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A post-market quality assessment of first-line, fixed-dose combination antiretrovirals in South Africa ARTICLE INFO


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South Africa has the world's largest antiretroviral (ARV) program and despite having stringent upstream medicine's regulatory oversight, the post-market reassessment of ARV quality is prohibitively resource intensive. The aim of this study was to evaluate and compare the post-market quality of four fixed-dose combination (FDC) generics containing efavirenz (EFV) 600 mg, emtricitabine 200 mg, and tenofovir 300 mg against the innovator, Atripla ® and according to the International Pharmacopoeia (IP). Generic tablet samples, sourced from a South African provincial depot, were subjected to the identification, content assay, dissolution, uniformity of weight and disintegration tests. An in-house reversed-phase high-performance liquid chromatography (RP-HPLC) method was developed and validated in lieu of the RP-HPLC IP method which proved to be unsuitable. All samples passed the identification, assay, uniformity of weight and disintegration tests and one generic FDC failed the dissolution test (at both stage 1 and 2), releasing 62.23% (standard deviation 20.43) of EFV in 30 minutes. One generic first-line ARV combination that is currently supplied to the South African public health sector was found to be substandard and this reinforces the need for routine ARV post-market surveillance, as well as reliable compendial methods to facilitate this undertaking.
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Journal of Applied Pharmaceutical Science Vol. 9(02), pp 097-104, February, 2019
Available online at
DOI: 10.7324/JAPS.2019.90213
ISSN 2231-3354
A post-market quality assessment of first-line, fixed-dose
combination antiretrovirals in South Africa
Kim Ward*, Reem Suleiman, Yunus Kippie, Admire Dube
School of Pharmacy, University of the Western Cape, Bellville, South Africa.
Received on: 22/11/2018
Accepted on: 24/12/2018
Available online: 28/02/2019
Key words:
Quality control,
antiretrovirals, dissolution,
HPLC, fixed-dose
combination, post-marketing
South Africa has the world’s largest antiretroviral (ARV) program and despite having stringent upstream medicine’s
regulatory oversight, the post-market reassessment of ARV quality is prohibitively resource intensive. The aim of this
study was to evaluate and compare the post-market quality of four xed-dose combination (FDC) generics containing
efavirenz (EFV) 600 mg, emtricitabine 200 mg, and tenofovir 300 mg against the innovator, Atripla® and according
to the International Pharmacopoeia (IP). Generic tablet samples, sourced from a South African provincial depot, were
subjected to the identication, content assay, dissolution, uniformity of weight and disintegration tests. An in-house
reversed-phase high-performance liquid chromatography (RP-HPLC) method was developed and validated in lieu
of the RP-HPLC IP method which proved to be unsuitable. All samples passed the identication, assay, uniformity
of weight and disintegration tests and one generic FDC failed the dissolution test (at both stage 1 and 2), releasing
62.23% (standard deviation 20.43) of EFV in 30 minutes. One generic rst-line ARV combination that is currently
supplied to the South African public health sector was found to be substandard and this reinforces the need for routine
ARV post-market surveillance, as well as reliable compendial methods to facilitate this undertaking.
Over the last two decades, funding from international
donors, increased political will, and international trade exibilities
have contributed towards strengthened HIV and AIDS programs
and improved access to antiretroviral (ARV) medicines in sub-
Saharan Africa. Regrettably, market proliferation with ARVs
has met with an inux of poor quality generics, which threaten
to undermine country program gains accrued (WHO, 2007).
South Africa’s (SA) HIV epidemic is amongst the largest in the
world (UNAIDS, 2012) and by 2015, the ARV program provided
treatment for nearly 3.4 million people (mainly) in the public sector
(UNAIDS, 2016). Moreover, the country’s adoption of a universal
test and treat and pre-exposure prophylaxis policy in 2016 has
resulted in further expansion of the program (DOH, 2016).
