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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
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