Determining the Point of Exhaustion for Absorbable Medical Devices

Medical device manufacturers understand the critical role extractables studies play in ensuring patient safety and meeting regulatory expectations. For absorbable devices, these studies are particularly important, as they help identify the compounds these devices may release during use and provide valuable data for toxicological risk assessments to ensure patient safety.

A medical device is considered absorbable, according to ISO 10993-6:2016, when the “non-endogenous (foreign) material or substances, or its decomposition products, [pass] through or [are] assimilated by cells and/or tissue over time.” Similarly, ISO/TS 37137-1:2021 defines absorbable implants as those that are “intentionally designed to degrade and therefore release degradation products into the patient, a feature making these products fundamentally different from other medical devices that are not intended to be absorbed by the patient’s body.”

When performing extractables studies with absorbable devices, determining the point of “exhaustion”—i.e., when the majority of relevant compounds have been extracted—can be a complex challenge to address. In extracables studies, exhaustion does not mean removing every compound a device might eventually release over an indefinite period. Instead, the goal is to reach a practical, scientifically-supported endpoint. It is the moment when extractable compounds most likely to impact patients during the device’s intended use are appreciably migrated into the testing solvent. Without a standardized, mathematical point of exhaustion, there is a risk of stopping the extractables study too soon and missing critical compounds, or continuing too long, and diluting key findings and wasting resources.

In determining the point of exhaustion for absorbable devices, dissolution of the bulk material may overshadow compounds of concern, diluting their presence during testing. Thus, it is crucial to use mathematically defined criteria to accurately pinpoint the point of exhaustion. Doing so ensures consistency across devices and labs, helping scientists deliver reliable, actionable data for toxicological risk assessments.

This paper explores the methodologies and criteria for determining exhaustion in extractables studies, focusing on their specific application to absorbable medical devices. It illustrates how a device’s composition and the solvents chosen can influence study timelines, and how advancements in this field can shape future medical device testing.

Ensuring Precision & Efficiency in Extractables Studies

Medical devices are often subjected to chemical characterization, which may include exaggerated or exhaustive exaggerated extraction in predetermined media. For the latter, the determination of exhaustion is a critical milestone that determines the number of iterations needing to be performed in order to ensure the exhaustive extraction provides an appropriate and accurate assessment of the compounds that may pose a risk to patients.

In cases of absorbable devices, however, the determination of exhaustion can be complicated by the quick rate of dissolution in some solvents, non-uniform dissolution when devices have complex compositions, and the ambiguity in determining at which point extractables have ceased migrating (e.g., when the absorbable material itself begins degrading). This is particularly evident in solvents like isopropyl alcohol (IPA), where residue mass may plateau or exhibit undulating patterns of increase and decrease, defying the traditional mathematical models used to define exhaustion. Due to these difficulties, an iterative extraction may proceed well past the iteration at which exhaustion is eventually assigned while the experimental data is scrutinized.

While it is critical to exercise sound and well-supported scientific judgment in assigning the final iteration of exhaustion, the number of iterations performed directly impacts the amount of resources used and may result in time delays that hinder the submission process.

At NAMSA, we address these complexities by adhering to mathematical calculations whenever possible, ensuring an objective and replicable foundation for our assessments. When traditional methods fall short, we incorporate visual inspections to evaluate whether the device shows signs of breaking down, though we recognize the inherent subjectivity of this approach. To strengthen these evaluations, we draw on our knowledge of the device’s composition, extensive experience with similar devices, and advanced analytical techniques, such as FTIR, to identify the composition of particulate matter. This multifaceted approach ensures that our exhaustion determinations are both scientifically robust and grounded in practical insights, even in the face of challenging scenarios.

Materials of Construction

Table 1. Structures and acronyms of common compounds in absorbable medical devices.

Common Absorbable Compounds
Carboxymethyl Cellulose (CMC)	Ethylenediamine tetra(methylene phosphonic acid) (EDTMP)	(Hydroxypropyl) methyl cellulose (HPMC)
Polydioxanone (PDS)	Polyethylene Glycol (PEG)	Poly(glycolic acid) (PGA)
Poly(glycolide-lactide) (PGLA)	Poly(L-lactide) (PLLA)	Trimethylene carbonate (TMC)
Sodium Tripolyphosphate (STPP)	Silk	Collagen

Non-Volatile Residue Analysis (NVR)

Non-volatile residue (NVR) refers to the material (e.g., solids, high-boiling point liquids, etc.) left behind after a solvent used in an extractables study has evaporated. In these studies, a solvent is combined with a medical device and incubated for a specific period, allowing compounds to be extracted from the device into the solvent. The resulting mixture of solvent and extracted compounds is called the “extract.” The extract is positioned to evaporate to dryness safely, then the residue is used for NVR analysis.

Exhaustion is typically determined using NVR analysis. At each iteration, the evaporated residue mass of each replicate is blank-subtracted and compared to the corresponding replicate mass of the first iteration. Exhaustion is determined by assessing whether the replicate mass is below the method’s limit of detection (LOD) or limit of quantification (LOQ), or has reached <10% of the first iteration. In some cases, the residue mass plateaus—i.e., the same mass of residue is measured at each subsequent iteration—in which case a determination must be made to select the most appropriate iteration for exhaustion.