In 2013, SA recommended a generic xed-dose
combination of emtricitabine (FTC) (200 mg), tenofovir (TDF)
(300 mg), and efavirenz (EFV) (600 mg) as the rst-line treatment
(once daily dose) for HIV in adults (DOH, 2013) to reduce the pill
and supply burden. As of 2017, four of these generic combinations
were supplied on public tender by local, licensed pharmaceutical
companies. While the generic nished pharmaceutical products
(FPP) and the innovator, Atripla®, are registered by the South
African Health Products Regulatory Authority (SAHPRA) based
on bioequivalence and in vitro quality data, there is uncertainty
about the level of surveillance of these products after their market
authorization, apart from port clearance controls and routine
inspections of companies against Good Manufacturing Practice
and Good Distribution Practices (GDP) standards. The demand for
new ARV xed-dose combinations (FDCs) has seen many national
regulatory authorities adopt an accelerated approval process at a
pace that exceeds the development of pharmacopoeial monographs
for these combination medicines. As such, approval is based on
available compendial specications for the individual ingredients
or existing combinations containing two of the three ingredients.
Post-market quality control involves routine quality
testing of products at various levels of the supply chain, as well as
voluntary reporting and testing of suspected poor quality medicines
*Corresponding Author
Kim Ward, School of Pharmacy, University of the Western Cape, Bellville,
South Africa. E-mail: kward @
© 2019 Kim Ward et al. This is an open access article distributed under the terms of the Creative Commons Attribution 4.0 International License
Kim Ward et al. / Journal of Applied Pharmaceutical Science 9 (02); 2019: 097-104
by healthcare workers and trained personnel, respectively. This
quality assurance undertaking for thousands of products on the
market requires intensive nancial and physical investment,
which poses a challenge for South Africa’s stringent, yet resource
constrained, regulatory authority, where surveillance of quality,
though legislated, is generally reactionary to reported quality
complaints (Lehmann et al., 2018a; Maigetter et al., 2015; Patel
et al., 2012). In response to reports of quality defects, SAHPRA
submits suspect samples to independent WHO-accredited
laboratories for identity and content assays and if the substandard
quality is conrmed, an investigation (including supplier audit)
and possible medicine recall ensues.
Generic companies are the main suppliers of rst-
line ARV FDCs to the global market (Chien, 2007). A generic
formulation typically includes pre-formulation studies to
characterize aqueous solubility and particle size distribution of
the active pharmaceutical ingredient (API), as well as API to API
and API-excipient compatibility (Aulton and Taylor, 2017). The
inherent complexities of mixing two or three APIs in an FDC
increase the risk of manufacturing challenges, instability, and
consequent bioequivalence issues (EMA, 2007; WHO, 2003). To
the extent described in the summary of product characteristics of
the originator FPP, the generic manufacturer typically uses similar
excipients in the generic FPP. However, excipient grades and
amounts, as well as the method of manufacture may differ and
could potentially lead to poor quality FPPs.
Poor quality medicines can be classied as falsied
(deliberate mislabeling with respect to source, ingredients, or
quantities), substandard (authorized for use but fails to meet
specications or quality standards), and unregistered (not
authorized for use by National Regulatory Authority) (WHO,
2017). The distinction is important in developing strategic
interventions to circumvent their supply and consumption
(Newton et al., 2010). There are several reports of falsied ARV
combinations on the market of several African countries assisted
by USAID (Primo-Carpenter and McGinnis, 2008). Fewer
accounts of substandard ARVs are documented; in a WHO survey
to assess the quality of ARVs either as single or multiple compound
preparations in various African countries, the percentage of “out
of specication” medicine was very low (1.8%). Interestingly,
three ARV FDC products failed either dissolution, disintegration,
or content assays, in spite of being WHO-prequalied1 products
(WHO, 2007). This underscores the need for routine post-market
surveillance of products irrespective of their authorization for in-
country use. Contrastingly, a post-market quality study conducted
on ARV combination products sampled at various levels of the
supply chain in Cameroon conrmed the quality of these WHO-
prequalied products by in vitro testing and those sourced from
local drug stores in Nigeria also met desired specications (Djobet
et al., 2017; Joshi et al., 2010).
