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Medical Device Material Development: Considerations to

Minimize Extractables and Leachables
Dr. Ben MacCreath
Waters Corporation, Milford, MA, USA

INTRODUCTION
While the study of extractables and leachables (E&L) is being demanded by the regulatory
authorities, the information gathered is important for many other aspects of medical device
development and release including product design, process optimization, troubleshooting
and quality.

Whereas the regulators are dictating that this information is to be used to help ascertain the safety,
help direct the biological testing, E&L testing provides a wealth of information covering the full
product lifecycle. Figure 1. below illustrates a simplified view of a plastics medical device lifecycle.

Figure 1. Medical device supply chain.

One can consider all the E&L present within a device as either Intentionally or Non-Intentionally
Added Substances (IAS and NIAS, respectively) from the various stages of the lifecycle. If they
are intentionally added, they have a purpose, so simply removing them is not a trivial undertaking
– you need to satisfy their purpose another way. Non-intentionally added substances can be
considered as removable without an impact on the devices’ intended properties, however, the
source of these can be more

difficult to pinpoint, and sometimes they can be the product of an IAS – either a degradation
product or the result of a chemical reaction caused through the various stresses a device
undergoes during its production.

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REDUCING OR ELIMINATING EXTRACTABLES AND LEACHABLES

Of course, the simplest scenario is that there are no moieties that will transfer from the device to a
patient, but this is rarely the case, especially for polymeric devices. Meeting increasingly functional
and aesthetic requirements of medical device manufacturers, without compromising compliance
with regulatory requirements, is a big challenge. This puts increased pressure on formulation,
compounding, and processing. Medical device manufacturers benefit greatly from working with
the supply chain early in the development process, permitting the application of Quality by Design
(QbD) principles. Discussions with a toxicologist will help inform of the maximum levels of the
various substances that can be permitted. In certain cases, full removal or replacement might be
required whereas in others, it might be a required reduction of the substance to below a certain
level. There are too many scenarios to be covered in this piece, however some examples are
highlighted below.

RAW MATERIAL SUPPLIERS

Material at the very start of the supply chain can impact the E&L profile of the final product.
Side-products, residuals and other impurities can all be present that might simply carry through
as are. A worse scenario is that they can be part of a reaction somewhere along the process
and produce a hard-to-spot, and critically, hard to confidently identify, NIAS. This will take time
in chemical identification and then further time in identifying the source to rectify the situation.
Following reactions and ascertaining the purity by the raw material suppliers to avoid this
are both commonly achieved using LC or for extra confidence with increased sensitivity and
selectivity LC/MS. Ensuring high-purity products at this stage helps the final product’s E&L
study, reducing elucidation studies and identification of source.

Figure 2. Process and meterial time.

Medical Device Material Development: Considerations to Minimize Extractables and Leachables 2

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POLYMER PRODUCERS Product quality and performance during processing or in the

The manufacturing and processing stages are critical, final application are not only dependent on the actual or final
and tight control of these is required for medical device structure of the material, but also on the time-dependent
applications. By understanding the material behavior, the changes and external conditions. Thermal analysis and
processing conditions can be optimized to induce the least rheology have become the most important characterization
stress on the material, optimize levels of additives required techniques because of their sensitivity to small changes in
or even remove the need for certain additives altogether. structure and the ease to monitor these structure changes.
There is often a complex interplay requiring a high level of
characterization to fully understand material behavior, with
COMPOUNDERS/MASTERBATCHERS
rheology and thermal analysis being key techniques.
This is a rich area of activity for the medical device industry,
In general, the development and optimization are similar to
with skilled formulators achieving the desired requirements
many other use cases. However, there is an increased focus
through specific additive packages.
on avoiding adding to the E&L profile.
One of the key additives are stabilizers, critical for the long-
Most polymers utilized for medical devices are commodity
term performance, and indeed safety of the device. However,
polymers and most of these, due to cost constraints and
these can migrate from the material so one must understand
primary intended applications, are created in bulk and
the levels present both in terms of patient exposure as well
undergo little to no clean-up processes. They also have
as the impact on product stability. This is often studied using
quality release criteria based around the bulk properties,
differential scanning calorimetry (DSC), or more recently
focused on primary intended use cases, of which a medical
using the more sensitive microcalorimetry.
device is not. This means that for the more stringent
requirements of medical devices moieties can be present at
a variable level batch-to-batch which will impact the E&L
profile. Residual monomers (NIAS) or plasticizers (IAS) are Unstabilised 120˚C air
400
examples. Therefore, especially for medical devices that fall
within class II or III, sourcing polymers that are graded by
Heatflow (uW/g)

