The US regulatory situation
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).
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.
Table I: US regulations affecting drug-product packaging.
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 container–closure 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 container–closure 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
Thomas Feinberg, PhD, is a director in the Development & Analytical Solutions business of Catalent Pharma Solutions, firstname.lastname@example.org