Nanomedicine is still a Revolutionary Technology, there are still no fix Guidelines provided by any Regulatory Agencies. EMA has provided Reflection papers through CHMP. Refer the links provided in the Reference.

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European Medicines
Agency’s scientific
guidelines on
Nanomedicines
Name : Anushree A. Jadhav
PG DRA

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What are nanomedicines ?
“nano” is a Greek word
meaning “dwarf” or “very
small”
Convergence of
Nanotechnology and
medicines.
Ranging from 1 to 100nm
Comprehensive
monitoring, control,
construct, repair, defence
and improvement
Nanotherapeutics: improve
bioavailability, reduced
toxicity, greater dose
response and enhanced
solubility, compared with
conventional medicines
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Physical Features of Nano particles
• range of 1 to 100 nm
• improved solubility
• ability to convert insoluble or poorly soluble drugs into soluble aqueous
suspensions
• increased bioavailability and circulation time
Size
• spheres, discs, hemispheres, cylinders, cones, tubes, and wires
• hollow, porous, or solid
• selected on the basis of interactivity, loading capacity, and transport capabilities
• example, a hollow NP may be an attractive carrier for drug therapies or imaging
contrast agents
Shape
• unique physical properties is a large surface area relative to size
• particle size decreases, total surface area increases exponentially
• enhanced water solubility and bioavailability
Surface area
• their small size can enable them to cross physiological barriers to deliver drugs
to sites that are not normally accessible by traditional means
• The increased permeability of NPs may also allow them to cross the blood–brain
barrier through the use of different uptake mechanisms.
Permeability
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Barriers found throughout the development of
nanomedicine product
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• Particle size, shape and
size distribution,
aggregation and
agglomeration state,
crystal structure, specific
surface area, porosity,
chemical composition,
surface chemistry, charge,
photocatalytic activity, zeta
potential, water solubility,
dissolution rate/kinetics,
and dustiness
• Pre-clinical assessment of nanomaterials involve
a thorough biocompatibility testing program,
which typically comprises in vivo studies
complemented by selected in vitro assays to
prove safety.
• If the biocompatibility of nanomaterials cannot
be warranted, potentially advantageous
properties of nano-systems may raise
toxicological concerns.
• Note that some of the
physicochemical
characteristics of
nanomaterials can change
during the manufacturing
process, which compromises
the quality and safety of the
final nanomedicine.
• The basis of QbD relies on
the identification of the
Quality Attributes (QA),
which refers to the chemical,
physical or biological
properties or another
relevant characteristic of the
nanomaterial.
• The absorption, distribution, elimination,
and metabolism, the potential for more
easily cross biological barriers, toxic
properties and their persistence in the
environment and human body

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Nanomedicine Uses
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•Nanoparticles as Anticancer Drugs
•Nanoparticulate Delivery Vehicles
•As Targeting
•As Delivery of Macromolecular Biopharmaceuticals
Biological Barriers
•As Stimuli-Responsive Release
•As Alternative Delivery Strategies
•As Regulating Cells with RNA
•As Inorganic NP-Mediated Cell Death
•As Killing Cells with Inorganic NPs upon External
•As Biodegradation
•Nano- and Micro-engineered Implants
•Toward Interfacing Electrically Active Tissues
•Biological Cell-Based Implants
•Toward Artificial Organs
•Antibacterial Coatings
•Screening based on Fluorescence read out
•Screening based on surface plasmon
resonance
•Screening based on surface-enhanced
Raman scattering
•Screening based on electronic read-out
•Biomechanical Assay
•Computed Tomography
•Magnetic Resonance Imaging
•Imaging Radiolabels
•Fluorescence Imaging
In vivo
diagnostic
In vitro
diagnostic
In vivo
therapeutics
Implantable
nanomaterials

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Brief on Nanomedicines
 To avoid any concern, it is necessary establishing an unambiguous definition to identify the presence of
nanomaterials. The European Commission (EC) created a definition based on the European Commission
Joint Research Center and on the Scientific Committee on Emerging and Newly Identified Health Risks. This
definition is only used as a reference to determine whether a material is considered a nanomaterial or not;
however, it is not classified as hazardous or safe. The EC claims that it should be used as a reference for
additional regulatory and policy frameworks related to quality, safety, efficacy, and risks assessment.
