Page 23 - Assurance of Sterility for Sensitive Combination Products and Materials

12 Assurance of sterility for sensitive combination products and materials

have been investigated and numerous drug degradation products have been
detected in a β-radiation dose-dependent manner, together with poly-
mer degradants [11]. Combined LC-MS-MS analysis of these DES post-
sterilization indicated that water addition and oxidative processes together
with the isomerization were largely responsible for the degradation of the
drug; so tight control of the combined product specification may be neces-
sary to prevent catalytic amounts of water adversely affecting downstream
processes. In general, however, many small molecules coated onto DES have
been shown to be stable to gamma irradiation which remains a mainstay
sterilization process. Although larger biological entities tend to be more
sensitive to all modes of sterilization, it was reported that stents coated with
polymer containing the antibody fragment GPIIb/IIa inhibitor, abiciximab
(or c7e3) absorbed within it, maintained its antiplatelet effect even after
sterilization and storage for several months [12]. The selection of a suitable
method is therefore trial and error and very much depends on the individual
components selected.

Case study 3: Sterilization of drug-eluting embolization beads
In the case of the DEBs described earlier, the embolization device on its
own presented hydrated in buffer in glass vials and is terminally sterilized
using steam. Testing was necessary to demonstrate that the steam did not
induce any degradation of the material and that the device dimensions
were unchanged and remained the same as per the specification and prod-
uct labeling. The steam sterilization process was validated using inoculation
standards to prove that all samples within the sterilizer chamber experi-
−6
enced sufficient heat to guarantee a 10 SAL. Endotoxin levels were also
measured and specifications set to ensure that the amount of bioburden
introduced during manufacture was at acceptably low level.
A preloaded version of the DEB was developed in which the drug
was loaded into the microspheres during manufacturing and provided to
physicians as the combined product. When this product format was initially
prototyped in a hydrated form in vials and steam sterilized as per the device
alone, the drug underwent complete degradation. A lyophilization processes
had to be developed to remove all moisture from the microspheres after
the drug was loaded, and the combination sterilized as a dry free-flowing
powder in vials by gamma irradiation. For this process, it was necessary to
demonstrate that the additional special processes employed did not affect
either device or drug component and that when the combination was re-
hydrated in water at the point of use, the product attributes were the same
as that supplied separately and combined in the pharmacy. Not only did
this involve validating a new sterilization method, but also shelf-life test-
ing had to be repeated as the product format and primary packaging had