Biosimilars

Question 1

What are biosimilars?

Answer 1

a copy of a commercially available biopharmaceutical that is no longer protected by a patent which has:
-undergone rigorous analytical and clinical assessment, in comparison to its reference product
-been approved by a regulatory agency according to a specific pathway for biosimilar evaluation
highly similar to its reference product in physicochemical characteristics, efficacy, and safety

Question 2

True or false: biosimilar is essentially the same as the reference biologic medicine with some allowed variability

Answer 2

true

Question 3

True or false: biosimilars have a degree of natural variability, but this variability should not affect safety anf effectiveness

Answer 3

true

Question 4

What are the key requirements for comparability for biosimilars?

Answer 4

highly similar structure and function
equivalent PK/PD
comparable efficacy and safety
same presentation, dose, and administration mode

Question 5

Why do we need biosimilars?

Answer 5

cost savings
-biosimilars are expected to have a robust impact on lowering
health care costs
more treatment options
other potentials impacts and advantages
-additional services for patients
-cost savings that can be used for investment

Question 6

What is involved in the development of biosimilars?

Answer 6

reverse engineering

Question 7

Describe process customization of biosimilars.

Answer 7

reference product manufacturing info is proprietary and not publicly available
begins with characterizing the reference biologic
a custom cell line is then created and procedures developed for all manufacturing stages
checkpoints to verify CQA similarity with respect to the reference product

Question 8

What is CQA?

Answer 8

once a cell line is developed for the biosimilar, the candidate molecule is analyzed and carefully compared to the reference product using a number of characteristics, called critical quality attributes

Question 9

What is the importance of CQAs?

Answer 9

features associated with the drug product can impact safety, potency, PK, and overall quality
CQAs can induce post-translational modifications to a protein
-can impact PK, immunogenicity, safety, and efficacy

Question 10

How is understanding of the biosimilar molecule provided?

Answer 10

integration of data from multiple analytical and biological tests
-combined data from 45 different methods provide
information on multiple attributes
-every attribute is evaluated more than once

Question 11

Describe the complexities of biosimilars development.

Answer 11

produced through an intricate, multistep process, using living cells
cell line and manufacturing process of the reference product are proprietary and belong only to the original manufacturer
bio similarity for antibodies can only be established through evaluation of the biosimilar in active comparator clinical trials and experiments with the reference product

Question 12

What is the main goal of the originator? What about the manufacturer developing a biosimilar?

Answer 12

originator: determine clinical effect
biosimilar: determine similarity

Question 13

Describe step 1 of the development of biosimilars.

Answer 13

characterization of reference product:
-reference product is characterized to identify the products
CQAs, characteristics that affect identity, purity, biological
activity, and stability of a drug
-multiple batches of reference products are tested in order to
establish equivalence margins, or “goal posts” for each CQA

Question 14

What is involved in step 2 of the development of biosimilars?

Answer 14

cell line creation:
-amino acid sequence
-gene synthesis (relevant gene is cloned into DNA vector)
-expression vector (transferred into host cell)
-expression cell line

Question 15

Describe step 3 of the development of biosimilars.

Answer 15

cultivation and production
-cell line with high similarity to reference product is selected
and expanded in a fermentation medium to establish a
master cell bank
-cells from master bank are cultured and produced in volumes
of up to thousands of liters in bioreactors

Question 16

Describe step 4 of the development of biosimilars.

Answer 16

isolation and purification
-biosimilar protein secreted into the culture medium is
recovered through filtration or centrifugation
-volume of the product-containing fraction is reduced utilizing
techniques such as high-affinity absorption
-product purification is done to remove buffers and impurities
biosimilar CQAs are sensitive to variations in the manufacturing process
ensure scale-up has no impact

Question 17

Describe step 5 of the development of biosimilars.

Answer 17

formulation, fill, and finish
-concentrated protein is formulated using ultrafiltration
techniques
-stored under appropriate conditions to maintain shelf life
differences between biosimilar and reference biologic in formulation, excipients, and primary packaging are identified

Question 18

What are interchangeables?

Answer 18

product that may be substituted for the reference product without the involvement of the prescriber
meets requirements based on evaluation and testing
to receive biosimilar instead of reference product, the patient may need an Rx from a prescriber

Question 19

How are biosimilars regulated in Canada?

Answer 19

under the Food and Drugs Act and the Food and Drugs Regulations
manufactured to the same regulatory standards as other biologic drugs

Question 20

Are biosimilars the same as biobetters?

Answer 20

no
-structurally different from originally licensed
biopharmaceutical
-intended to improve performance while preserving MOA

Question 21

Are biosimilars the same as generics?

Answer 21

no
-small molecule drugs that are less complex than biosimilars
-manufacturing process is several orders of magnitude less
complex

Question 22

Describe differences between generics, new biologic, and biosimilars. Based on the following:
time to market
clinical studies
patients
post-approval studies

Answer 22

generic:
-time to market: 2-3yrs
-clinical studies: bioequivalence studies in healthy volunteers
-patients: 20-50
-post approval studies: pharmacovigilance, risk management
new biologic:
-time to market: 8-10yrs
-clinical studies; phase I, II, III efficacy and safety studies
-patients: 800-1000
-post approval studies: phase IV, risk management, pvigilance
biosimilar:
-time to market: 7-8yrs
-clinical studies: comparative phase I, PK, phase III
-patients: 500
-post approval studies: phase IV, risk management, pvigilance

Question 23

What are non-comparables?

Answer 23

copies of licensed biologic medicines that are marketed in some countries, but have not followed the rigorous regulatory pathways required for biosimilars
may have clinically significant differences in quality, efficacy, and safety
reduced biological potency or higher rates of adverse events

Question 24

How are biologics produced?

Answer 24

from living organisms
-modify host cells–>grow cells–>extract, refold, purify–>formulate to stable drug product

Question 25

What are the two types of biologics?

Answer 25

therapeutic proteins:
-replace or augment beneficial human proteins
monoclonal antibodies:
-strike disease targets with enhanced precision

Question 26

True or false: biologics are small and are uniform in size

Answer 26

false
large and vary in size and complexity

Question 27

Describe the properties studied during extensive analytical characterization of a biosimilar.

Answer 27

primary structure
higher order structure
biological function
general properties and excipients
stability
receptor binding and immuno-chemical properties

Question 28

Differentiate between biosimilars and generic drugs based on the following:
chemical structure
analytical characterization
manufacturing process
impact of a process change
development cost
immunogenicity

Answer 28

chemical structure:
-biosimilars: complex
-generics: simple, identical to reference product
analytical characterization:
-biosimilars: impossible to characterize
-generics: identical to reference product
manufacturing process:
-biosimilars: complex, several stages
-generics: simple organic chemistry
impact of a process change:
-biosimilars: alters protein structure and function
-generics: negligible
cost:
-biosimilars: $100-200 million/molecule
-generics: $3-5 million/molecule
immunogenicity:
-biosimilars: immunogenic
-generics: nonimmunogenic