What is an Extractables and Leachables testing test in pharmaceuticals?

Definition:

Extractables and leachables testing definition as above,

  1. Extractables:
    • Extractables are chemical substances that can be released or extracted from a container or packaging material when it is intentionally exposed to certain extraction conditions.
    • Extractables can include components of the packaging material itself, such as additives, stabilizers, plasticizers, or impurities introduced during the manufacturing process. .
    • Extractables are typically evaluated under exaggerated or aggressive conditions to identify and quantify potential substances that could migrate into the product.
  2. Leachables:
    • Leachables are chemical substances that can migrate from a container or packaging material into the product during storage or use.
    • Leachables are typically assessed by subjecting the packaging material to realistic or accelerated conditions that simulate the intended storage or use of the product.
    • These conditions can include factors such as temperature, light exposure, humidity, and contact with the product formulation.
    • Leachables are of concern because they have the potential to affect the quality, safety, or efficacy of the product.
Extractables and Leachables testing test in pharmaceuticals

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What is an extractable test in pharmaceuticals?

  • In the pharmaceutical industry, an extractable test refers to a type of analysis conducted to evaluate and identify the potential chemical compounds that can be extracted from a pharmaceutical product or its packaging materials.
  • These tests are typically performed to ensure that the product and its packaging are safe for use and do not introduce harmful substances or contaminants.
  • Extractable testing involves subjecting the product or its components to various extraction conditions, such as solvents, temperatures, and time periods, in order to simulate potential real-world scenarios. The extracted substances are then analyzed using analytical techniques to identify and quantify any compounds of concern.
  • The results of extractable testing help pharmaceutical companies assess the potential risks associated with their products and make informed decisions regarding product safety and quality.

What is leachability in pharmaceuticals?

  • Leachability in pharmaceuticals refers to the process by which chemical compounds or substances are released or “leached” from a pharmaceutical product’s container or packaging materials into the drug product itself.
  • These leached substances can potentially affect the quality, safety, or efficacy of the pharmaceutical product. Leachability studies are conducted to assess the potential migration of such compounds from the packaging into the drug product over time.
  • During leachability testing, the pharmaceutical product is in direct contact with its packaging material under controlled conditions, simulating normal storage or usage.
  • The packaging materials may include vials, ampoules, blister packs, plastic containers, or any other material in direct contact with the drug product.
  • The testing involves exposing the drug product to various extraction conditions, such as different solvents, temperatures, and durations, to mimic real-world scenarios.
  • The leached substances are then analyzed and identified using appropriate analytical techniques.
  • These studies help pharmaceutical companies evaluate and understand any potential risks associated with the migration of chemical compounds from packaging materials into the drug product, ensuring the safety, quality, and regulatory compliance of the pharmaceutical products.

Difference between extractability and leachability

  • Extractables and leachables are two related concepts in pharmaceutical testing, but they refer to different aspects of potential chemical migration from packaging materials into the drug product. Here’s the difference between extractables and leachables:
  • Extractables:
    • Extractables refer to the chemical compounds that can be extracted from the packaging material when it is subjected to specific extraction conditions, such as exposure to solvents, elevated temperatures, or extended durations.
    • Extractables testing involves intentionally extracting substances from the packaging material under controlled laboratory conditions to determine what compounds are present and their potential quantity.
    • The goal of extractables testing is to identify all possible compounds that have the potential to migrate from the packaging into the drug product during storage or usage.
  • Leachables:
    • Leachables, on the other hand, are the chemical compounds that actually migrate or leach from the packaging material into the drug product under normal storage or usage conditions.
    • Leachables testing aims to evaluate the presence and concentration of these migrating compounds in the drug product.
    • Unlike extractables, leachables are determined by exposing the drug product to its intended packaging material under realistic conditions over a specified time period.
    • Leachables can include impurities, degradation products, or substances derived from the packaging material itself.
  • In summary, extractables are the substances that can be extracted from the packaging material under controlled laboratory conditions, while leachables are the compounds that actually migrate from the packaging material into the drug product during normal storage or usage.
  • Extractables testing helps identify potential migration sources, while leachables testing focuses on assessing the actual chemical compounds that can impact the drug product’s quality, safety, or efficacy. .
  • Both extractables and leachables testing are important in ensuring the safety and integrity of pharmaceutical products.

What is extractables and leachables testing?

