Particulate and Extractables Analysis in Medical Device Coatings

Introduction: Cleanliness as a Critical Performance and Safety Attribute

The role of cleanliness in medical device coatings has changed over the years. What started as a hygienic manufacturing standard of cleanliness has become one of the most important factors determining patient safety, regulatory approval, and clinical performance. 

At the same time the use of surface coatings, such as hydrophilic coatings continues to increase. That is because they are essential for enhancing device lubricity, drug release, antimicrobial protection, and barrier properties. Medical device coatings are much more than merely surface treatments. They are chemically sophisticated interfaces that interact with the blood, tissues, and physiological fluids directly. 

Surface coatings have many benefits, but they must be formulated and tested to ensure they are safe. That is because poor quality coatings may also increase the risk of particulate shedding and chemical leaching. 

Therefore, regulatory authorities require thorough scientific support for the coated devices that demonstrate, in a defined manner, that they are particulate clean and safe from chemicals. In turn, there is now a significant increase in particulate matter analysis and the analysis of extractable and leachable materials. 

In this article we dive into analytical strategies to ensure compliance with USP <788> and ISO 10993 requirements. 

Regulatory Context: Understanding USP <788> to the ISO 10993 Framework

1. USP <788>: Particulate Matter Considerations Beyond Injectables ^1-3

What does clean mean in terms of medical device coatings? 

Answering this question requires an understanding of the regulations that define cleanliness expectations. 

One standard to consider is USP <788>, which was created as a standard for the control of particulate matter in injectable pharmaceutical products. It is now widely used as a reference for medical devices used to infuse or connect to body fluids or to the vascular system.

USP <788>, Particulate Matter in Injections, was originally developed for parenteral drug products. However, its principles have become widely adopted as a benchmark for evaluating particulate contamination in medical devices that:

• Contact blood or cerebrospinal fluid
• Are flushed or rinsed prior to use
• Introduce fluids into the body

Although medical devices are not directly regulated under USP <788>, regulators frequently expect USP-like particulate characterization for intravascular devices such as:

• Catheters
• Guidewires
• Introducer sheaths
• Stents and delivery systems

USP <788> defines particle size thresholds at those stated below, and mandates validated counting techniques, including light obscuration and microscopic analysis.

• ≥10 µm
• ≥25 µm

2. ISO 10993: Chemical Characterization and Biological Risk^4-6

The ISO 10993 series provides a comprehensive and internationally harmonized framework for the biological evaluation of medical devices. They define the global gold standard for biocompatibility assessment of medical devices. Several parts of ISO 10993 are particularly relevant to medical device coatings:

• ISO 10993-1: Risk-based biological evaluation
• ISO 10993-12: Sample preparation and extraction conditions
• ISO 10993-18: Chemical characterization of materials
• ISO 10993-17: Toxicological risk assessment of leachables

Together, these standards make it clear that coatings must be evaluated as independent contributors to biological risk, not merely as extensions of the underlying substrate.

ISO 10993 explicitly requires manufacturers to:

1. Identify chemical constituents of device materials
2. Characterize extractable compounds under exaggerated conditions
3. Quantify leachables under simulated clinical use
4. Assess patient exposure risk

For coated devices, this means that both the bulk substrate and surface coating must be evaluated as potential sources of chemical release.

Understanding Particulate Contamination in Medical Device Coatings ^7-9

Various factors contribute to particulate contamination in medical device coatings. These may include:

• Lack of proper coating adhesion to the substrate
• Improper polymerization, or incomplete curing of the coating
• Physical wear on the coating as a result of regular use in laboratory settings
• Contamination from handling and manufacturing processes

A coating may appear visually smooth and uniform. However, microscopic particles can break off due to shear forces, moisture, and repetitive mechanical stresses.​

The swelling property of hydrophilic, lubricious coatings and their polymer chain mobility make them susceptible to particle release. The particles released may include residual processing debris (polymer flakes and agglomerates) as well as inorganic contaminants. 

Clinically, if these particles were to enter the patient’s blood stream or nearby body tissues, they could pose health threats to the patient. The smaller the size of a particle, the higher the potential risk that particle could pose to the patient.

In turn, reliable and sensitive testing methods must be developed for identification and determination of the size and composition of these potential health hazards. 

For lubricious coatings, particulate shedding is often linked to poor adhesion, inadequate curing, or mechanical abrasion during use. In turn, formulation, preparation, and application of these coatings is of critical importance. 

Consequences of Particulate Contamination 

Particulate contamination has been associated with the following clinical risks:

• Microvascular occlusion
• Embolism
• Localized inflammation
• Foreign body reactions
• Device malfunction or loss of lubricity

Analytical Techniques for Particulate Analysis

Particle analysis includes various methods, such as Light obscuration (LO). Microscopy, and dynamic image analysis. We discuss these in a bit more detail below. 

1. Light Obscuration Particle Counting

Light obscuration (LO) is the most widely accepted quantitative method for particle counting.

