Lessons Learned from Pharmaceutical Nanomaterials - Safety of Nanomaterials along Their Lifecycle - page 127

further hydrophilic polymer (PEG) with an adamantane end and an optional tar-
geting ligand (transferrin in the case of CALAA-01) enables iv administration and
tumor targeting (Davis 2009). Calando Pharmaceuticals Inc. as part of Arrowhead
Research Corporation took this nanopharmaceutical in a clinical phase 1 study as
therapy for solid tumors. This study not only demonstrated knock-down efficacy
of the target but also observed adverse effects (Davis et al. 2010). The Phase 1b
study evaluated the possibilities to overcome the adverse effects with a pretreat-
ment. Recently, Arrowhead decided not to take CALAA-01 into phase II studies
(genomeweb.com 2013).
6.5.3 r equirements for n anoPharmaCeutiCals
The key for the success of the aforementioned formulations and pharmaceutical
nanoparticulate formulations in general lies within their benefits for therapeutic out-
come (Figure 6.1) combined with their safe use and cost-effective production.
International regulations on medicinal and pharmaceutical products are rather
strict, putting high demands on proving their quality , efficacy , and safety, before
getting marketing approval or even entering clinical trials. As nanopharmaceuticals
are understood as a subgroup of pharmaceutical products, the same regulations not
only hold for “normal” drug products but also for nanopharmaceuticals in particular.
Safety is typically tested first, usually in vitro and in vivo before entering clinical
trials, while demonstrating efficacy is typically done afterwards. A basis for safety is
of course the use of appropriate materials and the appropriate testing of final formu-
lation. Quality is another factor that has to be taken into account while developing a
nanopharmaceutical formulation for market purposes. Generally, consistent quality
is achieved in the manufacturing process and the characterization of the formula-
tion. With respect to the possibility of designing and tuning properties of nanopar-
ticulate formulations various drug delivery systems are available: platforms such as
liposomes and albumin-based particles are already approved, various polymer-drug
composites are now in clinical trials, and dendrimers are in pre clinical trials (Davis,
Chen, and Shin 2008). Taking this into consideration, it is obvious that the more
complicated a nanoparticulate formulation is (nanocrystals of one material vs. mul-
ticomponent nature) the more complicated is its manufacturing and characteriza-
tion. Manufacturing from an industry point of view includes the ability to scale-up
processes, developed at small scale in the lab, as well as cost management. Although
proof-of-concept studies are widely published, there is a difference in producing
multifunctional nanoparticles in milligram quantities or in gram to kilogram quan-
tities for clinical trials with batch to batch consistency (McNeil 2009). On the one
hand, processes such as wet-ball-milling are well established, easy to scale up, and
used for nanoparticle production on the market today (e.g., Nanocrystal Technology).
On the other hand, processes such as precipitation are known for encapsulation of
biopharmaceuticals and applied at the lab scale. Industry production is challenging,
as batch to batch variation can be quite high. Specific good-manufacturing proce-
dures (GMP), as they are known for common medicinal products production, have
not yet been established for nanoparticle production and the current GMP guidelines
cannot readily be applied to multifunctional nanoparticle production (McNeil 2009).