Pharmaceutical Processing - November/December 2013

cles in parenteral products. However, particles do slip through these stringent procedures, and on these occasions, the source of the problem needs to be identified.

GETTING TO THE SOURCE OF THE PROBLEM

Sources of particles include environmental debris, such as fibers and fiber fragments. Processing equipment may generate foreign particles. Particles may also originate from the container or packaging itself or interaction of the product with the packaging. Less commonly, the product itself may react and form particulate matter over time. These types of particles often manifest themselves during accelerated stability studies in the drug development process.

Parenteral containers are inspected for the presence of particles, either manually by trained inspectors and/or using automated methods. Products with high rejection rates are often submitted for particle identification to identify the root cause and prevent further problems. The size range for visible particles has not been fully established, but is usually defined as greater than 50 µm. Parenteral products are tested for the presence of subvisible particles using the USP <788> method. Part I of the method outlines the light obscuration method to test for particles in the > 10 µm and > 25 µm size ranges. The second part of USP <788> is a microscopic method utilizing filtration of the product onto a gridded filter membrane, then using a light microscope to obtain a particle count. The second part of the method is often used when particle counts are high, or the product is not suitable for the light obscuration method.

Silicone oil, used in pharmaceutical containers as a lubri-
cant for vial stoppers and cartridge (syringe) plungers, is a
common source of particulate; it is also applied to the tops
of the stoppers as an aid in processing. Under normal condi-
tions, the silicone used in the packaging does not present a
problem. However, if higher amounts of silicone are present
in the samples, it interferes with the USP <788> light obscu-
ration method and can result in high particle counts. The
samples are filtered through the membrane and the particles
are counted using a microscope. The oil is absorbed into
the filter and is not observed as particles. The silicone oil
can be confirmed by filtration of the product onto a differ-
ent type of filter membrane - usually a polycarbonate filter
membrane. The oil, if present, can be observed more easily
and can be extracted from the membrane and analyzed using
Fourier Transform Infrared Spectroscopy (FTIR) to confirm
the presence of silicone. High amounts of silicone may also
Sterilization is the process used to remove or kill any micro-
biological activity such as fungi, bacteria, viruses and spores on
surfaces or in solution. Steam sterilization and sterile filtration
are most commonly used in the pharmaceutical industry. The
sterile filtration process involves passing the product through
a 0.2 µm filter and has the
added benefit of removing
unwanted particulate that
may be present. The filtra-
tion and filling processes
are performed in cleanroom
facilities to further reduce
the chance of introducing
particles. The containers
(vials or syringe cartridges)
are cleaned prior to filling.

These processes are usually well-controlled and are very effective in reducing or eliminating unwanted parti-

■ By Gretchen Shearer, Senior Microscopist, McCrone Associates and Instructor, Hooke College of Applied
Sciences
Helping to ensure safety in parenteral processing

Empty containers that were labeled Sterile were rinsed with filtered deionized water and emptied through polycarbonate filters. These images show particulate that collected on the filters. The containers may have been sterile, but were obviously not particle free. These images were captured at 60X and 48X on an Olympus SZX12 stereomicroscope using dual oblique illumination.