The Pharmaceutical Journal
Vol 277 (Supplement) F32-33
October 2006

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FIP Congress 2006

What are biotechnological medicines and how are they delivered and used?

Pharmaceutical biotechnology is an exciting and expanding area within pharmacy as a consequence of recent advances in molecular therapies and a series of novel drugs and formulations being developed and becoming available on the market.

In addition, the fact that biogenerics or biosimilars are becoming more widely available as patents for existing biotech products expire opens up new opportunities for treating patients with drugs that, until now, were beyond the reach of all but the most affluent populations.

It is imperative, therefore, that pharmacists familiarise themselves with this new technology and become aware of the benefits and pitfalls (especially regarding storage, handling and manufacture) of biotech products.

Beginning the presentations, Antonio Moreira, of the University of Maryland, US, asked: “What are biotechnological drugs? How are they different from other drugs?” He began by comparing conventional pharmaceutical drugs with biotech products.

He said that most conventional drugs, eg, ibuprofen and naproxen, are synthetic, organic compounds that have a defined structure and physicochemical characteristics, are invariably easy to handle, can be formulated in various dosage forms and are stable.

In contrast, biotechnological drugs are protein- or carbohydrate-based products that are extracted from living organisms (in cell culture or via fermentation) and are large, macromolecules (>500kDa; for example, erythropoietin is approximately 160 times larger than aspirin) with complex physicochemical structures.

Biotech products also are extremely heat- and shear-sensitive and can be irreparably damaged by friction (eg, in a syringe) and during manufacture as a consequence of problems associated with pumping, mixing and transportation of large volumes of such agents. Such characteristics are vitally important for pharmacists to appreciate because small changes in pH, temperature or salt concentration can permanently damage the structure and function of these drugs, said Dr Moreira.

Other differences between conventional and biotech-derived drugs are that the former can be manufactured almost anywhere, to the same standard and in any desired amount. In addition sterile facilities are rarely required for their manufacture. The reverse is true for biotech products.

Although most biotech products are developed to treat a number of diseases where no known conventional cure is available, they are more likely than small conventional drug molecules to trigger immune reactions. They are associated with contamination problems, eg, prions and nucleic acids. Also, they suffer from deamidation and oxidation, and scale up can prove difficult, leading to poor yield and poor product quality.

Development and production costs associated with biotech drugs are high compared with those associated with conventional medicines (where development costs are also high but production costs are comparatively low). Drug interactions with biotech drugs are rare, and they are essentially non-carcinogenic. Furthermore, a 25 per cent success rate is seen with biotech drugs that reach phase I–III trials compared with a meagre 6 per cent of conventional drugs that make it through these stages, said Dr Moreira.

The potential returns for biotech companies and investors in biotech products are lucrative and the market continues to grow. For example, in 2004, the revenue generated by the top two biotech drugs, Epogen and Aranesp — both manufactured by Amgen for the treatment of anaemia — was $2.601m and $2.473m, respectively.

Indeed, drugs in this class achieved up to a 60 per cent increase in revenues from 2003 to 2004. By 2006, approximately 600 potential new biotech drugs were either in phase I–III trials or have been filed with the US Food and Drug Administration, illustrating the importance of this emerging market for the treatment of human disease.

The final area that Dr Moreira covered was the emerging area of biogenerics (also referred to as “biosimilars” and “follow-ons”). A biogeneric product is defined as a new protein product that is pharmaceutically and therapeutically equivalent to the original (patented) product. A number of companies are considering developing biogeneric drugs since the potential returns, as discussed above, are high.

The FDA argues that it is difficult to create a copy of a biotech product due to the fact that they are complex biological structures and that quality issues are extremely difficult to control for between different manufacturing processes. So most companies find biogenerics too complicated to copy and those that have tried often have approval turned down as a consequence of having insufficient clinical trials data to back up the effectiveness of their product.

One of the problems in the US is that no regulatory system exists to approve generic versions of biotech drugs although other countries are making some progress towards the first generation of biogenerics. For example, Teva Pharmaceuticals in Israel and Pliva in Croatia are developing a range of biogenerics. On 30 May 2006, the FDA gave Sandoz approval to manufacture and distribute Omnitrope (somatropin) as a human growth hormone replacement.

The FDA claims that Omnitrope is not therapeutically equivalent to any other approved human growth hormone product and instead refers to it as a “follow-on protein product”. Others in the field do not agree with the FDA terminology and see the approval of Omnitrope as the first step in opening the market for approval of many other biogeneric drugs.

Product delivery

Daan Crommelin, of the Utrecht Institute for Pharmaceutical Sciences, the Netherlands, spoke on the delivery of therapeutic biotech products.

He discussed the problems associated with the formulation and delivery of biotech products that are large, unstable molecules whose structure is held together by weak, non-covalent forces leading to them becoming easily destroyed if they are not handled appropriately.

