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Introduction


of the introduction of many safe and effective alternatives to innovative medicines. However, this approach has been so far only applied to products that can be fully characterised. Changes in the composition and morphology of an NBCD can substantially influence the quality, biological properties and therapeutic profile of the medicinal product and result from minute variations in the manufacturing process.12,13


However, not all structural 4


changes and mechanisms that affect the therapeutic profile are fully understood. Notably, the complexity of NBCDs prevents establishing full proof of pharmaceutical equivalence by state-of- art analytical means, which comprises one of the two pillars in the evaluation of a generic medicinal product. In contrast to the mainly direct and systemic drug-target interaction of small molecules with defined receptors in a concentration-dependent manner, most NBCDs comprise nanoparticles from which the active ingredient can negatively affect the safety and efficacy of an NBCD or its follow-on product. The example of products for intravenous iron therapy is developed further. Hence, the biological activity of an NBCD is not necessarily correlated to its serum pharmacokinetics (central compartment); the second pillar in the


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generic pathway is to show bioequivalence.


NBCD products and their follow- on versions Iron carbohydrate complexes An iron–sugar nanoparticle consists of a polynuclear iron(III) hydroxide core surrounded by sugar molecules. Apart from the size, the reduction potential of the iron (III/II) and the strength of the interaction between the iron core and the surrounding sugar define the product’s quality, safety, efficacy and immunogenicity profile. The totality of the physicochemical properties of iron nanoparticle products define the bio-interference including their ability to interact with physiological acceptors (transferrin, ferritin, enzymes, specific cells such as monocytes, etc). The iron nanoparticles are defined by proprietary manufacturing processes, which complicates the development of comparable or even interchangeable follow-on products.12


The


pharmacokinetic parameters including the dissociation of the complex in plasma and biodistribution of the product into different tissues as well as the kinetics of the release of the active ingredient (iron) and the uptake into the physiological iron metabolism pathways may be profoundly different


between products. Differences in efficacy and safety between originator iron sucrose and formerly authorised similar preparations have been published.14–17


These data raise concerns


about interchangeability of such products based on both efficacy and safety. Patients treated in a recent study with an iron sucrose similar product required on average 34% more iron compared to patients treated with the originator product.14


Given the most


common use of chronic intravenous (IV) iron treatment is for anaemia in haemodialysis patients, and knowing that the excretion of iron in humans is limited and not well regulated, concern must be raised regarding what potential harmful effects this excess iron may cause.18


Both the FDA and EMA acknowledge that nanoparticle (colloidal) iron (sucrose) preparations cannot be authorised by the so far, well- established (classical) generic approval paradigm for small molecules, which is based on the sameness of the product shown by physicochemical full characterisation and a bioequivalence in healthy volunteers. But the situation is changing: both the EMA19


and FDA20


have issued ‘reflection papers’ and ‘draft guidance’ documents respectively, regarding data requirements. There is


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