Composition is unique for each device and has a direct impact on the number of iterations needed to reach exhaustion. NVR data for absorbable devices extracted over the past four years were compiled to provide a summary of how composition impacts the determination of exhaustion. There are four main ways to determine exhaustion:

1. The residue reaches below LOD, in which case exhaustion is determined at the previous iteration.
2. The residue reaches below LOQ or <10% of the mass of the first iteration, in which case exhaustion is determined at that iteration.
3. The NVR profile shows increasing residue over 2+ iterations, in which case exhaustion is determined at the iteration prior to the increase.
4. The NVR profile plateaus or shows undulating release that does not have a clear downward or upward trend, in which case exhaustion is determined by plateau at an iteration that appropriately captures the extractables without including the portion that may be a result of dissolution.

These four scenarios can be seen in Table 2, where two values are provided for each device composition and solvent pair. The first value is the iteration of exhaustion and the second value is the total number of iterations performed. This summary table shows trends in how each solvent-composition pair tend to reach exhaustion. Such information may assist in determining estimated timelines of exhaustive extraction studies.

1. When usually exhausting by LOD, the number of iterations performed is 1 greater than the iteration of exhaustion.
2. When usually exhausting by LOQ or <10% of the mass of the first iteration, the number of iterations performed is equal to the iteration of exhaustion.
3. When residue quickly increases due to material dissolution, the number of iterations performed is often 2-3 more than the iteration at which exhaustion is determined, and exhaustion is often determined at the second iteration. This scenario most often occurs in aqueous solvents as they are the solvents most representative of conditions of use. For an example, see Figure 1.
4. When the exhaustion profile undulates or slowly reaches a plateau, the number of iterations performed is often greater than five and exhaustion may be determined at more than two iterations prior to the final iteration performed. For an example, see Figure 1.

Table 2. A summary of exhaustion data collected from in-house experiments for absorbable medical devices of varying composition. Multiple experiments were averaged for each composition and solvent pair. The data is in the format (iteration of exhaustion)/(number of iterations performed).

Figure 1. Example non-volatile residue (NVR) profiles for a medical device composed of PGA-TMC, extracted in IPA (left) and water (right).

Timelines of Complete Dissolution

Complete dissolution describes the total breakdown of a device, such as a mesh scaffold, into its fundamental components. This process is relevant for absorbable devices because they degrade in the body and are reabsorbed, leaving little to no trace of their original form. Discussion regarding the value of performing complete dissolution for absorbable devices is ongoing.

An important factor to consider is the timeline for complete dissolution. The determination of exhaustion is typically performed as a separate extraction prior to the analytical extraction, which means the total extraction time could be twice that of one extraction (or more in complex studies that require additional evaluation to determine the most appropriate point of exhaustion). Assuming these extractions are performed sequentially (not in parallel), they have an iteration turnover every three days, and use the standard solvent polarity progression (e.g., water, IPA, hexane), an extraction slated for one iteration could be completed within the week, while an extraction needing 10 iterations may take more than 60 days.

If complete dissolution is required, the best opportunity for improvement in decreasing this timeline is to select an appropriate solvent that encourages dissolution in a reasonable timeframe. For example, Figure 1 shows the mass released from absorbable devices can reach a plateau in some solvents (e.g., IPA) while in other solvents the mass rapidly releases from the device (e.g., water). Furthermore, absorbable devices in hexane often release such low masses in NVR that exhaustion is determined most often by LOD or LOQ at the first or second iteration and are unlikely to fully dissolve (see Table 2).

Under the current model of extractables studies (i.e., replacing solvent every 3 days) using the standard solvent polarity progression, Table 3 illustrates the potential pitfall of choosing a solvent that does not promote dissolution in the material (e.g., hexane with PGA:TMC). This table provides a simple calculation to determine the number of iterations until complete dissolution for a range of devices of different masses, assuming linear mass lost per iteration. For a 2 g device with an average dissolution of 400 mg per iteration, complete dissolution should occur within five iterations, or 15 days. In contrast, a 2 g device with an average dissolution of 5 mg per iteration would completely dissolve in 400 iterations, or 1200 days. The solvent selected for the complete dissolution of an absorbable device should enable dissolution in an efficient timeline (e.g., saline, water, simulate buffers, etc.) rather than use a solvent that prolongs testing to an unreasonable degree.

Table 3. Number of iterations until complete dissolution for a range of device masses, assuming an average mass lost per iteration. Iterations typically turn over every 3 days; multiply the number of iterations by 3 for a timeline estimate until complete dissolution.

Conclusion

Determining the point of exhaustion in extractables studies for absorbable medical devices is more than a technical exercise, it is a critical step in ensuring patient safety, regulatory compliance, and the reliability of medical devices. Absorbable devices pose unique challenges, behaving differently from traditional devices due to their dissolution properties. Without clear criteria for exhaustion, scientists risk missing compounds that could pose risks to patients or diluting critical findings through excessive iterations.

This analysis is particularly timely as absorbable devices remain a focal point in regulatory discussions. Their unique behavior demands a community-driven consensus on how best to approach extractables studies. Aligning on reliable methods for determining exhaustion may improve the safety of these devices and provide consistency and predictability in study design, streamlining the path to regulatory clearance or approval.

This article was originally published in MPO Magazine.