What are biosimilar medicines?

Page last updated: 14 November 2017

A biosimilar medicine is a highly similar version of an already registered biological medicine (the reference biological medicine). A biosimilar medicine has been assessed to be highly similar to the reference biological medicine in terms of:

  • safety
  • effectiveness
  • physicochemical characteristics
  • biological characteristics
  • immunological characteristics.

Biosimilar medicines are marketed under a different brand name once the patent on the reference biological medicine has expired.

A medicine cannot be identified as a biosimilar medicine until it is evaluated by the Therapeutic Goods Administration (TGA) and shown to be as safe and effective as the reference biological medicine. The similarity of the biosimilar medicine to its reference biological medicine is assessed by the TGA using comprehensive comparability studies.

Biological medicines are medicines that contain one or more active substances that are derived from living cells or organisms.

Typically, biological medicines are protein-containing agents produced by biotechnology processes (e.g. using recombinant DNA techniques and manufactured in cell culture). They are usually made of proteins that are naturally produced in the human body.

Biological medicines, including biosimilar medicines, are used to treat serious diseases such as cancers, diabetes, rheumatoid arthritis, severe psoriasis, kidney disease, multiple sclerosis and inflammatory bowel diseases such as ulcerative colitis and Crohn’s disease.

Biological medicines include:

  • certain hormones for hormone deficiencies (e.g. insulin for diabetes and growth hormone for growth hormone disorders)
  • monoclonal antibodies for the treatment of autoimmune diseases and cancers
  • blood products (e.g. for the treatment of haemophilia)
  • immunomodulators (e.g. β-interferon for multiple sclerosis)
  • enzymes (e.g. to remove blood clots)
  • vaccines to prevent a number of diseases.

Although synthetic chemical medicines still represent the largest proportion of medicines that are used today, technical advances in areas such as recombinant DNA technology, genomics and immunology have delivered many biological medicines to the market in recent years.

Biosimilar medicines currently listed on the Pharmaceutical Benefits Scheme (PBS) and approved by the Therapeutic Goods Administration (TGA) are available at 'Which biosimilar medicines are available in Australia?'.

Table 2 Differences between chemical medicines and biological and biosimilar medicines
Aspect Chemical medicines Biological and biosimilar medicines
Molecular structure

Small, simple structure that is easy to characterise

For example, the average size of an aspirin molecule is 21 atoms:

Diagram of an asprin molecule with 21 atoms

Medium to very large, complex structure that is difficult to characterise

For example, the average size of a human growth hormone is 3091 atoms:

Human growth hormone with thousands of atoms

And the average size of an antibody is more than 20,000 atoms:

An antibody with tens of thousands of atoms

Homogenous—structures are identical, and have predictable chemical structure and properties Heterogeneous—structures are mixed with less-predictable structure and properties
Manufacture Produced by a step-by-step simple chemical synthesis process; medicines can be produced in days Produced by a biological synthesis process using modified living cells via complex fermentation and purification processes; medicines take weeks or months to produce
Checking Quality checks needed, but only on the performance of the final product Quality checks needed throughout the manufacturing process, and on the performance of final product and between batches
Stability Relatively stable in a range of storage conditions Sensitive to storage and handling conditions
Immune reaction Lower potential Higher potential

Both biosimilar medicines and generics are versions of reference medicines that are marketed once the patent on the reference medicine has expired. However, there are some differences:

  • A generic medicine has exactly the same active ingredients as a chemical reference biological medicine. For example, APO-Atorvastatin® is a generic version of Lipitor®(atorvastatin).
  • A biosimilar medicine is highly similar to a biological reference biological medicine in terms of safety, effectiveness and quality. For example, Inflectra® is a biosimilar version of Remicade®(infliximab).

Biological medicines, including biosimilar medicines, are generally produced using genetically modified cells. These are cells whose genes have been changed using recombinant DNA techniques, so that they produce a substance or perform a function (i.e. the genes for a certain protein would be introduced into the genes of a host cell, such as a bacteria or yeast cell, which would then produce that protein).

