Regulatory requirements on nanomedicines

REGULATORY REQUIREMENTS ON
NANOMEDICINES
Presented By
P. Raghu Yadav
617209507001
II/II M. Pharmacy
Pharmaceutical Management and Drug Regulatory Affairs
1A.U. COLLEGE OF PHARMACEUTICAL SCIENCES

Contents
• What are Nanomedicines
• Need for regulations
• Regulations on nanomedicines
❖USFDA
❖EMEA
• REACH
• Post market monitoring
• Analytical techniques used
• Regulatory development For “Next Generation” nanomedicines
• Nanomedicines in the market
• Conclusion
• References
2
A.U. COLLEGE OF PHARMACEUTICAL SCIENCES

What are nanomedicines
According to European Science Foundation (E.S.F) nanomedicine
is defined as the area of nanotechnology used for diagnosing,
treating and preventing disease and traumatic injury, of relieving
pain and of preserving and improving human health.
Nanomedicines aim to provide most effective treatment without
side-effects.

According to the definition given by the US-National
Institute of Health Road map for Medical Research in
Nanomedicines “Nanomedicine is an offshoot of
nanotechnology referring to highly specific medicine
interventions at the molecular scale(100nm) for curing
diseases or repairing damaged tissues”

Need for regulations
• Due to size related physicochemical properties, nanomedicines require additional
quality and safety testing compared to products with standard size.
• For the safe evaluation and supervision of nanomedicines, critical quality attributes
and safety parameter have to be identified and translated into standardized and
regulatory accepted test methods/testing strategies.
• Nanomedicine properties alter not only by changing raw materials but also by small
change in the manufacturing process.
• Sometimes nanomedicines have ability to interact with immune cells and absorb
plasma cells, thus during preclinical assessment bio compatibility and
immunotoxicity should be considered.

• Additionally before commercialization of nanomedicines, it will be essential to
perform to pharmacoeconomic studies to demonstrate social and economic added
values.
• QALY's (Quality-adjusted life expectancy years) or costs shall be considered in the
development of new and sophisticated nanomedicine.
A.U. COLLEGE OF PHARMACEUTICAL SCIENCES 6

Nanomedicine product
Physicochemical
properties
Biocompatibility and
Nanotoxicology
Pharmacokinetics
and
Pharmacodynamics
Process control and
scaleup responsibility
Barriers found throughout the development of a nanomedicine product
Marketed
product
Source: https://www.frontiersin.org/articles/10.3389/fchem.2018.00360/full

Parameters for quality and safety evaluation of nanotechnology-based medicinal products for
biomedical use
8
Source: https://doi.org/10.1016/j.bbrc.2015.08.023

Regulations on nanomedicine
• USFDA:
As nanomedicine is still under developmental stages there are no particular established
standards for the study of regulatory evaluation of these products.
1. Nanotechnology may challenge the drug device because it may be difficult to
distinguish modes of action at nano scale
2. Intense knowledge is needed about the biological interaction, detection and
measurement.
3. Current testing approaches to assess safety, effectiveness and quality of products
with nanoscale materials should be evaluated.
4. Participate in development of characterisation methods and standards for nanoscale
materials.

• Development of models for behaviour of nanoscale particles in vitro and in vivo.
• Physio-chemical properties of nanoparticles can impact on bio-distribution:
➢ size
➢ surface charge
➢ stability
➢ density
➢ crystallinity
➢ surface characteristics
➢ solubility
• Bioavailability of encapsulated and free drug may need to be assessed separately.

NDA (New Drug Application)
• The product-specific approvals under the full Section 505(b) (1) NDA process pose
the fewest concerns for FDA assurance of the safety of nanotechnology-based drugs.
• On request, the FDA may require applicants to supply information about a drug’s
particle size as part of its review of the product’s safety early in the IND process.
• In 2010, CDER asked its reviewers in the Office of Pharmaceutical Sciences (OPS)
to document nanotechnology related information received in drug application
submissions by gathering nanotechnology-related information that is reported on a
drug application.

ANDA (Abbreviated New Drug Application)
• For drugs that contain the same or similar active ingredients as previously approved
drugs, premarket approval may proceed via a Section 505(b) (2) application or an
ANDA.
• To date, there have been no generic nanotechnology-based drugs approved under the
ANDA pathway.
• The FFDCA does not differentiate between active ingredients on the basis of particle
size, so a nanotechnology-based active ingredient might be considered the same as a
traditional drug, thereby shortening the time necessary for approval and,
consequently, getting the product to market faster.
• In other words, because a nanotechnology-based drug will likely exhibit different
pharmacokinetic properties than a traditional drug, it may not perform in exactly the
same manner.
• Nanotechnology may also be used to produce inactive ingredients, which could
influence absorption or toxicity of the product.

Registration, Evaluation, Authorization and Restriction of Chemicals
(REACH)
• REACH is based on the principle that manufacturers, importers and
downstream users have to ensure that they manufacture, place on market
or use such substances that do not adversely effect human health or the
environment.
• According to REACH registration dossier should be produced for
substance that is imported or manufactured in quantity greater than
1tonne

Post market monitoring
• FDA will continue to monitor market place for products containing
nanomaterials and will take actions, as needed toprotect consumers.
• Therefore industries must work with current information in product
development and continue to monitor product once marketed
• FDA offers technnical advice and guidance, as needed, to help
industriesmeet its regulations and statuatory obligations.