300
producers for medical use is a necessity. Unfortunately, there 100 ppm
have been examples where medical device manufacturers 200 ppm
200
have switched from a high-grade to a lower grade polymer
resulting in harm to patients. While there is no accepted 400 ppm
100
definition of a medical grade polymer, material manufacturers
turn to chemical and material characterization techniques
to provide assurances to those downstream. As regulators 0
0 1 2 3
are now pointing out, characterization from the supply chain
is key in understanding the final product’s risk profile. There
Figure 3. Heatflow versus time for polyamide 6 film stabilized with different
has been a standard created by the VDI, which defines and
amounts of Irganox 1098 in air at 120OC.
describes what is to be understood by the term “Medical
Grade Plastics”.¹

There are many IAS within polymeric formulations. One

example are chemical nucleators, which are often added to,
for example, polypropylene to improve processing cycle time
and impart desired properties such as clarity and increased
modulus. The study of the crystallization behavior and the
impact of nucleators can be accomplished using differential
scanning calorimetry (DSC).

Medical Device Material Development: Considerations to Minimize Extractables and Leachables 3

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MEDICAL DEVICE MANUFACTURERS healthcare greenhouse gases emissions are 2.2 GT/year,
The regulations are increasingly expanding to include more of almost 5% of the total global emissions. In the United States
the supply chain, but the burden remains on the company that alone, 14,000 metric tons of healthcare waste is generated
places the product on the market, typically the medical device per day. This not only has an environmental cost, but also
manufacturer. In designing out potentially harmful chemicals an immediate monetary cost too, recent reports stating
from the device, it is critical to understand what impact this is that despite efforts to reduce spending on waste, it’s still
going to have in the intended application. around 25% of healthcare spending in the US and healthcare
spending itself is at 18% of GDP.²
A key piece here is durability testing. Also referred to as
fatigue or stress testing, durability tests ensure that devices This being said, there are efforts to introduce more
are fit for purpose – most importantly that they do not fail sustainability to the medical device market.
unintentionally in humans and lead to severe consequences.
The primary purpose is to physically and repetitively load
SUMMARY
(with forces, torques, rotations, strains, displacements or
Developing materials for medical devices is a complex
pressures) the devices, or portions of it, in a way that is very
challenge. The safest route to satisfy regulations is to simplify
similar to the loading encountered in the body over time.
the formulation but doing this at the same time as improving
Implantable medical devices that withstand repeated loading
properties is counter intuitive. The regulations themselves
throughout their lifetimes such as spinal implants, breast
recognize this, and the increased emphasis on quality not only
implants or heart valves must be thoroughly evaluated for
of the final product, but of the product development process
performance and reliability in many aspects. For example,
itself. Therefore, the entire value chain will be working closer
the durability and fatigue resistance of the implant can be
together to satisfy the product demands and to generate the
evaluated by performing a complete device fatigue test-to-
chemical and material characterization required to ensure
success to prove adequate lifetime such as ISO 5840 for heart
product safety.
valves, or test-to-failure of breast implants as defined in ISO
14607. Insights from tests such as these are crucial for both
References
the design optimization to minimize failure risks and final
1. VDI, Medical Grade Plastics, July 2019.
validation that is required for regulation.
2. W.H. Strank, T.L. Rogstad, N. Parekh, JAMA, 2019;322(15):1501-
1509. doi:10.1001/jama.2019.13978, https://jamanetwork.com/
journals/jama/article-abstract/2752664.
END-OF-LIFE
With the focus on patient safety being of paramount
importance, the sustainability aspects of the healthcare
industry make for stark reading. Most, if not all, the steps
taken to reduce contamination, to reduce risk, such as single-
use products, incineration or landfill rather than reclaiming/
recycling adversely impacts the environment. The global

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