543091

research-article2014
TAW0010.1177/2042098614543091Therapeutic Advances in Drug SafetyVeronin et al.

Therapeutic Advances in Drug Safety Original Research

Quantification of active pharmaceutical

Ther Adv Drug Saf

2014, Vol. 5(5) 180­–189

ingredient and impurities in sildenafil DOI: 10.1177/

2042098614543091

citrate obtained from the Internet

© The Author(s), 2014.
Reprints and permissions:
http://www.sagepub.co.uk/
journalsPermissions.nav

Michael A. Veronin, Mohammad T. Nutan and Uday Krishna Reddy Dodla

Abstract
Background: The accessibility of prescription drugs produced outside of the United States,
most notably sildenafil citrate (innovator product, Viagra®), has been made much easier by
the Internet. Of greatest concern to clinicians and policymakers is product quality and patient
safety. The US Food and Drug Administration (FDA) has issued warnings to potential buyers
that the safety of drugs purchased from the Internet cannot be guaranteed, and may present a
health risk to consumers from substandard products.
Objective: The objective of this study was to determine whether generic sildenafil citrate
tablets from international markets obtained via the Internet are equivalent to the US innovator
product regarding major aspects of pharmaceutical quality: potency, accuracy of labeling, and
presence and level of impurities. This will help identify aspects of drug quality that may impact
public health risks.
Methods: A total of 15 sildenafil citrate tablets were obtained for pharmaceutical analysis:
14 generic samples from international Internet pharmacy websites and the US innovator
product. According to US Pharmacopeial guidelines, tablet samples were tested using high-
performance liquid chromatography for potency of active pharmaceutical ingredient (API)
and levels of impurities (impurities A, B, C, and D). Impurity levels were compared with
International Conference on Harmonisation (ICH) limits.
Results: Among the 15 samples, 4 samples possessed higher impurity B levels than the
ICH qualification threshold, 8 samples possessed higher impurity C levels than the ICH
qualification threshold, and 4 samples possessed more than 1% impurity quantity of maximum
daily dose (MDD). For API, 6 of the samples failed to fall within the 5% assay limit.
Conclusions: Quality assurance tests are often used to detect formulation defects of
drug products during the manufacturing and/or storage process. Results suggest that
manufacturing standards for sildenafil citrate generic drug products compared with the US Correspondence to:
Michael A. Veronin, BS
innovator product are not equivalent with regards to potency and levels of impurities. These Pharm, MS, PhD
findings have implications for safety and effectiveness that should be addressed by clinicians Texas A&M University
Health Science
to safeguard consumers who choose to purchase sildenafil citrate and foreign-manufactured Center Rangel
College of Pharmacy -
drugs, in general, via the Internet. Pharmaceutical Sciences,
MSC 131 1010 West
Avenue B, Kingsville, TX
Keywords:  drug importation, drug quality, drug safety, Internet pharmacy, quality assurance 78363-8202, USA
Mohammad T. Nutan, PhD
testing, sildenafil citrate, Viagra® Texas A&M University
Health Science
Center Rangel
College of Pharmacy -
Introduction [National Association of Boards of Pharmacy, Pharmaceutical Sciences,
According to the National Association of Boards 2014]. Sildenafil (Viagra®) is a top-selling, per- Kingsville, TX, USA
Uday Krishna Reddy
of Pharmacy (NABP), 97% of the over  10,000 haps the best-selling, illicit drug sold on the Dodla, MS
Internet drug ‘outlets’ that NABP has assessed Internet [BBC News, 2002]. In fact, the pharma- TechData Service
Company, LLC - Statistical
maybe illegitimate or illegal, and out of compli- ceutical company Pfizer, who first brought Viagra Programming, Morrisville,
ance with pharmacy laws and practice standards to market in 1998, is setting up its own site to sell NC, USA

