Counterfeiting
Our coverage of the British Pharmaceutical Conference
in Harrogate resumes with details of efforts to reduce the amount of
counterfeit medicines
circulating around the world, described at a session on 16 September.
Christine Clark reports Counterfeiting abroad and at home
Dora Akunyili: the evil of fake medicines is worse than malaria,
AIDS and armed robbery |
In some parts of the world,
organised crime has shifted from smuggling of narcotics and weapons to
counterfeiting of medicines — a lucrative
but relatively low risk activity — according to Dr Dora Akunyili,
chief executive of the Nigerian National Agency for Food and Drug Administration
and Control (NAFDAC). Pharmaceuticals worth millions of dollars, including
counterfeit, expired, repackaged and relabelled products are often shipped
through unauthorised channels, she explained.
Counterfeiting of medicines is a global problem (although it is not a
huge problem in the United Kingdom, see p454), however, there is no common
definition that captures all aspects of the problem. The World Health
Organization definition is: “A counterfeit medicine is one which
is deliberately and fraudulently mislabelled with respect to identity
or source. Counterfeiting can apply to both branded and generic products
and counterfeit products may include products with the correct ingredients
or with the wrong ingredients, without active ingredients, with insufficient
ingredients or with fake packaging.”
Categories of counterfeits
NAFDAC has identified a number of categories of counterfeit drugs. These
include:
• Medicines with the same quantity of active ingredient as the genuine
brand. These are commonly described as “clones” and usually
hide behind fast-moving products to make rapid profits without any of
the liabilities of the genuine manufacturer
• Medicines with insufficient or no active ingredients
• Medicines with active ingredients different from what is stated on
the package, for example, paracetamol tablets packaged and labelled as
Fansidar, a sulphadoxine/pyrimethamine combination preparation
• Expired medicines, or medicines whose expiry date is imminent relabelled
to extend the shelf-life
• Herbal preparations that are toxic, harmful, ineffective or mixed with
orthodox medicines
• Medicines that do not bear the name and address of the manufacturer
• Medicines not certified and registered by NAFDAC
Of these, the second and third groups are the most dangerous but medicines
in the first group are unlikely to produce the desired therapeutic effects
because the formulations — and therefore bioavailability of the
active ingredients — are unlikely to be the same as those of the
original products.
Dr Akunyili said that factors that contribute to medicine counterfeiting
are their high value in relation to their bulk and that demand for them
is endless. Worldwide, corruption and conflicts of interest result in
weak regulation and lack of enforcement. When she took up her appointment
at NAFDAC she found many instances of corrupt practices in the medicines
supply chain and even within the agency itself. A series of new laws
and regulations has been put in place and opportunities for corruption
reduced.
Other important factors are the chaotic drug distribution system in many
developing countries, false declarations by importers and an insecure
environment. Dr Akunyili had experienced threats against her life, vandalism
of the agency’s offices and deposition of fetish objects in her
office. In August 2001, six armed men invaded her residence, but she
was not at home. Lack of co-operation between Government agencies also
hampered the work of NAFDAC.
For export only
Discriminatory regulation and control of medicines intended for export
as opposed to use in the country of manufacture have compromised the
quality of medicines moving in international commerce, said Dr Akunyili.
Often, medicines labelled “For export only” are not subject
to the same strict regulation as those for internal use, she added.
A case in point was some poorly packaged paracetamol tablets labelled, “Not
for use in South East Asia”, which were obviously fake. Poor
regulation of exports from manufacturing countries exposes countries
with weak or non-existent regulation to dumping of fake pharmaceuticals.
As a result of these findings NAFDAC has now prohibited importation
into Nigeria of products marked “For export only”.
Other contributory factors included ignorance and poor public awareness
about counterfeit medicines, illegal and deceitful advertisements and
indifference by governments.
The evil of fake medicines is worse than the combined scourges of malaria,
HIV/AIDS and armed robbery, claimed Dr Akunyili. Their use has led to
treatment failures and deaths, has eroded public confidence in the health
care system and has destroyed local industries.
Counterfeiting of medicines was first mentioned at the international
level at a WHO Conference of Experts on the Rational Use of Drugs held
in Nairobi, Kenya, in 1985.
WHO has been collating information about counterfeiting activities since
1984. Between 1984 and 1999, 771 reports of counterfeit drugs were received
and added to the WHO database. The majority (78 per cent) of these reports
came from developing countries. In recent years the trend has shifted
somewhat; from January 1999 to October 2000, 46 confidential reports
of counterfeit drugs were received from 20 countries — 60 per cent
from developing countries and 40 per cent from developed countries. Most
of these reports are not independently verified and only a few countries
are willing to provide information about cases detected. This silence
is one of the driving forces for counterfeiting, said Dr Akunyili.
A recent report from Russia showed that 12 per cent of medicines in circulation
were counterfeit products and it was as high as 40 per cent in the Ukraine.
Reports indicate that much manufacture and distribution of counterfeit
medicines is masterminded from Asia. It is believed that in some extreme
cases, companies may be producing legitimate goods at one end of the
factory and counterfeits at the other, said Dr Akunyili.
A recent WHO report suggested that India is responsible for about 35
per cent of the world’s counterfeit medicines and that this illicit
business is worth about $200m. Many governments refuse to acknowledge
the counterfeiting problems for fear that patients will be put at risk
if fear of fakes prevents them from taking the real product. In Africa,
a variety of factors, including weak regulatory authorities, political
instability and low levels of literacy, make it difficult to estimate
the true prevalence of fake medicines.
In 2000, the Essential Drug Monitor report noted: “Drug quality
was questionable and pharmacy premises were often unsuitable, hot, humid
and cluttered with piles of drugs, some of them expired. Pharmacists
had low professional visibility.” A study published in 2001 showed
that 54 per cent of medicines in each major pharmacy shop in 1990 were
fakes and this figure rose to 80 per cent in 1991.