  • Extractables and leachables testing is a critical process in the pharmaceutical industry to evaluate the potential migration of chemical compounds from packaging materials into the drug product. Let’s define each testing process:

Extractables Testing:

  1. Extractables testing involves intentionally extracting chemical compounds from the packaging materials under controlled laboratory conditions.
  2. It aims to identify and quantify the range of potential substances that can be extracted from the packaging.
  3. Packaging materials, such as vials, ampoules, blister packs, plastic containers, or closure systems, are subjected to specific extraction conditions, including solvents, temperatures, and durations.
  4. The extracted substances are then analyzed using appropriate analytical techniques, such as chromatography, mass spectrometry, or spectroscopy, to identify and quantify the compounds present.
  5. Extractables testing helps identify the potential sources of chemical compounds that could migrate into the drug product during storage or usage.

Leachables Testing:

  1. Leachables testing focuses on evaluating the actual migration or leaching of chemical compounds from the packaging materials into the drug product under normal storage or usage conditions.
  2. It involves exposing the drug product to its intended packaging material and monitoring the contact over a specified period.
  3. The purpose is to assess the presence, concentration, and potential impact of migrating compounds on the drug product’s quality, safety, or efficacy.
  4. Leachables testing typically involves collecting samples of the drug product at various time intervals during storage or simulated usage.
  5. The collected samples are then analyzed using suitable analytical techniques to identify and quantify any leached compounds.
  6. Comparing the results with safety thresholds or regulatory guidelines helps determine if the identified leachables pose any potential risks.
  • Both extractables and leachables testing are essential to ensure the safety, quality, and regulatory compliance of pharmaceutical products.
  • Extractables testing identifies potential migration sources, while leachables testing assesses the actual presence and impact of migrating compounds. These testing processes help pharmaceutical companies make informed decisions about packaging materials, assess potential risks, and ensure the integrity of their products throughout their lifecycle.

What are the Different types of extractables and leachables testing?

There are different types of extractables and leachables (E&L) testing methods used in the pharmaceutical industry to evaluate potential migration from packaging materials into the drug product. Here are some common types of E&L testing:

1. Total Organic Carbon (TOC) Analysis:

  •  TOC analysis measures the total amount of organic carbon present in the extracted or leached samples.
  • It provides a general indication of organic compounds that could potentially migrate into the drug product.

2. Liquid Chromatography (LC):

  • LC is a widely used analytical technique in E&L testing.
  • High-performance liquid chromatography (HPLC) or ultra-high-performance liquid chromatography (UHPLC) can be employed for the separation, identification, and quantification of specific organic compounds in the extracted or leached samples.

3. Gas Chromatography (GC):

4. Inductively Coupled Plasma-Mass Spectrometry (ICP-MS):

  • ICP-MS is utilized for the detection and quantification of inorganic elements, such as heavy metals, in the extracted or leached samples.
  •  It can identify and measure trace amounts of metallic impurities that could migrate from packaging materials.

5. Fourier Transform Infrared Spectroscopy (FTIR):

  • FTIR spectroscopy is used to analyze the functional groups and chemical bonds present in the extracted or leached samples.
  •  It helps identify specific compounds or chemical moieties that may migrate from the packaging materials.

6. Solid-Phase Microextraction (SPME):

  •  SPME is a sampling technique that involves the extraction of volatile and semi-volatile compounds from the headspace of the extracted or leached samples.
  •  It allows for the identification and quantification of volatile compounds that could migrate into the drug product.
Different types of extractables and leachables testing

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  • These are just a few examples of the different types of E&L testing methods.
  • The specific selection of testing techniques depends on the compounds of interest, the nature of the packaging materials, and the regulatory requirements.
  • The combination of multiple analytical techniques is often employed to comprehensively evaluate the extractables and leachables in pharmaceutical products and ensure their safety and quality.

Which are the common products that have extractables and leachables?

A wide range of pharmaceutical products can potentially have extractables and leachables (E&L) concerns. The presence of E&L compounds can arise from various packaging materials and components used in the manufacturing, storage, and administration of pharmaceuticals. Here are some common products that may require E&L assessment:

1. Parenteral Products: Injectable drugs, including solutions, suspensions, or emulsions packaged in vials, ampoules, prefilled syringes, or infusion bags. Intravenous (IV) bags, tubing, and connectors used for administration.

2. Oral Solid Dosage Forms: Tablets, capsules, and powders packaged in blister packs, bottle caps, closures, or container systems.

3. Inhalation Products: Metered-dose inhalers (MDIs), dry powder inhalers (DPIs), and nebulizers. Components such as canisters, valves, actuators, and mouthpieces.

