GUIDELINES FOR IMPLEMENTING A SAFE-BY-DESIGN APPROACH FOR MEDICINAL POLYMERIC NANOCARRIERS - Empa
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GUIDELINES FOR
IMPLEMENTING A SAFE-BY-DESIGN
APPROACH FOR MEDICINAL POLYMERIC NANOCARRIERS
GoNanoBioMat 1
COVER IMAGE: Tommaso Casalini „Nanocarrier passing through the cellular membrane“ 2 GoNanoBioMat
Impressum
PROJECT COORDINATION: Peter Wick, Claudia Som
PROJECT MANAGEMENT: Mélanie Schmutz
AUTHORS: Mélanie Schmutz, Claudia Som
CITATION: Som, C., Schmutz, M., Borges O., Jesus S., Borchard G., Nguyen V., Perale G., Casalini T., Zinn M., Amstutz V., Hanik N., Nowack B.,
Hauser M., Hernandez E., Wick P.: Guidelines for implementing a Safe-by-Design approach for medicinal polymeric nanocarriers,
Empa St.Gallen, June 2019
ACKNOWLEDGEMENT: Adriënne Sips, Lya Soeteman-Hernandez, Cornelle Noorlander and Robert Geertsma of the National Institute for Public
Health and the Environment (RIVM) for their external review and making the link to NanoReg and NanoReg2; Louis Schlappbach (Innosuisse),
Pierangelo Gröning (Empa), Christoph Studer, Sabine Frey (FOPH), Stefan Mühlebach (Vifor Pharma AG), Susanne Lauber Fürst (NTN Inartis Network),
Louis Tiefenauer (PSI), Jan van Lochem (Qserve) and Marcus Textor (Prof. em ETHZ) for their work as advisory board members; Darren Hart (Publish
or Perish) for English proofreading; and Brigitte Bänziger for the layout.
CONSORTIUM:
Peter Wick, Claudia Som, Mélanie Schmutz, Bernd Nowack, Marina Hauser, Edgar Fernandez (Empa, Switzerland)
Gerrit Borchard, Van Nguyen (University of Geneva, Switzerland)
Olga Borges, Sandra Jesus, Patricia Marques (University of Coimbra, Portugal)
Giuseppe Perale, Tommaso Casalini, Carolina Yumi (SUPSI, Switzerland)
Manfred Zinn, Véronique Amstutz, Nils Hanik (HES-SO Valais-Wallis, Switzerland)
Adriana Isvora, Ostafe Vasile (University of West Timisoara, Romania)
Martin Bopp, Walter Bender, Beat Christen, Peter Frei (Hightech Zentrum Aarau AG (HTZ), Switzerland)
Roger Christinger, Youri Popowski (Acrostak AG, Switzerland)
Christian Winter, Bruno Krieg, Urs Laubscher (IPQ, Switzerland)
The content of these guidelines is based on a systematic review of scientific papers and the knowledge and experience of the consortium partners.
COPYRIGHT: GoNanoBioMat, EU-Horizon2020, Innosuisse, Empa, 2019
FUNDING:
This project received funding from: the European Union’s Horizon 2020 Framework Programme; the ProSafe Joint Transnational Call 2016;
the CTI (1.1.2018 Innosuisse), under grant agreement number 19267.1 PFNM-NM; and the Foundation for Science and Technology (FCT) under
project PROSAFE/0001/2016. HTZ, IPQ and Acrostak AG were implementation partners.
GoNanoBioMat 3
CONTENT
IMPRESSUM 3
CONTENT 4
THE GONANOBIOMAT FRAMEWORK 6
Guidelines‘ goals 6
Scope and limitations 6
SAFE-BY-DESIGN 7
The origins of SbD 7
SbD in the context of polymeric nanobiomaterials for drug delivery 8
MATERIAL DESIGN 10
What are polymeric nanobiomaterials for drug delivery? 10
What to consider when designing polymeric nanobiomaterials for drug delivery? 11
The immune system as a barrier to drug delivery 14
Material properties and impact on safety 14
Current knowledge of physicochemical properties and their effects on safety 14
Non-testing tools 16
Polymeric nanobiomaterial production methods 16
Case Study: PHA nanobiomaterials preparation method 19
REGULATORY FRAMEWORK 20
What are the regulatory frameworks in Switzerland and the EU? 20
What is special about nanomedicines? 20
Which quality system should be followed? 23
Are there any nano-specific guidelines? 23
Case study: Polymers and regulation 24
4 GoNanoBioMat
CHARACTERIZATION OF POLYMERIC NANOBIOMATERIALS 28
When and how to characterise nanobiomaterials 28
HUMAN HEALTH RISKS OF POLYMERIC NANOBIOMATERIALS 31
Human health risks – an overview 31
Exposure 31
Pharmacokinetics and pharmacodynamics of polymeric nanobiomaterials 34
Nanobiomaterial degradation and elimination 37
How can exposure to a polymeric nanobiomaterial be evaluated? 37
What are the challenges of testing realistic exposure in vitro? 38
Hazard 38
How can a polymeric nanobiomaterial’s hazard potential be assessed? 42
What are the challenges of toxicity testing studies and the evaluation of their results? 44
Case study: immunotoxicity of chitosan nanobiomaterial 44
Human Health Risks 46
ENVIRONMENTAL RISKS OF POLYMERIC NANOBIOMATERIALS 48
An overview of environmental risks 48
Current knowledge for environmental exposure 48
Current knowledge of environmental hazards 50
What conclusions can we draw for environmental risks? 50
CHEMISTRY, MANUFACTURING AND CONTROL 52
STORAGE AND TRANSPORT 55
GLOSSARY 56
LEGAL AND PUBLISHING DETAILS 58
GoNanoBioMat 5
THE GoNanoBioMat FRAMEWORK
The GoNanoBioMat framework provides misguided investments, and (4) to en- The guidelines:
elaborate current knowledge to small and able SMEs to deliver safe products in an • provide information on nanocarriers
medium-sized enterprises (SMEs), their internationally competitive market. These in general and not on nanocarrier
suppliers, service providers and research guidelines are not only addressed to SMEs systems for specific drugs;
institutes at the interface of nanomaterials developing nanocarriers, but also to SMEs • only take into account the early pha-
and nanomedicine. The aim is to support having some link to the topic. These guide- ses of development (early research
SMEs in their decision making when deve- lines are intended to accompany SMEs and development and the pre-clinical
loping and producing polymeric nanobio- through the implementation of an SbD phase);
materials1 (NBMs) for drug delivery by im- approach in the early research and devel- • emphasise the safety aspects by
plementing a Safe-by-Design (SbD) ap- opment phases of medicinal polymeric implementing an SbD approach dur-
proach. The GoNanoBioMat framework nanocarriers (being considered as nano- ing the development of nanocarriers.
contains: medicines).
