products that meet regulations and maintain compliance. Effective E&L documentation is key to prove this compliance as well as ensure products are safe. This documentation process should be considered a life cycle approach with early risk assessments performed in pre-clinicals, which is then followed up with detailed toxicological assessments that align with USP <1663>, USP <1664> and ISO 10993-18 standards. Best practices emphasize orthogonal analytical techniques like LC-MS, GC-MS, and ICP-MS to create a traceable and comprehensive paper trail that proves safety and compliance. Final reporting should be submitted via eCTD Technical Conformance Guide. All documentation should also follow ALCOA Plus principles, meaning they are Attribute, Legible, Contemporaneous, Original, Accurate, Complete, Consistent, Enduring, and Available.
Contact Us at BA Sciences
Extractables and leachables are an issue that must be addressed within the pharmaceutical industry. Robust and innovative E&L testing and analysis leads to enhanced pharmaceutical safety and compliance. At BA Sciences, we offer our extractables and leachables testing services to create a safer product and manufacturing environment. Contact us today to learn more about this and to partner with a service that has provided the highest quality analytical testing services to life science companies since 1987.