180 http://taw.sagepub.com

Viagra online, in what it says is an effort to curb
the sale of counterfeit versions of the drug
[Isidore, 2013].
Viagra was the first treatment for erectile dysfunc-
tion in an oral dosage form. Initially, it was stud-
ied for treatment of hypertension and angina
pectoris, but early clinical trials suggested that
although it had little effect on angina, it was
observed to induce penile erections. As a result,
Pfizer made the decision to market Viagra for
erectile dysfunction [Ghofrani et al. 2006]. What
followed was an immediate healthcare, if not
absolute, business success. According to reports
at the time: ‘Within two weeks, newspapers
reported physicians were writing 15,000 to
20,000 prescriptions a day for the medication’
[Rodriguez, 1998]. In the week of 8 May 1998,
and 1 month after Viagra’s release, more than
300,000 total prescriptions were written for
Viagra in the US, and Pfizer reported that more
than US$400 million worth of Viagra was sold in
the first quarter [Keith, 2000].
More recently, according to the healthcare con-
sulting firm IMS Health, approximately 8 million
prescriptions for Viagra were written in 2012,
which translates into total sales of about US$2
billion. And of the ‘market share’ for pharmaceu-
ticals for erectile dysfunction, which also includes
Cialis, Levitra, and Staxyn [Drugs.com, 2014],
Viagra has approximately 45% of the market, just
ahead of Eli Lilly’s Cialis [Wilson, 2013].
As an illustration of the popularity of online silde-
nafil, an Internet search using the search terms
‘online sale Viagra’ resulted in over 1.5 million
hits, directing the user to locations of Internet
pharmacies selling generic versions of this prod-
uct [Lowe and Costabile, 2011]. Email spam for
Viagra is so pervasive that Microsoft and Pfizer
jointly filed several lawsuits against pharmacy
spam rings running sites that allegedly sell generic
Viagra. Millions of disruptive email messages
potentially lure consumers to those URLs selling
illegal Viagra. According to some estimates, Viagra
and other erectile dysfunction medicines or cures
may account for as much as a quarter of all spam
[Information Week, 2005].
An important key issue of Internet drug importa-
tion, and of considerable concern to clinicians and
healthcare policymakers, is patient safety due to
poor product quality. According to the US Food
and Drug Administration, ‘FDA cannot ensure
http://taw.sagepub.com 181
MA Veronin, MT Nutan et al.
the safety and effectiveness of products that are
not FDA-approved and come from unknown
sources and foreign locations, or that may not have
been manufactured under proper conditions.
These unknowns put patient’s health at risk if they
cannot be sure of the products identity, purity, and
source. For these reasons, FDA recommends only
obtaining medicines from legal sources in the U.S.’
[US Food and Drug Administration, 2010].
Several reports validate the assertion that drugs
produced in many foreign countries do not meet
equivalent standards of quality as in the US [US
Food and Drug Administration, 2004; Qureshi
and McGilveray, 1998; Westenberger et al. 2005;
Veronin and Youan, 2004].
In a previous study, a high-performance liquid
chromatography (HPLC) assay method was
developed and validated for sildenafil citrate and
its related substances that might coexist in tablets’
formulation [Daraghmeh et al. 2001]. These com-
pounds related to sildenafil may be impurities or
may appear as degradation products and were
prepared and identified as impurity A, impurity
B, impurity C, and impurity D.
The requirements for assessing safety of impuri-
ties in drug products can be found in the guide-
lines from the International Conference on
Harmonisation of Technical Requirements for
Registration of Pharmaceuticals for Human Use
(ICH). Founded in 1990, the ICH is ‘unique in
bringing together the regulatory authorities and
pharmaceutical industry of Europe, Japan and the
US to discuss scientific and technical aspects of
drug registration.’ [ICH, 2014].
ICH has developed guidelines for threshold of
impurity quantity in new drug products [ICH,
2006], which are presented in Table 1. Per ICH
guidelines, identification threshold is the limit
above which a degradation product should be
identified. Reporting threshold is the limit above
which the degradation product should be reported
to regulatory bodies. Qualification is the process
of acquiring and evaluating data which establishes
the biological safety of an individual impurity or a
given degradation profile at a specified level. TDI
is the total daily intake of the drug. If the impurity
is unusually toxic, lower threshold values are
appropriate. Maximum daily dose (MDD) is the
maximum amount of drug administered per day.
This study reports on the drug product variability
of sildenafil. The objective of this study is to
Therapeutic Advances in Drug Safety 5(5)
Table 1.  Thresholds for impurities in new drug products [ICH, 2006].
Reporting thresholds
Maximum daily dose
≤ 1 g
> 1 g
  Identification thresholds
Maximum daily dose
< 1 mg
1–10 mg
> 10 mg–2 g
2g
  Qualification thresholds
Maximum daily dose
< 10 mg
10–100 mg
> 100 mg–2 g
2g
TDI, total daily intake
determine whether generic sildenafil tablets from
international markets obtained via the Internet
are comparable with the US innovator product
with regard to major aspects of pharmaceutical
quality: potency and accuracy of labeled amount,
and level of impurities.
Currently, the innovator product for sildenafil
(Viagra®, Pfizer) is protected by a US patent
[Milford, 2011], yet is readily available to con-
sumers in generic form from the Internet. The
maximum recommended daily dose of sildenafil
citrate is 100 mg [Drugs.com, 2014], and for this
reason, this was the dosage strength chosen for
analysis in this study.
Materials and methods
Sample acquisition
Searches of the World Wide Web were conducted
with the browser Internet Explorer 7.0. The web-
sites for the Internet pharmacies were located by
using the advanced search options of Google
(http://www.google.com.) The keywords selected
for entry into the query box of the browser
included the search terms ‘generic Viagra’,
‘generic sildenafil’, ‘online pharmacy’, and
‘Internet pharmacy’. All proprietary forms of
sildenafil 100 mg tablets were identified on the
Websites for prospective procurement. Our per-
spective was that of a consumer seeking to pur-
chase these prescription medications online or
182 http://taw.sagepub.com
 