• a knowledge base presenting the These guidelines also discuss certain as-
current state of the science, including The guidelines are based on the know- pects of the concept of Quality-by-Design
trends, gaps and uncertainties; ledge base built up from peer-reviewed (QbD) because this is mandatory for phar-
• guidelines for implementing an SbD scientific publications. All the scientific re- maceutical market approval and because
approach for medicinal polymeric ferences for these publications can be QbD and SbD are interconnected.
nanocarriers; found in the knowledge base, but are not
• and case studies involving an in-depth mentioned in the guidelines to facilitate its
investigation of three selected materi- reading. However, links to other guidance
als: chitosan, polylactic acid (PLA) and documents which may be useful when
polyhydroxyalkanoates (PHAs). developing a nanomedicine are provided
in these guidelines.
GUIDELINES’ GOALS
The guidelines’ goals are to (1) support in- SCOPE AND LIMITATIONS
formed decision-making in the field of pol- These guidelines focus on polymeric NBMs
ymeric NBMs for use in drug delivery, (2) to for use in drug delivery systems (nanocar-
improve and facilitate communication riers), but the principles laid out in them
(develop a common language) between could be extrapolated, to a certain extent,
the different stakeholders contributing to to others, e.g. inorganic NBMs, such as
the value chain and between industry metal and metal oxide nanobiomaterials.
and regulatory authorities, (3) to prevent
1
Biomaterials are materials that interact with specific biological systems and can either be derived from nature or be synthetically produced. Nanobiomaterials are therefore biomaterials in the nanoscale (up to 1,000 nm).
https://ec.europa.eu/research/industrial_technologies/pdf/biomaterials-roadmap-for-horizon-2020_en.pdf
6 GoNanoBioMat
SAFE-BY-DESIGN
THE ORIGINS OF SBD
Safe-by-Design (SbD) is a general approach
or concept used to identify the risks and
uncertainties involved in human health and
environmental safety during the early
stages of product development; it supports
efficient processes towards creating safe
products, safe production methods and
safe handling. The general approach to
SbD in the field of nanomaterials started
with the EU’s NANoREG project (www.
nanoreg.eu) and was propagated by its
H2020 ProSafe initiative (www.h2020-
prosafe.eu) and H2020’s NanoReg2 pro-
ject. In the GoNanoBioMat project, a trans-
national effort has been made to imple-
ment an SbD approach in the development
of NBMs for drug delivery systems. This
challenging goal required drawing to-
gether knowledge from several different
fields (chemistry, biology, medicine and
pharmaceutical sciences).
GoNanoBioMat 7SBD IN THE CONTEXT OF POLYMERIC of the material (red arrows) after each SbD their effects. This means that a thorough
NANOBIOMATERIALS FOR DRUG DELI- action. SbD actions are meant to maximise characterisation of the NBM is needed to
VERY safety while optimising efficacy and costs. be able to correlate the NBM’s properties
Within the GoNanoBioMat framework, the Bullet points inside boxes correspond to to their effects and therefore enable an
SbD approach focuses on addressing hu- the possible methods, tools or endpoints SbD approach. This can involve iterations
man health and environmental safety that may be used or tested in each step. until an optimum solution is found – one
throughout the development phase of na- that is safer for both human health and the
nocarriers (excluding use and disposal The SbD approach begins by generating environment and which shows higher effi-
phases, as these are beyond the project’s ideas for the design of NBMs as nanocar- cacy at lower costs (the second SbD ac-
scope). The SbD approach described here riers. This step can be seen as a brainstorm- tion). Once the final candidate (experimen-
is an iterative, interdisciplinary process in- ring step and is meant to help set the con- tal nanomedicine) is selected, the stan-
cluding the following aspects (Figure 1): text and open the door to exploring new dards of Good Manufacturing Practice
I. Safe Nanobiomaterials: designing opportunities by answering a few questi- (GMP) (Manufacturing and Control box)
low-hazard nanocarriers for specific ons (see Set the context and generate have to be fulfilled in order to begin clinical
applications by assessing human ideas). The following steps define the desi- trials. When safety and efficacy have been
health and environmental risks early red material properties, collect information proven in clinical trials, information will be
on in the development process in the literature to screen for unwanted required about the nanomedicine’s stabili-
II. Safe Production: manufacturing and toxicity by using the answers from the pre- ty and shelf-life (Storage and Transport
control of nanocarriers to ensure their vious step, and use “non-testing tools”. box) in accordance with Good Distribution
safety and quality Efficacy should also be screened for, as is Practice (GDP) standards. All the activities
III. Safe Storage and Transport: ensuring mentioned in Figure 1, but this aspect is shown in Figure 1 – from the earliest stage
the safety and quality of nanocarriers beyond this project’s scope as efficacy is of innovation – will have to follow the reg-
drug-carrier system specific (also depen- ulatory framework determined by the
In addition, the regulatory frameworks ap- ding on the drug that will be loaded onto type of application planned (this was
plied in Switzerland and European Union the nanocarrier). A first SbD action is taken already answered in the first step of the
are incorporated into the guidelines’ at this point. If no unwanted side effects or Material Design).
different chapters (see the yellow box in environmental toxicity have been found in
Figure 1). the literature on a particular NBM or All the boxes shown in Figure 1 correspond
with “non-testing” tools, the selected pro- to a specific chapter in these guidelines.
In Figure 1, the blue arrows represent the totype(s) can be produced. This step is Each chapter provides the relevant current
flow of polymeric nanobiomaterials for use followed by a first experimental evaluation knowledge, an evaluation of that know-
in drug delivery from their design to their of its safety profile (potential human health ledge, useful methods and tools, and
storage and transport. Feedback loops and environmental risks) by connecting the sometimes a case study as an example.
enable developers to go back to the design material’s physicochemical properties to
8 GoNanoBioMatFigure 1
GoNanobioMat framework. Blue arrows correspond to the flow of polymeric nanobiomaterials as drug delivery
systems from design to storage and transport, red arrows are feedback loops used whenever the nanobiomaterial
product is unsafe, inefficient or has unwanted side effects, and bullet points represent the methods/tools or
endpoints at each step.
