Shifting paradigms: biopharmaceuticals versus low molecular weight drugs
Introduction
Biopharmaceuticals are defined as ‘pharmaceutical products consisting of (glyco)proteins and/or nucleic acids’ (Schellekens, 2002). In this contribution the term only applies to (glyco)protein products used for therapeutic purposes and vaccines. Biopharmaceuticals still make up only a small part of the total arsenal of medicines that is used by mankind. But, the growth of this category of medicines is much faster than the introduction and growth of ‘conventional’, low molecular weight medicines. Recent statistics show that the FDA approved 130 biotechnology derived protein medicines and vaccines (Biotechnology Industry Organization Site, 2002), 70% of which were approved in the last 6 years. Currently, over 350 biopharmaceuticals are in clinical trials.
These biopharmaceuticals deserve specific attention by pharmaceutical scientists as they have a number of characteristics that set them aside from low molecular weight drugs. These specific characteristics center around a number of issues listed in Table 1. The issues on this list will be discussed in more detail below.
Section snippets
Molecular characteristics
Biopharmaceuticals are (glyco)proteins. The building blocks for these molecules are l-amino acids and different sugar molecules. They form three-dimensional structures based on secondary structures (alfa-helices, beta-sheets and random coil areas), tertiary structures (folding of the secondary structures into complicated three-dimensional structures) and in some cases quaternary structures (where different monomers interact). Such special structures do not exist in low molecular weight drug
Life threatening and serious diseases
Table 4 shows a list of biopharmaceuticals marketed in the USA in early 2002 (Evens and Sindelar (2002)). When considering the therapeutic indications, it is clear that these biopharmaceuticals were introduced to treat severe and/or life threatening diseases. The list includes monoclonal antibodies for immune modulation and treatment of cancer; biological response modifiers to stimulate cell growth; hormones such as insulin and hGH; enzymes such as alteplase to remove blood clots; and last but
Formulation
Proper protein formulation development is crucial for the optimal therapeutic performance of biopharmaceuticals. As mentioned above, immunogenicity is in some way related to the presence of aggregates and contaminants. As all systemically active proteins are administered parenterally, sterility and non-pyrogenicity are standard requirements for these products. Removal of viruses and other contaminants should be an integral part of the downstream process (Crommelin, 2002). To reach the desired
Handling
During manufacturing and transport to the (hospital) pharmacy the manufacturers should take care of ‘Good Transport Practices’. That means that cold chain conditions should be maintained, if so dictated. The receiving pharmacist should do his/her utmost to ensure that these delicate, often expensive, biopharmaceuticals are stored and used as stipulated at the ward by medical staff, or at the patient’s home by the patient him/herself. There is a general lack of awareness with regard to the
Generics: the possibility to launch biogenerics(?)
In the production of biopharmaceuticals, seemingly minor changes in production conditions may lead to subtle changes in molecular structure of the protein. Folding might be different, or glycosylation patterns might change. For relatively small proteins such as insulin, equivalence might be established using a set of assays from our ‘analytical toolbox’ (Table 3): this is the category of the ‘well characterized biopharmaceutical’. But, for larger proteins, it is almost impossible to guarantee
Conclusions
Biopharmaceuticals are very different from low molecular weight drugs. The complicated protein production processes and structures ask for a paradigm shift in thinking compared to low molecular weight drugs. No absolute description of drug and drug product is possible with these materials. Our analytical toolbox content and bioassays, including animal testing, are important in ensuring drug quality, efficacy and safety issues in the development phase. But, the biopharmaceuticals rely critically
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