Extractables and Leachables Testing in Canada: Best Practices for Risk Assessment

Introduction

Extractables and Leachables (E&L) testing has become a critical aspect of product development and safety in several industries, including pharmaceuticals, medical devices, and consumer goods. In Canada, stringent regulations and safety guidelines dictate the necessity of E&L testing to ensure that materials do not release harmful substances into the product, which could affect safety, efficacy, and quality.

For manufacturers in Canada, it is crucial to not only comply with national standards but also to ensure that the materials used in medical devices, drug packaging, and other products meet the highest safety standards for both consumer health and environmental sustainability. This article will delve into the importance of E&L testing, its regulatory requirements, the best practices for conducting tests, and strategies for mitigating risks associated with extractables and leachables.

Understanding Extractables and Leachables

Before diving into the testing process itself, it is vital to understand what extractables and leachables are, their implications, and how they differ from each other.

What Are Extractables?

Extractables refer to substances that can be leached or removed from materials when they are exposed to specific conditions such as solvents, high temperatures, or other extreme conditions. These substances are typically identified during accelerated extraction testing, which simulates the worst-case scenario for a product. Extractables can include plasticizers, stabilizers, residual monomers, and additives used during the manufacturing process. Their identification is essential as they may pose risks such as toxicity or other negative impacts on the drug or device performance.

For example, in the pharmaceutical industry, packaging materials might release extractables when exposed to solvents like alcohol or saline solutions, potentially contaminating the drug. In medical devices, extractables could compromise the safety of patients if they migrate into the body.

What Are Leachables?

Leachables, in contrast, are substances that migrate from the material under normal or real-use conditions, typically over a product’s shelf life. Leachables can come from the materials used in drug packaging, medical devices, and other consumables. These substances are of particular concern when a product is in contact with drugs, biological systems, or consumers for long periods. Leachables are typically evaluated during stability studies, where substances are detected and quantified after a product has been exposed to its expected use conditions.

For instance, a drug delivery system might allow leachables to migrate from its plastic components into the drug solution, which can alter the drug’s effectiveness or create adverse reactions in patients. In both cases, identifying leachables is crucial for ensuring the safety and effectiveness of the product.

Extractables vs. Leachables

The key difference between extractables and leachables is that extractables are substances released under extreme conditions in a controlled testing environment, while leachables are substances that migrate during typical usage or over the lifespan of the product. Both types of compounds are essential to consider in the safety assessment process for any product, especially those that come into direct contact with consumers, drugs, or biological systems.

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Importance of E&L Testing in Canada

In Canada, Extractables and Leachables testing is a critical part of the product lifecycle for medical devices, drug packaging, and consumer products. The primary objective of this testing is to evaluate whether substances leach from materials into a drug, medical device, or other product under normal usage conditions, and if so, to identify the type, concentration, and potential risks of those substances. This is particularly important because:

• Patient Safety: Certain extractables and leachables, such as heavy metals or toxic chemical additives, can pose significant health risks to patients or consumers. These risks can be life-threatening, especially in drug-delivery devices or packaging that come in direct contact with drugs or biological fluids.
• Regulatory Compliance: In Canada, the Food and Drugs Act and other regulations, including the Medical Devices Regulations and the Natural Health Products Regulations, require manufacturers to prove that their products are safe. This includes providing data on the potential risks of extractables and leachables, ensuring that products meet stringent health and safety standards. Manufacturers must also comply with international guidelines, such as those issued by the International Organization for Standardization (ISO) and the United States Pharmacopeia (USP).
• Environmental Impact: Besides health concerns, some extractables and leachables may have an environmental impact, particularly when they end up in wastewater or soil. Understanding and controlling the release of such substances is important for reducing environmental pollution and ensuring sustainable practices.
• Product Quality and Integrity: E&L testing ensures that the release of substances from materials does not affect the quality or integrity of the product. For example, a drug packaged in a plastic container that leaches chemicals could lose potency or undergo chemical reactions that change its composition.

By performing E&L testing, manufacturers can identify harmful substances early in the development process and take appropriate action to mitigate or eliminate potential risks, thereby ensuring both product safety and regulatory compliance.