Analytical techniques used for characterization of nanopaticles in-vitro
and in-vivo
• Choosing right method for characterization of nanoparticles is a challenging task since one should be
aware that each technique has its own limitations.
• Characterization of nanoparticles is carried out through various micro and nanotechnologies for
Biotechnology techniques such as
❖ In vitro
➢ Dynamic Light Scattering (DLS)
➢ Scanning Electron Microscopy (SEM)
➢ Transmission Electron Microscopy (TEM)
➢ Nuclear Magnetic Resonance (NMR)
➢ Fourier-Transform Infrared Spectroscopy (FTIR)
➢ UV-Visible Spectroscopy (UV-VIS)
➢ Confocal Laser Scanning Microscopy (CLSM)
➢ Flow Cytometry
❖ In vivo
➢ In vivo imaging system
➢ Drug biodistribution

Regulatory &
analytical aspects of
tiny particles
US Food and Drug Administration
(FDA) and Abbreviated New Drug
Application (ANDA) for
Nanoformulation
Analytical techniques used for
characterization of
nanoparticles
Nanoparticles properties and
safety
REACH and nanomaterials
• Partical size and Zeta potential
• XRD and DSC
• DLS
• AFM
• TEM and SEM
• NMR, FTIR and UV-Vis spectroscopy
• CLSM
• In vitro drug release profile
• In vivo imaging system
• Drug biodistribution studies
• In vivo drug targeting studies Source: https://www.frontiersin.org/articles/10.3389/fchem.2018.00360/full

EMEA (European Medicines Evaluation Agency)
• EMEA was established for the authorization and supervision of medicinal products
for human and veterinary use.
• In order to assess potential needs for regulatory requirements for evaluation and
assessment of nanomedicines EMA created a cross agency Nanomedicine Expert
group in 2006.
• In 2009, this was further expanded via establishment of International Regulatory
Subgroup on Nanomedicines, an initiative jointly launched by the medical regulatory
agencies of EU, USA, Japan and Canada.
• Experts from this group organized first international workshop on nanomedicines in
2010 in London.

• There are a wide range of legislations related to issues relevant for nanotechnology
currently in existence or being elaborated. These issues primarily have to do with risk
assessment
Examples of legislation relevant for nanomedicine are the following:
1. Medicinal products marketed in the European Union are covered by comprehensive
EU legislation.
2. According to the EU legislation any substance or combination of substances which
may be administered to human beings with a view to making a medical diagnosis or
to restoring, correcting or modifying physiological functions in human beings is
likewise considered a medicinal product.
3. All medicinal products marketed in the European Union must obtain an EU product
authorization.

• The European regulatory system for medicinal products offers two routes for
authorizing medicinal products:
1. A “centralized procedure” with applications made directly to EMEA, leading to the
grant of a European marketing authorization by the Commission. This procedure is
compulsory for products derived from biotechnology, and optional for other
innovative medicinal products.
2. A “mutual recognition” procedure, which is applicable to the majority of
conventional medicinal products.
Both procedures are based on a wide range of requirements laid down in
implementing rules and guidance documents.
EU regulatory system is unique in providing a network between all national
regulatory bodies, coordinated by EMEA.

Medical Devices
• Medical devices are also covered by EU regulation.
• A Medical Device is defined as “any instrument, apparatus, appliance, software,
material or other article, whether used alone or in combination, together with any
accessories, including the software necessary for its proper application intended by
the manufacturer to be used for medical purposes for human beings for the purpose
of diagnosis, prevention, monitoring, treatment or alleviation of disease,
investigation, replacement or modification of the anatomy or of a physiological
process, control of conception, and which does not achieve its principal intended
action in or on the human body by pharmacological, immunological or metabolic
means, but which may be assisted in its function by such means.”

• The Directive on medical devices does not make placing on the market subject to a
prior marketing authorization but sometimes depending on risks involved, devices
can only be placed on the market if they have been subject to a conformity
assessment procedure involving a third party
• The Directive deals primarily with risk management. Manufacturers are obliged to
carry out an assessment of the risks and to adopt a risk management strategy.

Overview of regulatory presence on the R&D of product life cycle
22
Quality Management System (requirements)
GMPs GLPs GCPs
QUALITY NON CLINICAL CLINICAL
Drug substance
Drug product
Pharmacodynamics
& Pharmacokinetics
Toxicology
Phase I
Phase II
Phase III
Increased presence of regulators in the early phases of R&D
(including scientific advice before first in human trails)
FDA's INDA
FDA's NDA
EMEA/EC, MA
Source: https://www.frontiersin.org/articles/10.3389/fchem.2018.00360/full

Regulatory development for “Next Generation” nanomedicines
• An increase concern both at Europe and US level has been the question of the
harmonization of methodology essential to characterize the quality requirements.
• The NCL(Nanotechnology Characterization Laboratory) at NCI(National Cancer
Institute) in US provided major contribution for development of nanomedicines in
oncology.
• Critical role will be played by regulatory bodies through their scientific advice
procedures and an increased pressure will be present to have more co-operative work
between different regional regulatory bodies(EMA, FDA, PDMA/MHL), major
academic and industrial stake holders.

