USP-NF 1664 Evaluation of Drug Product Leakage Associated with Pharmaceutical Packaging/Shipping Systems

In the standard “USP-NF 1664 Evaluation of drug product leaks associated with drug packaging/shipping systems” published by the American Pharmacopeia (USP),

Assessing drug product leaks associated with pharmaceutical packaging and shipping systems is a critical component of ensuring drug safety and quality. This process evaluates leachates, which are chemical compounds that can migrate from packaging or shipping systems into the drug product under normal storage conditions.

Leakages are substances that migrate from the packaging or delivery components (e.g., vials, rubber stoppers, plastic containers, inhalers) into the drug product. These leaks can occur due to:

• Polymers, adhesives, inks, lubricants or additives used in packaging
• Decomposition products originating from materials used in the system

These compounds may affect the safety, efficacy and stability of the drug.

Key steps in leak assessment include:

• Extractables study (precursors of leaks)
  • Controlled extraction is performed using solvents and elevated conditions.
  • Identifies potential leaks by simulating aggressive conditions.
  • Helps create a leak profile.
  • It is usually performed on packaging or delivery system materials.
• Leakage study
  • Real-time or accelerated stability studies using the actual drug product and final packaging system
  • Detects and quantifies actual leaks into the medication over time
  • It usually includes analytical techniques such as: GC-MS (gas chromatography-mass spectrometry), LC-MS (liquid chromatography-mass spectrometry), ICP-MS (for metals), UV/Vis or FTIR.
• Toxicological risk assessment
  • Identified leaks are evaluated for toxicological risk.
  • Compared with permissible daily exposure values ​​or safety concern thresholds
  • Complies with ISO 10993, ICH M7 and FDA/EMA guidelines.
• Compliance with legal regulations
  • USP-NF 1664.1 and USP-NF 1664.2 standards
  • ICH Q3D (elemental impurities)
  • FDA's industry guidance for container closure systems

In short, the USP-NF 1664 standard is considered important because it helps ensure the safety, efficacy, and quality of drug products by addressing the risk posed by substances leaching from packaging and distribution systems. The key reasons for this standard's importance are:

• Protects patient safety: Leaching substances may be toxic, carcinogenic, or cause immune reactions. Without proper assessment, these substances can migrate into the drug product and pose health risks to patients, particularly in injectables, inhalers, ophthalmic medications, and long-term medications. This standard ensures the identification, quantification, and control of potentially harmful substances.
• Provides scientific and regulatory certainty: Provides a systematic, risk-based framework for evaluating leached substances and helps demonstrate compliance with regulatory expectations of: U.S. Food and Drug Administration (FDA), International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH), etc. Enables industry to implement validated analytical methods and toxicological assessments.
• Bridges chemistry and toxicology: This standard bridges chemical analysis (what compounds are present) and toxicological assessments (how much is acceptable). This dual focus enables not only the detection but also the risk assessment of compounds that may affect drug safety.
• Supports quality through product development and design: Identifying potential leaks early helps select safer materials, reduce reformulation costs, and ensure consistent product performance. This is a key part of the packaging compliance efforts required for drug approval and lifecycle management.
• Required for regulatory submissions: Health authorities require leachate assessments as part of combination product applications and post-approval changes to packaging. This standard provides the technical basis for these submissions.
• Reduces risk of product recalls or failures: By detecting leaks before they reach market, manufacturers reduce the risk of: contamination incidents, product recalls, and regulatory warnings or holdups.

In short, the USP-NF 1664 standard is important because it ensures that packaging materials do not compromise drug safety, meet regulatory expectations, and support quality assurance throughout a drug product's life cycle.

Our organization, which has been supporting businesses across all sectors for years through a wide range of testing, measurement, analysis, and evaluation activities, has a strong team of employees who closely follow global developments in science and technology and are constantly improving themselves. In this context, we also provide testing services in accordance with the USP-NF 1664 standard, "Assessment of drug product leaks associated with drug packaging/shipping systems."