be detected visually as a haze in the solution. Silicone may
also interact with protein-based drugs and form amorphous
stringy particulate that collapses onto the filter membrane.
The amorphous residue is not defined or counted as a particle using the USP <788> microscopic method and is not readily observed on the gridded filter membranes. Using proper
filters and lighting methods, the protein/silicone residue can
be isolated and confirmed using FTIR.
Particles can also be generated from the glass containers.
Glass provides a relatively stable material for sterile packaging, but it is not an entirely inert material and can be subject
to degradation. In severe cases, glass delamination flakes (or
lamellae) appear in solution. These flakes are very thin and
vials are often described as having a “twinkling” appearance
when examined using a fiber optic light source. However, the
flakes themselves are difficult to see on the filter membrane,
so if glass delamination is suspected, it is crucial to use the
proper filter membrane and lighting to see the flakes. It is
also important to inspect the inside surfaces of the vial to
look for evidence of delamination. Glass delamination may
occur due to irregularities in the glass container or interactions with the product. Processing of the vials and products
may also lead to delamination. Some active ingredients may
attack the glass.
By the time the glass flakes appear in solution, the problem is hard to fix and can result in product recalls and possible shortages of vital drugs. It is important to check for
product interactions with glass during the early stages of
new drug development. Vial manufacturers offer many different types of glass vials that can be tested for compatibility
with the drug product as part of the stability study.
Particles can also be generated during the use of the product. When a drug product is administered as an infusion,
the contents of the product vial are removed using a syringe
with a hypodermic needle, then added to the infusion bag.
The needle may remove a portion of the stopper rubber,
which is added to the bag along with the drug. The stopper
coring particle is then observed in the infusion bag as a potential contaminant, and the product is not administered to
the patient. The coring particle can be isolated and analyzed
to confirm that it was related to the packaging and is not an
As previously mentioned, vials are cleaned prior to sterile filling and these processes are carried out in cleanroom
environments. On rare occasions, fibers may be introduced
during filling and observed during the inspection of the vial.
The most common type of fibers observed are cotton and
paper fibers and fiber fragments (linters). Polyester fibers
may also be observed. Glass vials are cleaned prior to use
and then heated at high temperature (depyrogenation) to kill
endotoxins. If fibers or plastic wrap are not removed from
the vials prior to depyrogenation, they are charred and may
appear in the filled vials as charred organic material. The
charring may prevent the identification of the original mate-
rial, but the presence of charred material usually indicates
that it was present prior to depyro-
In summary, pharmaceutical
products and devices that enter
the blood stream must be sterile
and should also be essentially
particle-free. However, sterilization
does not guarantee that products
are clean. Monitoring for particles is
important and should be included
in all phases of drug development
and stability studies, as the identification of particles is necessary to
determine the source (root cause),
prevent future problems and help ensure patient safety. ■
Top: Glass delamination flakes on a polycarbonate filter viewed at 15X magnification
using coaxial illumination.
Bottom: Glass delamination flakes on a
polycarbonate filter viewed at 60X magnification using coaxial illumination. Photos by
Kristen Wiley, ©2012 McCrone Associates,
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