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Daan JA Crommelin
Department of Pharmaceutics
Recombinant DNA technology-derived therapeutics (biologicals) are being taken up in our therapeutic arsenal at a rapid pace. The total turnover worldwide is now an estimated €50bn and with one-third of all new drugs in the pipeline being biologicals, a total market size of €75bn is foreseen in 2011.
Biologicals are developed for serious life-threatening or debilitating diseases. Generally speaking they are highly effective and expensive. Patent protection for the first generation of biologicals, such as human growth hormone, erythropoietin and granulocyte-colony stimulating factor (G-CSF), has expired or is expiring soon.
As a result of this there is a drive for generic versions of biologicals.
However, the rules regarding the introduction of generic versions of biologicals are different from those for small, low-molecular-weight medicines. This contribution deals with the new regulations regarding generic versions of biologicals as they have emerged in Europe under the term “biosimilars”.
Biologicals have a number of characteristics that set them aside from small, low-molecular-weight, therapeutically active molecules.
For a start, they are large, protein-based molecules with a complex three-dimensional structure, consisting of amino acids and often sugar elements.
These structural elements make biologicals special and have led to a special regulatory framework. The structure of (glyco)proteins is essential for their action and safety pattern.
The three-dimensional structure of proteins often contains secondary structures such as alfa-helices or beta sheets. These structures are maintained by a set of rather weak interactions between the building blocks of the protein (amino acids). This means that the three-dimensional structures are easily and irreversibly disturbed.
Structural changes have an impact not only on the efficacy but also on the safety profile of the biological. Subtle changes in structure can lead to immunogenicity that was not seen before. Even low levels (a few percent) of protein aggregates may lead to breaking of tolerance and antibody formation against the biological.
Therefore biologicals have to be handled with care. Shaking, temperature increase, freezing, pH and ionic strength changes and high shear conditions may affect their structure.
Thus, biologicals stand out. Nowadays, with all the sophisticated spectroscopic and chromatographic techniques available, it is easy to monitor the stability of small molecules and to identify (even minor) changes in their molecular structure. With biologicals, which range in molecular weight between 5,000 and 900,000 (from insulin to IgM, respectively), the situation is rather different.
A monoclonal antibody of the IgG class consists of 1,200 or more amino acids and two sugar chains. At present, our analytical toolbox does not allow us to identify small changes in such huge molecular structures.
The traditional animal- or cell-based assays similarly lack the sensitivity and reproducibility to do this. What this means is that assurance of product quality of a biological requires full control over the production process: the quality is in the process.
It is not only production process in the fermentors that should be totally validated, but the downstream process of isolation, formulation, filling and finishing must also be.
A dramatic example of the critical importance of how a change in formulation may impact on the performance of a biological is the sudden occurrence of pure red cell aplasia after reformulating an erythropoietin product.
Thus, on the one hand there is the drive to develop generic versions of first-generation biologicals, but on the other hand it is clear that the well-established rules for granting market authorisation to small molecules are not applicable. For small molecules, the generic version of the innovator’s product must be pharmaceutically equivalent and bioequivalent.
The EMEA, recognising this problem, embarked on developing new guidelines for admitting generic versions of biologicals to the market. This required a new term for rDNA-derived generic therapeutics. The term “biosimilars” was coined.
A number of guidelines are now available pointing out the general policy of the EMEA regarding the admittance of biosimilars. There is also a set of guidance documents for four specific biologicals (insulin, human growth hormone, G-CSF and erythropoietin; see Resources).
Two biosimilar products have passed the EMEA’s marketing approval route: Omnitrope® and Valtropin®, both biosimilar versions of hGH. More biosimilar therapeutic proteins are expected to follow. The question is how the pharmaceutical professional will respond to this new challenge. What should the pharmacist use – the innovator’s product or the biosimilar? And on what grounds should he or she do this? In 2005 a checklist to assist with this decision-making process was made available on a CD (see Resources). This list is currently being updated and improved on the basis of the issuance of EMEA guidelines on biosimilars as well as experience gained. The EMEA takes the position that substitution is a national-level competence and recently a law was passed in France banning the automatic substitution of one biological medicine for another.
In conclusion, pharmaceutical proteins (rDNA-derived) form a special class within our pharmaceutical arsenal.
A special regulatory protocol is used to allow the generic version to enter the market. The EMEA has developed the concept and the operational tools to deal with biosimilars.
Now that the first biosimilars have passed the EMEA bar, the profession has to find out how to handle the issue of biosimilars.
What is needed is a solid training programme to teach the pharmaceutical professional how to deal with therapeutic proteins in general and advise the medical professional in cases where a choice has to be made between an originator’s product and the biosimilar version.
This means that a (Europe-wide) training programme for (hospital) pharmacists is highly desired, and immediate action needs to be taken to set up such a programme.
Crommelin DJA, Sindelar, RD. Pharmaceutical biotechnology London: Informa; 2002.
Crommelin DJA, Storm G, Verrijk R, et al. Shifting paradigms: biopharmaceuticals versus low molecular weight drugs. Int J Pharm 2003;266;1-2:3-16.