Borioni, Anna

Gaudiano, Maria Cristina

Mustazza, Carlo

Valvo, Luisa

Annali dell'Istituto Superiore di Sanità

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Ann Ist Super Sanità 2018 | Vol. 54, No. 4: 267-269
DOI: 10.4415/ANN_18_04_01
Editorial
The evolution of the illegal market  
of falsified medicines and the experience 
of the Italian OMCL:  
from control to research 
Carlo Mustazza, Maria Cristina Gaudiano, Anna Borioni and Luisa Valvo
Centro Nazionale per il Controllo e la Valutazione dei Farmaci, Istituto Superiore di Sanità, Rome, Italy
Health risks due to low-quality or falsified drugs are 
a major concern for regulatory pharmaceutical authori-
ties throughout the world.
Falsification of medicines is not limited to develop-
ing Countries, but is a global health problem [1, 2], 
mainly due to the increasing medicines sale through il-
legal markets (including gyms, sexy-shops, ethno-shops 
and illegal Internet pharmacies). To prevent the trade 
of falsified medicinal products through the legal supply 
chain, the EU Authorities developed specific legisla-
tive instruments, in particular the European Directive 
2011/62/UE. The Directive also regulates the market 
of legal medicines through Internet by indicating the 
obligations of legal on-line pharmacies, for instance the 
obligation of exhibiting a “common logo” in each page 
of the web-site devoted to medicines sale [3].
The Community Directive is incorporated into the 
Italian Legislative Decree No. 17, February 19, 2014 
which prohibits the sale at a distance of under-pre-
scription medicinal products. Concurrently, a National 
Anti-Falsification task-force involving the Italian Medi-
cines Agency (AIFA), the Italian National Institute of 
Health (Istituto Superiore di Sanità, ISS), the Ministry 
of Health, the Police Force “Carabinieri NAS”, and the 
Customs and Monopolies Agency was established; the 
National task-force also benefits from the cooperation 
of other involved Ministries and from the support of the 
Italian Patent and Trademark Office of the Ministry of 
Economic Development [4].
In Italy, the first case of falsified medicines from the 
illegal market was analyzed by the Official Medicines 
Control Laboratory (OMCL) of the ISS in 2005. At 
the beginning the seized samples were mainly anabolic 
steroids and medicines for the treatment of erectile 
dysfunctions [5-7] but, successively, the illegal market 
modified its characteristics and evolved into “medicines 
in disguise”, i.e. dietary supplements, cosmetics, medi-
cal devices and other products for health, fraudulently 
added with undeclared pharmaceutical active substanc-
es. In particular, the problem regards dietary supple-
ments adulterated with synthetic drugs which increase 
their physiological effects.  In most cases, adulteration 
regards sexual performance enhancers, body-building 
or athletic performance enhancers, nootropics and 
weight-loss supplements [8, 9]. Among the adulterants 
we found registered pharmaceutical substances but 
also drugs withdrawn from the market (as the anorec-
tic sibutramine in plant food supplements) and even 
new chemicals of unknown toxicity. A very recent re-
view [10] lists 80 new chemicals mimicking approved 
phosphodiesterase-5 inhibitors – PDE5-i (sildenafil, 
vardenafil, tadalafil) detected in illegally marketed sex-
ual performance enhancers. Most of them are chemi-
cal products reported in Patents, but never approved 
for pharmaceutical use, while others are entirely new 
chemical entities; in both cases they show only minor 
differences in respect to an original patented molecule 
(analogues). The use of analogues as adulterants is a 
strategy adopted by many illegal laboratories, as the 
modified structures could deceive some analytical tests 
of the official laboratories of control.
New chemical substances are a great risk for consum-
ers, as physiological effects, side effects and toxicity are 
unpredictable and outcomes can be very serious; cases 
of lethal consequences have even been reported [10].
Tracking new molecules constitutes a major challenge 
for OMCLs, whose activity cannot be limited to the 
identification of known chemicals in the illegal samples 
(usually by means of reference standards or spectral da-
tabases), but must be extended to the identification and 
structural characterization of unexpected chemical en-
tities. In this regard, Mass (MS) and Nuclear Magnetic 
Resonance (NMR) spectrometry are first choice tech-
niques to achieve a task which is not always straight-
forward (e.g. reference [10] mentions an example of 
disagreement between official laboratories about the 
formula of an adulterant). Chemical synthesis of the 
hypothesized compound, with the aim of obtaining a 
