Medical Design Briefs: 2022 Technology Leaders - 8

TECHNOLOGY LEADERS Test & Measurement
also be reviewed by the toxicologist
who will make the claim (toxicologists
have very specific re -
quirements on data quality).
Shifting Requirements for
Chemical Characterization
The most significant shifts in
strategy with regard to chemical
characterization pertain to two key
points: the sensitivity of analysis
and required system suitability
information. The required sensitivity
is the so-called analytical
evaluation threshold (AET), a
term that became widely accepted
after the 2020 published update to
10993-18. What is critical today is
the manner in which the AET is
established.
The FDA expects a dose-based
threshold to be the foundation of
the AET, divided by an uncertainty
factor that ensures that chemicals
observed but underreported are
captured for assessment. Importantly,
the FDA accepts only one
formula for AET while there are a
couple of options published in
10993-18, and the uncertainty factors
have certain requirements
(such as being supported by labspecific
data). The newly required system
suitability data is more variable, but
in general includes a minimum number
of fully validated surrogates for each
method, across a spectrum of chemical
properties, where it is proven that the
sensitivity of analysis for these surrogates
is at least as good as the proposed AET.
Another recent system suitability re -
quirement is the need for spike and
recovery data across sample preparation
steps that often include liquid-to-liquid
solvent transfers and concentration
steps. All of the following main parameters
should be specified as part of the
BEP: extraction time and temperature,
solvents to be used, and AET.
Shifting Requirements Regarding
Shelf-Life
During the height of the COVID-19
pandemic, there was an acute shortage
of N95 masks for use in healthcare settings.
Work was happening at a breakneck
pace to attempt validation of
processes to clean masks for reuse while
8
ducing respirable particles that in
the environment of the lungs further
hydrolyses into mildly acidic
molecules known to cause temporary
respiratory irritation. The
remaining masks were destroyed.
The mask case study described
is an excellent example of a situation
weighing on the mind of
FDA: how do we know whether
the biocompatibility of a device
slowly changes for the worse on
the shelf? End-of-shelf-life testing
hasn't been a requirement historically,
but there are examples of
patient harm resulting in recalls
due to this. Therefore, end of
shelf-life biocompatibility should,
at a minimum, be directly discussed
in a BEP.
The Hippocratic Oath, attributed to the Greek physician Hippocrates,
required doctors of the time to " abstain from whatever is deleterious
and mischievous, " to " give no deadly medicine, " and otherwise avoid
any voluntary act that may cause harm.
manufacturers ramped up production.
Nurses were wearing old and soiled
masks, wearing unvalidated masks, or
making their own to give themselves
some level of protection.
Against this backdrop, a large manufacturer
of N95 masks found several
hundred thousand masks in a warehouse.
These particular masks had a
shelf life of four years, but had sat on the
shelf eight years. Due to the gravity of
the need, the masks were sent to hospitals
for use. Many users of the masks
made complaints of respiratory irritation.
Of course, use was paused, and the
manufacturer reviewed the historical
biocompatibility of the devices. It was
clear that they had passed all required
biocompatibility.
Upon review by the Expert Advisory
Services team at Nelson Labs, it was
found that these particular masks had a
polyester foam strip along the nose
piece to help prevent breath from fogging
the user's glasses. Polyester foam
can slowly degrade and particulate, prowww.medicaldesignbriefs.com
Most
often, this discussion is
short and doesn't require any
additional testing. " We know that
Ti6Al4V is a material extraordinarily
resistant to any degradation or
corrosion under conditions ex -
tremely exaggerated compared to
those used in storage; therefore,
the biocompatibility at end of
shelf life is expected to be
unchanged. " However, sometimes,
upon review it is clear that a
limited amount of testing such as cytotoxicity
and comparative FTIR is warranted
to establish material stability.
Conclusion
Modern evaluation of biocompatibility
uses a risk-based approach that requires
finesse. The testing burden is generally
less than a decade ago, but much more
attention and effort is needed in the formulation
of an appropriate strategy. For
most devices, expert knowledge of materials
is needed, along with feedback from
a toxicologist, and an up-to date pulse on
expectations of regulators. BEPs have
expanded from 1-2-page documents to
20 pages long, a reflection of the
thoughtfulness required as doctors,
device manufacturers, expert advisors,
and labs partner to ensure that what
makes it to market " first, does no harm. "
This article was written by Matthew R.
Jorgensen, PhD, DABT, Chemist, Materials
Scientist, and Toxicologist for Nelson Labs,
Salt Lake City, UT. For more information,
visit http://info.hotims.com/82318-342.
Medical Design Briefs 2022 Technology Leaders
http://info.hotims.com/82318-342 http://www.medicaldesignbriefs.com
Medical Design Briefs: 2022 Technology Leaders

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