Survey
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
Update Biopharmaceuticals COUNTERFEIT PROTEIN DRUGS: HOW TO DISCOVER AND HOW TO PREVENT? Frank M Jung, PhD In developed countries, counterfeit protein drugs are mainly observed in illegal markets. However, counterfeits have made their way onto the shelves of hospital and community pharmacies. This article gives an overview of prominent cases and some advice on strategies for discovery and prevention. Introduction inhibitors (like Viagra (sildenafil)) and fake as the following examples will According to the WHO, a counterfeit medicines for weight loss have traditional- show. medicine is “a medicine, which is delib- ly been the main targets for counterfeiting. erately and fraudulently mislabelled Because these types of medicines are often Counterfeit and substandard with respect to identity and/or source”. not covered by reimbursement in public somatropin formulations in the Although exact numbers are not avail- healthcare systems, patients are tempted to illegal market able, it is reasonable to estimate that the look for prescription-free, cheap buys In addition to their legitimate use in their prevalence of counterfeit mediapproved indication fields, some cines ranges from far less than Figure 1: The photograph shows an example of a protein drugs such as somatropin 1% of sales in developed councounterfeit protein drug found in the and epoietin are illegally used for tries, to over 10% in developing illegal market doping purposes, resulting in a countries [1]. high demand for these products on the black market. Somatropin Counterfeit and substandard drugs is also used off-label as a have long been recognised as lifestyle-drug against aging and being mainly a problem of develobesity. Outside of the regular oping countries with weak strucsupply chain, preparations of tures of drug regulatory systems doubtful origin with substantial and market control. However, lack of quality are frequently during the last decade it has offered on the black market. In the become evident that industrialised last few years counterfeited, concountries are also affected by the taminated and low quality somatproblem, mainly in illegal market ropin has been found, both in the Corpormon is a regularly licensed drug in Japan, a counterfeit scenarios, but also in the tightly European Union and in the United found on the German black market which contained pregnancy controlled legal supply chain. States. Laboratory analysis of hormone (HCG) instead of the declared recombinant human seized products performed by growth hormone. FDA counterfeit drug investigaOfficial Medicines Control tions have increased to over 20 per year Laboratories (OMCLs) demonstrated that since 2000, after averaging only five per from often illegitimate sources, leading to instead of the expected recombinant human growth hormone some counterfeit year through the late 1990’s [2]. Recent a demand on the illegal market. products contained the pregnancy horcases of batch recalls in the UK have shown that the legitimate supply chain in In spite of more complex production mone HCG, growth hormone extracted European countries is also vulnerable to technologies, the inherently high price from human pituitary glands, immunocounterfeits [3]. A detailed survey on the of protein drugs offers the chance of genic somatropin variants or somatropin situation in Europe has recently been high profits and thus makes them attrac- from other species [5, 6]. Looking at the provided by the Council of Europe [4]. tive targets for counterfeiters. Criminals more than 50 proven cases of the transhave become increasingly sophisticated mission of the deadly Creutzfeldt-JakobProtein drugs – an attractive in their ability to fake and package more Disease by contaminated growth hormone target for counterfeiters complex injectable dosage forms such as preparations in the beginning of the Due to their relatively simple production lyophylisates. While the authentic pro- 1980's, people must be urgently warned technology, solid dosage forms of so tein drug products are often very diffi- not to use such substandard products from called “lifestyle” drugs, such as PDE5- cult to make, they are not so difficult to the illegal markets [7-10]. • Volume 13 • 2007/3 EJHP is the Official Journal of the European Association of Hospital Pharmacists (EAHP) www.ejhp.eu 61 Update Counterfeit protein drugs in the legitimate supply chain During the last decade, several cases have emerged in the US where counterfeit protein drugs have made their way onto the shelves of hospital or community pharmacies and into patients. This has led to several batch recalls. Health warnings have been issued by the FDA and manufacturers of the affected authentic products. Examples of protein drugs and their active pharmaceutical ingredient (APIs) affected by counterfeiting are Procrit [11] (epoietin alpha), Epogen [12] (epoietin alpha), Serostim [13] (somatropin), Nutropin [14] (somatropin) and Neupogen [15] (filgrastim). The counterfeit products contained either no active pharmaceutical ingredient, less than the declared amount of API, APIs other than those declared (e.g. steroids or insulin instead of somatropin) and in some cases were contaminated with bacteria and endotoxins. All counterfeit products led to serious health risks for patients. Most of the counterfeit products slipped into the regular supply chain by unscrupulous or careless secondary wholesalers who, willingly or unwillingly, bought from criminal sources. How to discover? As the printing and manufacturing capabilities of counterfeiters have become more sophisticated, counterfeit protein drugs are becoming increasingly difficult to discover. In the past, labelling of counterfeits sometimes showed slightly different font types and different print quality than the authentic product. Thus it was possible to distinguish the counterfeit from the authentic product by visual comparison of primary and/or secondary packaging [13-15]. However, past cases have also shown that subtle differences in packaging or printing which could provide a hint to counterfeited