 The EMA working definition of Nanomedicines
 Purposely designed systems for clinical applications
 At least one component at nano-scale size
 Resulting in definable specific properties and characteristics
- related to the specific nanotechnology application and characteristics for the intended use (route of
admin, dose)
- associated with the expected clinical advantages of the nano-engineering (e.g. preferential organ/tissue
distribution)
And needs to meet definition as a medicinal product according to European legislation.
 Food and Drug Administration (FDA) has not established its own definition for “nanotechnology,”
“nanomaterial,” “nanoscale,” or other related terms.
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Scientific Challenges
 Innovative and evolving scientific field
 EMA to align with state of the art knowledge and evolve methods to evaluate:
1. Characterization and stability of nano-systems
2. Functionalities of the nano-systems, bio-interface and reactivity of the final product
including coating and “excipients”
3. Biomarkers for nano-functionalities
4. Bio-distribution and Bio-persistence of nanomaterials and degradation products for
long-term safety
5. Dose selection/schedule
6. Unique aspects of associated treatment procedures (e.g. impact of energy sources
within and outside the clinical setting, re-administration)
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Regulatory challenges
Nanomedicines in the
Pharmaceutical Market
• In the European Union, the
nanomedicine market is
composed by nanoparticles,
liposomes, nanocrystals,
nano-emulsions, polymeric-
protein conjugates, and
nanocomplexes
• examples of commercially
available nanomedicines in
the EU
Nanomedicines and Nano-
similars
• The development of a
framework for the evaluation
of the follow-on
nanomedicines at the time of
reference medicine patent
expiration.
• The framework set by
European Medicines Agency
is a regulatory approach for
the follow-on biological
nanomedicines, which include
recommendations for
comparative quality, non-
clinical and clinical studies.
• EMA already released some
reflection papers regarding
nanomedicines with surface
coating, intravenous
liposomal, block copolymer
micelle, and iron-based nano-
colloidal nanomedicines
Market Access and
Pharmacoeconomics
• The pricing and
reimbursement decisions for
medicines are taken at an
individual level in each
member state of the EU.
• Through HTA, information
about medicine safety,
effectiveness and cost-
effectiveness is generated so
as support health and political
decision-makers.
• The EUnetHTA was created
to harmonize and enhance
the entry of new medicines in
the clinical practice, so as to
provide patients with novel
medicines.
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CHMP nanomedicines drafting groups-
Reflection papers
 In 2011 the CHMP commissioned the multidisciplinary drafting group to develop a
series of four reflection papers on current scientific and regulatory thinking for
nanomedicines.
 These documents cover the development both of new nanomedicines, and of nano-
similars (since the first generation of nanomedicines, including liposomal
formulations, iron-based preparations and nanocrystal-based medicines, have
started to come off patent).
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EMA’s Scientific guidelines on Nanomedicines
The European Medicines Agency's scientific guidelines on
nanomedicines help medicine developers prepare marketing
authorization applications for human medicines.
 Data requirements for intravenous iron-based nano-colloidal products developed
with reference to an innovator medicinal product
 Data requirements for intravenous liposomal products developed with reference to
an innovator liposomal product
 Development of block-copolymer-micelle medicinal products
 Surface coatings: general issues for consideration regarding parenteral
administration of coated nanomedicine products
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Reflection paper on data requirements for
Intravenous iron-based nano-colloidal products
 This reflection paper discusses the data requirements for nano-sized colloidal intravenous
iron-based preparations developed as a treatment for iron deficiency with reference to an
innovator product.
 To assist in the generation of relevant quality, non-clinical and clinical comparative data to
support a marketing authorization of a nano-sized colloidal intravenous iron-based
preparation developed as a treatment for iron deficiency anaemia with reference to a
nano-sized colloidal innovator product .