Principle:
Particles passing through a light beam block or scatter light. The resulting signal correlates with particle size and count.

Advantages of LO:

• High throughput
• Quantitative size distribution
• USP-recognized method

2. Microscopic Particle Analysis

Optical microscopy and scanning electron microscopy (SEM) allow direct visualization of particulates.

Advantages of Microscopy:

• Size and morphology assessment
• Identification of fibrous vs spherical particles
• Surface texture and fracture analysis

When combined with energy-dispersive X-ray spectroscopy (EDS), SEM can provide elemental composition, helping distinguish coating-derived particles from environmental contaminants.

3. Dynamic Image Analysis

Dynamic imaging systems capture thousands of particle images in flow, enabling:

• Automated size and shape classification
• Morphological discrimination
• High statistical confidence

The dynamic imaging method is particularly valuable for complex coating systems where particle morphology correlates with failure mechanisms.

Chemical Cleanliness and the Role of Extractables and Leachables ^10,11

In addition to analyzing for particulate matter, chemical cleanliness of medical device coatings is evaluated through extractables and leachables studies as required by ISO 10993. 

“Extractables” refer to any contaminating agents that may leach from a material when tested in a highly energized laboratory environment, such as accelerated extraction testing. Extractables studies provide a comprehensive list of possible contaminants. 

Conversely, “leachables” refers to compounds that migrate from the coating when used clinically under natural (real-world user) or appropriately simulated conditions. 

The distinction between extractable and leachable studies is important to recognize. Extractables analysis provides a “predicted” estimation of contamination. A leachables study data exposes patients’s risk to actual environmental contaminants.

Sources of Extractables and Leachables in Coatings

Common extractable sources include:

• Unreacted monomers
• Plasticizers
• Surfactants and wetting agents
• Oligomers
• Residual solvents
• Catalysts and stabilizers
• Hydrophilic coatings, in particular, may contain water-soluble components prone to migration.

Guidance on Designing Extractables Studies for Coated Medical Devices

• Extractables studies have to have a scientific justification for their design and should represent the intended use of the device. 
• Consideration should be given to the type of solvent that is selected for the extractables study. That is because coatings may contain multiple components with very different polarities. Therefore, a combination of both aqueous and organic solvents will most likely be used during the extractables study. This is to ensure that a complete chemical profile can be extracted. 
• The extraction conditions may include but are not limited to temperature, duration of extraction, and surface area to volume ratio. They must be chosen such that the amount of chemical will be maximized, while simultaneously avoiding artifacts or degradation pathways that are not clinically relevant.

Extractables studies are intentionally conservative. However, they must remain scientifically defensible. The reason is because regulators increasingly scrutinize the rationale behind extraction protocols.

Analytical Techniques for Chemical Characterization ^12,13

Once extracts are generated, a range of analytical techniques is used to identify and quantify chemical constituents. These techniques include: 

1. High-Performance Liquid Chromatography (HPLC)

HPLC, coupled with UV or MS detection, is used for:

• Polar and semi-polar compounds
• Non-volatile oligomers
• Surfactants and additives

LC-MS (Liquid Chromatography-Mass Spectrometry) significantly enhances structural identification.

2. Gas Chromatography–Mass Spectrometry (GC-MS)

GC-MS is ideal for:

• Volatile organic compounds
• Residual solvents
• Low-molecular-weight monomers

GC-MS provides excellent sensitivity and compound identification through spectral libraries.

3. Fourier Transform Infrared Spectroscopy (FTIR)

FTIR supports:

• Polymer fingerprinting
• Functional group identification
• Confirmation of coating chemistry

FTIR is often used for solid residues or isolated particulates.

4. Inductively Coupled Plasma–Mass Spectrometry (ICP-MS)

ICP-MS detects trace metals such as:

• Nickel
• Chromium
• Cobalt
• Platinum

ICP-MS is critical for coated metallic implants and delivery systems.

Leachables Evaluation Under Simulated Clinical Use

Leachable studies are built based on the data gathered from the extractable study. These aim to discover specific chemicals that could potentially migrate under conditions that mimic how a device will be used in a clinical environment. The objective of a leachable study is to produce an estimate of how much of the specific leachables would actually be absorbed by patients during normal use of the device. 

The parameters for the leachable study replicate the clinical exposure (e.g., temperature and media). They provide an accurate estimate of the level of exposure to the patients and are, therefore, used for the toxicological risk assessment.

Leachables testing mimics realistic clinical exposure. This testing uses: 

• Physiological media
• Clinically relevant temperatures
• Timepoints aligned with device use duration

Targeted analytical methods quantify compounds previously identified during extractables studies.

Toxicological Risk Assessment and Patient Safety¹⁴

The presence of a leachable compound can negatively affect product quality and/or patient safety. However, it does not necessarily mean that an unacceptable risk is present. 

As outlined in ISO 10993-17, a toxicological risk audit must be completed by the manufacturer to evaluate whether any detected leachables represent a substantial risk to the safety of a patient. 