• Meanwhile, the need for adequate standardization and characterization of nano based
systems has moved the US to a specific platform initiative(NCL at NCI) while
Europe is still looking for a more integrated way to address it.
• Nanomedicine is bringing converging sciences to an adequate platform providing
better health care and also enabling design and clinical use of innovative solution to
unmet clinical needs
• Innovative Medicines Initiative(IMI) in Europe and National Center for Advancing
Translational Sciences(NCATS/NIH) in the US are both major platforms that
contribute in the future towards better regulatory science in innovative technology as
well as nanomedicines.

Nanomedicines in the market
• For nanomedicines to be marketed they need drug market approval many
nanomedicines are already in the market.
• Doxil® is the first FDA approved nanomedicine which is used to treat
ovarian cancer, kaposi sarcoma in HIV patient.
• Ambisome® is the first EMA approved nanmedicine which is used to
treat fungal infections.

List of nanomedicines marketed in US
S.NO. Trade Name Indication
1. Ambisome Antifungal
2. Daunoxome Antineoplastic
3. Depocyte Lymphomatous meningitis
4. Estrasorb Vasomotor symptoms
5. Triglide Hypercholesterolemia
6. Helioblock sx sunscreen
cream
Sunscreen
7. Rapamune Immunosuppresant
8. Somatuline depot Acromegaly
9. Megace es Anorexia, Cachexia in AIDS patients

List of nanomedicines marketed in Europe
S.No. Medicinal Product Nanotechnology Purpose
1. Abraxane(paclitaxel) Solvent-free colloidal suspension of albumin
bound nanoparticles to increase water
solubility.
2. Caelyx(doxorubicin) Pegylated liposome to increase blood
circulation (long acting).
3. Emend(aprepitant) Colloidal dispersion of nanoparticles to
increase bioavailability.
4. Mepact(mifamurtide) Liposome encapsulation to facilitate activation
of macrophages.
5. Myocet(doxorubicin) Liposome encapsulation to reduce cardiac
toxicity and to increase tumour tissue
distribution.
6. Rapamune(sirolimus) Colloidal nanodispersion stabilised with
poloxamer to reduce particle size for increased
stability and bioavailability.
27

Conclusion
• There are currently no proper regulatory guidelines developed specifically for
nanomedicines, due to inadequate knowledge regarding nanoparticle behaviour.
• Regulatory guidance assumes priority as the nanomedicines are fast developing.
• Regulations of nanomedicines should be different from regular medicines as the
properties vary widely due to size variation.
• Since regulatory agencies around the world are struggling with regulatory issues of
nanomedicines, there may be benefits from attempting to harmonise national
regulations.

References
• http://ipimediaworld.com/wp-content/uploads/2014/07/Regulatory.pdf (accessed on:
24-01-2019)
• https://www.frontiersin.org/articles/10.3389/fchem.2018.00360/full (accessed on: 09-
03-2019)
• https://ipapharma.org/wp-content/uploads/2019/02/oct2018.pdf (accessed on: 06-03-
2019)
• https://www.sciencedirect.com/science/article/pii/S0006291X15012395 (accessed
on: 07-01-2019)
• https://www.cov.com/files/Publication/8dc7cd17-d1f6-4290-ac47-
2fde70df9c3b/Presentation/PublicationAttachment/a80c793a-7fbf-4407-b6df-
9dd39dbd4cdf/NanomedicinesRegulatory.pdf (accessed on: 24-01-2019)
• https://www.sciencedirect.com/science/article/pii/S0006291X15304137 (accessed
on: 07-01-2019)

• https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6192267/ (accessed on: 08-01-2019)
• https://www.fda.gov/scienceresearch/specialtopics/nanotechnology/ucm301114.htm
(accessed on: 07-01-2019)
• https://www.ncbi.nlm.nih.gov/pubmed/23656268 (accessed on: 09-03-2019)
• http://webbut.unitbv.ro/BU2012/Series%20VII/BULETIN%20VII/17_Toma-
Bianov%202-2012.pdf (accessed on: 24-01-2019)
• https://ec.europa.eu/jrc/en/publication/regulatory-aspects-nanomaterials-eu (accessed
on: 18-12-2018)
• https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/
Guidances/UCM588857.pdf (accessed on: 07-01-2019)
• https://www.researchgate.net/publication/40541616_International_Harmonization_of
_Regulation_of_Nanomedicine (accessed on: 24-01-2019)
• https://onlinelibrary.wiley.com/doi/full/10.1002/jin2.34 (accessed on: 07-01-2019)

THANKYOU

Regulatory requirements on nanomedicines

Recomendados

Recomendados

Más contenido relacionado

La actualidad más candente

La actualidad más candente (20)

Similar a Regulatory requirements on nanomedicines

Similar a Regulatory requirements on nanomedicines (20)

Último

Último (20)

Regulatory requirements on nanomedicines