products are often not noticed by end users or distributors. In addition, some counterfeits are so good that simple visual comparison will not be sufficient to distinguish them from the authentic product. As pharmaceutical manufacturers have gradually introduced new overt and hidden security marks in their packaging design, there are now 62 • Volume 13 • 2007/3 additional ways to identify counterfeits by analysis of the packaging. In the future new track and trace and authentication technologies using 2D-matrix-codes and/or radio frequency identification devices may provide further options. In addition, an extensive physicochemical and biochemical analysis of the finished [ by some fairly simple means [18]. Medicines should only be bought from qualified suppliers with appropriate wholesaler licences. Don’t buy from suspicious sources! If a product is offered at an unusually cheap price, treat with extra caution. Look for signs of a removed or switched product label. Look for altered expiry dates. Look for subtle changes in All counterfeit products led to serious health risks for patients. Don’t buy from suspicious sources! dosage form, covering parameters like identity, content and purity of the API, composition of excipients and microbiological quality is usually required to characterise and to evaluate a suspect counterfeit in terms of health risks. Due to the complexity of therapeutic proteins usually a combination of sophisticated protein analytical technologies has to be used for analysis. In cases of a lack of therapeutic effects or unexplainable adverse reactions the hospital pharmacist should consider the possibility of a counterfeit drug being the root cause and seek further evidence. The competent authorities [16] should be contacted using established rapid alert pathways for product defects. It is also advisable to secure sufficient material for subsequent laboratory testing. Competent authorities can then initiate independent testing of suspect counterfeits to be performed by Official Medicines Control Laboratories [17]. In addition to the investigation of suspect samples, risk based, routine market surveillance testing performed by OMCLs in the European countries provides an independent means of identifying substandard or counterfeit protein drugs. In many countries OMCL sampling procedures have now been optimised to cover the complete supply chain of pharmaceuticals in a risk based approach. ] the product’s package (compare with previously purchased products). Look for variations in the size of the container. Pharmaceutical companies, industry organisations, the European Commission, EU Heads of Medicines Agencies Working Groups, the Council of Europe and WHO, as well as the national authorities of the European Countries and other stakeholders are currently undertaking massive efforts in developing and improving anti-counterfeit strategies. Conclusion In the industrialised European countries counterfeit drugs in the legitimate supply chain have been extremely rare. However, recent events have shown that the threat is real and that even tightly regulated pharmaceutical supply chains are not impenetrable. Hospital pharmacists can best contribute to discover and combat counterfeits by keeping a high level of awareness of the problem and by notifying suspect cases to the competent authorities. Author Frank M Jung, PhD Institute of Public Health NRW Official Medicines Control Laboratory 36 Von-Stauffenberg-Str D-48151 Münster, Germany [email protected] How to prevent? References The risk of counterfeit medicines entering the legitimate supply chain can be reduced 1. WHO: IMPACT: The new estimates on the prevalence of counterfeit medicines. 15.11.2006. www.ejhp.eu Biopharmaceuticals http://www.who.int/medicines/services/counterfeit/impact/TheNewEstimatesCounterfeit.pdf 2. US FDA: Combating counterfeit drugs. A Report of the Food and Drug Administration. February 2004. http://www.fda.gov/oc/initiatives/counterfeit/report02_04.html#purpose 3. UK MHRA: Press release - Recall of counterfeit Lipitor®. 19.07.2006. http://www.mhra. gov.uk/home/idcplg?IdcService=SS_GET_PA GE&useSecondary=true&ssDocName=CON2 024151&ssTargetNodeId=389 4. Harper J. Counterfeit medicines survey report, Council of Europe. Strasbourg: Council of Europe Publishing, 2006. 5. Jung F, Scherges M und Fürst P, Illegale und gefälschte Wachstumshormonpräparate. Deutsche Apotheker Zeitung 2003;142:550413. 6. Charton A et al. A somatropin counterfeit challenging the European Pharmacopeia monogra- • Volume 13 • 2007/3 ph. Pharm Pharmacol Commun 1999;5:61-6. 7. Brown P, Preece MA and Will RG. “Friendly fire” in medicine: hormones, homografts, and Creutzfeldt-Jakob disease. Lancet 1992; 340:24-7. 8. Billette de Villemeur T et al. Creutzfeldt-Jakob disease from contaminated growth hormone extracts in France. Neurology 1996;47: 690-5. 9. Huillard d’Aignaux J et al. Incubation period of Creutzfeldt- Jakob disease in human growth hormone recipients in France. Neurology 1999;53:1197-201. 10. Brown P et al. Iatrogenic Creutzfeldt-Jakob disease at the millennium. Neurology 2001;55:1075-81. 11. FDA notifications. FDA uncovers counterfeit Procrit (epoetin alfa). AIDS Alert. 2003 Jun;18(6):79-80. Medline PMID: 12866479 12. FDA warns about counterfeit Epogen. AIDS Alert. 2002 Aug;17(8):102-3. Medline PMID: 12647693 13. FDA notifications. Watch for counterfeit lot of Serostim. AIDS Alert. 2002 Aug;17(8):102. Medline PMID: 12647692 14. Genentech: Important counterfeit drug warning: Counterfeiting of Nutropin AQ® 2001 May 22. http://www.gene.com/gene/products/information/opportunistic/nutropinaq/update.jsp 15. Danger: counterfeit Neupogen (filgrastim). AIDS Treat News. 2001 May 25;(365):5. Medline PMID: 11547413 16. EMEA: Links to regulatory bodies in Europe. http://www.emea.europa.eu/Inspections/Links .html 17. EDQM: OMCL network general activities. http://www.edqm.eu/site/page_612.php 18. MHRA and RPSGB: Counterfeit medicines. Guidance for Pharmacists.http://www.rpsgb. org.uk/pdfs/counterfeitmedsguid.pdf EJHP is the Official Journal of the European Association of Hospital Pharmacists (EAHP) www.ejhp.eu 62-1