Threshold
0.10%
0.05%
 
Threshold
1.0 % or 5 µg TDI, whichever is lower
0.5% or 20 µg TDI, whichever is lower
0.2% or 2 mg TDI, whichever is lower
0.10%
 
Threshold
1.0 % or 50 µg TDI, whichever is lower
0.5% or 200 µg TDI, whichever is lower
0.2% or 3 mg TDI, whichever is lower
0.15%
comparison price shopping. If necessary, drug
products were purchased a second time from the
same website to validate test findings of the initial
sample.
During January 2010 through July 2010, 15 sam-
ple lots were purchased from the US and interna-
tional markets. The US innovator product was
obtained by prescription from Harrel’s Kingsville
Pharmacy (Kingsville, TX, USA), and other sam-
ples from Internet pharmacy websites. A checklist
of attributes was created for each specific drug
product (Table 2).
For analyses involving HPLC, the pure pharma-
ceutical grade chemical for sildenafil was obtained
from Toronto Research Chemicals Inc. (Toronto,
Ontario, Canada; Lot #5-KPA-93-1, Catalog
#A617415). Impurity A was obtained from
ChemPacific (Baltimore, MD; Lot #CHP-20-
10232-207-6, Catalog #33854), impurity B was
obtained from Equinox Chemicals (Albany, GA;
Lot EQX-2009-D-030, Catalog #E-03-0316),
impurity C was obtained from Specs (The
Netherlands; Product ID #AP-312/40633649),
impurity D was obtained from Sigma-Aldrich (St.
Louis, MO; Lot #04710EH, Product #535524).
Preparation of solutions
To prepare standard solutions of active pharma-
ceutical ingredient (API), 25 mg of sildenafil cit-
rate was accurately weighed and dissolved in 50
 MA Veronin, MT Nutan et al.

Table 2.  Characteristics of sildenafil tablet samples.

Sample Product Name Product Source Lot No. Expiration Shipping Product Source (website URL)
No. (Dosage form) (Laboratory) date Source
1 Viagra Innovator Pfizer A023501 29 Feb 16 Not Harrell’s Pharmacy (Kingsville,
product - Pfizer applicable TX)
(tablet)
2 Aurogra-100 Aurochem Labs SD 239 May 13 Mumbai, PrescriptionRxPharma.com
India http://www.
  prescriptionrxpharma.com
3 Mygra-100 Jpee Drugs SK9001 Oct 12 Mumbai, My-xlpharmacy.com
India http://www.my-xlpharmacy.
  com
4 Kamagra Ajanta Pharma BN10039K Oct 13 Mumbai, Generic4u
India http://www.generic4u.com
5 Perfopil-100 Aurochem SD224M2 Jan 13 Mumbai, ShopPillRx
Laboratories India http://ww2.shoppillrx.com.
6 P-Force-100 Sunrise Remedies SC- 492 Dec 12 Mumbai, Half Price Pharmacy
(capsule) India http://www.half-price-
  pharmacy.com.
7 Malegra-100 Sunrise Remedies E- 134 May 13 Mumbai, Online Pharmacy VG
India http://onlinepharmacy.vg
8 Sildigra-100 DRJLPL S-06 Apr 13 Nagpur, Quality-Online-Generics
(Tablet) India http://review-pharmacy.net/
Quality-Online-Generics.com.
htm.
9 Viprogra-100 Vipro Life Science 10SGDT026 Mar 12 Ahmedabad, Official Canadian Pharmacy
India http://www.ednf.org/index.
php?option=com_content&task=
view&id=1204&Itemid=88888988
10 Vigora-100 Cadila VG020001 Jan 12 Ahmedabad, ED Pharmacy
HealthCare India http://www.buysildenafil.eu
11 Integra (tablet) G.S. 1003003 Feb 12 Ahmedabad, 1drugstore-online
Pharmaceuticals, India http://www.1drugstore-online.
Pvt., Ltd. com.
12 G.S. 1004056 Mar 12 Ahmedabad, Mexican Online Pharmacy
Pharmaceuticals, India http://www.
Pvt., Ltd. mexicanonlinepharmacy.net.
13 Sildenafil tablets Not labeled SD 234 Mar 13 Mumbai, XL Pharmacy
100 mg (no brand India http://www.xlpharmacy.com
name specified)
14 Not labeled SD 237M5 Mar 13 Mumbai, Mexican Export Pharmacy
India http://www.
mexicanexportpharmacy.com.
15 Not labeled SD 184M3 Feb 12 Victoria, International drug mart.com
Seychelles http://www.
internationaldrugmart.com.