This quantitative cross-sectional study compared the
quality prole of four generics combinations containing EFV
(600 mg), FTC (200 mg), and TDF (300 mg) in the tablet dosage
form against the innovator product (Atripla®) and according
to the only available monograph for this FDC published in the
International Pharmacopoeia (IP) (WHO, 2016a). To date, no
studies have assessed the post-market quality of generic FDCs
containing these three ingredients and this paper sheds light on
the quality of products at the distribution level of a relatively well-
regulated market.
Acetonitrile [99.9% high-performance liquid
chromatography (HPLC) gradient grade], methanol (99.8%
HPLC grade), sodium dodecyl sulfate, sodium dihydrogen
orthophosphate monohydrate, and potassium phosphate dibasic
were purchased from Merck, Germany and South Africa. Fumaric
acid was obtained from Sigma Aldrich, SA. Primary reference
standards (RS) for EFV (99.8% w/w), FTC (99.7% w/w), and TDF
(98.8% w/w) were sourced from the European Directorate for the
Quality of Medicines and Healthcare, France and stored at 5°C ±
3°C. High purity de-ionized water was obtained from the Milli-
RO 4 water purication system, USA.
Four generics on the public sector tender for the period
2015–2018 were sourced from a provincial depot (with recently
updated Medicines Registration Authority licensure, conrming
compliance with GDP) in one of South Africa’s nine geographical
provinces. The originator FDC was purchased from a local private
sector community pharmacy. The generic and originator samples,
all lm-coated tablets, were stored in their original container
closure system under controlled climatic conditions (temperature
not exceeding 30°C) for the duration of experimentation (2015–
2016). All samples were batch specic and remained within
expiry by the end of the last experiments. The names of the tender
companies and the trade names of FDCs are not disclosed so as to
protect the anonymity of the companies. The FDCs are hereafter
referred to as originator (O), generic 1 (G1), generic 2 (G2),
generic 3 (G3), and generic 4 (G4).
Uniformity of weight
Twenty tablets (n = 20) were randomly selected from
each container of the different FPPs and weighed individually
using an electronic analytical balance and the average, standard
deviation (SD), and the % relative standard deviation (RSD) of the
20 tablets were calculated. Tablets passed the weight uniformity
tests if not more than two weights of the 20 individual tablets had
more than 10% RSD (WHO, 2016b).
HPLC assay
The HPLC assay test conditions stipulated, as per the
monograph (WHO, 2016a) were: reversed phase (RP) HPLC
using an analytical HPLC column (25 cm × 4.6 mm) packed with
chemically-bonded silica (5 µm), i.e. C18, as the stationary phase
maintained at a temperature of 35°C; potassium dihydrogen
phosphate (5%) in high purity deionized water and 70%:25%
acetonitrile:potassium dihydrogen phosphate constituted mobile
phases A and B, respectively, at a ow rate of 1 ml/minute and
with UV detection of the analytes at 280 nm. In line with these
requirements, the local system best suited was an Agilent 1200 series
modular HPLC system equipped with a quaternary pump, diode-
array detector, and a thermostatted column compartment housing an
Ascentis® C18 column 5 μm particle size (25 cm × 4.6 mm) with the
Kim Ward et al. / Journal of Applied Pharmaceutical Science 9 (02); 2019: 097-104 099
column temperature, mobile phases ow rate, and UV wavelength
maintained as per the monograph. Transferring the monograph assay
method onto the available HPLC system proved unsuccessful, in
that peak resolution between the compounds of interest could not
be resolved according to International Conference on Harmonization
(ICH) guidelines (ICH, 2005).
Development of an alternative “in-house” RP-HPLC
assay proceeded using the Perkin Elmer Flexar HPLC system with
slight modications to the method described by Raju and Begum
(2008). The modular HPLC system comprised an autosampler
equipped with a 100 µl injection loop, a binary LC pump, and a
photodiode-array detector. The Discovery® HS C18 column (15 cm
× 4.6 mm internal diameter × 5 µm particle size) was intuitively
determined as the column of choice for optimum retention and
resolution. Column temperature was controlled at ambient
laboratory conditions of 20°C. The mobile phases consisting of
0.02 M sodium dihydrogen orthophosphate monohydrate buffer
(Mobile Phase A) adjusted to pH 3.6 and (85:15) methanol:water
(Mobile phase B) pumped at a ow rate of 1.0 ml/minute.