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Best Practices for E&L Testing in Canada

1. Risk Assessment and Material Selection

Before beginning E&L testing, manufacturers must conduct a risk assessment to evaluate the potential for harmful extractables and leachables to migrate into their products. This step involves understanding the material composition and evaluating factors such as:

• Chemical Composition: The raw materials used in the manufacturing process should be carefully chosen. For example, materials containing phthalates or bisphenol A (BPA) may present risks as they can leach out and cause adverse health effects.
• Processing Conditions: The temperature, pressure, and type of solvent used in manufacturing can influence the extent to which substances migrate from materials. Manufacturers need to consider these factors when developing their testing protocols.
• Exposure Conditions: The product’s intended use should also be considered. For instance, if a device will be in direct contact with a drug, body fluids, or human tissues for an extended period, the risks of leaching are more significant and must be carefully evaluated.

2. Development of Testing Protocols

Once the risk assessment is completed, manufacturers must establish testing protocols that are appropriate for their products. The testing should include:

• Solvent Extraction Tests: This testing simulates harsh conditions to identify any extractables that may be released from the material. Typically, solvents such as water, alcohol, or saline are used to extract potential contaminants. These substances are then analyzed to determine their chemical nature, quantity, and potential risks.
• Leaching Studies: After performing extraction tests, leaching studies are performed under normal usage conditions to evaluate how substances migrate from materials during typical conditions, including temperature, pressure, and contact with drugs or biological systems.
• Characterization and Identification: Once the extractables and leachables are detected, manufacturers must employ advanced analytical techniques such as Gas Chromatography-Mass Spectrometry (GC-MS), High-Performance Liquid Chromatography (HPLC), and Liquid Chromatography-Mass Spectrometry (LC-MS) to identify and quantify the compounds. This characterization is crucial for determining the potential risks and classifying substances according to their toxicological profiles.

3. Consideration of Regulatory Guidelines

In Canada, manufacturers are required to adhere to several regulations and guidelines to ensure that their products meet safety standards. Key regulations include:

• Health Canada’s Medical Device Regulations (MDR): Health Canada requires medical devices to undergo safety testing, including E&L testing. The MDR is based on international standards such as ISO 10993, which provides guidelines for assessing the biological safety of medical devices.
• USP <661>: The United States Pharmacopeia (USP) provides guidelines for plastic materials of construction used in drug packaging. These guidelines cover the requirements for E&L testing, ensuring that packaging materials do not contaminate pharmaceutical products.
• ISO 10993-18: This standard provides guidelines for the chemical characterization of materials used in medical devices. It requires manufacturers to perform E&L testing to assess the potential for chemical migration from materials.

By following these standards and guidelines, manufacturers can ensure that their products meet both Canadian and international safety requirements.

4. Risk Mitigation and Control Strategies

After performing E&L testing, manufacturers must implement strategies to mitigate any risks identified. These strategies may include:

• Material Substitution: If a particular material is found to release harmful extractables or leachables, manufacturers should consider switching to alternative materials that are biocompatible and have minimal leaching potential.
• Process Optimization: Adjusting manufacturing processes to minimize the introduction of contaminants is another crucial step in risk mitigation. For example, improving cleanliness in manufacturing environments or optimizing curing processes can reduce the release of potentially harmful substances.
• Protective Coatings and Barriers: In some cases, protective coatings or barriers can be applied to materials to prevent the migration of extractables or leachables into the product.

5. Ongoing Monitoring and Surveillance

E&L testing should not be a one-time process. Manufacturers should implement ongoing monitoring and quality control measures to ensure that the products continue to meet safety standards throughout their lifecycle. This is especially important when making changes to the manufacturing process, switching suppliers, or introducing new materials.

Conclusion

Extractables and Leachables testing is a critical aspect of ensuring the safety and quality of medical devices, drug packaging, and consumer products in Canada. Manufacturers must adhere to stringent regulatory requirements and implement best practices in risk assessment, testing protocols, and risk mitigation strategies. By conducting thorough E&L testing, manufacturers can ensure that their products are safe for consumers, compliant with regulations, and free from harmful substances.

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References

1. ISO 10993-18: Biological Evaluation of Medical Devices—Part 18: Chemical Characterization of Materials.
2. USP <661> Plastic Materials of Construction.
3. FDA Guidance for Industry: Extractables and Leachables Testing.