GoNanoBioMat 9MATERIAL DESIGN
WHAT ARE POLYMERIC NANOBIOMA- surface structure, in the nanoscale range • Enable targeted drug delivery
TERIALS FOR DRUG DELIVERY? (approximately 1 nm to 100 nm)“, or • Increase the bioavailability of poorly
In medicine, a nanobiomaterial is a nano- „a material or end product engineered to water-soluble drugs
scale material able to give an appropriate exhibit properties or phenomena, inclu- • Promote controlled drug delivery;
host response for a drug in a specific appli- ding physical or chemical properties or • Increase the stability of drugs in
cation. The definition of a nanomaterial biological effects, that are attributable to biological fluids
differs according to the regulatory au- its dimension(s), even if these dimensions • Increase drug circulation time in
thorities around the world. For example, in fall outside the nanoscale range, up to one the body
medical applications, the European Medi- micrometre (1000 nm)”2 . The GoNanoBio- • Confer drugs protection from
cines Agency (EMA) defines nanomaterials Mat framework considers NBMs smaller biological fluids
as being in the range of 1 nm to 100 nm, than 1000 nm in the three dimensions. • Permeate through various biological
whereas the US Food and Drug Administ- barriers
ration (FDA) has not established a regula- Different materials can be used for drug • Enable surface modifications to
tory definition. The latter, however, may delivery, and these can vary from lipid and increase interaction with biological
consider a nanomaterial to be „a material polymer-based to inorganic NBMs. Poly- targets
or end product engineered to have at least mer-based nanocarriers have interesting
one external dimension, or an internal or characteristics for drug delivery, as they can:
Figure 2
Examples of natural Polymers
(the polymerisation step is
made by a living organism)
and synthetic (the poly-
merisation step is not made Natural
Synthetic
by a living organism) polymers (Biodegradable)
used in drug delivery.
Proteins Polysaccharides Polyesters Biodegradable Non-biodegradable
Albumin Chitosan Poly(R- Poly(lactid) acid (PLA) Poly(methyl methacrylate) (PMMA)
Colagen Alginate hydroxyalkanoate) Poly(glycolic) acid (PGA) Polyethylene glycol (PEG)
Gelatin Dextran (PHA) Poly(caprolactone) (PCL) Poly(etilene) (PE)
Hyaluronic acid Poly(anhydrides) Epoxi polymers
Cyclodextrins Poly(R,S-hydroxyalkanoate)
(PHA)
2
FDA Draft Guidance Document: https://www.fda.gov/regulatory-information/search-fda-guidance-documents/drug-products-including-biological-products-contain-nanomaterials-guidance-industry
10 GoNanoBioMatPolymers are very versatile and can be meric micelles and drug conjugates. Poly- All these factors influence the NBM design.
either natural or synthetic, as shown in meric NPs, called thereafter polymeric na- For example, the design of NBMs will not
Figure 2. Natural polymers and their resul- nocarriers, comprise both vesicular sys- be the same for treating diseases as it will
tant NBMs generally suffer from problems tems (nanocapsules) and matrix systems be for vaccination. The disease to be treat-
of stability in biological media, and they (nanospheres). ed will also determine the type of drug to
also present poor batch-to-batch reprodu- be used, which in turn is the most impor-
cibility. Because of their natural source and WHAT TO CONSIDER WHEN DESIGNING tant factor influencing nanocarrier design.
biodegradability, they are more prone to POLYMERIC NANOBIOMATERIALS FOR Another important factor is the route of
antigenicity and degradation. The chemi- DRUG DELIVERY? administration. Various routes of adminis-
cal modification of certain natural poly- Designing NBMs for drug delivery means tration (see chapter on Human Health
mers has generated some of the most tailoring their physicochemical properties Risks) are used to deliver NBMs to the tar-
widely used synthetic polymers, such as to the goal at hand. Physicochemical pro- get, including the oral, parenteral (intrave-
the poly (D,L -lactide). perties have an impact on the efficacy, nous, subcutaneous, intradermal and in-
safety and quality of the final product. tramuscular), respiratory and transdermal
The selection of the polymer used to pro- NBMs as drug delivery systems should routes. On entering the body, drug nano-
duce a drug delivery system is dependent be fit for their intended use, that is, to con- carriers need to pass through various bi-
on several factors, such as the final product sistently deliver their active substance at ological barriers (e.g. epithelia, endothelia,
and its degradation product’s antigenicity, the site of action at the required dose and cell membranes, and lysosomal and nuc-
biocompatibility and toxicity, the kinetics be stable throughout their shelf-life. In or- lear membranes) before reaching their
of its biodegradability3, the drug release der to fulfil this objective, one should con- site of action (target). Targeting can be
profile, solubility and stability of the encap- sider the following major factors (non- achieved by passive diffusion (e.g. by
sulated drug, and other physicochemical exhaustive) for a well-designed NBM: exploiting specific physiological condi-
properties such as particle size and surface • Type of disease and target population tions, as seen in tumour tissues, which
characteristics. The characteristics of most (patients) show enhanced permeation and retention
natural polymers are usually less reprodu- • Type of drug (e.g. poor water effects for NBMs) and by active targeting.
cible than those of synthetic polymers. solubility) The latter includes the attachment of tar-
Importantly, a polymer’s biodegradability • Route of administration geting moieties such as antibodies (or their
influences the mechanisms by which it is • Type of barriers (e.g. blood-brain fragments), aptamers or small molecules
eliminated from the body. barrier, cell membranes, intestine) to the NBM’s surface. These targeting moi-
• Target cell (e.g. tumour cells) eties will specifically interact with proteins
Polymeric NBMs can be assembled into • Release kinetics (over-) expressed on target-cell mem-
different medicinal nanocarriers, such as • Dose needed branes and may thus trigger cellular up-
polymeric nanoparticles, dendrimers, poly- take. On the one hand, the nanocarrier
3
Biodegradable means “susceptible of breakdown into simpler components by such biological processes as bacterial or other enzymatic action” https://medical-dictionary.thefreedictionary.com/biodegradable.
GoNanoBioMat 11should be able to deliver the drug to the vaccines, with the latter only conferring
right site of action, and on the other hand, the antigen’s genetic information to the
it should release the drug at a rate suitable vaccinated individual. Physicochemical
to maintain an effective therapeutic con- properties and other parameters (antigen/
centration for a given period (release kine- adjuvant loading and release, size, size dis-
tics). Drug release kinetics may be modulat- tribution, surface charge, etc.) are being
ted by changing the type of biomaterial measured as described previously, and the
employed or by the formulation process of choice of NBM is dependent on the appli-
the NBMs. Finally, the dose of the active cation route, type and dose of the antigen
pharmaceutical ingredient is a decisive fac- to be delivered.
tor in any treatment’s success. It can be
influenced by the NBMs physicochemical Figure 3 presents a general decision tree
properties, such as the size of the NBMs or concerning the factors discussed above. It
the encapsulation efficiency, which in turn follows a methodological approach, is in-
depend on the difference in lipo/hydrophi- dicative and does not claim to be com-
licity between the drug and the polymeric plete. However, it does offer a potential
NBM. pathway for any application, and it sup-
plies guidance on choosing polymeric
Therapeutic or preventive vaccines utilise NBMs for the preparation of nanocarriers
polymeric materials to form nano-sized for drug delivery.
materials as carriers for antigens and adju-
vants. Indeed, the particulate form and
shape of NBMs are recognised as being
foreign to the body (resembling pathogens
also in size) by the immune system. Like
drug carriers, NBMs for vaccine delivery
can be equipped with targeting moieties
that interact directly with immune cell-
specific receptors, which trigger their up-
take or stimulate the targeted immune cell.
