April 9, 2019

Extractables of Metallic Devices

Do I have to do chemical characterization? 

hip implant ball joint with screws.jpg

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.

ISO 10993_1_2018_Table_A.1.png

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
May 14, 2018

No Use Crying Over Spilled Chocolate

Spilled Chocolate.jpg 

Last summer, we wrote about a hagfish accident that covered an Oregon highway in slime.  Another sticky situation has come to our attention – on May 9 at 5:30 a.m., a tanker of liquid milk chocolate flipped over on the A2 in western Poland, spilling a dozen tons onto the six lane highway. Until authorities closed the motorway, drivers continued to drive over the spilled chocolate, tracking it a mile in either direction.

Cleanup crews sprayed the congealed chocolate with hot water to re-melt it and wash it off the road. Additionally, a bulldozer pushed chocolate sludge off the motorway – a technique also used to clear the Oregon highway of hagfish slime.

"Removing the chocolate will take a couple of hours. The chocolate congeals on the pavement, and it's worse than snow," one member of the fire brigade told TVN24

At the time of the accident, the temperature in Slupca, Poland was 12 °C, a bit lower than the 20-25 °C usually considered room temperature but not nearly as cold as the 0° to -4°C of a Western Polish January.  What if the temperature had been much lower? Could cars and people have been trapped in the sugary non-Newtonian fluid as it quickly cooled, like the victims of the 1919 Boston Molasses Flood?

The ease at which drivers sped through the spilled chocolate seems to indicate the muck was not impassably sticky. The air temperature must have been warm enough to keep the flow thin enough to allow for mobility. Fortunately, injuries from the May 9th accident were limited to the tanker driver’s broken arm and a reporter’s wounded pride after slipping into a chocolate-filled ditch.

Our CPG application note on chocolate mentions the importance of slow cooling for successful chocolate tempering. Did the change in temperature from tanker (>28 °C) to brisk morning air (12 °C) allow for proper tempering of the highway chocolate? The brown goo would have cooled too quickly for optimal confectionery quality. Probably a moot point, considering highway chocolate will never meet the quality standards of 21CFR163, Subpart B: Requirements for Specific Standardized Cacao Products or EU Directive 2000/36/EC. The only consumers of the Slupca spill are likely to be local wildlife.


Posted by CatherineCerasuolo
April 13, 2018

Vikings and Polarization

Calcite Crystal.jpg

We previously wrote about the Mantis shrimp’s use of birefringence as a means of hunting for transparent aquatic prey. Vikings are alleged to have used birefringence as well, but for navigational purposes. A calcite crystal found in a British warship that sank in 1592 was included amongst other navigational tools in the wreck.

The crystal would refract light depending on its orientation relative to the principle axis of the incoming light. When the crystal's principle axis is aligned east-west, an image viewed through the crystal resolves from a double image into a single image, thus providing a means of orientation. Since magnetic compasses were not fully utilized until the end of the 16th century, the crystal may have been used to augment compasses.

Called “sunstones” in Viking sagas, these crystals were believed to be used by Vikings in the 10th century, well before the use of compasses in Europe, to navigate from Norway to Greenland, a journey of 1,600 miles. They can be used in cloudy weather to locate the sun, as well as the afore-mentioned east-west orientation. There is still not direct evidence that Vikings used the sunstones for navigation, but computer simulation has shown that Viking navigation with these crystals would have been possible.

Calcite crystals are still used today as polarizers for the more pedestrian use of examining crystal structure and stress concentration in polymeric materials.

Posted by CatherineCerasuolo
April 6, 2018

New ASTM F2459-18 Standard Test Method for Extracting Residue


ASTM F2459 Standard Test Method for Extracting Residue from Metallic Medical Components and Quantifying via Gravimetric Analysis

The latest draft of ASTM F2459 Standard Test Method for Extracting Residue from Metallic Medical Components and Quantifying via Gravimetric Analysis just published. The key difference in this version is the inclusion of the method to determine extractable residue by measuring the medical device before and after extraction. This approach is particularly useful for smaller parts, a method CPG routinely uses to assist clients in cleaning validation. Please contact us if you have any questions about this standard or the associated testing.

Posted by CatherineCerasuolo