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 - Empa
GUIDELINES FOR
IMPLEMENTING A SAFE-BY-DESIGN
APPROACH FOR MEDICINAL POLYMERIC NANOCARRIERS

                                                GoNanoBioMat   1
GUIDELINES FOR IMPLEMENTING A SAFE-BY-DESIGN APPROACH FOR MEDICINAL POLYMERIC NANOCARRIERS - Empa
COVER IMAGE: Tommaso Casalini „Nanocarrier passing through the cellular membrane“

2   GoNanoBioMat
GUIDELINES FOR IMPLEMENTING A SAFE-BY-DESIGN APPROACH FOR MEDICINAL POLYMERIC NANOCARRIERS - Empa
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
GUIDELINES FOR IMPLEMENTING A SAFE-BY-DESIGN APPROACH FOR MEDICINAL POLYMERIC NANOCARRIERS - Empa
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
GUIDELINES FOR IMPLEMENTING A SAFE-BY-DESIGN APPROACH FOR MEDICINAL POLYMERIC NANOCARRIERS - Empa
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
GUIDELINES FOR IMPLEMENTING A SAFE-BY-DESIGN APPROACH FOR MEDICINAL POLYMERIC NANOCARRIERS - Empa
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

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GUIDELINES FOR IMPLEMENTING A SAFE-BY-DESIGN APPROACH FOR MEDICINAL POLYMERIC NANOCARRIERS - Empa
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   7
SBD 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   GoNanoBioMat
Figure 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          9
MATERIAL 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        GoNanoBioMat
Polymers 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   11
should 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   GoNanoBioMat
Figure 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   13
The 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        GoNanoBioMat
Table 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    15
Non-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       GoNanoBioMat
Table 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       17
Table 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   GoNanoBioMat
Figure 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       19
REGULATORY 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        GoNanoBioMat
Table 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        GoNanoBioMat
Quality 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   23
It 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      GoNanoBioMat
Figure 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       25
Figure 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   GoNanoBioMat
Figure 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       27
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