This article was published in the May-June 2017 edition of Pharmaceutical Engineering^®magazine.

The pharmaceutical industry’s challenges are:

• Prevent misinterpretation of regulatory requirements for E&L as they are used on finished product containers by applying them to process contact materials as well.
• Bridge the gaps between end user expectations and supplier capabilities by defining the limit of responsibilities and the scope of operations for both.

This paper presents risk-based approaches for evaluating E&L from SUS. In fact, regulations on single-use-technologies (SUT) do not exist yet, although the basis for such regulation exists. In the United States, for instance, 21 CFR 211.65 states, “Equipment shall be constructed so that surfaces that contact components, in-process materials, or drug products shall not be reactive, additive, or absorptive so as to alter the safety, identity, strength, quality, or purity of the drug product beyond the official or other established requirements.”¹

Two Words, Two Perspectives

SUT has been part of the biopharmaceutical industry for about a decade. Because terminology is a key element in preparing and understanding any new area, it is of crucial importance to define common terms and use them properly.

Many people use “extractables and leachables” as a single term, but these concepts reflect two very different chemical species, although both migrate from the component.

Extractables are chemical compounds that migrate from SUS into model solvent solutions under controlled and exaggerated conditions depending on temperature, pH, polarity, and time. SUS are normally not exposed to such conditions in biopharmaceutical processes.

Leachables are chemical compounds that migrate from SUS into process solutions under normal biopharmaceutical process conditions; they may end up in the final drug product formulation. For the most part, leachables are a subset of extractables, although interaction with product components may produce leachables not seen as extractables.

Extractable and leachable studies pursue different objectives: Extractable studies are designed to obtain a fingerprint of chemical components that can be extracted under exaggerated conditions. Toxicological review of these fingerprints and risk assessments for potentially problematic components helps select appropriate SUS. Extractable studies can also be used as a baseline to ensure SUS consistency over time.

Leachable studies determine the chemical compounds that migrate from SUS into process solutions and characterize possible adsorption and/or absorption of process fluid (under normal process conditions). This data enables a toxicologist to determine if components that can compromise Patient Safety are present in the drug product. In addition, leachables data can indicate the presence of chemical components that could potentially interact with the drug product itself, and can help assess the potential for alterations of the drug potency and/or stability. Since leaching continues over time, posing a risk to patient safety and drug product efficacy, leachables may also appear in stability studies.

These definitions (especially for extractables) are not totally balanced. Different applications and situations in biomanufacturing process must be categorized to highlight the weight and criticality of both E&L profiles in product contact material.

Collaboration

Regulatory authorities expect that the final dosage form will have a well-characterized degradant profile, including leachables from process contact materials, even if they do not pose any major health risk for the patient. As part of this profile, E&Ls must be targeted, assessed, and mitigated. This is challenging due to the number of parameters that can affect E&L evaluation and the need for trace-level analysis.

Collaboration and clear definition of roles between SUS manufacturers, suppliers, and end users (drug product manufacturers) are crucial to ensuring patient safety and product efficacy. This is true even for the transportation and storage of single-use components and assemblies prior to use in the drug product manufacturing process.

The easiest way to determine responsibilities is to establish clear communication and transparent exchange of documentation (certification, report, conclusion, minutes of decision meeting, and any legal agreements). Tools such as a RACI (responsible, accountable, consulted, informed) responsibility assignment table could be used to determine stakeholder responsibilities.

Risk-Based Approach 

A risk assessment for both extractables and leachables that balances business risk and patient safety should be established for different phases of SUS manufacturing and drug development. Business risk must be considered, but never at the expense of patient safety. Suppliers have considerable commitment to the cost of extractable analysis with regard to end user expectations (user requirement specifications) and the feasibility of conducting a more complex extractables study.

Both end users and suppliers have a stake in the business impact analysis. Ultimately, the main consideration must be on product quality and safety, which should be assessed with appropriate risk assessment and mitigation strategies (such as quality risk management). The amount of leachables per unit of final drug product dosage form (along with posology) is the final regulatory expectation. End users must comply with this patient-risk approach as required by regulatory bodies.

By: Nassrine Lablack, Mathieu Tricot, and Malik Belattar

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References

1. US Food and Drug Administration. Code of Federal Regulations, Title 21, Chapter I, Subchapter C, Part 211, Subpart D, Sec. 211.65, “Equipment Construction.” https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/cfrsearch.cfm?fr=211.65

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