Address for correspondence: Carlo Mustazza, Centro Nazionale per il Controllo e la Valutazione dei Farmaci, Istituto Superiore di Sanità, Viale Regina 
Elena 299, 00161 Rome, Italy. E-mail: carlo.mustazza@iss.it.
Carlo Mustazza, Maria Cristina Gaudiano, Anna Borioni and Luisa Valvo
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reference material, can sometimes be decisive for the 
structural elucidation of the adulterant.
In this scenario, it is fundamental to develop research 
activities to deal with the evolving challenges of the il-
legal market. The identification of MS and NMR di-
agnostic spectral features of a family of compounds is 
useful for the characterization of chemical analogues in 
suspicious samples. An example of this activity is the 
reported contribution of the Italian OMCL [11]. 
In short, fifteen analogues of PDE5-i, belonging to 
the sildenafil, acetildenafil and thio-sildenafil families, 
were synthesized and their high-resolution MS/MS and 
NMR spectra were compared. The study allowed to 
identify the fundamental spectral features of the three 
families of compounds. Mass spectra were obtained 
with an ESI source in positive targeted MS/MS mode 
with a Q-TOF instrument. MS data as the fragmenta-
tion patterns, the accurate mass and the relative inten-
sities of fragments, are strongly related to the specific 
families and to the specific substituent within the fam-
ily, becoming a predictive tool of the structure. NMR 
spectra gave a complete unambiguous characterization 
of each single analogue even in the case of isomers. It 
is also of importance the capability of NMR to perform 
quantification of molecules with no need of specific ref-
erence standards [12].
The diffusion of peptides employed for doping and 
cosmetics in the illegal market, is another main chal-
lenge concerning the European OMCLs [13]. These 
peptides can be substances unauthorized for use in hu-
mans, or still in investigational phase or authorized only 
for pathologies not corresponding to the suggested use 
in the illegal products advertisement. 
In any case, it is important to highlight the constant 
risk for the consumer of falsified products: in the case of 
illegal/falsified medicines even if the active pharmaceu-
tical ingredient is present in the correct dosage, unex-
pected impurities and residual solvents from the illegal 
manufacturing process and degradation products from 
uncontrolled storage conditions represent a serious 
danger for health. The risk is higher for medicines in 
disguise, because the consumer unawares takes a “bad 
medicine”. 
The Italian OMCL analyzed unlabeled vials seized by 
the Customs and identified different molecules: manni-
tol (an osmotic diuretic illegally used as a masking agent 
in doping), the hormone Somatropin, the Growth Hor-
mone Releasing Peptide-2 (GHRP-2) used as a doping 
agent [14] and Melanotan II, a peptide which is ille-
gally used as a skin tanning agent. In all cases, from the 
exact molecular formula obtained from high-resolution 
MS analysis it was possible to confirm the hypothesized 
structure by both MS/MS and NMR data; quantifica-
tion and identification were performed without the sup-
port of any reference standard or database.
The cooperative application of various techniques 
based on different physicochemical principles, such as 
MS and NMR spectrometry, FT-IR spectroscopy and 
chromatography (GC and LC), is essential for success-
fully resolving many cases of falsified medicinal prod-
ucts, both medicines very well mimicking the branded 
product and the new molecules, often contained in un-
labeled vials or in “medicines in disguise” [15]. The con-
tinuous updating on the new substances found in falsi-
fied medicines/dietary supplements and the knowledge 
of the trend of the illegal market are very important for 
the resolution of the different cases of falsification. For 
this purpose, particular attention should also be paid to 
the Grey Literature, Social Networks, and Body-build-
ers forums to take information on illegal or off-label use 
of slimming agents, new analogues of PDE5-i and new 
drugs.
This contribution evidences that an OMCL is not 
only a laboratory where standard procedures are per-
formed, but also a center where control and research 
activities are effectively joined to solve non-routine cas-
es. In this context the presence of a chemical synthesis 
facility is an added value.  
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The evolution of the illegal market of falsified medicines and the experience of the Italian OMCL: from control to research.

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The evolution of the illegal market of falsified medicines and the experience of the Italian OMCL: from control to research.

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