Such carriers are being examined for the
delivery of (adjuvant) subunit and DNA
12 GoNanoBioMatFigure 3
Decision tree for choosing a
nanobiomaterial taking into
account the various factors
discussed in this chapter. In
blue, the route of administra-
tion; in green, the factors to
consider; and in pink, exam-
ples of nanobiomaterials
that can be used as delivery
systems.
GoNanoBioMat 13The immune system as a barrier to drug cells, and their accumulation, degradation face can be „designed“ to adsorb selected
delivery and toxicity. Proteins forming the corona proteins, which then interact with specific
The key factor in the efficacy and safety of may adopt another combination after in- receptors on the target site, or by pre-
NBMs is their interaction with their physio- teracting with the NBM modifying bind- forming the corona with chosen proteins
logical environment, or more precisely, ings with other proteins and influence prior to injection4.
with biomolecules, as these are the body’s signal transductions and gene transcrip-
main constituents. In the case of drug tions. Moreover, protein adsorption on the MATERIAL PROPERTIES AND
delivery for treating disease, interaction NBM surface can be recognised by the IMPACT ON SAFETY
with the immune system should be avoid- immune system, which then initiates an Regulatory bodies require that the safety
ed (which is the contrary for vaccines). immune reaction (this process is also and efficacy of new drug-nanocarrier sys-
Moreover, most NBMs used as drug deliv- referred to as opsonisation). tems must be determined. This includes
ery vectors are administered parenterally. not only the evaluation of the drug-nano-
Thus, as soon as they are injected into the To avoid recognition by the immune sys- carrier combination, but also the evalua-
bloodstream, their surface becomes co- tem and enable longer plasma circulation tion of the nanocarrier alone (the NBM).
vered by plasma components, most of times for a drug’s vector, it is important to There are two ways of screening NBM’s
which are proteins which form the protein design „stealth“ NBMs that can at least toxicity: firstly, based on current know-
corona. The composition of this corona, temporarily avoid opsonisation. The most ledge (literature review), and secondly, by
and the kinetics which lead to its forma- important factor is the architecture of the using “non-testing tools“.
tion, determine the „biological identity“ material’s surface. The NBM surface may
of the NBMs. be functionalised with polyethylene glycol Current knowledge of physicochemical
(PEG), polyethylene oxide (PEO) or surfac- properties and their effects on safety
The protein corona is not a stable surface. tants such as poloxamers, poloxamines, At the nanoscale, small variations in physi-
It can be modulated according to the mo- polysorbates (Tween-80) and lauryl ethers cochemical properties may have very signi-
bility and affinities of blood proteins (Vro- (Brij-35). PEGylation is by far the most com- ficant effects on a NBM’s biological inter-
man effect). The first proteins adsorbed (to monly used technique, with the „stealth“ actions and its therapeutic efficacy and
form a “soft” corona) are later replaced by effect being attributed to the surface‘s safety. Table 1 shows an overview of cur-
higher affinity proteins of lower mobility, higher hydrophilicity, which reduces or rent knowledge about the influence of
which form a “harder” corona. The inter- delays protein adsorption. The same effect physicochemical properties (size, shape,
action of NBMs with plasma proteins de- is probably achieved via the steric hin- surface charge and surface chemistry) on
pends strongly on the particles’ physico- drance induced by the PEG chains protrud- various factors which have an impact on
chemical properties, especially their sur- ing from the NBM surface. In addition, safety.
face properties. This can affect their immu- recent studies have shown that in order to
nogenicity, their internalisation by immune achieve specific targeting, the NBM sur-
4
For further information, other barriers are described in the knowledge base on “Polymeric nanobiomaterials for drug delivery“ www.empa.ch/gonanobiomat
14 GoNanoBioMatTable 1
Physicochemical properties which have an
Size Shape Surface chemistry and surface
impact on endpoints having an influence charge
on the NBM’ safety. The √s are based on
scientific literature5. Targeting efficacy √ √ √
Stability √ √
Biodistribution √ √ √
Elimination and degradation √
Toxicity √ √ √
Drug loading √ √
Drug release √ √
Surface area √
Protein corona √ √
Cellular uptake √ √ √
Biocompatibility √ √
Blood circulation time √ √ √
Aggregation √ √
Drug interaction √
Opsonisation √
5
See knowledge base on “Polymeric nanobiomaterials for drug delivery”: www.empa.ch/gonanobiomat
GoNanoBioMat 15Non-testing tools interpolate where data may be missing. formation of the protein corona, and ii)
Assessing the safety of NBMs using non- The premise is that similar materials be- interactions between the nanocarrier and
traditional methods is being ever more have in similar ways and have similar pro- the cellular membrane. However, it cannot
greatly encouraged in order to reduce the perties. Thus, by using the interpolation replace laboratory experiments complete-
need for animal testing. Various tools are mentioned above, a material‘s endpoint ly, nor can it currently be used purely as a
regarded as “non-testing tools”. For ex- can be predicted even if that material‘s prediction tool. This is due, on the one
ample, to evaluate NBM toxicity or better data is not experimentally available. hand, to the intrinsic complexity of the sys-
understand how nanocarriers interact with tem under investigation, and on the other
biological interfaces, the following tools The Organisation for Economic Coopera- hand, to the lack of any systematic valida-
may be used: tion and Development (OECD) published tion with experimental data.