ml of mobile phase (500 µg/ml concentration),
sonicated for 15 minutes and filtered through
0.45 µm filter. Further dilutions were carried out
to obtain sildenafil citrate within a target concen-
tration range of 5–500 µg/ml.
To prepare standard solution of impurities, 1 mg
each of impurities A, B, C, and D were weighed
and dissolved in 100 ml of mobile phase (10 µg/ml
concentration), sonicated for 15 minutes, and fil-
tered through a standard 0.45 µm filter. Further
dilutions were carried out to obtain impurities
with in target concentration range of 5–100 µg/ml.
HPLC analysis
Prior to testing, HPLC analytical equipment was
calibrated according to manufacturer’s specifica-
tions by certified technicians. Where applicable,
the appropriate USP guidelines were applied for
testing procedures [United States Pharmacopeial
Convention, 2003].

http://taw.sagepub.com 183
Therapeutic Advances in Drug Safety 5(5)
An HPLC methodology for sildenafil analysis has
been reported previously by Daraghmeh and col-
leagues [Daraghmeh et al. 2001], and this analyti-
cal method was modified and employed in this
study.
HPLC analysis was performed on a Waters 1525
Binary HPLC pump equipped with an inline
degasser AF, a Waters 2487 dual λ absorbance
detector, and a Waters 717 plus autosampler.
Data was analyzed using Waters Breeze Software.
Centrifugation was performed by the Eppendorf
Centrifuge 5430, and sonification was performed
with the Fisher Scientific Ultrasonic Cleaner
FS20.
Measurements were made with a 20 µl injection
volume at 30°C; the detector wavelength was set
at 240 nm and the retention time was 6.4 min-
utes. Routine analyses were carried out isocrati-
cally on a Waters X Bridge C18, 5 µm column
(250 mm × 4.6 mm), eluted with a mobile phase
consisting of acetonitrile/ammonium acetate
buffer (50:50 v/v), pH 7.0, at a flow rate of 1.0 ml/
min. Pure sildenafil (Sigma-Aldrich, St. Louis,
MO) acetonitrile (Aldrich Laboratories,
Milwaukee, WI), ammonium acetate buffer
(Fisher Scientific, Rochester, NY), water
(Barnstead Nanopure ultrapure water purifica-
tion system, Fisher Scientific, Rochester, NY),
were used to prepare standard curves for each
assay. Quantitation was accomplished through
comparison of peak area to a standard curve. All
analyses were performed in triplicate and the
error expressed as standard deviation.
To prepare a solution of tablet samples of 1 mg/ml
concentration, 10 tablets were pulverized with
mortar and pestle and portions equivalent to
100 mg sildenafil citrate were weighed and trans-
ferred into 100 ml standard volumetric flasks.
Upon addition of mobile phase (100 ml), sonica-
tion, centrifugation (15 minutes at 3000 rpm), 20
µl of the supernatant was injected into the chro-
matograph. This analysis was used to calculate
the average impurity and average API quantity
present in a dosage form one individual sample
set. This method can remove the error caused by
tablet weight variation in determination of aver-
age impurity and API quantities.
To quantify the impurity and API levels, the cali-
bration curve method using standard plots was
used. For sildenafil, and impurities A, B, C, and
D, linear curves were plotted using respective
184 http://taw.sagepub.com
standard compounds. As per ICH Q2R1 guide-
lines for analytical procedure validation, the
standard plot range should be at least 80–120%
of the sample. For sildenafil citrate the standard
plot range was 0.8–1.2 mg and for impurities the
range was 2–20 µg, which meets the ICH
guidelines.
Results
A total of 15 sildenafil citrate tablets were obtained
for pharmaceutical analysis: 14 generic samples
from international Internet pharmacy websites
and one sample of the US innovator product
(Table 2).
HPLC analysis
For sildenafil, an official assay method for content
uniformity using HPLC has not been reported in
the United States Pharmacopeia (USP), the British
Pharmacopoeia (BP), or European Pharmacopoeia
(EP). For the 100 mg tablet dosage form of silde-
nafil, general acceptable assay limits have been
published in scientific journals. Daraghmeh and
colleagues report an assay limit for sildenafil citrate
of 98–102% and any individual impurity should
not exceed 0.5% of the MDD with total impurity
quantity not exceed 1% of the total daily dose
[Daraghmeh et al. 2001]. However, most USP
product monographs (as compared with substance
monographs) have the standard range for both
manufactured products and compounded prepa-
rations as 90.0–110.0% [United States
Pharmacopeial Convention, 2003; Allen, 2012].
HPLC analysis indicated that 14 of the 15 drug
samples were within the general USP range of
90–110% of the labeled claim for each tablet dos-
age unit. However, for the range of 98–102% of
the labeled claim, only six of the drug samples
were within this range (Table 3).
Using the linear regression method, linear curves
were plotted using respective standard com-
pounds for impurities A–D. HPLC analysis of the
15 samples provides variable data about the quan-
tities of impurities (Table 4).
According to ICH guidelines, the qualification
threshold for a dosage form with a MDD of
100 mg, such as sildenafil, is 200 µg. For impurity
A, all of the samples were observed to be under the
qualification threshold. The maximum impurity
observed was 174.3 µg for sample lot number
 MA Veronin, MT Nutan et al.

