Every year, numerous injectable/par- enteral drugs are recalled from the market due to the presence of visible
and subvisible particulate contamination.
Between the years of 2008 to 2012, 22 percent of sterile injectable drugs were recalled
due to the presence of particulate matter.
Adverse effects ranging from phlebitis and
pulmonary emboli to anaphylactic shock
and death can result from the administration of contaminated drugs to patients.
Every parenteral drug contains subvisible particles, and to ensure a safe product
and prevent a market recall, the particulate
content needs to be comprehensively characterized to verify its identity as either part
of the therapeutic formulation, or contamination from the manufacturing process
or packaging materials. Each container of
parenteral drug must have no visible particles (greater than 40 µm) and any subvisible particulate matter must comply with
the size and count concentrations outlined
in USP <788>.
Experts have deemed the methods for
particle characterization outlined in USP
<788> to no longer be sufficient for a
comprehensive analysis of the full particle
profile. The two accepted particle analysis
methods for USP <788> compliance are
light obscuration (LO) and membrane
microscopy. Since the publication of USP
<788>, studies have shown these methods
to be insufficient, and orthogonal methods
are now recommended to verify their results and obtain a comprehensive characterization of the particulate content.
LO quickly and easily delivers particle
counts, size and concentration, however
this method often undercounts translucent
particles and inaccurately sizes non-spheri-
cal particles. Therapeutic proteins are often
translucent and amorphous in nature,
and therefore the results of a LO analysis
should be verified by another method.
Additionally, LO generates only a particle
size distribution and particle count. It is
possible that particulate contamination can
go unnoticed if it falls within the approved
size range and concentrations outlined
in USP <788>, as LO has no method to
view or verify the identity of the particu-
late detected by the analyzer. Membrane
microscopy is time-consuming and labor
intensive and is only used when LO cannot
Particulate formation and
In conjunction with LO analysis, parti-
cle images from flow imaging microscopes
enable thorough particle characterization,
higher quality assurance and ensure greater
product safety. Flow imaging microscopy
captures an image of each particle in the
sample. These images are recorded and used
to calculate particle measurements, such as
size and concentration. Particle morphology
can be used to identify the particle and its
source, as well as observe any changes in
protein nature that could make the thera-
peutic formulation ineffective or harmful.
Today’s drug manufacturers are under
increasing pressure not only to understand
the particulate composition of their drugs,
but also to reduce and control particulate in
their formulations. To reduce and control
particulate matter, manufacturers must first
understand its source.
Changes to particulate matter can
happen at any point during a drug’s life-
The Value of Imaging
in Quality Assurance
Sensitive particle analysis methods detect contamination better
than current standards, leading to less recalls and safer drugs.
by Kent Peterson, President & CEO, Fluid Imaging Technologies
Protein agglomerates imaged using flow imaging microscopy.