Falsification of biotechnology drugs: current dangers and/or future disasters?

Falsified medical products have become a global threat since they were first mentioned to the general public at the conference of experts on the rational use of drugs organized by the world health organization (WHO) in 1985. Today, official estimates of the annual death toll due to falsified medical products range between two hundred thousand and one million. Although the extent of this global problem is the most significant in the developing world, an increasing number of reports have demonstrated the presence of a substantial (black) market for falsified medical products in the developed world. In recent years, also biotechnology drugs (synthetic peptide drugs and protein drugs) have been reported to be prone for falsifications. Next to the traditional doping related substances and image-enhancing polypeptides (e.g., human growth hormone, melanotan II) also essential medicines such as insulin, oxytocin and monoclonal antibodies have been falsified. The danger regarding the use of these falsified polypeptide drugs lies in the fact that end-users have no guarantee of the safety and efficacy of these preparations. Multiple reports have namely described the presence of the wrong active pharmaceutical ingredient (API), the wrong dosage or the absence of the API. Additionally, adverse health effects have been reported in the past due to toxic contaminations and product or process related impurities. Moreover, also unauthorized polypeptides or polypeptides which failed clinical trials or are still subject of clinical or pre-clinical assessments have been found in seizures of regulatory agencies. It stands to reason that regulatory agencies and analytical laboratories handling falsified biotechnology drugs have stepped up efforts to counter these grievous practices. The analysis of these falsified polypeptides and putative impurities is however not always straightforward. Often (bio)analytical laboratories have to resort to a combination of electrophoretic techniques, immunological assays and mass spectrometry based approaches to merely identify the content of seized samples. In addition, the difference in size (peptide vs proteins vs monoclonal antibodies), complexity (e.g., isoforms, glycosylations) and different synthesis techniques (chemical synthesis, recombinant expression, native protein isolation) result in a wide range of putative health risks. This review therefore aims to provide a brief overview of the genuine biotherapeutics present on the market and their quality prerequisites. Next, we describe the identification strategy utilised by our lab to identify the API in falsified biotherapeutics, followed by a discussion of the putative hazards due to impurities and contaminations that were found or could be encountered in falsified biotherapeutics. Finally, we terminate with an educational prediction of what may happen in the future and possible ways to counteract putative future disasters.