Lessons Learned from Pharmaceutical Nanomaterials - Safety of Nanomaterials along Their Lifecycle - page 119

interaction), which can lead to either negative or positive results with regard to assist-
ing or counteracting the active ingredients effect. In several cases, the particle tox-
icity was reported to impact not via direct contact but via mediators (Hatakeyama
et al. 2011). Real-time PCR or microarrays are means to study such effects. This sort
of analysis due to the complexity and difficulty to discriminate between nonrelevant
and relevant changes is still at the very beginning.
In conclusion, there are more than a few methods, in particular for cytotoxicity
tests of nanopharmaceuticals, but in the nanoparticle-cell interaction area we are
missing established and standardized systems. One big issue is that some assay con-
stituents interact with the nanoparticulate formulation and present false true or false
negative results (Wahl et al. 2008). Already described methods have to be validated
and adapted for nanopharmaceutical investigations. Validation of specific nanochar-
acterization assays requires more attention and maybe institutions such as the NCL
or OECD are predestinated to concentrate on these topics.
6.4 SAFETY AND QUALITY BY DESIGN
The specific medical application should direct the carrier design. The physiologi-
cal/pathophysiological and anatomical settings are important initial considerations.
Designing a system with the minimum of needed components and fewest possible
steps of robust production methods and powerful analytics for quality control are
the keys for successful formulations. By starting from a known system and trying to
eliminate the shortcomings by addition of further functional components, the sys-
tems are endangered to get too complicated for quality control and raise production
cost, which will hamper their translation into the clinic. In an ideal world, nano-
pharmaceuticals would be developed following Quality by Design (QbD) strategies.
These were developed for the pharmaceutical production of chemicals and are in
the process of implementation in the manufacturing of biotechnological products
(Rathore 2009). A prerequisite for the implementation of QbD is a sound knowledge
of the dependence of critical quality attributes and the desired functional perfor-
mance (e.g., medical behavior). In addition, also the impact of raw materials and the
understanding of the manufacturing process steps have to be established. Following
the principle of QbD the initial step is the identification of attributes with significant
impact on product performance. For nanopharmaceuticals, the product performance
is the combination of drug efficacy and safety. The aimed product profile is defined
by its characteristics. The second step is then to identify the critical quality attri-
butes. These are the properties, which are important to safeguard the product quality
and could be of physical (size, size distribution, shape, aggregation, etc.), chemi-
cal (hydrophobicity, surface functional groups, solubility, etc.), or biological nature
(toxicology, biodegradability, protein binding capacity, complement interaction,
antibody generation, etc.). This includes not only the naming of the key properties
but also to define the acceptable range (threshold) for each parameter. Subsequently
product design space is defined. Variations in process parameters are performed
using statistical methods such as Design of Experiment to gain a thorough under-
standing of the input variables and process parameters. Manufacturing methods with
a few steps, scalability, and high reproducibility are preferable. The use of hazardous