• (Q)SAR: (Quantitative) guidance on the validation of QSAR mod-
Structure-Activity-Relationship els in 20076. Appendix R6.1 gives guidance POLYMERIC NANOBIOMATERIAL PRO-
• Grouping and Read-Across on information requirements, and chemi- DUCTION METHODS
• Molecular modelling cal safety assessment frameworks from There are two ways to prepare polymeric
ECHA may also be used7. NBMs: from pre-formed polymers or by the
A (Q)SAR is a type of regression analysis polymerisation of monomers. The most
traditionally used for drug discovery. It Molecular modelling techniques 8 are common methods are:
aims to find a correlation between a NBM’s powerful tools for investigating the inter- • Emulsification/solvent evaporation
properties (extrinsic and/or intrinsic) and actions between polymer surfaces that or diffusion
the desired activity (e.g. fewer side effects, mimic microparticles, nanoparticles and • Spontaneous emulsification/solvent
greater efficacy or reduced toxicity) and it small or macromolecules (e.g. proteins and diffusion
expresses this relationship in a quantitative nucleic acids). Entire nanoparticles can be • Emulsification/reverse salting-out
manner. This means that given certain simulated, but their maximum size is re- • Nanoprecipitation
NBM characteristics as inputs, the model stricted to 10 nm to 20 nm for computa- (or solvent displacement)
will give a numerical prediction which can tional reasons. Molecular modelling is an • Dialysis
be used to assess, for example, whether a ideal complementary tool to laboratory • Freeze-drying
material is safe for medical purposes. experiments as it allows information to be • Spray-drying
gathered that is challenging or even • Supercritical fluid techniques
The goals of Grouping and Read-Across impossible to achieve experimentally. For • Emulsion/polymerisation
are filling in data gaps, firstly by having example, it can be used for better under- • Ionotropic gelation and polyelectro-
groupings based on a certain NBM proper- standing: i) interactions between the na- lyte complexion techniques
ty or effect, and secondly by using this to nocarrier and plasma proteins during the
6
http://www.oecd.org/officialdocuments/publicdisplaydocumentpdf/?cote=env/jm/mono%282007%292&doclanguage=en
7
https://echa.europa.eu/documents/10162/23036412/appendix_r6_nanomaterials_en.pdf
8
More information in the knowledge base on “Polymeric nanobiomaterials for drug delivery”: www.empa.ch/gonanobiomat
16 GoNanoBioMatTable 2
Advantages and disadvantages of the most
commonly used NBM production methods.
Process Advantages Disadvantages
Single / double emulsion • Particle size can be tuned acting on several • High shear rate
variables (solvent, surfactant, shear rate, MW, • High volumes of water to be removed
NPs concentration, stabilizer concentration, and
viscosity of the dispersed phase)
Nanoprecipitation9 • NBMshave a well-defined size and a narrow • Extensive optimization of polymer/solvent/non-solvent system
size distribution
• Less toxic solvents
Salting out • No heating process required • Requires an extensive optimization of process conditions (salt type
• No hazardous / chlorinated solvents are and concentration, type of polymer and solvent, and their ratios)
employed
Spray drying • The residual organic phase is immediately • Difficult to control drug distribution into the NBM
evaporated • Adhesion of nanoparticles to the inner walls of spray dryer
• Easy to set up • Broad size distribution
• Possibility to scale up
Ionotropic gelation and polyelectro- • No expensive and toxic organic solvents needed • Extensive optimization of polymer/counter ion concentration
lyte complexion technique10
Most of these preparation methods require the droplets inside the continuous phase the choice of solvent may influence the
two steps: first, the formation of the emul- (usually Tween® and Span). size of polymeric NBMs, but not the intrin-
sion, and second, solvent elimination in sic properties of the polymer in terms of its
order to obtain NBMs. The emulsion can The choice of the appropriate preparation composition or molecular weight. More-
be formed in the presence of two non- method depends on the desired physico- over, this is crucial for the resultant drug-
miscible solvents, where the smaller vol- chemical properties of polymeric NBMs loading and drug-release profiles. The
ume phase is dispersed into the larger one. being created, the drug to be encapsulated advantages and disadvantages of each
Amphiphilic surfactants or emulsifying and the type of nanocarrier desired (nano- method are described in Table 211.
agents are generally added to stabilise spheres, nanocapsules, etc.). For example,
9
Method used for PLA nanoparticles in the case study. “Polymeric nanobiomaterials for drug delivery”: www.empa.ch/gonanobiomat
10
Method used for chitosan nanoparticles in the case study. See knowledge base on “Polymeric nanobiomaterials for drug delivery”: www.empa.ch/gonanobiomat
10
More information in the knowledge base on “Polymeric nanobiomaterials for drug delivery”: www.empa.ch/gonanobiomat
GoNanoBioMat 17Table 3
Examples of methods to
obtain solid NBMs.
Methods Main principles Advantages Disadvantages
Freeze-drying Elimination of water • In the presence of Iyoprotectants and • Requires considerable energy for freezing
(almost 50 % of biophar- by sublimation cryoprotectants, this method allows for • Needs a high vacuum
maceuticals listed by resuspension of NBMs and preserves • Long and expensive process
FDA and EMA) physiocochemical properties • Vial-to-vial variations in polymorphs
• Suitable for heat-sensitive molecules such as • Presence of residual moisture
proteins or vaccines
• Can be prepared in continuous mode or
batches, depending on production needs
Spray-dry Elimination of water • Rapid and cheap • Shear stress
by product aerosolisation • Can be prepared in continuous mode or batches, • Not suitable for heat-sensitive molecules
depending on production needs
Almost all therapeutic NBMs are obtained
in suspension using water-based solutions
as dispersion medium. In order to obtain
solid dosage forms, which are more stable
than liquid dosage forms and help to en-
sure a long-term stability of nanomedi-
cines, the methods in the Table 3 can be
used.
18 GoNanoBioMatFigure 4
Emulsion-evaporation
method for the prepa-
ration of tuneable PHA
NBM.
