2. CONTENTS
• Definition
• FDA Definition
• Principle
• Manufacturing process
• Product characterization
• Registration of medical products
• Registration of biological products
•
3. DEFINITION
Biopharmaceutical agents are medicinal products derived from a biological source.
These include vaccines, blood and blood components, allergenics, somatic cells,
gene therapy, tissues, recombinant therapeutic proteins, etc.
Biosimilars are similar in structure, function, activity, immunogenicity, and safety to
the innovator biologic product which is considered the “Reference Biologic”.
The approval of biosimilars is based on a step-wise comparability exercise.
Biosimilars can be defined as biotech drugs that have been shown to have
comparable quality, safety and efficacy to the original product.
4. FDA DEFINITION
The FDA describes biosimilars in the following way:
“The bio- logic product is highly similar to the reference
product not with- standing min or differences in clinically
inactive components and that there are no clinically meaningful
differences between the biologic product and the reference
product in terms of safety, purity, and potency of the product”
5. PRINCIPLE
Similar Biologics are developed through a sequential
process to demonstrate the similarity by extensive
characterization studies revealing the molecular and
quality attributes with regard to the Reference Biologic.
It is sufficient to ensure that the product meets
acceptable levels of safety, efficacy and quality to
ensure public health in accordance with international
guidelines (WHO 2013).
6. MANUFACTURING PROCESS
Data requirements pertaining to manufacturing process
include description of characteristics of host cells, vector
system, cell banks, stability of clone, cell culture/
fermentation, harvest, dosage form, excipients,
formulation, purification, filling into bulk or final
containers, storage, primary packaging interactions,
container closure system, and usage instructions, etc.
The manufacturing process is optimized to minimize
differences between the biosimilar and “Reference
Biologic”
7. PRODUCT CHARACTERIZATION
ASSESSMENT OF PRODUCT CHARACTERSTICS:
This involves studies to characterize the variety of quality
attributes of biosimilars, such as
1. Structure and composition,
2. Physicochemical properties,
3. Bioactivity,
4. Immunochemical properties, and
5. Purity, impurities, and contaminants.
8. REGISTRATION OF MEDICINAL
PRODUCTS:
Pre-market evaluation is conducted to determine the
risk versus benefit profile of medicinal products
before registration and HAS (Health Sciences
Authority) adopts a risk-based approach with
application of current international guidelines,
standards and scientific knowledge.
The three evaluation routes allow flexibility yet
ensuring robustness in the evaluation system.
9. 1. The Full dossier evaluation route is applicable to a product that has
not been approved by any drug regulatory agency at the time of
submission. The complete quality, non-clinical and clinical
documentation is evaluated.
2. The Abridged dossier evaluation route is applicable to a product
that has been approved by at least one drug regulatory agency at
the time of submission. The complete quality and abridged clinical
documentation is evaluated.
3. The Verification dossier evaluation route is applicable to a product
that has been approved by at least two of HSA’s reference
agencies. The evaluation leverages on the review conducted by the
reference agencies.
10. REGISTRATION OF SIMILAR
BIOLOGICAL (BIOSIMILAR) PRODUCTS
1. Biosimilar approach
2. Submission procedure and requirements:
3. IMMUNOGENECITY
4. Interchangeability and substitution
5. Pharmacovigilance
11. 1. BIOSIMILAR APPROACH
A biosimilar product is intended to be similar in
terms of quality, safety and efficacy to a registered
biological product (reference biological product), for
which there is substantial evidence of safety and
efficacy. The development of a biosimilar product
involves stepwise
Comparability exercises starting with comparison of
the quality characteristics of the biosimilar product
and the reference product.
12. 2. SUBMISSION PROCEDURE AND
REQUIREMENTS
The complete quality documentation for both the drug substance
and drug product is required. Comparability data between the
biosimilar product and the reference product is essential. The extent
of the comparability studies and the product class specific assessment
criteria will depend on the type of biologic molecule.
Non-clinical documentation should include comparative studies
designed to detect differences in the response between the biosimilar
product and the reference product.
Clinical comparability studies should be generated with the test
product produced with the final manufacturing process representing
the quality profile of the batches to be commercialized.
13. 3. IMMUNOGENECITY
The immunogenicity of a biosimilar product must always
be investigated. The extent of independent testing
needed will depend on a variety of scientific factors such
as the indication of whether the product is to be
administered for chronic conditions, the overall
assessment of the product’s immunogenic potential, and
whether there is the possibility of generating a cross-
reaction with an important endogenous molecule.
14. 4. Interchangeability and substitution
A biosimilar product is normally approved to be interchangeable
with the reference product. To establish that two products would
be substitutable, the applicant of a biosimilar product would
need additional clinical data.
A warning statement on the risks associated with switching of
products during treatment, and against product substitution, is
to be included in the package insert of the biosimilar product.
15. 5. Pharmacovigilance
Pharmacovigilance for all new medicines, marketing
authorization holders of biosimilars should make sure that
they have an appropriate system of pharmacovigilance in
place to assure responsibility for their products on the
market and to ensure that appropriate action can be taken
if necessary.
Many adverse effects may appear only after a biosimilar
drug isused more extensively, for a longer period of time, in
a greater number of patients.
16. Non-clinical studies:
Before initiating non-clinical
studies, results from the quality comparability
studies including physiochemical and biological
characterization studies should be reviewed from
the point of view of the potential impact on
efficacy and safety.
17. Clinical studies:
The clinical comparability exercises is a
stepwise approach that should ideally start with the
pharmacokinetics and pharmacodynamics studies
followed by the efficacy and clinical safety and clinical
efficacy trials will be required, the clinical studies and
nature of a biosimilar trial are likely to depend on the
product class. All the clinical studies should address the
immunogenicity characteristics.
18. Status of biosimilar regulation in
Europe:
In Europe, the Committee for Medicinal Products for
Human Use (CHMP), the European Medicines Agency
(EMEA) led the way for biosimilars, by issuing its first
specific regulatory guidance in October 2005. Two general
guidance documents addressing quality and nonclinical and
clinical perspectives (June 2006), five product-specific
annexes on nonclinical and clinical issues (June-July 2006)
and a manufacturing change comparability guideline
(November 2007) are now available.
19. Status of Biosimilar Regulation in
US:
In US, in March 2009, Representative Henry Waxman
introduced H.R. 1427 to the Congress “Promoting
Innovation and Access to Life-saving Medicines Act”,
which authorizes FDA to approve follow-on biologics in
an abbreviated manner. It has market exclusivity clauses
with time frames similar to ones used currently for drugs.
Other bills are expected to follow in the 2009 legislative
agenda in order to establish a pathway for approval of
these follow-on biologics.
20. Status of Biosimilars in Korea and
Singapore:
Korea and Singapore have released draft guidelines on
biosimilars in 2009. The Singapore guideline is derived
mainly from the EMEA guidelines and defines a similar
biological/ biosimilar product as “a biological medicinal
product referring to an existing registered product,
submitted for medicinal product registration by an
independent applicant, and is subject to all applicable data
protection periods and/or intellectual property rights for
the original product”.
21. Status of Biosimilars in India:
The Indian biotech industry is a thriving industry which got
its start from vaccine manufacturing. In addition to meeting
domestic demands, the Indian vaccine industry also fulfils
export requirements to a large extent. Therefore it is
evident that manufacturing expertise in producing biologic
products of required export quality already exists in the
country. What is not readily evident is whether these
products can prove to be “comparable” to innovator
products when we look into all categories of biologics.
