As the FDA continues to expand regulation of polymeric materials associated with medical devices and pharmaceuticals, extractables and leachables studies and impurity investigations are becoming more critical than ever. While typical polymer additives of concern include antioxidants, stabilizers, lubricants, plasticizers, and colorants, adhesive-specific impurities should not be overlooked. For example, acrylate monomers (and their low MW oligomers) are common impurities in adhesive formulations and can often be severe contact allergens. Examples of acrylate monomers used in adhesive and plastic formulations include methyl methacrylate, ethyl acrylate, and isobornyl acrylate. EKG Labs has recently evaluated several industry-standard adhesives shown to leach monomer-based impurities which could cause concern when used in medical device (or drug product) applications.
This study was initiated when EKG Labs was approached with a syringe that was failing cytotoxicity testing (specifically MEM elution testing), though it had been passing for years. An unidentified impurity, with a concentration around 0.5 mg/g, appeared to be reaching ICH reporting thresholds, thus forcing additional investigations and monitoring. Looking at the cytotoxicity scores, it was suggestive that the contamination issues were with the needle itself.
Because the needle shaft was composed of stainless steel (and cytotoxicity failure with medical grade stainless steel is nearly impossible), it was theorized the product had either not been processed/cleaned properly or there was manufacturing contamination.
By analyzing needles in a variety of construction stages and comparing to needles that had passed MEM elution testing, it was determined that the needles of concern were those that had been adhered to the needle seating. These samples were extracted at 37°C in isopropyl alcohol (IPA) for 24 hours alongside method controls. After extraction, sample and control extracts were analyzed via high resolution GC/MS.
EKG Labs optimized column technology and gradient elution parameters to quantify the peak of interest, which is observed below at an elution time just before 10 minutes. The first chromatogram (black) below shows a passing needle extraction. The second chromatogram (red) shows an extraction from the needle under investigation.
After method optimization and mass spectral analysis, the peak of interest was identified as isobornyl acrylate (see spectrum below), an irritant known to cause allergic contact dermatitis. Upon researching the syringe manufacturing process further, EKG obtained safety data associated with the adhesive in which was noted that isobornyl acrylate was a known impurity of toxicological concern. It was apparent that the more recently used lots of the adhesive had a higher concentration of unreacted monomer than previously observed.
Further testing at EKG Labs could include concomitant analysis of an isobornyl acrylate reference standard against samples and validation of a method to continuously monitor the quantity of this impurity in lots of devices over time. Similarly, lots of the adhesive could be tested prior to use in manufacturing to anticipate the appearance of this monomer and to prevent further impurity investigations.
A key way to mitigate risk is to perform an exhaustive extractable/leachable (E&L) study. Often an extractables (the chemical 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 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 analysis of storage stability under a variety of controlled conditions. In the course of these programs it is often necessary to characterize and identify all relevant extractables and leachables. It may also be necessary to develop and validate methods to monitor these chemicals if they are a potential concern.
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 impurities or need analytical services to support your product development, please contact us at 810-354-5229.