4. Transdermal Patches: Adhesive patches delivering drugs through the skin. The backing layer, adhesive, and other components may contribute to E&L concerns.

5. Ophthalmic Products: Eye drops, ointments, or contact lens solutions packaged in bottles, vials, or multidose containers. Eyedropper assemblies, caps, and seals.

6. Topical Formulations: Creams, gels, lotions, or ointments packaged in tubes, jars, or pumps. The packaging material and dispensing components can introduce E&L compounds.

7. Biological Products: Biologics, including vaccines, monoclonal antibodies, or cell-based therapies. The primary container, stoppers, closures, and delivery devices may contribute to E&L concerns.

8. Blood Products and Intravenous Solutions: Blood bags, collection systems, and administration sets. Intravenous solutions and additives packaged in bags or bottles.

What are the Risk associated with E&L in drug products ?

There are several risks associated with extractables and leachables (E&L) in drug products. These risks primarily stem from the potential presence of chemical compounds that can migrate from packaging materials into the drug product. Here are some key risks:

  1. Safety Concerns:
    • Toxicity: Some E&L compounds may have toxic or harmful effects on human health, even at low concentrations. This can include genotoxicity, carcinogenicity, or organ toxicity.
    • Allergic Reactions: Certain compounds can trigger allergic reactions in sensitive individuals, leading to adverse events.
    • Pharmacological Interactions: E&L compounds can interact with the drug substance, potentially altering its efficacy or safety profile.
  2. Product Quality:
    • Stability and Shelf Life: Leached compounds can degrade the drug product over time, reducing its stability and shelf life.
    • Physical Changes: E&L compounds can cause discoloration, precipitation, or other physical changes in the drug product, impacting its appearance and dosage form integrity.
  3. Regulatory Compliance:
    • Non-Compliance: If the identified E&L compounds exceed regulatory thresholds or guidelines, it can lead to non-compliance with regulatory requirements.
    • Product Recall: Significant E&L concerns may result in the need for product recalls, impacting patient safety, reputation, and financial implications for the manufacturer.
  4. Patient Exposure:
    • Cumulative Exposure: With chronic or long-term drug use, repeated exposure to low levels of leached compounds can result in cumulative exposure, potentially leading to adverse effects over time.
    • Vulnerable Populations: Certain patient populations, such as neonates, pregnant women, or immunocompromised individuals, may be more susceptible to the risks associated with E&L compounds.
  • To mitigate these risks, thorough E&L assessments are conducted during the drug product development phase and throughout the product lifecycle.
  • Regulatory agencies provide guidelines and requirements to ensure E&L risks are adequately addressed.
  • Pharmaceutical companies are responsible for selecting appropriate packaging materials, conducting E&L testing, and ensuring compliance with regulatory standards to minimize the associated risks and ensure patient safety.

Reference Guidelines for Extractables and Leachables (E&L) testing in the pharmaceutical industry :

There are several guidelines and regulatory documents available to provide guidance on extractables and leachables (E&L) testing in the pharmaceutical industry.

These guidelines help pharmaceutical companies and regulatory authorities establish appropriate approaches for assessing E&L risks. Here are some notable guidelines:

1. US Pharmacopeia (USP):

  • USP <1663> Assessment of Extractables Associated with Pharmaceutical Packaging/Delivery Systems: This general chapter provides guidance on extractables testing, including sample preparation, analytical methods, and reporting of results.

2. International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH):

  •  ICH Q3C(R6) Impurities: Guideline for Residual Solvents: This guideline focuses on the identification and control of residual solvents, including potential extractables from packaging materials.
  • ICH Q3D(R1) Elemental Impurities: This guideline addresses the control of elemental impurities, including those that could leach from packaging materials.

3. European Medicines Agency (EMA):

  •  EMA Reflection Paper on Leachable Compounds in Plastics and Elastomers: This document provides guidance on the evaluation of leachables from plastic and elastomeric materials used in the manufacturing of medicinal products.

4. Food and Drug Administration (FDA):

  • FDA Guidance for Industry: Container Closure Systems for Packaging Human Drugs and Biologics: This guidance outlines recommendations for the qualification of container closure systems, including E&L considerations.

5. Pharmaceutical and Healthcare Sciences Society (PHSS):

  • PHSS Technical Monograph No. 14: The Manufacture and Control of Synthetic Polymeric Materials Used in Pharmaceutical Applications: This monograph provides guidance on the manufacture and control of synthetic polymeric materials, including E&L considerations.

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