February 10, 2020

Seismic Shifts in ISO 10993-18:2020

Released this January, the new revision of ISO 10993-18 dramatically expands the scope of determining biocompatibility of medical devices by an additional 49 pages over the previous revision. The standard’s new title “Chemical Characterization of Medical Device Materials within a Risk Management Process” emphasizes the importance this revision places on risk assessment. The chemical risk assessment workflow may be viewed as a three-tiered structure composed of: 1) information gathering 2) extractables analysis, and 3) leachables analysis. The need to perform each successive tier of characterization depends on the nature of the device and the results of the previous stage.

Chemical Risk Assessment Workflow

Made explicit in ISO 10993-18:2020, the critical first step of the chemical risk assessment is information gathering. This involves collecting all available data on the medical device’s materials of construction, additive packages, surface treatments/coatings, etc. In addition to information on the compositional level, the information gathering step also includes collection of the manufacturing processing aids and processing conditions: e.g. machine oils, spin finishes, polishing compounds, sterilization modes, etc.

For devices of greater risk or more uncertainty in materials/manufacturing, an extractables study is likely to be required, at minimum. If an extractables study finds chemicals presenting a potential toxicological risk, a targeted leachable study may be necessary to evaluate the actual concentration of the compound when the device is subjected to simulated end-use conditions.


Other Major ISO 10993-18 Changes

  • ISO 10993-18:2020 formalizes the analytical evaluation threshold (AET) as a key concept in the chemical characterization of medical devices, guiding the required sensitivity of analytical methods and which compounds must be identified and assessed for toxicological risk.
  • Previous standards have indicated exhaustive extraction criteria are demonstrated by gravimetric means, however, ISO 10993-18:2020 offers the flexibility of demonstrating this by other more sensitive and relevant means.
  • As compared to previous standards, ISO 10993-18:2020 provides additional guidance on the selection, qualification, and implementation of analytical methods.
  • A major change in ISO 10993-18:2020 is the explicit requirement to address analytical method uncertainty. This stems from an inherent constraint of “broad screen” methods that aim to identify a multitude of possible chemical species on a medical device. This uncertainty must be addressed in both defining the AET as well as in performing semi-quantitation.

When Do I Need Chemical Risk Assessment?

  • Per ISO 10993-1:2018, “chemical characterization (see ISO 10993-18) shall precede any biological testing…chemical characterization with an appropriate toxicological threshold can be used to determine if further testing is needed…chemical risk assessment should be performed as the first step in performing a biocompatibility assessment.”
  • As part of regulatory submissions such as Investigational Device Exemption (IDE), 510(K) Premarket Notification, or Premarket Approval (PMA)
  • To evaluate a new material of composition or contact material as being chemically equivalent to an “old” material.
  • As a guideline for internal Quality Control. Chemical risk assessment process yields a wealth of information that may be leveraged not just for the purposes of a regulatory submission, but for better understanding and control of the device materials and manufacturing.

"But my device is made up of biomedical grade materials. Do I really have to do a chemical risk assessment?"

 It is true that the use of USP Class VI, ISO 5832, or FDA Master File Materials can reduce the risk of potentially toxic extractables. However, such designations are usually associated with the raw material, which may be transformed or change in composition during the process of converting it to the final finished form. Therefore, the use of a “biomedical” grade material is generally not sufficient justification to avoid chemical characterization or extractable testing.

How Do I Comply with ISO 10993-18:2020?

Given the dramatic changes and changing regulatory landscape, medical device manufacturers are encouraged to review the standards carefully, consult with expert practitioners, and where possible present a detailed experimental protocol to the FDA ahead of time.

CPG is experienced in designing chemical risk assessment studies and has a full, in-house analytical chemistry laboratory under ISO 9001/17025 quality management systems. We have a successful track record in helping our clients perform chemical characterizations as part of their broader biocompatibility risk assessments. Please contact us for more information on how we can assist in evaluating your devices to these new standards and workflows. 

For more information regarding changes to the standard, please see our Application Note #054 Chemical Characterization of Medical Devices: Seismic Shifts in ISO 10993-18:2020.


Posted by CatherineCerasuolo
July 25, 2019

Hydrogels: Bandages or Jello?


We have all experienced the challenges of keeping a bandage on a wound when the skin becomes wet from sweat, water, or blood. Traditional bandages rely on adhesion between a portion of the bandage and the skin. This adhesive bond is compromised when water or other fluids penetrate between the layer.

Hydrogels have been examined in the past as a potential alternative to traditional bandages. Hydrogels, which are three dimensional networks of a hydrophilic polymer that is crosslinked to prevent dissolution, can be designed to have adhesive qualities even in the presence of water.

Researchers at Harvard University are experimenting with two naturally occurring hydrogels (alginate, from seaweed, and chitosan, from the shells of crustaceans) to make a hydrogel bandage that looks like a patch. The hydrogels also incorporate a thermo-responsive polymer (NiPAAM) so that the patch shrinks upon skin exposure, bringing the edges of the wounds together. Early studies on mice show that wound closure is significantly faster than traditional bandages or hydrogels lacking the thermo-responsive polymers.