Table 3.  Analysis of API quantity in collected samples.

No. Sample Lot No. label claim Recovery

1 Viagra Pfizer A023501 100 mg 99.7%
2 Aurogra SD 239 100 mg 99.3%
3 Mygra SK9001 100 mg 101.9%
4 Kamagra BN10039K 100 mg 96.2%
5 Perfopil SD224 100 mg 94.6%
6 P-Force SC- 492 100 mg 93.0%
7 Malegra E- 134 100 mg 95.0%
8 Sildigra S-06 100 mg 96.7%
9 Viprogra 10SGDT026 100 mg 98.1%
10 Vigora VG020001 100 mg 87.2%
11 Integra 1003003 100 mg 99.8%
12 1004056 100 mg 105.5%
13 Sildenafil Citrate 100 (no brand name specified) SD 234 100 mg 93.6%
14 SD 237 100 mg 97.0%
15 SD 184 100 mg 100.1%
Note: Bold values are outside the +/- 2% assay range limit.

SD237. For impurity B, 4 of the 15 samples
showed more than 200 µg, with 2 samples more
than 6 times the qualification threshold. For impu-
rity C, eight samples showed higher impurity lim-
its than the qualification threshold. Impurity D
was observed to be present in only in two samples
in minute quantities. Among all samples, nine
samples showed more than 0.5% of the MDD. In
four samples, the total impurity quantity was more
than the 1% of MDD. In sample #7 (Malegra, lot
number E-134), the total impurity quantity was
more than the 1.5% of MDD, and for sample #11
(Integra lot number 1003003), the total impurity
quantity was more than 2% of MDD.
The innovator product contained relatively low
impurity quantities. Impurities C and D were
below the limit of detection, and impurities A and
B constituted less than 37 µg, which is far below
the qualification threshold.
Discussion
A ‘cultural icon’ can be described as ‘an object that
represents some aspect of the values, norms or ideals
perceived to be inherent in a culture, or section of a
culture’ [Wikipedia, 2014]. In ‘The Viagra
Phenomenon’ Tiefer asserts ‘certain medicines, such
as aspirin, penicillin, birth control pills, mood regula-
tors (Valium and Prozac), and now Viagra, have
become cultural icons, reaching far beyond just their
impact on human physiology to shape social norms
and practices’ [Tiefer, 2006]. In fact, the American
English word ‘viaggravated’ is being adopted in the
American lexicon, and is an adjective that means
‘exhibiting a degree of sexual interest that is incon-
gruent to one's age’ [Merriam-Webster, 2014].
Although still a multibillion dollar industry, the
market for Viagra and other ‘virility’ drugs has
slowed in recent years. In 2010, the total number
of prescriptions for drugs used for erectile dys-
function fell by 5% after growth of only 1% annu-
ally the previous 4 years. Specifically, prescriptions
for Viagra and Levitra declined 7% and 18%,
respectively [James, 2011].
This can be contrasted with massive growth of
Internet pharmacies, which have made prescrip-
tion-only medicine, such as Viagra, readily availa-
ble online, and the growth and popularity does not
appear to be declining [Maxwell and Webb, 2008].
For instance, a search for ‘Internet drug store’
revealed 6.4 million hits and of 7000 Internet
pharmacies identified by the Verified Internet
Pharmacy Practice Sites Program (VIPPS) [Young,
2013]. Of these sites that were identified, only 4%
were in proper compliance with regulations. What
would be the impact on domestic sales of Viagra?
According to Lowe and Costabile, ‘The role
Internet pharmacies play in counterfeit PDE5 or
abuse is not well documented; however based on
easy access, direct patient marketing, and low
advertised cost it is likely this role is underreported’
[Lowe and Costabile, 2011]. It is not unreasonable
to assume that illegal access to Viagra via the

http://taw.sagepub.com 185
Therapeutic Advances in Drug Safety 5(5)

Table 4.  Impurity quantities (in micrograms) in sildenafil samples.

Name Impurity A Impurity B Impurity C Impurity D Total

Viagra Pfizer 21.3 15.2 0.0 0.0 36.5
Aurogra 64.4 153.0 704.5 0.0 921.9
Mygra 98.9 177.2 32.6 22.6 331.3
Kamagra 106.5 187.3 66.1 1.1 361.0
Perfopil 58.4 109.4 704.9 0.0 872.7
P-Force 74.2 123.3 242.9 0.0 440.4
Malegra 155.7 1205.2 186.9 0.0 1547.7
Sildigra 139.9 141.0 3.4 0.0 284.3
Viprogra 135.8 119.9 284.7 0.0 540.4
Vigora 154.1 104.9 2.7 0.0 261.6
Integra (1003003) 132.3 1743.5 179.4 0.0 2055.2
Integra (1004056) 120.8 250.0 205.4 0.0 576.2
Sildenafil (SD 234) 66.1 122.9 648.3 0.0 837.4
Sildenafil (SD 237) 174.3 157.6 716.1 0.0 1048.0
Sildenafil (SD 184) 143.5 200.7 705.1 0.0 1049.3
Note: Bold values indicate values that are above the ICH qualification threshold. For total impurity levels, bold values
indicate total impurity quantity more than 1% of MDD.

