Inhalation products—which include metered dose inhalers (MDIs), dry powder inhalers (DPIs), nebulized solutions/suspensions, and nasal sprays — are drug-device combination products that incorporate drug products, drug delivery devices, and container closure systems. Due to the complex nature of these devices, risk assessments and subsequent extractable and leachable (E&L) analysis can be challenging.
These devices are often comprised of materials such as polymers that pose high leachable risk. The risk is elevated due to the direct interaction of drug product with the device/packaging and the delivery of drug product to the respiratory and/or nasal passages. Some typical polymer additives of concern include antioxidants, stabilizers, lubricants, plasticizers, and colorants. Due to the high risk classification of inhalation devices, these non-drug-related impurities must be thoroughly analyzed.
Often an extractables (the chemicals that can be forced out of a device or product) investigation is done in conjunction with, or prior to, a leachables (the chemicals that migrate from one material matrix into another under patient-use and/or normal storage conditions) study in order to get a full profile of the potential hazards of a medical device or a container of a pharmaceutical product. This typically incorporates an evaluation of storage stability under a variety of controlled conditions. In the course of these programs it is often necessary characterize and identify all relevant extractables and leachables.
EKG Labs has extensive experience evaluating extractables and leachables in inhalation drug devices.
EKG Labs performed a limited extractable study on commercially available inhalation drug devices, under the general guidance of ISO 10993-12. EKG evaluated multiple components including: six polymeric components that the liquid drug product was exposed to prior to final delivery, two types of metal device chambers containing the pressurized formulation, and three different atomizers. All samples, alongside controls, were extracted in methanol at 50°C for 72 hours, immersing with agitation.
After extraction, sample and control extracts were analyzed via LC/MS, ICP-MS, and high resolution GC/MS. Very few semi-volatile or non-volatile extractables were observed by LCMS. Notably, the presence of butylated hydroxytoluene (BHT) at ~4.5 mg/device was observed in an atomizer extraction.
From ICP-MS elemental impurities analysis, all of the three atomizers showed quantities of extracted lead between 30-100 µg/device. No elemental impurities were detected above 50 ng/device in the polymeric components or pressurized chambers.
The extractions were analyzed for volatile and semi-volatile compounds using GCMS. In one of the chambers analyzed, a total of ~52 mg/chamber of cyclic polydimethyl siloxanes were observed.
Various hydrocarbons and stearic acid were observed from a polymeric component extraction.
A number of extractable compounds were found in two of the three atomizers, including 2-ethylhexanol, BHT, cyclohexyl isocyanate, and various hydrocarbons. Additionally, one compound, whose identity could not be confirmed by a direct library search, was observed at ~10 mg/device.
The unknown compound was further evaluated. Based on consistent m/z differences of 44, ethylene glycol functionality was likely. High resolution MS with chemical ionization (CI) showed an exact mass of 217.1069 (formula C10H16O5, M+H). This formula along with the observed ethylene glycol losses led the highly skilled scientific staff at EKG Labs to identify the impurity as 1,4,7-trioxacyclotridecane-8,13-dione, a diethylene glycol adipate (DEGA).
In cases such as this one, in which extractables of concern are observed, it may be necessary to develop and validate methods to monitor these chemicals. As the FDA continues to expand regulation of polymeric materials associated with medical devices and pharmaceuticals, extractables and leachables (E&L) studies and impurity investigations are becoming more critical than ever.
About EKG Labs
EKG Labs is an analytical service provider for the medical device and pharmaceutical industries. Our analytical services support regulatory filings, product development, and analytical chemistry investigations. Specialty analytical services include: extractables, leachables, biocompatibility, characterization, impurity identification, method development, method validation, deformulation, and other investigational activities. EKG Labs operates out of Innovative Technology Enterprises (ITE) at the University of Missouri, St. Louis (UMSL).
If you are experiencing a challenge with E&L studies, impurities, or need analytical services to support your product development, please contact us at 810-354-5229 to find out how we can help you.