CASE STUDY: PHA NANOBIOMATE- ture with constant conditions. Moreover, a in the aqueous phase and of PHA
RIALS PREPARATION METHOD careful purification step is necessary to re- in the solvent phase, as well as the
Typical methods for producing polyhydro- move any endotoxins which could be surfactant-to-polymer mass ratio
xyalkanoate (PHA)12 micro- and nanobio- transferred from the cell wall of the gram- and solution-to-solvent volumetric
materials are emulsion-evaporation, dialy- negative producing bacteria. ratio
sis, nanoprecipitation, salting-out, super- • Means of generating the emulsion
critical fluid spray and electrospray. Emul- The emulsion-evaporation method ena- (e.g. stirring, high-speed stirring,
sion-evaporation is the most commonly bles the preparation of polymeric PHA ultrasonication), especially in terms
employed method due to the simplicity NBM with a wide range of physicochemi- of the total energy input
and flexibility of its synthesis parameters, cal properties (size, density, surface charge • Evaporation procedure, particularly
which enable it to create a wide variety of and surface structure, stability in various the rate of evaporation
NBMs. Figure 4 describes the main steps media, etc.) that can be tuned by varying (i.e. temperature, pressure, stirring)
involved in a typical emulsion-evaporation the following synthesis parameters: • Remaining concentration of surfactant
process for producing surfactant-stabilised • Chemical nature of the PHA polymer in the solution after rinsing and during
PHA micro- or nanobiomaterials. (side-chain length, chemical modifica- storage
tion, etc.) and its molecular weight • When a drug is added, the chemical
It should be noted that for drug delivery • Nature of the surfactant (polarity, nature of the drug molecule – as well
applications, the production of PHA mate- partition coefficient in both phases, as its size, its partition coefficient and
rials must reproduce constant quality. This size, chemical interaction with the its interaction with the polymeric
can be achieved using a chemostat fer- polymer, etc.) phase – may influence the physico-
mentation process i.e. a continuous cul- • Initial concentration of surfactant chemical properties of the final NBM
12
The complete PHA case study is found in the knowledge base “Polymeric nanobiomaterials for drug delivery”: www.empa.ch/gonanobiomat
GoNanoBioMat 19REGULATORY FRAMEWORK
WHAT ARE THE REGULATORY FRAME- livery and pharmaceutical products them- mended that SMEs contact their relevant
WORKS IN SWITZERLAND AND IN THE selves (nanopharmaceutical); (2) medical regulatory authorities (if these authorities
EU? devices; and (3) in vitro and in vivo diag- provide such services) or the newly estab-
One of the first steps towards developing nostics. The focus is on nanopharmaceuti- lished ContactPointNano. The Contact-
a marketable nanomedicine is understan- cals. However, some information on med- PointNano provides companies with con-
ding the relevant regulatory frameworks ical devices is also given. The third type of tact to experts, organises trainings and
and their requirements. These require- application is outside of the scope of the acts as a platform for the exchange of in-
ments are often underestimated and may guidelines and, therefore, will not be dis- formation. (http://contactpointnano.ch/)
put a product’s success (e.g. a nanocarri- cussed further. The chemical branch is also
er), or even that of its company, at risk. represented in Table 4, as raw materials According to recently published draft
Compliance requirements, such as the time often start in their bulk form before being guidance by the FDA13, the following
and money spent on product develop- transformed into nanobiomaterials and ul- factors should be considered for safety,
ment, place a substantial burden on SMEs, timately used in a nanomedicine prepara- efficacy and quality in the development of
despite this being in direct contradiction to tion. a nanomedicine (medical device or nano-
the need for affordable drugs. pharmaceutical):
WHAT IS SPECIAL ABOUT NANOMEDI- • The adequacy of the characterisation
The main goals of medicine regulations are CINES? of the material structure and its
to ensure the safety, efficacy and quality of Currently, there are no specific regulations function
new nanomedicines or any other medi- regarding nanocarriers for drug delivery • The complexity of the material
cines. Any potential risks associated with a (nanopharmaceuticals). These products structure
medicine should be eliminated or mitigat- are monitored by applying the same regu- • The understanding of the mechanism
ed in order to protect medical personnel, lations as for conventional medicines. by which the material’s physicochem-
patients and the environment. Different However, the authorities do have the pos- ical properties have an impact on
regulatory bodies are responsible for regu- sibility to ask additional nano-specific its biological effects (e.g. effects of
lating nanomedicines depending on the questions. In the upcoming regulations for particle size on pharmacokinetic
region where the products are to be mar- medical devices, the use of nanomaterials parameters)
keted and on their applications (Table 4). may require a specific and possibly higher • The understanding of in vivo release
classification depending on the risk of in- mechanisms based on the material’s
Nanomedicine has been defined as the ternal exposure (EU MDR 745/2017, Annex physicochemical properties
medical application of nanotechnology, VIII, chapter III, rule 19). A notified body • The predictability of in vivo release
and it can be divided into three different will have to decide whether clinical trials based upon established in vitro
applications: (1) nanocarriers for drug de- are needed. It is therefore highly recom- release methods
13
FDA Draft Guidance Document: https://www.fda.gov/regulatory-information/search-fda-guidance-documents/drug-products-including-biological-products-contain-nanomaterials-guidance-industry
20 GoNanoBioMatTable 4:
Comparison between the authorities, laws and registra-
tion processes in Switzerland and European Union for
any chemicals, pharmaceuticals and medical devices.
Chemicals Medicines Medical Devices
Authority Federal Office of Public Swissmedic Swissmedic
Health (FOPH);
Federal Office for the
Environment (FOEN);
State Secretariat for
Economic Affairs (SECO)
Law Chemicals Ordinance Ordinance on Medicinal Products (OMed) Medical Devices Ordinance
SWITZERLAND
(ChemO) (MedDO)14
Notification and Notification to notification Authorisation through Swissmedic Declaration of conformity by
Reporting authority at > 1 tonne/year Conformity Assessment Bodies
Authority Chemicals Agency The marketing authorization (MA) is done by Regulation through National
European Commission for centralised procedures15; Competence Authorities in
The EMA (European Medicines Agency) is each member state17
responsible for the scientific evaluation that
supports the MA16
National competent authorities are responsible for
marketing authorization and scientific evaluation
of non-centralised procedures
EUROPE
Law REACH EC (1907/2006) Directive 2001/83/EC and Regulation (EC) 726/2004 Regulation MDR 2017/745 and
IVDR 2017/746 (transitional
Directive 90/385/EEC, 93/42/
EEC and 98/79/EC)18
Registration proce ss Registration with ECHA at > Authorisation through EMA EC declaration of conformity by
1 tonne/year certified Notified Bodies
14
The MedDO is being revised according to EU regulations and will be applied in 2020. (More info is available at:
https://www.bag.admin.ch/bag/en/home/medizin-und-forschung/heilmittel/aktuelle-rechtsetzungsprojekte/revision-med-prod-verord-mepv.html)
15
See the groups of medicines that are eligible for the centralised procedure https://www.ema.europa.eu/en/about-us/what-we-do/authorisation-medicines
16
More information on MA under this link https://www.ema.europa.eu/en/human-regulatory/marketing-authorisation
17
List of Medicine Regulation Authorities in each member state: https://www.ema.europa.eu/en/partners-networks/eu-partners/eu-member-states/national-competent-authorities-human
18
Officially, MDR 745/2017 will be applied by 26 May 2020 (see MDR 745/2017 Art. 123) and IVDR (EU) 2017/746 by 26 May 2022. Before this date, the national laws and regulations of the member states are applicable.
However, if devices comply with the new MDR, they can be registered according to MDR 745/2017, Art. 120, Section 5, before this date.
