The EU Regulatory Landscape of Non-Biological Complex Drugs

Pita, Ruben

doi:10.1007/978-3-319-16241-6_11

Cited by 4 publications

(4 citation statements)

References 8 publications

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“…27 The anionic, sulfate groups give heparin the highest negative charge density of any known biomolecule. 28 The sulfates appear to be critical to heparin's fibril enhancement role, as their removal has been found to result in the loss of heparin's ability to promote the aggregation of Aβ 40 and Aβ 42 . 29,30 Proteins and polyelectrolytes such as heparin form complexes primarily due to electrostatic interactions.…”

Section: ■ Introductionmentioning

confidence: 99%

“…Heparin is an unbranched, linear polymer of disaccharide units consisting of N-sulfated glucosamine (GlcNS) and iduronic acid linked by a (1–4) glycosidic bond (Figure ). The anionic, sulfate groups give heparin the highest negative charge density of any known biomolecule . The sulfates appear to be critical to heparin’s fibril enhancement role, as their removal has been found to result in the loss of heparin’s ability to promote the aggregation of Aβ 40 and Aβ 42 . , …”

Section: Introductionmentioning

confidence: 99%

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Heparin-Assisted Amyloidogenesis Uncovered through Molecular Dynamics Simulations

et al. 2022

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Glycosaminoglycans (GAGs), in particular, heparan sulfate and heparin, are found colocalized with Aβ amyloid. They have been shown to enhance fibril formation, suggesting a possible pathological connection. We have investigated heparin’s assembly of the KLVFFA peptide fragment using molecular dynamics simulation, to gain a molecular-level mechanistic understanding of how GAGs enhance fibril formation. The simulations reveal an exquisite process wherein heparin accelerates peptide assembly by first “gathering” the peptide molecules and then assembling them. Heparin does not act as a mere template but is tightly coupled to the peptides, yielding a composite protofilament structure. The strong intermolecular interactions suggest composite formation to be a general feature of heparin’s interaction with peptides. Heparin’s chain flexibility is found to be essential to its fibril promotion activity, and the need for optimal heparin chain length and concentration has been rationalized. These insights yield design rules (flexibility; chain-length) and protocol guidance (heparin:peptide molar ratio) for developing effective heparin mimetics and other functional GAGs.

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Section: ■ Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Heparin-Assisted Amyloidogenesis Uncovered through Molecular Dynamics Simulations

et al. 2022

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“…Regulatory agencies require detailed studies to know the nano-drug's precise disposition, analyzing the encapsulated, non-encapsulated and total drug (encapsulated plus non-encapsulated) [316]. In recent years, it has become necessary to include PK of the concentrations of bound drug (non-encapsulated bound to plasma proteins) and unbound drug (non-encapsulated that has not bound to plasma proteins) because non-linear protein binding changes the pharmacokinetic profile of the nanoformulation [317]. Overlooking protein binding and assuming it does not influence the profile constitutes a bias error.…”

Section: Regulation Of Pharmacokinetic Studiesmentioning

confidence: 99%

The Hitchhiker’s Guide to Human Therapeutic Nanoparticle Development

et al. 2022

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Nanomedicine plays an essential role in developing new therapies through novel drug delivery systems, diagnostic and imaging systems, vaccine development, antibacterial tools, and high-throughput screening. One of the most promising drug delivery systems are nanoparticles, which can be designed with various compositions, sizes, shapes, and surface modifications. These nanosystems have improved therapeutic profiles, increased bioavailability, and reduced the toxicity of the product they carry. However, the clinical translation of nanomedicines requires a thorough understanding of their properties to avoid problems with the most questioned aspect of nanosystems: safety. The particular physicochemical properties of nano-drugs lead to the need for additional safety, quality, and efficacy testing. Consequently, challenges arise during the physicochemical characterization, the production process, in vitro characterization, in vivo characterization, and the clinical stages of development of these biopharmaceuticals. The lack of a specific regulatory framework for nanoformulations has caused significant gaps in the requirements needed to be successful during their approval, especially with tests that demonstrate their safety and efficacy. Researchers face many difficulties in establishing evidence to extrapolate results from one level of development to another, for example, from an in vitro demonstration phase to an in vivo demonstration phase. Additional guidance is required to cover the particularities of this type of product, as some challenges in the regulatory framework do not allow for an accurate assessment of NPs with sufficient evidence of clinical success. This work aims to identify current regulatory issues during the implementation of nanoparticle assays and describe the major challenges that researchers have faced when exposing a new formulation. We further reflect on the current regulatory standards required for the approval of these biopharmaceuticals and the requirements demanded by the regulatory agencies. Our work will provide helpful information to improve the success of nanomedicines by compiling the challenges described in the literature that support the development of this novel encapsulation system. We propose a step-by-step approach through the different stages of the development of nanoformulations, from their design to the clinical stage, exemplifying the different challenges and the measures taken by the regulatory agencies to respond to these challenges.

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“…As far as bioequivalence is concerned, in the case of complex active substances and complex formulations measuring plasma concentration of the free active substance may not be enough. This may be due to the properties of the nanocarrier, as in the case of liposomes, or to the local action of the drug, as in the case of Cyclosporine eye drops [6,12]. The FDA has issued regulations on assessing bioequivalence beyond plasma concentration, and it may consider other approaches, if deemed adequate (21 C.F.R.…”

Section: Nbcds Copies From a Regulatory Perspectivementioning

confidence: 99%

Copies of nonbiological complex drugs: generic, hybrid or biosimilar?

Rocco

Musazzi

Franzè

et al. 2019

Drug Discovery Today

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The experience gained with biosimilars has made it clear that copies of complex drugs are more challenging to produce and put on the market than generics. In the case of so-called nonbiological complex drugs (NBCDs), the complexity can arise either from a complex active substance or by other factors, such as formulation or route of delivery. Regulatory policies in the USA and the EU for the marketing of NBCD copies are reviewed, using glatiramer acetate copies as a case study. In the USA, they are approved and marketed as generics (although needing additional data), and so they are interchangeable with the originator. In the EU, they are managed with a hybrid application, and their interchangeability and substitution are established by individual member states.

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The EU Regulatory Landscape of Non-Biological Complex Drugs

Cited by 4 publications

References 8 publications

Heparin-Assisted Amyloidogenesis Uncovered through Molecular Dynamics Simulations

Heparin-Assisted Amyloidogenesis Uncovered through Molecular Dynamics Simulations

The Hitchhiker’s Guide to Human Therapeutic Nanoparticle Development

Copies of nonbiological complex drugs: generic, hybrid or biosimilar?

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