 Summary: For the comparison of intravenous iron-based nano-sized colloidal products
developed with reference to an innovator medicinal product, current scientific knowledge
and regulatory experience for characterization of nano-sized colloidal preparations indicate
that quality characterization on its own, would not provide sufficient assurance of the
similarity between the two products, even if the quality tests performed show similarity. In
the context of such iron based preparations, a “weight of evidence approach” including
data from quality, non-clinical and human pharmacokinetic studies is required.
 Not product specific
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Reflection paper on data requirements for
intravenous liposomal products
 This document should facilitate a decision on the following issues:
1. pharmaceutical data needed as evidence of product comparability between test and
reference or after changes to a liposomal product, to support comparative safety and
efficacy
2. Necessity of pre-clinical and clinical studies and circumstances which may allow to
waive certain studies
3. Consideration of the design of relevant in vivo non-clinical studies and the potential role
for in vitro models.
 Assist in the generation of relevant quality, non-clinical and clinical data to support a
marketing authorization of intravenous liposomal products developed with reference to an
innovator liposomal product;
 The principles are also valid to ‘liposome-like’ and vesicular products which may be under
development including those administered by routes other than intravenous
administration;
 Only where the PK of the active substance is affected
 Not product specific
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Reflection paper on data requirements on block
copolymer micelle medicinal product.
 Information for the pharmaceutical development, and nonclinical and early clinical
studies of block copolymer micelle medicinal products created to affect
pharmacokinetics, stability and distribution of incorporated or conjugated active
substances in vivo.
 Although the focus is on products designed for intravenous administration, the
principles outlined in this reflection paper might also be considered to be applicable to
block copolymer micelle products designed for other routes of administration.
 This document, being a reflection paper, should be read in connection with relevant
ICH guidelines (listed above) and regional guidelines (Annexes I and II)1 .
 Not product specific.
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Reflection paper on surface coating.
 General issues to consider during the development of nanomedicines that include a
covalent or non-covalent coating, e.g. the effect of the coating on the product
stability or on the product pharmacokinetics and bio-distribution (e.g. polymer-coated
liposomes);
 Consideration of quality, non-clinical and clinical data which will play an important
role in the definition of the critical product characteristics of a coated nanomedicine.
 When developing coated nanomedicines careful consideration should be given to
the potential impact of the coating on the efficacy and safety profile of the product.
This information is critical when evaluating studies designed to support first in man
clinical evaluation, pre- and post-authorization manufacturing changes for a coated
nanomedicine, and for the demonstration of similarity for a followon coated
nanomedicine product, developed with reference to an innovator product.
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15. z
Conclusion
 Nanotechnology is an emerging science with opportunities for medicines in the fields
of drug delivery, diagnostics, theranostics and regenerative medicine.
 Existing EU regulatory framework accommodates nanomedicines, and adapts to
address new challenges.
 The accumulation of experience allows to assess the need for the development of
guidance specific to nanomedicines.
 Applicants are encouraged to contact the EMA from early stages of development
through the Scientific Advice procedure or through informal briefing meetings with the
ITF.
 Particular regulatory challenges are presented by the evaluation of ‘nano-similars’,
and by advances in nanoscience giving rise to a new generation of complex, hybrid
structures.
 It is expected that nanotechnology will yield innovative products contributing to a more
proactive paradigm for the diagnosis and therapy of diseases.
 The focus of the EMA is to facilitate the development of such products.
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References
 https://www.ema.europa.eu/en/documents/presentation/presentation-quality-aspects-
nano-based-medicines-dolores-hernan-pacrez-de-la-ossa_en.pdf
 https://www.ema.europa.eu/en/human-regulatory/research-development/scientific-
guidelines/multidisciplinary/multidisciplinary-nanomedicines
 https://www.ema.europa.eu/en/documents/report/summary-report-workshop-
nanomedicines-2-3-september-2010_en.pdf
 https://www.ema.europa.eu/en/news/european-medicines-agency-publishes-
reflection-paper-general-issues-consideration-regarding-coated
 https://www.frontiersin.org/articles/10.3389/fchem.2018.00360/full#h4
 https://pqri.org/wp-
content/uploads/2015/08/pdf/Sabine.Haubenriesser.Presentation.pdf
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