Identifying Potential Leachables: PQRI, Literature, and Read-Across


Published on 09/12/2025

Identifying Potential Leachables: PQRI, Literature, and Read-Across

In the pharmaceutical industry, ensuring the safety and efficacy of drug products is paramount. Among the various challenges manufacturers face, the identification of potential leachables from container closure systems presents a critical area of concern. This tutorial will provide a detailed, step-by-step guide on how to effectively assess extractables and leachables (E&L) in pharmaceutical packaging, focusing on the recommendations from the Product Quality Research Institute (PQRI), as well as relevant regulatory guidelines from the US FDA, EMA, and other governing bodies.

Understanding Extractables and Leachables (E&L)

Extractables and leachables are chemicals that can migrate from packaging materials into the pharmaceutical product, potentially impacting product quality and patient safety. Extractables are substances that can be extracted under aggressive conditions, while leachables are compounds that can migrate under normal storage and use conditions. Understanding these processes is vital for risk assessment.

The first step toward ensuring the integrity of drug products is to conduct a thorough E&L risk assessment. This assessment should include the identification of potential sources of leachables, such as:

  • Container closure systems (CCS)
  • Single-use systems
  • Manufacturing equipment

Container closure integrity is a critical element in this evaluation, verified through techniques highlighted in the FDA’s process validation guidelines. Regulations outlined in EU GMP Annex 1 and the PQRI guideline emphasize the necessity for a robust E&L assessment to ensure that leachables do not compromise safety or efficacy.

Step 1: Identification of Potential Leachables

The identification of potential leachables begins with a comprehensive understanding of the materials used in the packaging. Manufacturers should create a detailed list of the materials involved in the container closure system, including:

  • Resins
  • Plasticizers
  • Stabilizers
  • Colorants

Once this inventory is established, consult relevant literature and databases to ascertain known extractables associated with these materials. Various studies and reports, including data from the PQRI and other scientific literature, can guide this process. Additionally, industry-standard methodologies provide insight into common extractables associated with each packaging component.

Step 2: Conducting a Literature Review

Next, a thorough literature review is essential to compile data regarding known extractables and leachables. This review should include:

  • Published studies on similar materials
  • Historical data from previous studies or tests
  • Regulatory guidance documents, such as those from the EMA and the PIC/S

Search for information on the specific grade of polymer or material, as extraction profiles can vary significantly depending on factors such as temperature, time, and the solvent used. This comprehensive examination allows for a more informed assessment of potential leachables.

Step 3: Applying Analytical Evaluation Threshold (AET) and Dose-Based Threshold (DBT)

Analytical evaluation thresholds (AET) are pivotal for E&L assessments, forming a baseline for how much of a substance can be present without requiring further risk analysis. The AET calculation is typically rooted in the acceptable daily exposure (ADE) and the dosage form of the drug product.

To compute AET, use the formula:

AET = (ADE / Daily Dose) x 10^6

Where:

  • ADE is the acceptable daily exposure (mg/kg/day).
  • Daily Dose is the amount of drug administered to a patient (mg).

For AET calculations, consult guidance from PQRI, which provides detailed methodologies for establishing these thresholds based on toxicological data.

On the other hand, the dose-based threshold (DBT) offers a logical threshold where the data collected can be interpreted with respect to the patient’s therapeutic dose. DBT incorporates pharmacological data, lending further relevance to E&L evaluations.

Step 4: Risk Assessment of E&L

A comprehensive E&L risk assessment combines qualitative and quantitative analyses of the identified leachables. Utilizing tools such as risk matrices and failure mode effects analysis (FMEA) can aid in scoring the likelihood of occurrence and severity of impact for each leachable.

The risk assessment process should include:

  • Prioritization of leachables based on their potential toxicity and patient exposure.
  • Integration of AET and DBT findings.
  • Assessment of extraction testing data across a range of conditions to identify worst-case scenarios.

Adhering to regulatory expectations from bodies such as the FDA and EMA in this risk assessment stage is crucial. Documentation practices delineating the rationale behind decisions made during this process should be meticulously maintained.

Step 5: Extractables Testing

After completing the risk assessment, the next step is to conduct extractables testing on the selected materials. This involves simulating the product environment to uncover potential E&L profiles. Key steps in this process include:

  • Selecting appropriate solvents for the extraction, which may include aqueous solutions, organic solvents, or specific combinations.
  • Utilizing various extraction techniques such as accelerated solvent extraction (ASE), soxhlet extraction, or static extraction, depending on the material and the intended drug product.
  • Conducting studies at elevated temperatures and longer time periods to model storage and use conditions.

Following extraction, the resultant samples must be analyzed using applicable analytical techniques, such as gas chromatography-mass spectrometry (GC-MS), high-performance liquid chromatography (HPLC), and inductively coupled plasma mass spectrometry (ICP-MS). These analyses determine the presence and concentration of extractables in the samples.

Step 6: Leachables Testing During Product Stability Studies

Leachables testing should not be limited to the initial evaluation; ongoing testing during product stability studies is necessary. This ensures that E&L assessments cover a drug product’s entire lifecycle, further protecting patient safety. Consider the following points:

  • Conduct leachables testing on products stored in their final packaging under relevant storage conditions.
  • Monitor how leachables change over time, particularly in terms of concentration, as stability testing progresses.
  • Evaluate results against the AET and DBT established earlier to ensure ongoing compliance.

Maintain clear records of all leachables testing results, including trends over time and any actions taken based on findings. This extends to documentation for regulatory inspections and demonstrates a commitment to compliance with safety standards across regions, including the US, EU, and UK.

Step 7: Container Closure Integrity (CCI) Testing

The integrity of the container closure system is critical to preventing contamination and ensuring product safety. Container closure integrity testing is a regulatory requirement and must be part of the E&L assessment. The methods used for CCI testing can include:

  • Helium leak testing
  • Vacuum decay
  • Pressure decay methods

Follow United States Pharmacopeia (USP) standards to ensure CCI testing aligns with industry best practices. The tests should confirm that no transport of fluid or gas occurs through the closure, thus safeguarding the product’s integrity.

Conclusion: Ensuring a Defensible E&L Process

Identifying potential leachables and executing a thorough E&L risk assessment is indispensable in pharmaceutical manufacturing. Following this step-by-step guide ensures a systematic approach compliant with prevailing regulatory standards such as FDA, EMA, and PIC/S. Engaging with E&L practices reinforces safety in drug delivery, safeguarding patient health and maintaining trust in pharmaceuticals.

Invest in continued education and awareness regarding the evolving landscape of E&L regulations and methodologies. Conducting meticulous E&L assessments, supported by rigorous analytical evaluation thresholds and robust testing protocols, is essential to ensure quality throughout the lifecycle of pharmaceutical products.