USP 1663 Evaluation of Extraction Agents Associated with Pharmaceutical Packaging and Dispensing Systems

The American Pharmacopoeia (USP) standard, “USP 1663 Evaluation of extractable substances associated with pharmaceutical packaging and dispensing systems,” provides a framework for the design, justification, and implementation of extractable substance evaluation for pharmaceutical packaging and dispensing systems.

This standard identifies the critical dimensions of extractable substance assessment and discusses the practical and technical aspects of each dimension. While intended to be helpful and generally applicable, this standard is for informational purposes only and does not specify particular extraction conditions, analytical procedures, or mandatory extractable substance specifications and acceptance criteria for specific packaging and dispensing systems or dosage forms, nor does it detail every situation where extractable substance assessment is necessary.

A general discussion of extractable substances cannot possibly foresee and cover all situations where extractable substance assessment may be necessary. Designing an individual extractable substance assessment is a process that balances sound science, prudent resource allocation, and effective risk management. Achieving this balance is the responsibility and obligation of the pharmaceutical product manufacturer and requires consideration of all applicable legal and regulatory requirements. The principles and best practices outlined in this general section represent a common interpretation of sound science and are therefore applicable to any situation where extractable substance assessment is necessary for pharmaceutical application.

The USP 1663 standard provides a scientific framework for designing, justifying, and implementing the evaluation of leaching substances in pharmaceutical packaging and dispensing systems (coating systems). This standard helps ensure that materials used in pharmaceutical packaging (e.g., plastic containers, rubber stoppers, inhaler components, or elastomeric seals) do not release unwanted chemical substances that could compromise the quality, safety, or efficacy of the pharmaceutical product.

This is generally addressed in conjunction with the USP 1664 standard, which focuses on substances that actually migrate into the pharmaceutical product under normal storage and use conditions (leaching agents).

The basic definitions are as follows:

• Extraction agents: Organic or inorganic chemical substances released from packaging materials, components, or systems into an extraction solvent under laboratory (exaggerated or accelerated) conditions. These conditions (e.g., specific solvents, high temperatures, or long contact times) are designed to reveal the full potential of substances that may migrate.
• Leachate: Substances that actually migrate into the pharmaceutical product under normal storage and use conditions. Leachate is generally a subset of extraction agents or chemically derived from them.

The aim of extraction agent studies is to establish a comprehensive extraction agent profile that forms the basis for risk assessment and subsequent leachate testing.

The USP 1663 standard emphasizes a risk-based, science-driven approach. This guidance is geared towards:

• Pharmaceutical manufacturers
• Packaging suppliers
• Drug delivery system developers

The key points are as follows:

• The chemical structure of the drug formulation (polarity, pH value, aqueous vs. anhydrous form, etc.)
• Route of administration (such as injections, inhalers, ophthalmics)
• Packaging material composition (plastics, elastomers, glass, etc.)

This standard does not specify definitive pass/fail limits or mandatory test methods. Instead, it offers best practices and a flexible framework for justifying study design.

According to the USP 1663 standard, the main elements of extraction evaluation are as follows:

• Material characterization: It is necessary to understand the composition of the packaging components (polymers, additives, processing aids, etc.).
• Extraction study design: Appropriate solvents, temperatures, durations, and extraction techniques are selected to simulate or exaggerate contact with the pharmaceutical product.
  • Solvents are selected according to the drug formulation (e.g., organic solvents or mixtures such as water, isopropanol, or hexane at different pH levels).
  • Examples given in this standard include MDI valves, inhaler mouthpieces, vial stoppers, or different media for IV bags.
• Extraction techniques: Common methods include solvent extraction, reflux, Soxhlet, or accelerated conditions (high temperature/time) to achieve equilibrium or worst-case release.
• Analytical tests: Sensitive techniques (e.g., GC-MS, LC-MS, ICP-MS) are used to identify and quantify organic and inorganic extractable substances. A threshold (often referred to as the analytical evaluation threshold) helps determine which peaks need to be identified.
• Data evaluation and reporting: An extractable substance profile is created, potential safety/toxicological risks are assessed, and it is determined whether further leaching studies (USP 1664 standard) or mitigation are required.

This standard emphasizes that extraction conditions must be justified according to the specific product and packaging. There is no single set of standard conditions that can be applied to all situations.

While USP 1663 focuses on potentially migrating substances (extractable substances) under exaggerated conditions, USP 1664 focuses on actual migrating substances (leaching substances) under real-world conditions of use and includes toxicological evaluation.

This standard is considered important for the following reasons:

• Extraction and leakage substances can cause the following:
  • It can affect drug stability (e.g., degradation)
  • It can form impurities.
  • It may pose safety risks (toxicity, immunogenicity, or off-target effects).
• A well-designed USP 1663 standard study helps manufacturers in the following ways:
  • Choosing appropriate packaging materials early in development
  • Demonstrating compliance and safety to regulators.
  • To avoid costly recalls or reformulations later.

For many years, our organization, with its competent and experienced team, has been understanding the needs of its clients, providing the advanced testing services they require, and assisting them in the establishment, implementation, and improvement of management systems. Within this framework, we also provide testing services compliant with the USP 1663 standard.