GoNanoBioMat 21• Physical and chemical stability Due to their complex structure, drug- a nanoscale coating are identical to those
• The maturity of the nanotechnology loaded nanocarriers are considered to be for conventional medical devices. This
involved (including manufacturing non-biological complex drugs (NBCDs). means that conformity is dependent solely
and analytical methods) The combination of the nanobiomaterial on the class of medical device, which for
• The potential impact of manufactur- and the drug is decisive for the efficacy and devices incorporating or consisting of
ing changes, including in-process safety of this drug class, and in its entirety nanobiomaterials are classes III, IIa or IIb,
controls and the robustness of the it represents the active pharmaceutical in- depending on their potential for internal
control strategy on the drug product’s gredient. As with their biological counter- exposure. However, the certified body res-
critical quality attributes parts (e.g. therapeutic proteins), NBCDs ponsible for the European Commission
• The material’s physical state upon cannot be fully characterised, and there- declaration of conformity must be accredi-
administration fore the manufacture and registration of ted for the certification of devices incorpo-
• The route of administration “follow-on” drug nanomedicines as gener- rating or consisting of nanobiomaterials.
• The material’s dissolution, bioavailabi- ics appear to be impossible. Although such For medical devices, this audit process may
lity, distribution, biodegradation and nanomedicine follow-on products have be problematic because of the limited
accumulation, as well as the predic- received marketing authorisations in the availability of accredited notified bodies
tability of these elements based on past, by following the generic pathway, for medical devices of all classes. Currently,
physicochemical parameters and discussions among stakeholders are ongo- 57 notified bodies exist in the EU and af-
animal studies ing about putting in place a regulatory filiated countries. A few years ago, they
strategy for “nanosimilars” – in analogy to were more than 80 and this number is ex-
In the case of nanocarriers, registration the biosimilars for complex biological pected to become significantly lower in the
with the relevant authority requires a full drugs. This will represent an additional next few years, as this is the current trend
set of pre-clinical and clinical studies be- hurdle in the development and marketing with regards to EU Regulations 2017/745
cause they are all considered to be new of future follow-on nanomedicines as they and 2017/746. Switzerland has just two
drug entities, even if the drug or the nano- will require studies going beyond the de- conformity assessment bodies (equivalent
carrier material used have previously been monstration of bioequivalence between to Europe Commission’s notified bodies).
approved. The rationale behind this is that the originator drug and the intended However, neither Switzerland nor the EU
nanocarriers can be used to change a “nanosimilar”. has yet issued accreditations to audit med-
drug’s bioavailability, for example, thus ical devices containing nanoscale parts19,
changing its pharmacokinetic and pharma- The European Commission’s conformity which means that the developer has to get
codynamic profiles, which may ultimately assessments for medical devices incorpo- accreditation from already existing notified
have an impact on its safety. rating or consisting of nanobiomaterials or bodies or conformity assessment bodies.
19
The list of accredited notified bodies under 93/42/EEC and 2017/745 can be found on the “NANDO” platform, under this link:
https://ec.europa.eu/growth/tools-databases/nando/index.cfm?fuseaction=directive.pdf&refe_cd=93%2F42%2FEEC&requesttimeout=900
22 GoNanoBioMatQuality systems along nanomedicine life cycle
Figure 5
Quality systems for nanopharmaceuticals.
WHICH QUALITY SYSTEM SHOULD BE tured according to the principles of GMP21. ensures that the rights, safety and well-
FOLLOWED? Indeed, this aspect should already have being of the trial’s participants are protect-
As with any pharmaceutical, developing a been considered in earlier phases, ed and that the data produced during
successful nanopharmaceutical requires meaning that collaboration with the man- clinical trials are credible.
strict adherence to quality-system regula- ufacturer should begin as soon as possible Quality management systems of medical
tions. Different quality systems apply in order to ensure the quality required for device manufacturers and the technical
(Figure 5) depending on the phase of de- the clinical phases. GMP is also the document file of the product shall comply
velopment. During the preclinical testing standard for meeting the requirements of with ISO 13485:201623.
phase, all tests must be done using the a marketing authorisation (MA). Another
principles of Good Laboratory Practice important aspect to remember is that ARE THERE ANY NANO-SPECIFIC
(GLP), which were developed in accordance changes in the value chain (e.g. production GUIDELINES?
with the OECD20. They concern the organi- processes, suppliers) may cause new test Various organisations have drafted guide-
sational processes and conditions under requirements. lines to help companies through the differ-
which non-clinical health and environmen- ent steps in the development of a medici-
tal safety studies are planned, performed, Before entering clinical phases, a nano- nal product:
monitored, recorded, archived and report- pharmaceutical must be agreed by a com-
ed, and they ensure the quality and va- petent Ethics Committee. Clinical phases ECHA: “Guidance describing the infor-
li-dity of data produced during this phase. must follow the standards of Good Clinical mation requirements under REACH with
Practice (GCP)22. GCP encompasses the de- regard to substance properties, exposure,
Before entering the phase of clinical trials, sign, recording and reporting of trials in- use and risk management measures, in the
a nanopharmaceutical must be manufac- volving human subjects. This ultimately context of the chemical safety assessment.
20
OECD good laboratory webpage: http://www.oecd.org/env/ehs/testing/goodlaboratorypracticeglp.htm
21
More information under this link: https://www.swissmedic.ch/swissmedic/en/home/news/mitteilungen/good-manufacturing-practices-gmp-vorgehen-abweichungen-zwischen-eu-und-pics-gmp.html
22
ICH efficacy guidelines E6: https://www.ich.org/products/guidelines/efficacy/article/efficacy-guidelines.html
23
https://www.iso.org/standard/59752.html
GoNanoBioMat 23It is part of a series of guidance documents Common Technical Document (CTD), which CASE STUDY: POLYMERS AND REGU-
that aim to help all stakeholders with their assembles all quality, safety and efficacy LATION
preparation for fulfilling their obligations information in a common format. Polymers are regulated differently depen-
under the REACH Regulation. This docu- ding on the type of application and the
ment gives specific guidance regarding the EMA: The European Medicines Agency has countries in which they will be marketed.
testing of nanomaterials24. created guidelines on nanomedicines in The three decision trees below (Figures 6,
order to help medicine developers prepare 7 and 8) represent three case studies:
OECD guidelines: The OECD guidelines MA applications for human medicines. For • Companies producing monomers
enable the assessment of the potential ef- example, a reflection paper was produced and/or polymers in Switzerland
fects of chemicals on human health and about the Development of block-copo- • Companies producing monomers
the environment. The OECD has also pro- lymer-micelle medicinal products28. and/or polymers in the European
duced a Guidance Manual for the Testing Union (EU)
of Manufactured Nanomaterials25 as well SCENIHR: The European Commission’s • Companies developing either
as Guidance on Sample Preparation and Scientific Committee on Emerging and polymeric nano-platforms or polyme-
Dosimetry for the Safety Testing of Manu- Newly Identified Health Risks has establi- ric nanocarriers for drug delivery in
factured Nanomaterials26. shed Guidance on the Determination of Switzerland and EU
Potential Health Effects of Nanomaterials
ICH guidelines: The International Confer- Used in Medical Devices29. In Switzerland and European Union, poly-
ence on Harmonisation‘s goal is to har- mers which are only used for therapeutic
monise the testing carried out during FDA: The US Food and Drug Administra- products (e.g. polymeric nanocarriers for
research and development of new medi- tion established a draft guidance docu- drug delivery) are exempt from notification
cines. The ICH has created diverse guide- ment in 2017 about Drug Products, Inclu- (Switzerland) and registration (EU) because
lines encompassing quality, efficacy and ding Biological Products, that Contain these polymers (which, here, are interme-
safety as well as multidisciplinary guide- Nanomaterials – Guidance for Industry30. diary products) are regulated by other re-
lines27. For example, it has created the gulations.
