Page 30 - Assurance of Sterility for Sensitive Combination Products and Materials

18 Assurance of sterility for sensitive combination products and materials

• autologous chondrocytes and scaffold for the repair of cartilage
defects;
• autologous cell therapy and delivery device to treat cardiovascular
disease;
• cultured bone marrow cells and bone void filler with handling agent for
bone repair;
• artificial replacement organs (e.g., bioartificial pancreas).
The very nature of biologics makes them difficult to provide in a sterile
form, in particular those containing live cellular components. Protein-based
therapeutics need to maintain their sensitive three-dimensional conforma-
tions in order to remain physiologically active, which can be a significant
challenge during production and sterilization processes and can also ad-
versely affect the product shelf life. Physical and chemical degradation, de-
stabilization, and aggregation of proteins can all occur as a consequence of
changes in temperature, exposure to radiation, and initiation of hydrolytic
processes during manufacture.

Case study 6: Sterilization of a spinal fusion system
The Medtronic Infuse Bone Graft/LT-CAGE lumbar tapered fusion device
is a device-biologic combination product for certain spinal fusion proce-
dures in patients with degenerative disc disease. The product is composed
of a bone graft kit containing an absorbable collagen scaffold (ACS), a lyo-
philized bone morphogenetic protein (rhBMP-2) plus accessories, which is
labeled for use with the LT-CAGE threaded implant-grade titanium alloy
(Ti-6Al-4V) device (Fig. 2.7). At the point of use, the rhBMP-2 is reconsti-
tuted in sterile water and soaked into the ACS matrix; this is then rolled and
inserted into the hollow interior section of the threaded titanium implant to
form the complete combination product (titanium fixation device—collagen
scaffold device—protein biologic, Fig. 2.7D). Two of these assemblies are
then inserted and screwed into place between the two vertebrae where the
disc has been damaged. The protein elutes from the ACS in a controlled and
sustained manner over time, encouraging the in-growth of bone through
the windows in the fixation device and eventually filling the space as the
ACS resorbs, creating a bone bridge between the vertebrae [16].
Sterilization of this product is a little simplified in that the three main
components of this combination product are all sterilized separately by
different methods and provided in a kit or labeled for use together. The
titanium fixation cage is sold separately and can be terminally sterilized by
any of the conventional sterilization methods that will not affect the alloy,
such as gamma irradiation. The ACS manufacture involves lyophilization of
a dispersion of bovine Achilles tendon collagen followed by cross-linking