A gradient was applied as shown in Table 1. The detection
wavelength was determined at 260 nm by investigation of the
UV spectra. The developed method was validated for system
suitability, robustness, limit of detection, limit of quantitation,
specicity, linearity, precision, and accuracy in accordance with
ICH guidelines.
Preparation of standard solutions for HPLC assay validation
The validation targeted the quantitation of samples
subjected to the dissolution test. Individual stock solutions for
each RS were accurately weighed and diluted to the 100 ml
mark with methanol (containing 0.4% w/v SDS) into different
volumetric asks, followed by vortex for 2 minutes to effect
dissolution and thereafter ltered through a 0.22 µm nylon
syringe lter. A standard combination stock solution of 10 ml
containing a combination of 5 mg of EFZ RS, 2.5 mg of TDF RS,
and 1.6 mg of FTC RS was then prepared. Working standards
were prepared from the standard combination stock solution
by dilution of stock aliquots with methanol to six different
concentrations for each API (0.08, 0.1, 0.11, 0.12, 0.13, and 0.14
mg/ml for EFV; 0.04 mg, 0.05 mg/ml, 0.055 mg/ml, 0.06 mg/ml,
0.065 mg/ml, and 0.07 mg/ml for TDF; and 0.026, 0.033, 0.036,
0.04, 0.043, and 0.046 mg/ml for FTC).
Assay test
The assay test proceeded by weighing 20 tablets for each
FPP, powdering by mortar and pestle and accurately weighing and
dispersing a quantity of each of the powders containing 10 mg TDF
into 100 ml of methanol, followed by sonication and ltering of
the resulting solution through a 0.22 µm Nylon syringe lter. Six
replicates for each FDC, having a nal solution concentration of
0.0667 mg/ml of FTC, 0.1 mg/ml of TDF, and 0.2 mg/ml of EFV,
were prepared. This was completed by an injection of 10 μl of
each replicate into the HPLC and resulting peak areas determined
by integration. The average and the SD were calculated. All the
FPP FDCs were stored at 20°C until the time of the analysis, none
of the products exceeded its expiry date before the end of the
Dissolution test
Dissolution tests were carried out as described in the IP
6th Edition (WHO, 2016a) to compare the quality of each generic
FDC to the originator counterpart. The test was conducted using
the USP Type II apparatus (paddle) at a speed of 100 rpm, at
a temperature of 37°C ± 0.5°C. The medium comprised 1,000
ml of 2% v/v sodium dodecyl sulfate (SDS) and samples were
collected at 30 minutes. Six tablets from each FPP were used.
After 30 minutes, samples of 5 ml each were automatically
withdrawn, ltered using 0.22 µm Nylon syringe lters, and
thereafter diluted with methanol to obtain a nal concentration of
0.4% w/v SDS. This sample was injected (10 µl) onto the HPLC
for quantication of FTC, TDF, and EFV in accordance with the
in-house RP-HPLC conditions described above. According to
the IP monograph for this FDC, not less than 80% (Q) of the
labelled amount of each active ingredient should be released in
30 minutes.
Disintegration test
The test was done using a disintegration apparatus
(Electrolab® disintegration tester ED 2AL) as per the IP general
method (WHO, 2016c). The media were heated to 37°C and the
timer was set at 30 minutes. Six tablets (n = 6) were randomly
selected from each sample bottle and placed into each of the
six tubes of the basket. The disks were added to the top of the
tablets. The apparatus was operated using distilled water as the
media. After 30 minutes, the basket was lifted to observe the tablet
Statistical analysis
Graph Pad Prism 6 (GraphPad Software, Inc., San Diego,
CA) was used to analyze the data. Results are presented as mean,
SD, and percentage SD (%SD). Statistical analysis using One-
way ANOVA, Tukey’s multiple comparisons test was carried out
to compare the release (dissolution testing) and the content (assay)
of EFV, FTC, and TDF between the originator and the generics
and between the generics themselves with alpha set at 0.05.