24
https://echa.europa.eu/guidance-documents/guidance-on-information-requirements-and-chemical-safety-assessment
25
http://www.oecd.org/officialdocuments/publicdisplaydocumentpdf/?cote=env/jm/mono(2009)20/rev&doclanguage=en
26
http://www.oecd.org/officialdocuments/publicdisplaydocumentpdf/?cote=ENV/JM/MONO(2012)40&docLanguage=En
27
http://www.ich.org/products/guidelines.html
28
http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/general/general_content_000564.jsp&mid=WC0b01ac05806403e0
29
SCENIHR (Scientific Committee on Emerging and Newly Identified Health Risks), Final Opinion on the Guidance on the Determination of Potential Health Effects of Nanomaterials Used in Medi Devices,
January 2015. https://ec.europa.eu/health/scientific_committees/emerging/docs/scenihr_o_045.pdf
30
https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM588857.pdf
24 GoNanoBioMatFigure 6
Decision tree for companies producing monomers
or polymers in Switzerland.
Decision tree for companies producing monomers or polymers in Switzerland
DECISION TREE FOR COMPANIES PRODUCING MONOMERS OR POLYMERS IN
SWITZERLAND
Exempt from Notification
Are the and Reporting Are the
Are you yes monomers only yes polymers only Are you
yes yes
producing used for Remark: this is because it is used for producing
monomers? therapeutic regulated in another therapeutic polymers?
products? regulation «Omed» (See Art. products?
26 and 54 of ChemO)
no no
Need to notify your Do your polymers
Is (Are) your monomer(s) contain monomer
monomer(s) a yes Is your yes Is your units considered
yes yes
new substance? production > Remark: the polymer are production > as new
(check the 1t/y? exempt of notification but not 1t/y? substances?
EINECS list) their monomer units (See Art. (check the EINECS
no no
26 of ChemO) list)
no
no
Self-Regulations
(See Article 5 of ChemO)
Need to report your Is (Are) your monomer(s)
monomer(s) classified as:
yes · dangerous? no
Exempt from reporting
Remark: the polymer are · a PBT or vPvB substances?
your monomer(s)
exempt of reporting but not · or a substances listed in
their monomer units (See Art. Annex 3 ChemO?
54 of ChemO) (See Art. 19 of ChemO)
GoNanoBioMat 25Figure 7
Decision tree for companies producing monomers
or polymers in the EU.
Decision tree for companies producing monomers or polymers in the EU
DECISION TREE FOR COMPANIES PRODUCING MONOMERS OR POLYMERS IN THE EU
Exempt from Registration
Are you Remark: this is because it is Are you
producing regulated in another regulation producing
monomers? (Directive 2001/83/EC and polymers?
Regulation (EC) 726/2004)
yes yes
Monomers and Polymers are
Are the Exempt from Registration Are the
monomers only but Classification and polymers only
yes yes
used for Labelling, Information down used for
therapeutic the supply chain and general therapeutic
products? rules on restrictions apply products?
no no
Need to register your monomer(s)
as laid down in Art. 6 (2) of REACH
Is your 1. Do the polymers consist of 2%
no Remark: when monomers are not used
production > for the manufacturing of polymers, the weight by weight (w/w) or more of
1t/y? monomers are considered as non- no monomer substance(s) or other
yes monomeric intermediates and substance(s) in the form of
registration should be done according to monomeric units and chemically
Art.17 and 18 of REACH bound substance(s)?
2. And is your production > 1t/y?
no
Are the
monomers only Need to register your yes
used for the monomer(s) with a «standard»
manufacturing registration dossier as laid
of polymers? down in Art. 6 of REACH Have the monomer units
yes no already been registered
by someone else .up in
the supply chain?
Sharing of data and registration
of your monomer(s) with a yes
«standard» registration dossier
as laid down in Art. 6 of REACH
26 GoNanoBioMatFigure 8
Decision tree for companies producing either polymeric nanoplatforms or drug/nanocarrier
systems made of polymeric nanobiomaterials in Switzerland and in the EU.
Desision tree for companies producing either polymeric nanoplatforms or drug/nanocarrier system made
of polymeric nanobiomaterials in Switzerland and in the EU
DECISION TREE FOR COMPANIES PRODUCING EITHER POLYMERIC NANOPLATFORMS OR DRUG/
NANOCARRIER SYSTEM MADE OF POLYMERIC NANOBIOMATERIALS IN SWITZERLAND AND IN THE EU
Are you producing
Are you producing
polymeric
a drug/carrier
nanocarriers (or
system made of
nanoplatforms)?
polymeric
yes nanobiomaterials?
yes
Only the end product (drug/
carrier system) has to get
Is the platform/ Is the platform/ through a market authorization
carrier intended no carrier intended yes
Is the drug a
to be used for to be used for Remark: if the platform is used for
new drug?
medical devices medicinal drug delivery, the platform alone and
application(s)? application(s)? the platform with the loaded drug will yes no
both have to be tested for safety,
no yes
efficacy, and quality
Market authorization through EMA
Registration process by Conformity in the EU ((EC) 726/2004) and
Assessment Body in Switzerland (MedDO) Swissmedic in Switzerland (OMed)
Out of the scope of this and Certified Notified Body in the EU
Remark: even if the drug has already been
project. (Directive 90/385/EEC, 93/42/EEC, and
used and authorized, all tests must be
98/79/EC) done again, because the nanocarrier will
Remark: if the platform is used change the pharmacokinetic and
for foodstuffs ((EC) 1333/2008) or Remark: The CE conformity assessment of pharmacodynamic of the drug and
cosmetics ((EC) 1223/2009), refer medical devices incorporating or consisting of therefore change its safety and efficacy.
to the corresponding regulation nanomaterials or nanoscale coating (classified as Also, notice that centralized authorization
class III, IIb or IIa) is identical to conventional may be necessary for some nanomedicine.
medical devices.
GoNanoBioMat 27You can also read