Posted by CatherineCerasuolo
May 9, 2019

Cellulose: Missing the Forests for the Trees

Step 1- Cutting_and_Moisturizing_of_the_Bamboo_Shoots_smaller.jpgStep 4 -Pressing_the_Paper_smaller.jpg

Figure 1: Chinese woodprints of the papermaking process (Wikimedia Commons)

Cellulose is one of the most abundant organic compounds on earth and utilized in applications as diverse as textiles, papermaking, food packaging, filtration, drug delivery systems, wound care products, nanocomposites, bone tissue engineering, and countless others. Cellulose is a fibrilar and semi-crystalline biopolymer which may be plant-derived or bacterial-derived, and generally exhibits remarkable mechanical properties as well as desirable biodegradability, biocompatibility, renewability, chemical stability, and cost effectiveness.  [1]

Cellulose is notoriously difficult to process. Up until approximately 300 million years ago, there were no significant microorganisms capable of digesting cellulose—resulting in a high accumulation of organic matter. During this “carboniferous” period, the production of coal derived from biomass was 600 fold higher than estimated rates of production in modern day. [2]

Molecular Weight Analysis of Cellulose

As polymer and material scientists, we rely in fundamental measurements of polymer properties to understand the material performance in demanding circumstances. Typically, this includes measurement of the polymer molecular weight—however, this is a highly challenging measurement to obtain for un-modified cellulose materials. Simply put, cellulose doesn’t dissolve in most solvents as a consequence of its crystalline structure, hydrogen bonding, and hydrophobicity.

CPG has developed workflows for the molecular weight analysis of cellulose materials, including un-modified cellulose. Samples are carefully prepared in a series of matrix-modifying steps before ultimately  being dissolved in an aprotic solvent and in the presence of high inorganic salt concentrations. Once in solution, the cellulose materials are analyzed by triple detection GPC for absolute measurement of the polymer molecular weight as well as structural characterization. By obtaining such fundamental measurements of molecular weight and structure, cellulose products may be evaluated for (bio)degradation, aging, failure analysis, material compatibility, lot-to-lot consistency, among other properties. Contact CPG for additional information on the material characterization of cellulose or other biopolymers.

[1]           A. Amalraj, S. Gopi, S. Thomas, and J. T. Haponiuk, "Cellulose Nanomaterials in Biomedical, Food, and Nutraceutical Applications: A Review," Macromolecular Symposia, vol. 380, no. 1, p. 1800115, 2018.

[2]           P. Ward and J. Kirschvink, A New History of Life: The Radical New Discoveries about the Origins and Evolution of Life on Earth. Bloomsbury Publishing, 2015.

Posted by CatherineCerasuolo
April 9, 2019

Extractables of Metallic Devices

Do I have to do chemical characterization? 

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Is it appropriate to perform extractables testing and chemical risk assessment on metallic components?

As such evaluations are most commonly associated with polymeric constructs, it may seem strange to evaluate a solid metallic component in this way.

ISO & FDA Medical Device Guidance

For clarity on this issue, we turn to ISO 10993-1:2018 and the FDA 2016 guidance on biocompatibility assessment. These documents emphasize that the first step in assessing a device's biocompatibility is in compiling a detailed understanding of the physical/chemical properties and chemical composition of the device. Only once this information is in hand can an evaluation and risk assessment be performed with regard to toxicological endpoints such as carcinogenicity, genotoxicity, etc.

Base Alloy vs. Surface Residue 

For a metallic device, the question of chemical composition may seem straightforward: is it simply the alloy the device is machined or otherwise manufactured from? Unfortunately, considering only the base alloy does not take into account the processing aids which are used in the manufacture of the device and which may be left behind as residues on the surface of the part. These may include polishing compounds, lubricants, machine oils, cleaning agents, or adhesive residue from tape used to 'mask off' regions of the device. Inorganic residues (particulates, ions, elemental impurities, etc) that may be released should also be considered separately from the base material. An additional factor to consider is if the component has highly porous regions (e.g. to facilitate osseointegration) which may make the device more difficult to clean and in which manufacturing residues may linger.

Chemical Risk Assessment or Cleanline Validation? 

In some regards, extractables and chemical risk assessment on metallic components blurs the line with the scope of work performed as part of a cleanliness assessment or clean-line validation - the workflows are in many ways similar and involve extracting the device in solvents of varied polarity and analysis of resultant extracts using techniques such as GC-MS, LC-MS, and ICP-MS. The results of this testing are a list of the identified organic and inorganic extractables which may then be inputs into a toxicological risk assessment. Often this process--other than being a key starting point of the ISO 10993-1 biocompatibility assessment-- may mitigate the need for more extensive (and expensive!) animal testing.


Posted by CatherineCerasuolo
February 26, 2019

Extractables of a Short-Term Implant

 Do I have to do chemical characterization?

Drug_eluting_stent.pngOverheard at a recent conference: "Oh, our device isn't a permanent implant, so we don't need to do extractables testing."