Impurities in the “same” biotech product produced by different manufacturers suggest major problems with quality control. For example, electrophoretic analysis has shown that nine out of 11 erythropoeitin products on the market have different isoform distributions.

Professor Crommelin then considered whether there were alternatives to delivery of biotech products by injection. He emphasised the need to move away from the parenteral route of administration if at all possible but described studies where oral, rectal, nasal, transdermal and buccal routes of administration had all been tried but had failed to demonstrate effective delivery. One route of delivery that might hold promise is the pulmonary route.

Indeed, Exubera (inhaled insulin) has been available since January 2006 although bioavailability has been shown to be as low as 10 per cent of delivered drug into the lungs (the rest is lost in the delivery device itself or in non-lung tissue). Despite the low bioavailability, the drug is being delivered to the lungs of diabetic patients in sufficient concentrations to manage the disease.

One of the major considerations that must be taken into account by anyone who handles biotech products, including pharmacists, is their unstable nature. Such products must never be shaken but instead should be gently swirled or stirred.

Guidelines are available for hospital pharmacists for the safe storage and handling of biopharmaceuticals in hospitals. Stability of biotech products can be improved significantly during formulation by chemical modification, eg, by PEGylation, which masks uptake receptor sites (“stealth technology”), decreases glomerular filtration rates (by increasing the size of molecules) and, in most cases, decreases immunogenicity.

Two PEGylated biotech products are available on the market, namely, PEG-interferon-alfa and PEG-GCSF. In both cases, PEGylation improves stability and extends the half-life of the product, eg, PEG-GCSF is administered once weekly compared with once daily for the non-PEGylated product.

Microspheres also are used to improve stability of biotech products. For example, PLGA — poly(lactide-co-glycolide) — microspheres are commonly used to improve stability of peptides and a dextran-based hydrogel incorporating human growth hormone (hGH) in the form of microspheres displays a better pharmacokinetic profile than the equivalent PLGA-hGH microsphere product.

Genetically modified organisms: the future for plant derived pharmaceuticals appears bright

Leila Oda, president of the National Biosafety Association, Brazil, described how genetically modified organisms (GMOs) are being used as a source of biotech drugs. She highlighted advances that have been made with GMO products, including in the area of nutraceuticals, where genetically modified crops lead to increased yield and decreased cost of production.

Indeed, this form of “molecular farming” has produced crops that can survive with little water and that have a decreased reliance on pesticides.

In terms of human health, GMOs are used to produce large quantities of a number of medicinal products including vitamins, antibiotics, hormones, insulin and enzymes. As an example, it is estimated that 105 tonnes of antibiotics are used worldwide per annum which equates to an annual market of around $5bn, said Dr Oda. Antibiotics are used in animal feed to promote healthy growth in addition for treating human infections. GMOs are used to increase the yield of antibiotic production.

Molecular farming has been proposed as being the future for the pharmaceutical industry. In 1998, the first clinical trial in humans was initiated to investigate the safety and effectiveness of using vaccines against Escherichia coli that were produced in plants. The use of such “plantigens” has now advanced to produce second-generation vaccines that are edible.

These edible vaccines are produced from plants that have been genetically modified in such a way that two or three different vaccines can be produced from the same plant at the same time. Examples of edible vaccines include one produced in bananas for the treatment for diarrhoea and another in potatoes for the treatment of cholera and rotavirus.

There is also the possibility of producing antibodies in plants (“plantibodies”), eg, antibodies against Streptococcus mutans are being produced in modified tobacco plants. The purified antibodies are then applied to the teeth as a prevention for tooth decay.

One potential problem that needs to be considered when using plants for the production of genetically modified materials is gene flow, whereby the transformed genetic material from a genetically modified plant is transferred into the wild population. This problem can be avoided by using chloroplasts to undertake genetically modified work in place of seeds or cultivated plants, said Dr Oda.

Despite the potential problem with this technology, the availability of genetically modified plant-derived pharmaceuticals is growing. In 2006, there were a number of clinical trials in humans using such materials. For example:

• A gastric lipase produced from maize is being evaluated in a phase II trial for the treatment of cystic fibrosis

• The Streptococcus mutans antibody for tooth decay is in phase II/III

• A drug for the treatment of traveller’s diarrhoea from maize is in phase I

• A hepatitis B vaccine from potato is now in phase I

Furthermore, in February 2006 the US Food and Drug Administration approved a new vaccine for the treatment of Newcastle disease in poultry from non-nicotine plant cells.

The future of plant-derived pharmaceuticals appears bright and the fact that some drugs that are not available in sufficient quantities from other sources can be produced from plants in high yield suggest that this will become a major route for drug production. For example, insulin currently is being produced in safflower (Carthamus tinctorius) in high yield and at low cost in comparison with conventional routes.

However, as is the case with all biotech products, caution must be exercised by governments and the biotechnological/pharmaceutical industry to ensure that strict regulation and quality control are adhered to in order to maintain safety for patients, Dr Oda concluded.