Biomedical Engineering Reference
In-Depth Information
substances like solvents or chemical reagents should be minimized or replaced when
possible. Purification and sterilization methods should also be taken into account. It
is also important to mention the need for analytical methods, which need to be estab-
lished for testing each critical quality criteria in quality and/or quantity to evaluate
the fulfilling of the acceptance criteria. In the area of nanotechnology that sounds
easier than it actually is. For size and size distribution there is a whole range of
analytical techniques available (see also section 6.3.1) while no method is suitable
as standalone analysis to deliver a full, realistic picture. The challenge here is to use
a well-balanced combination of analytical methods to avoid misinterpretations. For
other properties it is difficult to find suitable analytical methods at all. The measure-
ment of hydrophobicity is such an example. The Bengal-Rose assay may serve this
purpose in some formulations, but the interaction with the dye may also be influ-
enced by other particle characteristics. The measurement of contact angle is another
possibility, but not suited to high throughput analysis. Other analytical methods have
to be developed together with the delivery system because they need to be tailored,
for example, measurement of surface decoration with functional ligands, including
the analysis of covalent binding versus adsorption. The developed control strategy
is performed in the experimental pilot scale as well as in the upscaling process, and
process validation is maintained as quality control finally in manufacturing. The
quality of pharmaceutics is always defined by safety also, as they have no chance of
passing the approval of regulatory agencies. Therefore, risk assessment is included
in each QbD approach by a systematic approach of risk identification, analysis, and
decision about the acceptability or need/option for reduction or elimination and the
risk communication. Many nanopharmaceuticals are complex systems combining
several materials. These raw materials should ideally have well defined, low variable
product quality, and be analyzed in powerful standard analytics. All raw materials
as well as known degradation products should be tested for biocompatibility and
biodegradability. Raw materials with significant effect on the product quality should
be categorized as critical raw materials, which then implicate their stronger control
for each incoming batch and during the storage life-time. Whenever possible, for
excipients with GRAS status and for nonbiodegradable polymers, molecular weights
enabling excretion via the kidneys should be used. Polymers should ideally be well
defined and be suitable for high throughput assays of quality control (batch to batch
variance, purity). A difficulty in carrier design is that there are many research reports
using new polymeric materials. Often the materials are chosen for smart material
function (like temperature, pH, or light trigger) but do not care for toxicological con-
siderations. Few excipients do have the GRAS status and often just for limited routes
of application. With the currently available knowledge, materials, and processes, a
QbD study for nanoparticulate drug carriers does not assure success. Better under-
standing of what quality attributes of nanoparticles have impact on drug efficacy,
biodistribution, and safety implications is needed. Until a few years ago the major
focus was much on the size as the main criterion. Only in recent years, researchers
started to look also closer for further properties like hydrophobicity, shape, protein-
binding profile, and so on. An appraisement of carrier properties as critical prop-
erties and less critical properties with impact on various host reactions and their
assignment to the respective host reaction is needed. The range of critical particle
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