Uniformity of weight
All generic FDCs and the originator (O) samples (G1,
G2, G3, and G4) passed uniformity of weight tests with all samples
below the 5% RSD of the average tablet weight (Table 2). These
ndings reect acceptable intra-batch consistency.
Assay method verification and method development
We found that the IP assay method as described in
the 6th Edition provided unsatisfactory resolution of the peaks
arising from FTC, TDF, and EFV when either pure reference
standards were injected simultaneously or when the tablet sample
was injected. Resolution between the peaks was less than 1.5
despite attempts to slightly modify the monograph method by, for
example, changing the sample diluent (increasing the percentage
of methanol from 50% to 80%). Figure 1 is a representative
chromatogram of the FTC, TDF, and EFV reference standards
when injected as a mixture.
Kim Ward et al. / Journal of Applied Pharmaceutical Science 9 (02); 2019: 097-104
The gradient RP-HPLC method which was developed
provided satisfactory separation of the peaks arising from FTC,
TDF, and EFV in both standard injections (Fig. 2) and when the
tablet sample was injected (Fig. 3). We found that the method
showed robustness with respect to changes in pH (from 3.5 to 3.69)
with a slight change in the retention times, while the decrease of the
ow rate (from 1 to 0.8 ml/minute) increased the retention times
of all the APIs, especially for EFV. The retention time increased
from 9.53 to 10.56 minutes for FTC, 12.56 to 13.88 minutes for
TDF, and from 14.25 minutes to more than 20 minutes for EFV.
A noteworthy observation made during the method development
stage was the phenomenon around the uctuating retention
behavior of EFV when storing solutions at low temperature in a
fridge or for a lengthy time in the autosampler carousel at room
temperature. Subsequent experimental investigation found that
by allowing cooled solutions to initially acclimatize to ambient
room temperature, then followed by a high vortex for at least 2
minutes immediately prior to the HPLC analysis, restored the
retention behavior of EFV. For time-exposed solutions, only the
2-minute high vortex sufced. This phenomenon, attributed to a
solubility issue of EFV in the prescribed diluent, did not require
further investigation as the additional preparation step adequately
resolved the retention issue and maintained estimation values. All
system suitability parameters were within acceptable limits.
The specicity, linearity, precision, and accuracy of the
assay (in-house method) were acceptable (Table 3). The three
APIs were identied and quantied (content assay) in all the
FPPs using the validated RP-HPLC method. The retention times
(Figs. 2 and 3) and UV spectra (Figs. 4 and 5) for FTC, TDF, and
EFV in the sample FDC tablets were comparable to the reference
Table 1: Mobile phases gradient elution conditions of the “in-house” HPLC
method for the simultaneous quantication of EFV, FTC, and TDF (Raju and
Begum, 2008).
Time Mobile phase A
% v/v
Mobile phase B
% v/v
0.01 90 10
5.00 90 10
6.00 35 65
9.00 10 90
11.00 10 90
13.00 90 10
15.00 90 10
Table 2: Uniformity of weight for each of the FDC samples.
Samples Weight of 20 tablets (g) Average (g) %RSD
O 31.89 1.59 0.01
G1 32.63 1.63 0.01
G2 31.94 1.59 0.02
G3 32.34 1.61 0.01
G4 30.95 1.54 0.01
Figure 1. Representative chromatogram for FTC, TDF, and EFV eluted under IP method conditions.
Figure 2. Representative chromatogram of FTC (9.53 minutes), TDF (12.61
minutes), and EFV (14.25 minutes) reference standards eluted under the “in-
house” method conditions.
Figure 3. Representative chromatogram of FTC (9.56 minutes), TDF (12.65
minutes), and EFV (14.37 minutes) identified in the originator tablet formulation.
Kim Ward et al. / Journal of Applied Pharmaceutical Science 9 (02); 2019: 097-104 101
standards, conrming the identity of the three active ingredients in
the generics and originator products.
Content of FTC, TDF, and EFV in the FDC products
In all samples, the percentage content of EFV, TDF,
and FTC was consistent with label claims and within the IP range
of 90%–110% (Fig. 6). Although all content was within limits,
statistically signicant differences in content were observed
between the originator and the generics, as well as among the
generics themselves (refer to Table 4).
