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This article summarizes a white paper by Kurt Moyer, Ph.D., Director of Research for NSF Pharmalytica.
Recent changes in the U.S. FDA’s 510(k) requirements for medical devices have spawned many inquiries from clients on how to address the request for extractables, leachables and drug compatibility data. Previously, only medical devices where the leachable route of entry was from direct tissue contact were required to undergo extractable and leachable testing. Changes now also require 1) an assessment of the stability and compatibility of each drug or biologic intended to be used with the medical device and 2) a safety evaluation of any leachables, extractables, impurities and degradants from the medical device into the drug product.
Meeting the new expectations of the FDA's Center for Devices and Radiological Health (CDRH) can be challenging as any given study design is not universally applicable to all devices. To help make this process easier, NSF Pharmalytica scientists developed and successfully implemented hybridized study designs, which incorporate the essential regulatory elements, for a variety of medical device applications and for two routes of entry for leachables:
Before evaluating drug compatibility and leachables from a medical device, an FDA-approved drug(s) intended for use with the medical device must be selected. If the device is intended for just one drug, like an insulin pump, the selection is obvious. If the device can be used with multiple drugs and multiple routes of administration, select three commonly used drugs from the three most common routes of administration. For example, if evaluating an infusion pump that is intended to deliver drugs intravenously and as an epidural, pick two common drugs for intravenous infusion and one for epidural infusion. Pick the simplest formulation of the drug to evaluate drug compatibility and leachables.
To address drug compatibility and leachables from the medical device, the first step is determination of extractables from the medical device in controlled extraction studies. Based on these results, analytical methods are developed to evaluate leachables. The second step is the evaluation of leachables from the medical device into the drug product, and the evaluation of drug stability in the medical device.
Only the components of the medical device that directly contact the drug product must be included in the controlled extraction study. Other components may be included if deemed to present a significant risk.
Once the extractable profile of the medical device has been determined, methods are developed to analyze the extractables present as leachables in the representative drug products. Hopefully GC-FID and HPLC-UV methods can be developed for organic leachables, but detection by MS may still be needed based on the extractables identified and the number of unknowns. For both methodologies, the drug may present significant interference for detection of potential leachables and extensive sample preparations, like liquid-liquid extractions, may be required. For inorganic leachables, ICP-MS is commonly used. All of these methods should be validated for accuracy, precision, specificity, LOD/LOQ and linearity. Acceptance criteria for validation should be set based on the demonstrated performance and intended use of the method.
Analytical assay methods are also needed to demonstrate the stability and compatibility of each drug with the medical device. If available, the USP method for the drug product should be used. If not, an analytical assay method will need to be developed and validated.
Acceptance criteria are not universally defined. For assay, we recommend setting the difference between the control and sample to be the same as the USP acceptance criteria for assay. For example, if the USP method has the assay value for a drug product to be ±10.0 % of label claim, the acceptance criteria for compatibility should be that the assay value for the sample is within ±10.0% of the assay value of the control. For leachables and medical device impurities, we recommend using the same acceptance criteria as process impurities of 0.05% of the drug product label claim.
To address extractables and leachables, two different extraction studies are done. The first is an exaggerated extraction study which is defined in ISO 10993-12 as “any extraction that is intended to result in a greater amount of a chemical constituent being released as compared to the amount generated under the simulated conditions of use.” An exaggerated extraction study is a forced extraction study to generate a complete extractable profile for hazard identification and is required by ISO 10993-12 to be exhaustive.
The second is a simulated use experiment which is defined in ISO 10993-12 as “evaluating leachable material levels available to the patient or user from devices during the routine use of a device using an extraction method that simulates product use.” The experimental conditions in a simulated use experiment are modeled after the intended tissue environment for the device with the goal of determining leachable exposure to the patient.
Solvent selection is key in exaggerated extraction study design and is based on the anticipated tissues the device will encounter. The extraction type is based on the solvent type and the analytical methods for analysis of extractables are the same for all extractions. The extraction must be proven to be exhaustive, therefore extraction time is established experimentally. Extractables are identified by MS and quantitated against structurally similar standards.
Selecting solvents is also key in simulated use extraction study design. Extraction solvents are selected based on the anticipated tissues the device will encounter and the results of the exaggerated extraction study. The extraction type is batch extraction with agitation and the methods for analysis of leachables are the same for all solvents. The extraction conditions should be the highest temperature listed that does not exceed the glass transition temperature of the material. Leachables are identified by MS and quantitated against structurally similar standards.
Acceptance criteria for levels of extractables and leachables in a medical device are not included in ISO 10993-12. ISO 10993-17 presents a risk-based method to set acceptance criteria, which includes a toxicological evaluation of each extractable and leachable, but this approach may not be recognized by the FDA. A second option is to use a predefined default level appropriate for the device and its intended use.
If the medical device contains a drug (e.g. a drug releasing implant), sample selection needs to be considered and can be different for the above two extraction studies. Depending upon the amount of drug in or on the device, a “placebo” device without drug may be considered for the exaggerated extraction study to avoid excessive interferences from the drug in the identification of extractables. However, the final medical device including the drug should be used in the simulated use experiment since the presence of the drug could affect the migration of the leachables from the device.