Internet has had a negative impact on sales of
Viagra through conventional healthcare channels.
The documented risks of taking Viagra include:
counterfeit drugs, potentially harmful drug inter-
actions, and accidental overdose, not to mention
improper packaging and labeling (Figure 1)
[Young, 2013; Webb et al. 1999; Hung and Yang,
2001; Veronin, 2011]. If one considers the poten-
tial harmful effects of drug impurities, perhaps we
have added to this list of health risks if a consumer
chooses to purchase sildenafil via the Internet.
According to the US Pharmacopeia, when it comes
to determining the quality of a drug product,
‘knowing its impurity profile is as important as
knowing about the quality of its active pharmaceu-
tical ingredient (API) and excipients’ [The
Standard, 2012]. What is the source of an impurity
in a drug product? An impurity can be produced as
a result of the drug’s manufacturing process, or it
can be a degradation byproduct formed when
improper environmental conditions exist, perhaps
during storage or transit. It may even be a substance
intentionally added during the manufacturing pro-
cess, such as a catalyst during drug synthesis. In
short, impurities are substances that can coexist in
pharmaceuticals that serve no purpose for which
the drug was designed [Rahman et al. 2006].
In a previous study, four major impurities were iso-
lated in the oral dosage form of sildenafil citrate,
and an HPLC method was developed and validated
that could differentiate between the active moiety
and these impurities. The question then arises, if
impurities have no functional role in a drug prod-
uct, is there a chance that their existence may be
detrimental to a person’s health or well-being?
At the different stages during the drug manufactur-
ing process, a variety of analytical tests are conducted
to ensure that the final drug product meets stand-
ards for identity, strength, quality, purity, and stabil-
ity as specified in the United States Pharmacopeia
and National Formulary (USP/NF). The USP/NF
provides guidelines for testing procedures and
acceptance criteria for these tests [Chow et al. 2002].
One of the most common methods for measuring
API assay in oral dosage forms is HPLC [Rudnic
and Schwartz, 2000]. HPLC analysis can assess
the potency of tablets, and hence safety if tablets
are found to be outside of the acceptable quality
assurance range.
For oral dosage forms, when considering devia-
tions from the label claim for potency, and levels
of impurities, a fair question would be, what are
the short- and long-term health risks?
Since there is no USP monograph for sildenafil
tablets, assay limits were derived from standard
assay guidelines for oral dosage forms and
research studies. For most commercial drugs

186 http://taw.sagepub.com
 MA Veronin, MT Nutan et al.

Figure 1.  Generic sildenafil tablets obtained via the Internet compared to the innovator product.
The picture shows the innovator product and typical generic sildenafil products from the Internet with impurity levels higher
than acceptable limits in the US. The generic products appear to be from legitimate drug manufacturers and similar in
appearance to the innovator product.
Photo courtesy of Andrew Ramirez, Digital Media Specialist, Office of Student Affairs, Rangel College of Pharmacy,
Kingsville, Texas.

manufactured in the US, the acceptable potency
range is 95–105% or 90–110% of the labeled
quantity [Allen, 2012]. Of 14 samples analyzed
from international markets, 6 of the products
were at or beyond the ±5% range, and 1 of the
products was beyond the ±10% range and hence
would not be acceptable for patients in the US
(Table 3).
Regarding levels of impurities, all samples regis-
tered detectable levels of impurities. Levels of
impurity A were detectable in all samples, but
none were above ICH qualification threshold.
For impurity D, only 2 samples registered detect-
able amounts, and 13 of the 15 samples regis-
tered no detectable amounts. However, for
impurities B and C, for several samples, the lev-
els detected were above the ICH threshold, and
the tablets would not be acceptable for patients
in the US. For impurity B, four samples were
above both the ICH qualification threshold. The
highest levels of impurities were evident for
impurity C. Eight samples were above both the
ICH qualification threshold limit. For samples
above ICH limits for impurities B and C, they
would not only be unacceptable therapeutic
agents for patients in the US, but also would be
a cause for alarm with regards to health risks.
These findings suggest dissimilar manufacturing
and/or storage processes compared with the US,
which in turn may affect quality, therapeutic
effectiveness, and safety. Based on this informa-
tion, tests of safety for short- and long-term use
are warranted.
Limitations of the study
The relatively small sample size in this study
may not be an accurate representation of other
sildenafil tablets sold on the Internet and to
generalize should be done with a large degree of
caution. However, the findings in this report
support results with previously published work
[Westenberger et al. 2005; Veronin and Youan,
2004], and further studies are warranted to
identify trends in accessibility and health risks
for these types of drug products sold on the
Internet.
When using analytical equipment, instrument
and user error must be allowed for when consid-
ering precision and accuracy of test results
[Watson, 2005]. In this report, although every
precaution was taken into account the possibility
exists that the values outside of acceptable ranges
may or may not be as extreme as observed, if