The statistical analysis indicated a signicant difference
(p < 0.05) in FTC content between the originator and G1 and
among other pairs of generics. A signicant difference was
observed in TDF content between the originator and G2 and
between two other generic pairs. In relation to EFV, signicant
differences in content were observed between the originator and all
four generics (G1–G4). However, it is important to note that these
statistically signicant differences in content may not translate to
any differences in clinical efcacy since all products were within
the pharmacopoeial allowable limits of 90%–110% at shelf-life.
Dissolution of FTC, TDF, and EFV from the FDC products
Three of the FDC products released at least 80% (Q) of
the active ingredients within 30 minutes. However, we observed
that G2 failed the pharmacopoeial dissolution test (refer to Fig. 7).
At stage 1, 73.99% ± 10.78% of EFV was released and only two of
the six tablets had a release of 85.07% and 81.08%. This product
also failed stage 2 limits as the average amount of EFV released
from 12 tablets was 62.23% ± 20.43%, and more than one tablet
released less than 60% [limits state that at stage 2 average of the
12 (S1 + S2) units should be ≥ Q and no unit should be less than
Q minus 15%]. The Q-release values of 10 out of the 12 tablets
ranged from 22.04% to 78.73%. The differences in Q-release of
EFV between G2 and other generics and against the originator
also yielded statistically signicant differences (see Table 5).
Table 3: Summary of validation results for the in-house RP-HPLC method for simultaneous
quantication of FTC, TDF, and EFV at 260 nm.
Validation FTC TDF EFV
Retention times (min) 9.52 12.62 14.24
Peak symmetry 0.94 1.00 1.11
Resolution factor 60.11 13.66 3.97
Calibration curve Y = 1E + 07X − 14,039 Y = 8E + 06X − 25,140 Y = 7E + 06X – 122,774
Calibration curve range 0.026–0.046 mg/ml 0.04–0.07 mg/ml 0.08–0.14 mg/ml
Correlation coefficient 0.9992 0.9965 0.9966
Limit of detection 1.81 μg/ml 5.61 μg/ml 11.06 μg/ml
Limit of quantitation 5.51 μg/ml 17.01 μg/ml 33.54 μg/ml
80: 113.00% ± 1.69%
100: 111.11% ± 0.17%
120: 109.00% ± 0.96%
80: 95.63% ± 2.00%
100: 90.90% ± 2.00%
120: 92.30% ± 1.87%
80: 92.44% ± 1.98%
100: 96.44% ± 0.86%
120: 97.68% ± 0.37%
Intra-day precision RSD: 0.32% RSD: 0.86% RSD: 1.39%
Inter-day precision RSD: 0.62% RSD: 1.30% RSD: 1.62%
Figure 4. Typical UV spectra for the reference standards (FTC, TDF, and EFV). Figure 5. Typical UV spectra for the FPP (tablets).
Kim Ward et al. / Journal of Applied Pharmaceutical Science 9 (02); 2019: 097-104
Disintegration test
The six selected tablets of each product disintegrated
completely within 30 minutes and comply with the WHO IP
specications for lm-coated tablets.
Apart from a few studies aimed at developing and
validating HPLC methods for the FDC containing EFV, TFV, and
FTC, none have attempted to assess and compare the quality prole
of these medicines subsequent to market authorization or approved
WHO status (prequalication) (Raju and Begum, 2008; Raju et
al., 2008; Ramaswamy and Dhas, 2014). Our study developed and
validated an RP-HPLC method and subsequently compared the
quality proles of different generic versions of this rst-line ARV
combination. We found that the identication and assay methods
described in the IP sixth edition (replicated in the seventh edition)
were unsuitable in this study for the simultaneous detection and
quantication of EFV, TDF, and FTC either as standards or within
the FDCs. With no other monograph available for this combination
ARV, apart from monographs for individual ingredients and
combinations of two ingredients (e.g. FDC + TDF)—which possibly
form the basis for specications in the registration process in South
Africa—it is imperative that the IP method is reproducible and thus
suitable for post-market quality assessments in various countries. We
recommend further studies to evaluate the suitability of this method.
