Page 25 - Assurance of Sterility for Sensitive Combination Products and Materials

14 Assurance of sterility for sensitive combination products and materials

need all external surfaces sterilized in its final format. It is possible to modify
existing processes to achieve this without adversely affecting the contents
of the syringe and vial. Mild EtO processing cycles employing shallow vac-
uums, low temperatures, low gas (H 2 O 2 or NO 2 ) concentrations, or re-
duced exposure times have been developed for this type of purpose, which
maintain sterility and provide a route to manufacture of such drug-device
combination that otherwise could be problematic.

Case study 4: Sterilization of Varithena (polidocanol injectable
microfoam) 1%
Varithena (polidocanol injectable microfoam) 1% is a drug-device combi-
nation product in which a canister device fitted with a filter stack generates
a microfoam with a defined bubble size distribution of polidocanol solution
and an oxygen:carbon dioxide gas mixture [14]. This unique product has
an excellent balance of foam stability to allow handling, administration, and
injection into a varicose vein, with enough cohesive property to displace
the blood from the vessel while collapsing the vein due to the sclerosing
action of the polidocanol surfactant. The low nitrogen gas mixture quickly
disperses in the body to reduce any adverse effects of bubbles circulating
around the body and in particular transient ischemic attacks from bubbles
that transit to the brain. The PMOA is that of the drug action on the vessel
wall, the device is responsible for reproducible creation of the stable micro-
foam to a defined specification.
The sterilization of this drug-device combination product is a classic
example of how long development programs that can span over a decade
will have changes in personnel, suppliers, product requirements and speci-
fications will lead to a manufacturing process that would be quite different
from a program that did not have these changes. Development programmes
that extend over long periods are at risk of the ever-changing regulatory
environment which can result in having to repeat certain performance tests
to revised standards, as well as new technologies that obtain approval in the
intervening time changing the requirements and raising the bar for data.
Fig. 2.5 shows an outline flowchart for the basic steps involved in the
manufacture of the Varithena (polidocanol injectable microfoam) 1% com-
bination product. What is evident from this chart is that despite the product
undergoing terminal steam sterilization, there are a number of other inter-
mediate sterilization steps involved. The valve assemblies that are used in the
canisters are created in a controlled environment but they are gamma irra-
diated to reduce bioburden prior to them entering a clean room environ-
ment. Exploratory work indicated that there was a risk that the polidocanol
may undergo some degradation if sterilized in the presence of oxygen and
so the product was split between two canisters, one containing the oxygen