There are several steps to the process (Figure 1):

  1. The genetic code (a sequence of DNA) of a chosen protein (e.g. a hormone, antibody, blood product) is identified and a functional DNA sequence created.
  2. The genetic code is inserted into various host cell lines (e.g. bacteria or yeast), so that the host cells produce this protein.
  3. The host cell line that produces the protein most effectively is chosen.
  4. This cell line is grown in a fermentation process in a bioreactor.
  5. The protein is separated out of the bioreactor (e.g. through filtration).
  6. The protein is purified, stabilised and processed into a medicine.
Figure 1 Steps in the production of biological or biosimilar medicines
Source: Based on IAPO (2013). Briefing paper on biological and biosimilar medicines. International Alliance of Patients’ Organizations, London.

Figure 1 Steps in the production of biological and biosimilar medicines

There may be small differences in the manufacturing process because the original manufacturer is not required to release the details of their manufacturing process when the patent on the reference biological medicine has expired. This means that the new manufacturer may use slightly different processes, such as the host cell line, and growth and storage conditions.

The manufacturing process for a biosimilar medicine must comply with the same quality requirements for any biological medicine, and thus must demonstrate that the production process can consistently produce a high-quality product.

The development process varies between biological and biosimilar medicines (Figure 2):

  • In biological medicine development, the majority of time and effort is spent in clinical studies that establish the clinical benefit of the medicine.
  • In biosimilar medicine development, the majority of time and effort is spent in analytical comparison studies that establish the similarity of the medicine to the reference biological medicine.
A diagram that compares the development pathways of reference biological vs biosimilar medicines. It shows that there are 3 stages of development. Pre-clinical assessments comprise stage one (analytical characterisation, structural and in-vitro functional tests) and stage two (animal pharmacokinetic, pharmacodynamic and toxicology studies), and clinical assessments are undertaken in stage 3 (human pharmacokinetic, efficacy and safety studies). The diagram shows that for reference biological medicines, most of the effort lies in phases 2 and 3, and for biosimilar medicines, most of the effort lies in phases 1 and 2.

 

A biosimilar medicine must be highly similar to the reference biological medicine. Therefore, the research and development of a biosimilar medicine involves extensive comparison with the reference biological medicine.

The purpose of the comparison is not to evaluate the benefits of the biosimilar medicine, because this has already been done for the reference biological medicine. The comparison is to establish the similarity between the biosimilar medicine and the reference product, and to determine that there are no significant differences in safety, effectiveness or quality.

In developing a biosimilar medicine, the structure and function of the reference biological medicine is defined using analytical tools and existing clinical knowledge. This is known as characterisation.

A production process for the biosimilar medicine is then developed. This is an iterative process that continues until the production process can consistently produce a highly similar molecular structure to the reference biological medicine.

Once the medicine is produced, it is compared with the reference biological medicine in a biosimilar comparability exercise, which compares the physicochemical and functional characteristics of the molecules.

There are usually three components of a comparability exercise:

  • Quality comparability—where the physicochemical and biological qualities are compared in a series of analytical tests.
  • Nonclinical comparability—includes dosing and animal studies to detect any differences between the biosimilar medicine and the reference product.
  • Clinical comparability—where the biosimilar medicine is tested in humans in a clinical trial to demonstrate comparable effectiveness with the reference biological medicine. A comparable safety profile in terms of seriousness and frequency of side effects must also be shown.

Biosimilar medicines are designed and engineered to be as similar as possible to the reference biological medicine. The similarity of the biosimilar medicine to its reference biological medicine is assessed by the Therapeutic Goods Administration using comprehensive comparability studies.

Reference and biosimilar medicines are considered to be highly similar, but not exactly the same. The minor differences between a reference biological medicine and biosimilar medicine do not affect the safety, effectiveness or quality of the biosimilar medicine. For a biosimilar medicine to be approved, the structural variability of the biosimilar medicine must not be greater than that of the reference biological medicine, and all critical quality attributes (i.e. those important for the function of the molecule) must be highly similar.

It is important to note that there are already minor differences between batches of the same reference biological medicines. This is because the inherent variability of the biological systems used in the manufacturing process means that the resulting products are also variable. No two batches of a biological medicine (even from the same manufacturer) are ever exactly the same.

The process of biosimilar development is designed to detect even small, potential, product-related differences between the biosimilar medicine and the reference biological medicine. The process involves extensive structural and functional characterisation and comparison of the biosimilar medicine and the reference biological medicine.

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