Although three out of four products passed all quality
tests, there are concerns about the EFV release in one of the
generic combinations currently on the South African market. A
failed dissolution test could impact the efcacy of a medicine,
potentially leading to therapeutic failure, development of drug
resistance and toxic or adverse reactions (WHO, 2007). During
the dissolution test, we observed that G2 appeared insoluble in the
dissolution media. This could explain the failure in the dissolution
of EFV, which is a more hydrophobic and poorly soluble API
in comparison to TDF and FTC. We subsequently investigated
this observation further by performing a disintegration test on all
the FDCs. We performed this test in water and water containing
1% sodium dodecyl sulfate. However, in both situations,
G2 disintegrated completely within 30 minutes. This led us
to speculate that the failure in the dissolution of G2 could be
related to the presence of an excipient that could be retarding
the release of EFV. Upon further inspection of the inactive and
lm-coating ingredients of all the FPPs, an excipient which was
unique to G2 was identied as a possible cause of its slower
dissolution rates since this excipient happens to be used in
extended-release and sustained release tablet formulations.
Apart from excipient selection, the unfavorable dissolution of
this FDC could also potentially be attributed to the company’s
specications for the particle size distribution of this API or their
manufacturing procedures (Al Ameri et al., 2012; Genazzani and
Pattarino, 2008). Although we concede that the IP specications
for dissolution of this FDC may differ from the manufacturer’s
specications prescribed in the dossier for market approval by
SAHPRA, these compendial standards remain a universally
recognized tool for post-marketing surveillance (Nkansah et al.,
Figure 6. Percentage content (w/w) of FTC, TDF, and EFV in the originator (O)
and generic FDCs (G1, G2, G3, and G4). All products were found to contain
FTC, TDF, and EFV within the pharmacopoeial limit of 90%–110% w/w (limit
indicated by the red rectangle).
Table 4: Comparative content (% w/w) of active ingredients between generics and originator and among the generics.
Active ingredients
OaG1bG2cG3dG4ep < 0.05
Mean % (SD %) 92.67 (0.58) 90.73 (0.43) 92.34 (0.32) 92.12 (1.35) 94.30 (1.38) pab, pbe, pce, pde
Mean % (SD %) 96.84 (0.49) 96.35 (1.41) 94.95 (0.98) 97.19 (0.54) 98.02 (1.34) pac, pcd, pce
Mean % (SD %) 109.46 (2.17) 105.0 (0.52) 104.5 (0.52) 106.20 (0.54) 105.76 (0.92) pab ,pac ,pad pae
O = originator; G1 = generic 1; G2 = Generic 2; G3 = Generic 3; G4 = Generic 4; SD = standard deviation.
Figure 7. Q-release values of FDCs after 30 minutes. Results shown are the
mean and SD of n = 6 tablets.
Kim Ward et al. / Journal of Applied Pharmaceutical Science 9 (02); 2019: 097-104 103
Although content assay ndings complied with
specications, some inter-product variability exists, which could
affect interchangeability of rst-line generic ARV regimens in
patients, who themselves display inter-individual differences
(Genazzani and Pattarino, 2008). When the quality of generic
medicines is brought into question, prescribers, dispensers, and
patients are reluctant to use them and the knock-on effect is a loss of
condence in the health system which could seriously undermine
health and economic gains accrued from health programs and
national policies (e.g., pro-generics policies) (Al-Tamimi et al.,
2013; Sharrad et al., 2009).
The rapid globalization of the pharmaceutical industry
has increased international trade of raw materials and/or
nished pharmaceutical products with many more intermediary
distributors and role players operating under different national
regulatory authorities but in the absence of global coordination.
Even stringent regulatory authorities and countries relying on
WHO pre-qualied medicine have experienced problems with
substandard medicines entering their markets, in spite of efforts to
rigorously review dossier applications, audit manufacturers, and
distribution centers, as well as clearing every batch of imported
medicine according to the manufacturer’s certicate of release
(WHO, 2017). