Page 21 - Assurance of Sterility for Sensitive Combination Products and Materials

10 Assurance of sterility for sensitive combination products and materials

Gamma and electron beam sterilization work on the same basic principle
that high energy radiation damages and breaks DNA of living organisms,
such as bacteria, resulting in cell death. Naturally, therefore, this mode of
sterilization may not be a good choice for treatment of a combination prod-
uct that is designed to deliver complex biomacromolecules such as oligo-
nucleotides, RNAs, or DNAs. A further drawback of terminal sterilization
is that remnants of the dead microbes remain associated with the product
post-processing. The cell wall of Gram-negative bacteria is composed of
lipopolysaccharides that are released upon death and these so-called endo-
toxins can elicit a significant immune reaction. Hence, demonstration of
endotoxin levels within recommended specification limits are also gener-
ally required for products sterilized in this manner. Terminal sterilization is
discussed in more details later in Chapter 3. A less attractive alternative to
terminal sterilization is the use of aseptic techniques, which are inherently
more labor-intensive and hence expensive and do not share the benefits of
robust process control and a high degree of sterility assurance recognized
with terminal sterilization. This, however, might be the only option for
a complex advanced medicinal product with cellular components for in-
stance and is the reason why there have been some advances in the guidance
provided to the sterilization standards community in this area. The topic of
aseptic processing is covered in great detail later in Chapter 4.
2.2.1 Drug-enhanced devices

Drug-enhanced devices are a class of combination product in which the
functionality, efficacy, or performance of the device is enhanced by the pres-
ence of a therapeutic agent. The drug can be added to address a particular
issue that is associated with the use of the device, or to augment the use of
the device, including examples such as
• an antiproliferative agent to prevent tissue regrowth (in-stent restenosis)
induced by the placement of a stent in the artery;
• an anti-infective agent delivered from an orthopedic cement to prevent
infection following surgical implantation of a prosthesis;
• an anti-inflammatory to reduce the inflammation and fibrotic reac-
tion around a hernia-repair mesh that might affect its flexibility when
implanted;
• an anti-inflammatory to reduce the inflammation and fibrosis around
pacemaker electrodes to make their removal less traumatic;
• a chemotherapeutic delivered from an embolization device to kill
those cells that do not die as a consequence of the nutrient and oxygen
reduction