This article was published in the May/June 2017 edition of Pharmaceutical Engineering® magazine. Missed Part 1?  Catch up now – Extractables and Leachables: Not the Same – Part 1

QBD Approach

An E&L program should be based on QBD principles and a thorough understanding of the biomanufacturing process. Using this approach, suppliers should conduct E&L studies on in-process SUS from sourcing of raw materials to disposal—including key milestones such as sterilization—in compliance with baseline safety assessment and chemical studies. End users should first evaluate the criticality of the SUS component regarding process flow, based on documentation provided by the supplier.

Chemical fingerprint analyses will ensure that no toxic substances are found (or are well below the limit) and that the product is unlikely to interact with the final drug product. Controlled extraction studies are needed to make an informed selection of materials, meet regulatory expectations, evaluate safety of materials, and control leachables absorbed in the final dosage form.

Extractable Evaluation Methodology

Before conducting an extractables study on an in-process SUS, end users should assess single-use material attributes—dosage form, formulation composition, intended use, and stability—within a risk-assessment approach, considering the intended use and process conditions of the SUS component. The experiment design should consider several factors (Figure 1) that could affect the quality of extraction and resulting analysis:

  • Model solvents selection
  • Surface area to volume ratio
  • Mass of each extractable or leachable per volume of model solvent
  • Time points of extraction
  • Type of material tested
  • Related structural and physical properties: SUT resin, film, component, assembly, and system

Extractables and Leachables Figure 1 - Pharmaceutical Engineering Magazine 2017 May/June Edition

Components should be tested using multiple extraction techniques and solvents of various polarities according to a wide range of targeted species and dosage forms. Because “most” does not mean “better,” one should not expect a maximal number of chemical compounds during contact material extraction (time of contact, concentration of solvent, extraction kinetic) but rather select appropriate extraction conditions and analytical approaches predictive for leachables produced in a specific application. The extract is then evaluated with analytical techniques based on sensitivity, limit of detection, and the target species properties (considering first volatiles, semivolatiles, or nonvolatiles).

Following a toxicological analysis, the extractable can be identified and evaluated for its potential toxicity and safety threshold. If potential toxicity is discovered, end users should report the results to suppliers and stop using the SUS component tested until a risk mitigation strategy has been enacted. Suppliers should follow common extraction methodology based on standards recognized by all industries, and communication to end users must be based on consensual reporting methods.

Leachable Evaluation Methodology

Evaluation of SUS leachables should be based on a risk- and science-based approach to ensure the safety and purity of the final drug product. Process knowledge, experience gained during development, and a comprehensive process understanding should be used to assess risk associated with implementing SUS. Risk management principles can identify, evaluate, communicate, and mitigate leachables that can affect product quality and patient safety. A leachable profile should be used to determine the residual chemical identity of the SUS in normal process conditions and the toxicological impact on drug product and on patient safety. A leachable material is objectionable if it adversely affects critical quality attributes such as purity, safety, efficacy, identity, strength of the final and/or intermediate product, or its successful production.

Risk may be based on severity of the harm caused by leachates from SUS, probability that leaching will occur, and probability of detecting the leached substances through in-process manufacturing controls. Once the overall risk rating of the single-use component of interest is finalized and ranked (low, medium, or high), qualification requirements should be established to qualify the single-use component for its intended use (Figure 2).

Extractables and Leachables Figure 2 - Pharmaceutical Engineering Magazine 2017 May/June Edition

We recommend a case-by-case approach to define which extractables should be analyzed in a leachables study. For medium and higher rated risks, product-specific assessments should be based on extractable data and conducted under a toxicologist’s supervision. Given high-quality data that is applicable to the end user bioprocess, extractables data can guide and define the depth of a leachables study. In addition, end users should consider that leachables may also be derived from the interaction between an extractable and a drug formulation compound.


A key advantage of implementing this approach for process contact materials is that it identifies where a leachable study is needed, and focuses the effort according to leaching propensity. QBD risk assessment and synergetic collaboration between suppliers and end users are leading principles that should facilitate SUS implementation by providing better understanding of industry expectations for suppliers. This drives uniformity of study design, allowing integration of data from multiple suppliers, and facilitating evaluations and comparisons between components.

By: Nassrine Lablack, Mathieu Tricot, and Malik Belattar

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