Regulatory Issues: Down to the Bare Bones - Engineered Bone: Tissue Engineering Intelligence Unit - page 218

be preserved, data must be given to confirm the final product stability under the scheduled
conditions. Detailed information must be provided concerning the supplier, address, compat-
ibility results and biological tests.
In the receiving center, an analysis of the container, its closure system, its compatibility with
the biological product together with the expiration date should be performed. For sterile prod-
ucts evidence of container and closure integrity is mandatory.
Release Criteria
To evaluate manufacturing consistency and standard adequacy of the products, at least
three set of results of quality control tests, performed on independently manufactured com-
plete products, must be submitted under the supervision of the officer responsible for the
clinical application.
The documentation should include release criteria, i.e., all procedures and parameters needed
to evaluate product transportation condition and its integrity and sterility. In this respect tem-
perature and pH indicators and means of visual inspection of the final product security are
recommended. Procedures for release refusal must also be planned.
Demineralized Bone
A separate evaluation is given for the demineralized bone. Decalcified freeze dried bone
allografts are considered as unclassified devices, rather than tissues. This view is due to the
more-than-minimal manipulations needed to obtain the final manufactured product. The de-
vice definition only applies if the allograft is processed to demineralize and preserve the bone to
be used as a bone filler in orthopaedic and/or dental applications. In this case, as a Class I
medical device, bone allograft would be exempted from premarket notifications and GMP
requirements. In contrast, powdered bone (freeze dried bone allografts) falls under a different
legislation 21 being defined as a minimally-manipulated tissue since the process does not change
the integral structure of the tissue.
Conclusions
The emerging field of tissue engineering is rich of activity and promises. In the bone and
cartilage repair area many of the tissue-engineered products are based on the use of a cell
component associated to a natural or synthetic biomaterial. As for classical pharmaceutical
drugs, the criteria for their manufacturing need to be refined and updated in the light of the
achievement of the safest and most efficient product. It must be considered, though, that the
cell components of the composites are extremely complex open systems, 22 on which our present
knowledge and control are much more limited than the ones needed to perform a rather simple
chemical synthesis. A great deal of research, data and understanding are therefore still needed
to improve the state of the art in the field. This involves the public institutions and the private
enterprises, but it also calls in for public discussions. New therapeutic approaches pose several
ethical questions along with technical doubts, as in germline therapy for example, but they also
demand solutions to widespread debates before society comes to their acceptance. 23 In this
respect the function of the regulatory boards in the different nations becomes extended not
only to define the rules, the standards and the manufacturing requirements but also to inform
the public opinion and represent it.
In the light of the new role that the patient will have in the future, possibly being the means
of his/her own cure, regulatory authorities have to take into account all the legal issues to
protect the patient/donor's rights. In spite of the differences of the legal, medical and political
issues in the different countries a wider distribution of the same standard techniques and refer-
ences will make possible for experts to compare different protocols and/or products, allowing a
better evaluation of the therapeutic advantages for the patients.