Extractables and Leachables: Best Practices & Key Considerations

Within the pharmaceutical industry, development and manufacturing, patient safety goes beyond just creating effective formulas. The materials used to package and deliver those formulas—from pill bottles to prefilled syringes and inhalers—can interact with the medicine in complex ways. This is where the concepts of extractables and leachables (E&L) become increasingly important. Recognizing and managing E&L is key to making sure that unintended substances, introduced by contact with packaging materials, don’t affect drug quality or pose risks to patients.

What are Extractables and Leachables?

Extractables are compounds—often chemicals or tiny particles—that can be pulled from packaging or container closure systems using solvents, often under laboratory-simulated “worst-case” or extreme conditions (for example, high heat or strong solvents). This simulates what could happen during the product’s lifecycle, revealing potential leachables.

Leachables are those substances that actually migrate from the packaging, manufacturing materials, or delivery device into the drug formulation during real storage conditions or typical usage. These substances are of particular concern because, unlike extractables, leachables are directly transferred to the patient along with the drug.

Understanding the difference matters: while extractables give us an idea of what could get into the product under stress, leachables show us what does get in during normal use.

Why Extractables and Leachables Testing is Essential

Identifying and controlling extractables and leachables is not just a regulatory box to check; it’s essential for protecting patients and ensuring drug products are both safe and effective. Chemicals from the packaging system may contaminate the drug, potentially causing toxicity, allergic reactions, or even changing the chemical stability and efficacy of active pharmaceutical ingredients (APIs). This is especially true for complex pharmaceuticals like biologics.

Our expert, Marie Sophie, stated that:

The sensitivity of biological products to leachables and extractables, particularly under extreme pH conditions mandated for stability or solubility, is a factor that your CDMO must consider when selecting materials. Leachables may cause conformational changes in proteins or lead to aggregation, while large-molecule drug products might chelate inorganic leachables. Such interactions can increase toxicity, reduce efficacy, or compromise stability. Thus, it is essential to thoroughly evaluate E&L risks to ensure product quality and safety and to avoid costly delays in bringing a product to market.

To safeguard against these issues, manufacturers carry out extractables and leachables testing to discover what compounds may be present, at what levels, and if they are harmful, in accordance with regulatory guidelines. This data allows manufacturers to evaluate risks, improve packaging, and avoid costly recalls or failed batches during late-stage development.

Key Terminologies Defined

Before delving deeper, it’s crucial to clarify some definitions that are core to any extractables and leachables discussion:

• Extractables: Compounds that can be “pulled out” of packaging, medical devices, or manufacturing surfaces under severe, controlled laboratory conditions. This is to anticipate every possible risk.
• Leachables: The subset of extractables that actually migrate into the drug (or medical device) during its real-world shelf life, storage, and use.
• Leachable impurities: Unintended chemical substances that make their way into the final drug product through leaching.
• Container closure systems: All the materials and components (like vials, stoppers, seals) that form the immediate packaging for a pharmaceutical product.
• Packaging system: All packaging-related parts, including primary, secondary, and other associated materials, that come into contact with the drug during manufacturing, storage, and delivery.

Overview of Regulatory Expectations

Regulatory agencies such as the FDA and equivalent organizations worldwide require pharmaceutical firms to leave nothing to chance when it comes to leachables. For example, the FDA guidance on Container Closure Systems for Packaging Human Drugs and Biologics notes that manufacturers must prove the safety of any material used in the packaging, processing, or delivery of drugs.

For medical devices, ISO standard 10993-18 outlines best practices for conducting E&L assessment and risk evaluation, which pharmaceutical manufacturers must adhere to. The Product Quality Research Institute (PQRI), in collaboration with the FDA, has also released influential recommendations that guide industry-wide best practices. Failing to demonstrate the safety of packaging components and materials can result in regulatory rejection, delayed approvals, or costly reformulation.

Packaging in Focus: All Components Matter

When you consider a drug product’s packaging, it’s not just the bottle or vial itself that requires attention, but the entire container closure system. The entire packaging system must be evaluated for its potential to introduce extractables and leachables. This includes:

• The primary container (directly holding the drug)
• Any secondary packaging for added protection or labeling
• Clo­sure materials such as stoppers, caps, seals
• Inks and adhesives used on labeling
• Other packaging material like cartons and leaflets
• Manufacturing equipment (like mixers or single use systems)

Even trace amounts of a harmful chemical from any one of these can contaminate a batch, underscoring the importance of scrutinizing the complete system for extractable and leachable impurities.

Types of Materials and Risks of Leaching

The types of materials used in pharmaceutical packaging—plastics, elastomers, glass, adhesives, paper, metals—each come with unique properties and challenges. Chemicals in these materials can potentially migrate into the drug or product upon exposure to certain conditions. Sometimes, these substances are benign; other times, they can interfere with the active ingredients, reduce shelf life, or even cause adverse patient health outcomes.

For instance, volatile organic compounds (VOCs) can evaporate and be inhaled; elemental impurities such as metals might accumulate and cause toxicity. Therefore, understanding material compatibility with both the drug and packaging is a fundamental quality concern.

Analytical Techniques for Detecting Extractables and Leachables

Effectively detecting leachables and extractables involves advanced scientific techniques, which are a crucial part of extractable and leachable studies:

a) GC-MS (Gas Chromatography-Mass Spectrometry)

Essential for analyzing volatile and semi volatile organic compounds, GC-MS separates potential contaminants and then identifies them by their unique ‘chemical fingerprints’. This method excels at tracing both known and unknown substances at very low concentrations.

b) LC-MS/MS (Liquid Chromatography-Mass Spectrometry)

This powerful tool analyzes non-volatile compounds—those that won’t evaporate or break down under normal test conditions. It is especially valuable for complex or high-molecular-weight compounds, such as those often seen in biopharmaceutical products.

c) ICP-MS (Inductively Coupled Plasma-Mass Spectrometry)

ICP-MS is typically used to detect and quantify trace amounts of metals, known as elemental impurities. These could be introduced from glass vials, stainless steel processing equipment, or other packaging components.

These techniques are often used together to ensure a comprehensive leachables analysis of all possible impurity classes.

Quantifying Potentially Harmful Leachables

Finding a leachable doesn’t automatically mean it is a risk to patients, but identifying leachables extractables is crucial for safety assessment. Therefore, each detected compound is compared to an analytical evaluation threshold (AET)—a scientifically determined level above which the compound must be evaluated for toxicity. This threshold helps focus attention and resources on substances that actually could cause harm, while minimizing unnecessary alarm over harmless low-level leachable impurities.

Professional toxicologists will assess the detected levels to determine what, if any, health risks exist, using a risk-based approach to inform further action.

Extractables and Leachables in Various Drug Delivery Systems

The E&L concern doesn’t stop at simple bottles or blisters; devices designed for direct contact or integration with the patient—like pre filled syringes, infusion pumps, inhalers, and combination products—must also be carefully assessed as part of the delivery system. Here, the interaction between the drug, device, and packaging materials can be even more complex due to longer contact periods, a wider variety of materials, or storage at multiple temperatures over time.

Planning and Performing Extractables and Leachables Studies

To assess E&L risk, studies typically start with a theoretical evaluation of all components and materials that might touch the pharmaceutical product. Extractables studies are performed first, in which packaging or device materials are exposed to exaggerated conditions in the lab to identify the “worst-case scenario” of what could possibly be extracted.

Once these potential contaminants are cataloged, leachable studies follow, in which the finished, packaged drug is stored under real-world or accelerated conditions. Researchers use sophisticated detection methods to see which extractable compounds actually migrate into the drug over its shelf life. The resulting data is then used for a comprehensive safety risk assessment.

Interpreting Data and Ensuring Safety

After analytical tests, all results are interpreted by toxicology experts to decide whether the quantities of leachables present in pharmaceutical products could pose health concerns. In cases where an unacceptable risk is identified, manufacturers might switch to alternative materials, add protective barriers, adjust processing, or improve cleaning procedures of manufacturing equipment. Reassessment and retesting are vital until the pharmaceutical packaging is proven safe.

Best Practice Guidelines for Success

To minimize surprises and satisfy regulators, pharmaceutical companies should:

• Begin extractables and leachables studies early in development.
• Choose packaging and processing materials proven to be compatible with drug substances.
• Follow guidance from recognized authorities like the PQRI, ISO, and united states pharmacopeia.
• Employ comprehensive and validated analytical methods such as GC-MS, LC-MS/MS, and ICP-MS.
• Maintain exhaustive documentation and transparent communication with regulatory agencies.
• Assess and adjust based on changes in packaging materials, manufacturing processes, or single use components.

By doing so, companies not only reduce regulatory surprises but also protect users from potentially harmful leachables.

Common Challenges in Extractables and Leachables Projects

Performing meticulous E&L work isn’t without obstacles, but there are solutions to address these challenges. For instance, advanced mass spectrometry data can be complicated to interpret, especially when identifying unknown substances in complex drug matrices. Matching laboratory manipulation results with real-world conditions demands careful study design. Changing drug formulations, moving to single use systems, or working with new, unfamiliar components can all introduce unforeseen risks.

Trends: Single Use Systems & Biopharmaceuticals

The rise of single use systems and single use products—such as plastic bioreactors, filters, or tubing—has made E&L assessment even more critical. These modern manufacturing aids are convenient, but often made of complex plastics and adhesives, raising potential for extractable and leachable impurities. Biopharmaceuticals, which can be unstable and highly sensitive, face higher-than-average risk from even trace levels of packaging-derived chemicals. As such, thorough extractables and leachables testing in these contexts is not just best practice, but a regulatory expectation worldwide.

Ensuring drug safety involves looking beyond what goes in—the active and inactive pharmaceutical ingredients—to what surrounds and delivers the medication. Effective extractables and leachables testing is essential to meeting global regulatory requirements, protecting end-users, and upholding the reputation of the pharmaceutical and medical device companies. By understanding all aspects of E&L, companies can design safer products, avoid regulatory issues, and deliver the highest drug product quality.

FAQs about Extractables and Leachables