http://taw.sagepub.com 187
Therapeutic Advances in Drug Safety 5(5)
taking into account the margin of error of labora-
tory measurement.
A goal of this study was to assess quality attrib-
utes of potency and impurity levels that may indi-
rectly convey information on safety and
effectiveness through the dosage form’s produc-
tion and/or storage properties. A direct associa-
tion between drug manufacturing attributes and
clinical outcomes has not been established, so the
findings in this report must be interpreted with
some reservation.
Conclusions
As this study has shown, consumers can obtain
prescription drugs via the Internet with little dif-
ficulty and without professional oversight.
Although generic drug substitution is acceptable
practice in the US, consumers need to be aware
that irrespective of advertising claims on Internet
pharmacy websites, consumers may receive a drug
product nonequivalent to the US counterpart and
unlike what would be allowed for consumers in
the US. In addition, it is quite likely that the aver-
age individual seeking to import sildenafil from
the Internet would obtain a product that does not
meet quality specifications equivalent to the
US-made product. Further, it is virtually impos-
sible to evaluate the quality of drugs purchased
from the Internet without specialized analytical
testing. The results of this study indicate variabil-
ity of sildenafil sold on the Internet based on
potency and impurity levels, which may give pause
to healthcare professionals and consumers of these
products.
At a minimum, findings of this study suggest
that sildenafil tablets purchased from the
Internet should not be considered interchange-
able with the US innovator product. These find-
ings have implications for safety and effectiveness
that should be considered by clinicians to poten-
tially safeguard patients who choose to purchase
foreign-manufactured drugs via the Internet.
Beyond this, further testing of the pharmacolog-
ical effects and drug interaction profiles of the
impurities A, B, C, and D are warranted, to
assess the potential short- and long-term health
risks.
Funding
This research project was funded in part by the
American Heart Association Texas Affiliate
#0565153Y.
188 http://taw.sagepub.com
Conflict of interest statement
The authors declare no conflict of interest in pre-
paring this article.
References
Allen, L. (2012) Science and technology for the
hospital pharmacist. Compounding with Commercial
Drug Products Can Cause Errors! Available at: http://
compoundingtoday.com/Newsletter/Science_and_
Tech_1205.cfm (accessed 10 June 2014).
BBC News (2002) Online Pharmacy Warning.
Available at: http://news.bbc.co.uk/2/hi/
health/1938890.stm (accessed 10 June 2014).
Chow, S., Shao, J. and Wang, H. (2002) Probability
lower bounds for USP/NF tests. J Biopharm Stat 12:
79-92.
Daraghmeh, N., Al-Omari, M., Badwan, A. and
Jaber, A. (2001) Determination of sildenafil citrate
and related substances in the commercial products
and tablet dosage form using HPLC. J Pharm Biomed
Anal 25: 483–492.
Drugs.com (2014) Erectile Dysfunction Medications.
Available at: http://www.drugs.com/condition/erectile-
dysfunction.html (accessed 10 June 2014).
Ghofrani, H., Osterloh, I. and Grimminger, F. (2006)
Sildenafil: from angina to erectile dysfunction to
pulmonary hypertension and beyond. Nat Rev Drug
Discov 5: 689-702.
Hung, D. and Yang, D. (2001) Sildenafil overdose in
a female patient. J Toxicol Clin Toxicol 39: 423-424.
ICH (2006) International Conference on Harmonisation
of Technical Requirements for Registration of
Pharmaceuticals for Human Use 2006. ICH Harmonised
Tripartite Guideline. Impurities in New Drug Products
Q3B(R2), Current Step 4Version, 2 June 2006. Available
at: http://www.ich.org/fileadmin/Public_Web_Site/ICH_
Products/Guidelines/Quality/Q3B_R2/Step4/Q3B_R2__
Guideline.pdf (accessed 10 June 2014).
ICH (2014) Harmonisation for Better Health 2014.
Available at: http://www.ich.org (accessed 10 June 2014).
Information Week (2005) Microsoft, Pfizer Sue Viagra
spammers. Available at: http://www.informationweek.
com/microsoft-pfizer-sue-viagra-spammers/60300237
(accessed 10 June 2014).
Isidore, C. (2013) Pfizer to Start Selling Viagra
Online, CNNMoney. Available at: http://money.cnn.
com/2013/05/06/news/companies/pfizer-viagra-online/
index.html (accessed 10 June 2014).
James, S. (2011) HoneymoonWithViagra Could Be Over,
Say Doctors, ABC News. Available at: http://abcnews.

