Page 19 - Assurance of Sterility for Sensitive Combination Products and Materials

8 Assurance of sterility for sensitive combination products and materials

Center for Devices and Radiologic Health (CDRH). This is analogous to
the case for drug-eluting stents (DES), where the PMOA is maintenance of
the arterial lumen and secondarily, delivery of a drug to prevent restenosis
in the vessel. The DEBs, however, have also been evaluated in the treatment
of other solid tumors; recent preclinical [4, 5] and clinical studies have eval-
uated the direct injection of DEBs into the resection cavity left post surgical
removal of a brain tumor. In this case, there is no physical arterial occlusion
involved; the microsphere acts to hold and deliver the drug locally into the
tissue in which it is injected, the primary therapeutic effect being provided
by the action of the chemotherapeutic. In this case, therefore, despite the
product being identical to that used to treat liver metastases by emboliza-
tion, the route of administration and hence the primary therapeutic effect
is different, and the combination product has a drug PMOA and would be
regulated as medicinal product [hence, in the United States by the Center
for Drug Evaluation and Research (CDER)].
As demonstrated in this case study, the term combination product de-
scribes the entity used to treat a patient at the point of use and can therefore
be essentially considered as including:
• chemically or physically combined products (e.g., DES, transdermal
patches, metered dose inhalers, and prefilled syringes);
• co-packaged products (e.g., drug or biological product packaged with a
delivery device, surgical kits, and first-aid kits);
• “cross-labeled” products [e.g., photosensitizing drug and activating laser
source, iontophoretic drug delivery patch, and controller (both labeled
specifically for use with one another)]
If the two components of the combination product are manufactured
separately and co-packaged or cross-labeled, each component can be devel-
oped independent of the other by the conventional methods used for their
manufacture. Where the components are physically or chemically com-
bined into one product and packaged together, a strategy must be employed
to ensure that the combined end product can be satisfactorily sterilized by
a method that will ensure that none of the components are degraded or
altered by the sterilization step. The remainder of this chapter will focus
on considerations for the sterilization of this type of sensitive combination
product.

2.2 Considerations for sterilization of combination products

Primum non nocere—“first do no harm” is the fundamental code adopted
by a physician when considering patient treatment options; and which is
similarly inherent to all medicines and devices provided to physicians by
their manufacturers. One generic risk associated with all products entering
the hospital environment, particularly if intended to be used in an invasive