Biosimilar

1
Biosimilar

• Siriwan Chaisomboonpan
• Bureau of Drug and Narcotic
• 25 December 2008

2
Outlines

• What is a biological medicine?
• What is a biopharmaceutical medicine?
• What is a biosimilar medicine?
• What is the importance of biosimilar?
• Which are the related guidelines?

3
What is a biological medicine ?

• Is a medicine whose active substance is made by
  or derived from a living organism.
• Example such as insulin can be produced by a
  living organism.

4
What is a biopharmaceutical medicine?

• Biopharmaceutical
• - A drug created by means of biotechnology,
  especially genetic engineering.
• - A pharmaceutical inherently biological in
  nature and manufactured using biotechnology.

5
How biopharmaceuticals made?

• Develop host cell
• Establish a cell bank
• Protein production
• Purification
• Analysis
• Formulation
• Storage and handling

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Develop host cell

• Identify the human DNA sequence for the desired
  protein
• Isolate the DNA sequence
• Select a vector to carry the gene
• Insert the gene into the genome of a host (a
  suitable bacterial or eukaryotic cell)
• The exact DNA sequence and the type of host cell
  used will significantly influence the
  characteristics of the product

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Establish a cell bank

• A cell bank is then established, using an
  iterative and elaborate cell screening and
  selection process, yielding a unique master cell
  bank.
• No two master cell banks are exactly alike.

8
Protein production

• The conditions under which cells are cultured can
  affect the nature of the end product.

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Purification

• Any change in the purification process can affect
  the clinical characteristics of the product.

10
Analysis

• Protein molecules are analyzed for uniformity in
  terms of structure and potency.
• A wide variety of analytical tools is used to
  examine
• 3D structure/Aggregation/
• Isoform profile, including glycosylation
  patterns/ Heterogeneity/Potency

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Analysis (cont.)

• These tests remain limited in their ability to
  detect all product characteristics that may
  affect clinical efficacy and safety.

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Formulation

• Formulation is a key step in stabilizing the
  protein.
• The components of the formulation, and the
  process used, can significantly affect the
  products behavior in patients.

13
Storage and handling

• Biopharmaceuticals are very sensitive to
  temperature changes and/or shaking.
• Strict storage and handling conditions are
  therefore essential for maintaining product
  integrity and stability.
• Poor adherence to (cold) storage requirements can
  affect clinical efficacy and safety.

14
Manufacturing low molecular weight drugs

• Low molecular weight drugs are made by adding
  and mixing together known chemicals and reagents,
  in a series of controlled and predictable
  chemical reactions.
• This is organic chemistry

15
Differences in manufacturing

• The manufacturing process for a biopharmaceutical
  is far more complex than that for a low molecular
  weight drug.
• For biopharmaceuticals, much more than for low
  molecular weight drugs, the quality of the end
  product (including therapeutic efficacy and
  safety) is depended on the manufacturing process.

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Quality of products

• Each of these stages can have a major influence
  on the characteristics of the biopharmaceutical
  end product.
• These differences clearly apply to biosimilars as
  well as to original biopharmaceuticals.

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What is a biosimilar medicine?

• Is a medicine which similar to biological
  /biopharmaceutical medicine that has already been
  authorized (the biological/ biopharmaceutical
  reference medicine).
• The active substance of a biosimilar is similar
  to the one of biological/ biopharmaceutical
  reference medicine.
• Used in the same dose to treat the same disease.

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What is a biosimilar medicine? (cont.)

• Similar biotechnology medicinal products a new
  type of generic biopharmaceutical approval in the
  EU.
• It is similar but not identical.

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What is the importance of biosimilar?

• Biopharmaceuticals represent one of the
  fastest-growing segments of pharmaceutical
  industry.
• By 2010 they are expected to represent 50 of the
  market.
• Patent of original product expired.
• Increase opportunity to healthcare services,
  decrease expenditures.

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Other related terms

• Biogeneric
• Follow-On Protein
• Follow-On Biologic

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Basic to view and define biosimilar

• Entity-Based (including Product Process)
• Regulatory-Based (under an abbreviated testing
  and/or filing scheme)
• Market-Based (same manufacturers, different trade
  name)

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Entity-Based

• Based on consideration of their
• Chemical and/or biological source
• Identity (structure)
• Activities
• Manufacturing process
• Specification
• Predictions of product safety and efficacy based
  on knowledge of one or more similar products.

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Example Process Product

• Cheddar cheese and red wine from different
  manufactures are unique (e.g. in flavor or
  texture).
• But they may be treated as the same (generic
  equivalent) and be assigned the same generic
  product name.

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Related Guidelines

• European Medicines Agency Evaluation of Medicines
  for Human Use

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EMEA Guidelines

• Similar biological medicinal products, Oct 2005
• Similar biological medicinal products containing
  biotechnology-derived proteins as active
  substance Quality Issues, Feb 2006
• Manufacturing process, comparability to reference
• Suitability of analytical method, physicochemical
  properties, biological activity, purity and
  impurities, specification

26
EMEA Guidelines (cont.)

• Similar biological medicinal products containing
  biotechnology-derived proteins as active
  substance Non-Clinical and Clinical Issues, Feb
  2006
• Non clinical data in vitro, in vivo studies
  (Pharmacodynamic effect, toxicity)
• Clinical studies Pharmacokinetic,
  Pharmacodynamic, Efficacy trials

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Non-Clinical and Clinical Issues, Feb 2006 (cont.)

• Clinical safety and pharmacovigilance requirement
• Immunogenicity
• Factor affecting immunogenicity
• Consequences of an immune response
• Principle for evaluation of immunogenicity
• Testing
• Evaluation of the clinical significance of the
  observed immune response

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Annex Non-Clinical and Clinical Issues

• Recombinant Erythropoietin
• Recombinant Human Soluble Insulin
• Recombinant Granulocyte-Colony Stimulating Factor
• Somatropin

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Conclusions

• The manufacturing process for biopharmaceuticals
  (and biosimilars) is far more complex than for
  low molecular weight drugs (and generics).
• Any (minor) change made at any stage may have a
  critical effect on the clinical efficacy and
  safety.
• Major manufacturing changes include
• producing a biosimilar
• opening/starting a new production site
• scaling-up to meet market demands
• The process is the product

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Points to consider

• Can a new manufacturer produce a biosimilar that
  is similar enough to the original
  biopharmaceutical to be considered the same?
• How can the level of similarity be established
  without access to the bulk material?
• Are there risks associated with currently
  undetectable differences?
• How similar is similar enough?

31
References

• Basant Sharma, PhD Manufacturing differences
  between biopharmaceuticals and low molecular
  weight drugs 2005.
• EMEA Guideline on Similar Biological Medicinal
  Product 2005-2006
• EMEA Question and Answers on biosimilar
  medicines 2006
• WWW.nature.com/naturebiotechnology