Is that right? If a device is implanted for less than 30 days (or even less than 24 hours), is extractables and chemical characterization unnecessary?

For clarity on this issue, we turn to ISO 10993-1:2018 and the FDA 2016 guidance on biocompatibility assessment. Each of these references contains a table which breaks down the biocompatibility evaluation endpoints associated with different implantation durations and the nature of body contact. Even in the case of a "limited" contact duration of less than 24 hours, these documents indicate that a biocompatibility assessment be performed. What does that entail, however?

The first step in performing any extent of biocompatibility assessment is to compile a detailed understanding of the physical/chemical properties and chemical composition of the device. Only once this information is in hand can an evaluation and risk assessment be performed with regard to toxicological endpoints such as carcinogenicity, genotoxicity, etc. For short term implants, the number of biocompatibility evaluation endpoints is generally less extensive than long term implants.

If the chemical composition of the device (both the raw materials as well as any manufacturing residues) are unknown or have not been previously characterized, an extractables assessment is typically necessary to determine the composition. Unless the device manufacturer has previous experience characterizing the material/manufacturing process by extractables, sufficient information on the device composition (including impurities, manufacturing residues, etc) is generally not available for this to be a pure paper exercise.

Note that from an analytical perspective, given the short term nature of the device, the analytical evaluation threshold (AET) employed will be less stringent than for a permanent implant. This means that when evaluating extractables data from techniques like GC-MS, and LC-MS, the number of peaks which must be identified and submitted for toxicological risk assessment is significantly lower than for a permanent implant--translating to generally lower cost and faster turnarounds.

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ISO 10993-1:2018 Table A.1

Posted by CatherineCerasuolo
June 29, 2018

In Hot Water


As summer sets in, it’s not unusual to leave a water bottle in the car and forget about it.  In the summer heat with the car windows down, it is possible for that PET (polyethylene terephthalate) water bottle to become a lens, concentrating the sun’s energy onto your car cushions (or that stack of junk mail you tossed into the backseat) and starting a fire.

Into Focus

Water is usually associated with putting out fires, rather than starting them.  Much like a kid burning ants with a magnifying glass, the clear, spherical bottle full of clear liquid converges the sunlight onto a flammable point.  Although your car cushion fabric is engineered to be as flame-retardant as possible, the pile of junk mail is not as well designed. Is it really likely that your forgotten water bottles will be optimally positioned to produce a focused beam capable of combustion? It is rare, but it can happen; some fire departments are urging the public not to leave bottles in cars.

Leachables in Your Bottled Water

Depending on how long the bottle has been sitting in your car, exposure to sunlight may accelerate the breakdown of the PET, releasing BPA and antimony into that disgustingly warm drink of water. As unappetizing as the leachables may sound, current research[1] has put those levels well below the safe limit, even for bottles stored in hot conditions for long periods of time. The FDA evaluates new research on BPA, but has not changed the acceptable levels of the material in food containers and packaging.

At Cambridge Polymer Group, we test leachables for packaging, pharmaceuticals, medical devices, food products, and cosmetics. Leachables aren’t always as harmless as the insignificant amount of BPA in your bottled water, and testing for them in the development stage of your product can reduce your litigation risk.

The odds of your car water bottle starting a fire or leaching unsafe levels of BPA and antimony are small, but it’s better to be safe than sorry. Keep calm and clean your car.

Posted by CatherineCerasuolo
May 31, 2018

New Thermoset Reduces Cost of Complex Shapes

Some of the main attractions of additive manufacturing include the ability to make complex shapes that elude standard machining or molding operations, and the ability to make small production runs without making expensive molds or fixtures. Researchers at the University of Illinois, Urbana-Champaign have discovered a way of producing shapes from a family of thermoset polymers at significantly lower energy cost.

Frontal Polymerization 

Their process makes use of a heat-curable monomer (DCPD) that, after curing has started by an external heat source, generates sufficient heat from the exothermic polymerization to sustain the curing process, producing a thermoset. The process is called frontal polymerization, so-named because the reaction moves as a front through the monomer.

Energy Efficient Custom Shapes in 3D Printing

Typically, these types of resins require the application of pressure and heat to effect the cure throughout the entire curing process, which requires much more energy and equipment. The FROMP (ruthenium-catalyzed frontal ring-opening metathesis polymerization) approach requires less energy and time and eliminates the need for large curing ovens.

Previous to this research, the FROMP technique was not industrially useful because the unheated DCPD resin cured in 30 minutes. By using alkyl phosphite inhibitors, the University of Illinois, Urbana-Champaign researchers were able to extend that time period to 30 hours, allowing enough time to shape the material before starting the frontal polymerization process.

These researchers generated quick-curing, high-quality spiral shapes and carbon-reinforced composite panels, and demonstrated similar mechanical properties to conventionally manufactured materials. Although the FROMP process has not yet been commercialized, this rapid fabrication of parts has a myriad of potential applications, including in the space, aircraft, and automotive industries. 


Posted by CatherineCerasuolo