The impact of counterfeit medicines in Nigeria is hard to estimate because
of poor reporting systems and the fact that deaths or worsening illness
are often attributed to witchcraft. In one case counterfeit adrenaline
was reported to have contributed to the deaths of two children undergoing
heart surgery at a hospital in Enugu. Investigations by NAFDAC revealed
that the muscle relaxant used was substandard and an infusion solution
was not sterile. Both products had been purchased from unregistered pharmacies
staffed by non-professionals. The adrenaline had been supplied by a registered
pharmacist but from an open drug market.
A variety of anticounterfeiting measures have been put into place by
pharmaceutical manufacturers, for example, the use of holograms and other
devices on the packaging. In Nigeria, NAFDAC, which had in the past relied
on prosecutions to deter counterfeiters, embarked on a public awareness
campaign. Essay competitions are held for secondary school students and
bimonthly newspaper articles describe the differences between available
fakes and real medicines.
Other NAFDAC initiatives have included consultative meetings with stakeholders,
and advertising on radio, television and billboards. Dr Akunyili believes
that resulting changes in public attitudes to counterfeit medicines were
a major factor in bringing the largest fake drug importer in Nigeria
to justice.
The agency has also increased seizures of counterfeit medicines at ports
of entry and has taken steps to mop up the counterfeit products in circulation.
Such has been their success that some other West African countries have
now lifted their bans on the importation of medicines bearing the label “Made
in Nigeria”.
Working against counterfeits in the United Kingdom
Ged Lee: clones are a problem |
The majority of counterfeit medicines found in the UK have been in
the illegal supply chain. The last example of a counterfeit product entering
the legal supply chain was counterfeit Zantac (ranitidine) approximately
20 years ago, Dr Ged Lee, group manager for laboratories and licensing,
Medicines and Healthcare products Regulatory Agency (MHRA), said.
Most of the work undertaken by the MHRA testing programme relates to
product surveillance — in 2002–03 this accounted for 1,714
items. A further 371 items were related to enforcement issues. The remainder
were demand-led samples. Enforcement samples are usually received from
the agency’s own officers and customs officers who collect them
from public houses, clubs and gymnasia. Viagra clones
The most frequently observed product is Viagra (sildenafil). Examples
found include a product labelled sildenafil that contained caffeine,
and tablets that looked like Viagra but which turned out to be crushed “clones” that
had been bulked out with lactose and recompressed to form tablets containing
about 30mg of sildenafil.
Some counterfeit products are difficult to identify as such from visual
examination; in one sample of counterfeit Viagra the only visible difference
was a minor change in the angle of slope of the letter “f” in
the name Pfizer. Analysis to standard specifications may not identify
such products as counterfeit, Dr Lee said.
A further problem arises with “cloned” products. India and
China do not recognise European patent laws and therefore legally manufacture
products that are illegal in the UK. For example, products under the
brand names Penagra, Kamagra, Powergra and Mount have been seen, each
containing sildenafil. The difficulty is that they are licensed products
in the country of origin and can be legally imported into the UK for
personal use but not traded here. Sometimes counterfeiters make obvious
mistakes, for example, another sample of counterfeit Viagra had been
packed in a screw-cap container, like the US product whereas the UK product
is strip-packaged.
Analysis
When it is difficult to identify a counterfeit product by visual inspection,
new analytical methods may be needed. This is particularly important
if a prosecution is anticipated. Infrared spectrographic analysis (attenuated
total reflectance spectra) show excipients as well as active ingredient.
They are useful for screening because they can be used to show differences
between genuine and counterfeit products although they cannot identify
the different constituents. More information can be gained by looking
at related substances using high-performance liquid chromatography
(HPLC) to examine extracts of products. Different manufacturing processes
lead to different impurity profiles and these are clearly visible in
HPLC spectra.
“The fingerprints of related substances are useful indicators of
the possibility that a product has been illegally manufactured,” said
Dr Lee. Residual solvents, which may become trapped in the crystal lattice
of the substance
during the manufacturing process, can also be useful indicators, because
counterfeit products may have been manufactured using different solvents.
These can be clearly distinguished by spectrographic analysis.
A much more powerful technique is near-infrared (NIR) spectroscopy. It
is a non-destructive technique that allows examination of the whole formulation
and not just the active ingredient. As a result, the spectrum gives much
more information about the manufacturing source than other methods. It
can provide both qualitative and quantitative data: “It fingerprints
the whole matrix.”
Overlaid NIR spectra of genuine products from different manufacturing
sites show almost complete overlap. Minor differences occur and more
detailed analytical techniques permit identification of genuine products
manufactured in different sites. When the NIR spectrum of a counterfeit
product is overlaid, it can be seen to diverge markedly in several places.
Bodybuilding counterfeits
One example of a counterfeit product found in the UK was a multidose
presentation of Nubain (nalbuphine). This anaesthetic is used illegally
by some bodybuilders to enable them to train for longer periods without
pain. This immediately aroused suspicion because the multidose presentation
of Nubain is not licensed in the UK; moreover, the genuine material
is packed in amber glass whereas the suspect product was packed in
clear glass. Dr Lee doubted that it would have been sterilised although
it was intended for use by several people.
Counterfeit steroid injections have also been found in the bodybuilding
world. Two recent samples of counterfeit steroid injections, originally
produced for animal use, had been found to contain no active substances
at all.
An International Laboratory Forum on Counterfeit Medicines has been formed
in an effort to combat global counterfeiting operations. This is an alliance
for collaboration and exchange of information on analysis and surveillance
of illegal medicines including counterfeit products. |