go.com/Health/viagra-prescription-sales-sexual-
expectations/story?id=13794726 (accessed 10 June 2014).
Keith, A. (2000) The economics of Viagra. Health
Affairs 19: 147-157.
Lowe, G. and Costabile, R. (2011) Phosphodiesterase
type 5 inhibitor abuse: a critical review. Curr Drug
Abuse Rev 4: 87-94.
Maxwell, S. and Webb, D. (2008) Internet pharmacy:
a web of mistrust? Br J Clin Pharmacol 66: 196-198.
Merriam-Webster (2014) New Words & Slang 2014:
Viaggravated. Available at: http://nws.merriam-
webster.com/opendictionary/newword_display_alpha.
php?letter=vi (accessed 10 June 2014).
Milford, P. (2011) Pfizer Wins Viagra Patent
Infringement Case Against Teva Pharmaceuticals,
Bloomberg. Available at: http://www.bloomberg.
com/news/2011-08-15/pfizer-wins-viagra-patent-
infringement-case-against-teva-pharmaceuticals.html
(accessed 10 June 2014).
National Association of Boards of Pharmacy (2014)
Buying Medicine Online. Available at: http://www.
nabp.net/programs/consumer-protection/buying-
medicine-online/ (accessed 10 June 2014).
Qureshi, S. and McGilveray, I. (1998) Assessment
of pharmaceutical quality of furosemide tablets from
multinational markets. Drug Dev Industr Pharm 24:
995-1005.
Rahman, N., Azmi, S. and Wu, H. (2006) The importance
of impurity analysis in pharmaceutical products: an
integrated approach. Accred Qual Assur 11: 69–74.
Rodriguez, A. (1998) Men clamoring to try out new
impotence pill. Chicago Sun-Times, 22 April, Section
A:1 column 2.
Rudnic, E. and Schwartz, J. (2000) Oral solid dosage
forms. In Gennaro, A. (ed.), Remington: the Science
and Practice of Pharmacy, 20th edn. Philadelphia
College of Pharmacy and Science. Philadelphia, PA:
Lippincott Williams & Wilkins.
Teasdale, A. (2011) Risk assessment of drug
impurities: how quality of medicines assures safety.
In American Association of Pharmaceutical Scientists
(AAPS) Annual Meeting and Exposition, Washington
DC. October 2011. Macclesfield: AstraZeneca R&D.
The Standard (2012) News and Information about
the United States Pharmacopeial Convention 2012,
USP Looks at Drug Impurities Across Multiple Fronts.
Available at: http://www.usp.org/sites/default/files/
http://taw.sagepub.com 189
MA Veronin, MT Nutan et al.
usp_pdf/EN/aboutUSP/standard_summer2012-web.
pdf (accessed 10 June 2014).
Tiefer, L. (2006) The Viagra phenomenon. Sexualities
9: 273-294.
United States Pharmacopeial Convention (2003) The
United States Pharmacopeia/The National Formulary
USP 26/NF 21. Rockville, MD: United States
Pharmacopeial Convention, Inc..
US Food and Drug Administration (2004) Recent
FDA/U.S. Customs Import Blitz Exams Continue
to Reveal Potentially Dangerous Illegally Imported
Drug Shipments. Available at: http://www.fda.gov/
NewsEvents/Newsroom/PressAnnouncements/2004/
ucm108232.htm (accessed 10 June 2014).
US Food and Drug Administration (2010) Importing
prescription drugs. Available at: http://www.fda.gov/
Drugs/DrugSafety/ucm170594.htm (accessed 10 June
2014).
Veronin, M. (2011) Packaging and labeling of
pharmaceutical products obtained from the Internet. J
Med Internet Res 13: e22.
Veronin, M. and Youan, B. (2004) Magic bullet gone
astray: medications and the Internet. Science 305: 481.
Watson, D. (2005) Control of the quality of analytical
methods. In Pharmaceutical Analysis. A Textbook for
Pharmacy Students and Pharmaceutical Chemists, 2nd
edn. London: Elsevier.
Webb, D., Freestone, S., Allen, M. and Muirhead, G.
(1999) Sildenafil citrate and blood-pressure-lowering
drugs: results of drug interaction studies with an
organic nitrate and a calcium antagonist. Am J Cardiol
83(5A): 21C-28C.
Westenberger, B., Ellison, C., Fussner, A., Jenney, S.,
Kolinski, R., Lipe, T. et al. (2005) Quality assessment
of Internet pharmaceutical products using traditional
and non-traditional analytical techniques. Int J Pharm
306: 56-70.
Wikipedia (2014) Cultural icon. Available at: http://
en.wikipedia.org/wiki/Cultural_icon (accessed 10 June
2014).
Wilson, J. (2013) The little blue pill that could, CNN
Health. Available at: http://www.cnn.com/2013/03/27/
health/viagra-anniversary-timeline/index.html
(accessed 10 June 2014).
Young, C. (2013) Pfizer launches website for purchasing
Viagra safely. Available at: http://www.pharmacist. Visit SAGE journals online
http://taw.sagepub.com
com/pfizer-launches-website-purchasing-viagra-safely
(accessed 10 June 2014). SAGE journals