Extractables and Leachables: Best Practices to Ensure Patient Safety - The author presents best practices for extractables and leachables. - BioPharm International


Extractables and Leachables: Best Practices to Ensure Patient Safety
The author presents best practices for extractables and leachables.

BioPharm International
pp. 34-37


In the US, both adulterated and misbranded products are banned from interstate commerce, under the provisions of the Federal Food, Drug and Cosmetic Act (5). Anything that is not intentionally added could, potentially, cause the product to be considered adulterated, even if it remains safe. Any extractable or leachable that finds its way into the drug product is automatically deemed an adulterant. The Act, in its clause on adulteration, also specifies that "if the container is composed, in whole or in part, of any poisonous or deleterious substance which may render the contents injurious to health," the product is equally deemed to be adulterated (5).

Table I: US regulations affecting drug-product packaging.
A collection of regulations (see Table I) also apply to drug packaging as well as cGMP regulations; these include regulations on food additives and indirect food additives that might inadvertently find their way into a product, such as adhesives and adjuvants. It is not only the packaging itself that has to be considered. The equipment used in the packaging process has the potential to introduce adulteration as well. Subpart D of 21 CFR 211 specifies that manufacturers need to ensure that the surfaces of the equipment do not alter the strength, quality, or purity of the drug product (6). Non-compliance with these regulations at a minimum will result in delays to any application and possible, as discussed previously, full product recalls.


Numerous guidance and best practice documents are available to assist companies in ensuring they comply fully with all regulations and requirements. The International Conference on Harmonization (ICH) produces many of these, covering topics, such as impurities, stability testing, specific processes, and devices. But not a single ICH guidance document addresses what should be done with regard to characterization and control of extractables and/or leachables. As stated in ICH Q3B (R2) Section 1.3: "[i]mpurities arising from excipients present in the new drug product or extracted or leached from the container closure system are not covered by this guideline" (7). The standard threshold of 0.1% for reporting of "unknowns" during release and stability testing does not apply to leachables.

The Product Quality Research Institute (PQRI) also provides advice and guidance. PQRI is a not-for-profit consortium of organizations that work together to generate and share timely, relevant, and impactful information that advances drug-product quality and development. In 2001, PQRI started work on developing scientifically justifiable thresholds for the reporting and safety qualification of leachables in orally inhaled and nasal-drug products, and best practices for characterization of extractables from crucial components used in corresponding containerclosure systems. Believing that the best practices would be sufficiently instructive, the safety qualification of extractables would be scientifically justified as they relate to leachables, except for special-case compounds such as polynuclear aromatic hydrocarbons (PAHs) and N-nitrosamines.

The outcomes of the studies conducted were published in 2006 as Safety Thresholds and Best Practices for Extractables and Leachables in Orally Inhaled and Nasal Drug Products (OINDPs) (8, 9). Prior to this publication, the question of safety being the driver for design of extractables and leachables studies was not agreed upon by industry, academia, or regulators. The key finding in the document was the Safety Concern Threshold (SCT), which sets the analytical level below which no additional safety margin would be necessary. This level, at 0.15 micrograms per day, is very low and is based on the most toxicologically sensitive endpoint for chronic exposure (i.e., genotoxicity). With the SCT, analytical scientists could design both extractables and leachables studies in a logical and safety-based manner. Additionally for regulators, the risk profile of unknown leachables was now controlled and based on sound science.

Having developed these threshold concepts for OINDPs, PQRI desired to extrapolate these principles into the evaluation and safety qualification of leachables in containerclosure systems for parenteral and ophthalmic drug products (PODPs). Starting in 2007, a new Working Group, functioning under the auspices of PQRI and its member organizations, designed work plans to address these dosage forms. The key difference between the challenge of OINDPs and PODPs has been summarized by many scientists as "The Dilemma."

Generally, "The Dilemma" refers to the extreme difference in dose volume between OINDP dosage forms and PODP dosage forms. A typical pressurized metered-dose inhaler (pMDI) dosing regimen, for example, may stipulate that patients receive 75 microliters of product twice a day while a typical large-volume parenteral product may entail up to 1 liter of product once per day. For either case, the target SCT will be 0.15 micrograms, meaning that the resulting level to be checked for the pMDI is 1 ppm while that for the parenteral is more than 6000-fold lower. These levels are a challenge to current analytical technology, as other factors such as the formulation, nature of these dosage forms, and possible duration of treatment need to be considered.

Regardless of the outcome of the current PQRI project, the logic behind devising a threshold and then designing the studies is established. No longer should analytical scientists be blindly setting levels of either sensitivity or selectivity with no regard to patient exposure. Similarly, no longer will toxicologists or regulators have no agreed-upon tolerable risk level for leachables.

Thomas Feinberg, PhD, is a director in the Development & Analytical Solutions business of Catalent Pharma Solutions,

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