Regulatory Issues: Down to the Bare Bones - Engineered Bone: Tissue Engineering Intelligence Unit - page 212

procedure. So far all official authorities of countries where a tissue engineering activity is
being performed have substantially agreed to request similar detailed information for the
evaluation process of those products that include cells, either for autologous or allogeneic
use. In particular they all request:
• scientific rationale and objectives of the clinical experimentation;
• characterization of the starting cell population and of the auxiliary components;
• procedures used to manipulate the cells and the auxiliary components;
• description of the cell banks (where needed);
• characterization of the final cell and/or tissue engineered product;
• procedures for quality control of lots of the final products;
• preclinical documentation on the toxicity of the final product;
• preclinical documentation of the final product efficacy.
To solve the lack of standards, new techniques must be set on a case-to-case basis. Typically
the active principle in the cell therapy based products is poorely durable. The available cells are
usually scarce and their number not sufficient for extensive quality control tests. In the case of
severely aggressive diseases, the use of autologous cells imposes defined temporal limitations: a
prolonged expectance before the implant may hinder the patient's condition or alter his/her
morbidity to the treatment. In addition cell products normally need to be used few hours to a
few days from the time of the product preparation.
Since autologous cells are to be used in the same donor/patient, and given the above men-
tioned limitations in lot quantities and timing, the number of applicable tests can be reduced. For
example the official sterility test of the European Pharmacopea takes no less than fourteen days to
be performed. Clearly, the short half-life of cell therapy products may require their use in advance
to the availability of test results; nonetheless“...the manufacturer must still employ appropriate
controls to provide assurance of safety, purity and potency of MAS cell products...”. 10
The requested documentation is necessary not only for the donor/patient's risk assessment,
but also for the analysis of the therapy efficacy. For the FDA, in order to use and market a MAS
product, there is no need to demonstrate its superiority with respect to other existing drugs/
therapies. 10 On the contrary, the Committee for Proprietary Medicinal Products of the EMEA
(CPMP), and therefore the national regulatory boards of the European Community countries,
require a clear evidence of its effectiveness. In fact the European Committee follows a more
restrictive rule, probably considering a higher intrinsic risk as associated to the autologous cell
therapy with respect to other approaches.
Risk Assessment Analysis
A proper application and risk management/assessment analysis should take into account all
the following factors: 8-12,16-17
Origin of Materials to Be Used in the Composite Product Manufacturing
All culturing media, either for cells or tissue cultures, should be certified for their composi-
tion, purity, salt and organic component content and indicate a defined expiry date. Similarly
all the auxiliary materials which will be part of the final product (i.e., scaffold matrices, biopoly-
mers, ceramic components) or that are used in the manufacturing processes (i.e., plasticware,
disposable materials, common reagents) should be certified by their respective producers through
identified quality assessments. Lot numbers must be registered. For each chemical used, in
addition to the lot number, one must register manufacturer, production date, purchase date,
expiry date, composition, purity grade, biological activity and known contaminants.
All material used in the manipulations of the cellular component of the composite should
be certified for clinical usage. Unfortunately for many of the culturing media components
(cytokines, growth factors, antibodies, etc.) this standard is not available; however, for the
ancillary products whose function is necessary only during the manufacturing procedures, a
proper assay that determines their absence in the final product would be sufficient to grant
their use.