Considerations for the toxicological risk audit

The toxicological risk audit will take into account: 

(1) Dose of exposure 

(2) Duration of exposure

(3) Route of administration

(4) Toxicological thresholds (as established in literature) 

Chemical data alone is insufficient. ISO 10993 requires a toxicological risk assessment (TRA) that evaluates:

• Patient exposure dose
• Toxicological thresholds
• Margin of safety

Approaches for this may include:

• Threshold of Toxicological Concern (TTC)
• Permitted Daily Exposure (PDE) calculations

This component assesses if leachable materials that were detected have an acceptable level of potential health impact. The threshold of toxicological concern (TTC) and the permitted daily exposure (PDE) are the main methods of establishing acceptable levels. If a leachable material exceeds TTC levels, then it is the responsibility of the manufacturer to reduce exposure by changing the formulation, optimizing processes, and improving the cleanliness and curing of products.

Integrating Particulate and Chemical Data in a Risk-Based Framework

Use of a risk-based approach will provide the most effective means of compliance by developing a singular integrated workflow. This approach uses all aspects of particulate data, chemical characterization, and toxicology to evaluate the materials used. 

Device use conditions and contact classifications direct the number of tests that must be completed. The coating composition assists in determining which analytical methods should be employed. Therefore, an evaluation of the analytical data for particulates, along with the results of extractables and leachables studies, must be conducted in order to provide a thorough assessment of the coating’s cleanliness. 

Comprehensive documentation of all analytical methods, results, and scientific rationale is very important. Regulatory reviewers are placing more emphasis on having transparent and logical defensible cleanliness evaluations.

Conclusion: Defining Cleanliness Through Scientific Evidence

The cleanliness medical device coatings is not simply a lack of visual or chemical contamination. Cleanliness requires substantive scientific evidence or justification to ensure contaminations do cause any health risks. It is important to implement a thorough analysis of particulate concentration along with extraction and leachable testing to meet the regulator’s expectations outlined in USP <788> and ISO 10993. There is a growing technological complexity and level of scrutiny surrounding medical devices today. Therefore, it is necessary that the definition of “clean” be established through a systematic, risk-based analytical process. 

References

Click to see all references for this article.

1. Hallab NJ, Hallab SR, Alexander A, Pourzal R. Characterization of residual debris on packaged hip arthroplasty stems demonstrates the dominance of less than 10 μm sized particulate: Updated USP788 guidelines for orthopedic implants. Journal of Biomedical Materials Research Part B: Applied Biomaterials. 2024;112(2):e35387. 

2. Schwartz J. Cardiovascular medical device evaluation of particulate following simulated use testing. 

3. Singh SK. Particulate matter in sterile parenteral products. Sterile Product Development: Formulation, Process, Quality and Regulatory Considerations. Springer; 2013:359-409.

4. ISO. Biological evaluation of medical device. International Standard Organization. 2017;

5. Thangaraju P, Varthya SB. ISO 10993: biological evaluation of medical devices. Medical device guidelines and regulations handbook. Springer; 2022:163-187.

6. Sharma A, Luthra G. Significance of ISO 10993 standards in ensuring biocompatibility of medical devices: a review. Journal of Pharmaceutical Research International. 2023;35(8):23-34. 

7. Barber TA. Control of particulate matter contamination in healthcare manufacturing. CRC Press; 1999.

8. Chopra AM. Analysis: Particulate Limits for Intravascular Devices: Considerations for Polymer Coating Embolism. Biomedical Instrumentation & Technology. 2019;53(6):426-432. 

9. Chopra AM, Rapkiewicz A, Daggubati R, et al. Analysis: intravascular devices with a higher risk of polymer emboli: the need for particulate generation testing. Biomedical instrumentation & technology. 2020;54(1):37-43. 

10. Sharma N, Brahmankar Y, Babar D, et al. Systematic approaches on extractable and leachable study designs in pharmaceuticals and medical devices: a review. Journal of Packaging Technology and Research. 2023;7(3):127-145. 

11. Smith EJ, Paskiet DM, Tullo EJ. The management of extractables and leachables in pharmaceutical products. Parenteral Medications, Fourth Edition. CRC Press; 2019:535-573.

12. Sica VP, Krivos KL, Kiehl DE, Pulliam CJ, Henry ID, Baker TR. The role of mass spectrometry and related techniques in the analysis of extractable and leachable chemicals. Mass Spectrometry Reviews. 2020;39(1-2):212-226. 

13. Mihalchik-Burhans AL, Rogers EN, Mihalchik-Burhans AL, Rogers EN, Mihalchik-Burhans AL, Rogers EN. Considerations for Leachables and Extractables Testing. Integrated Safety and Risk Assessment for Medical Devices and Combination Products. Springer; 2020:239-263.

14. Brown RP. Tolerable intake values for leachables: practical use of ISO 10993-17 standard. Biocompatibility and Performance of Medical Devices. Elsevier; 2020:101-122.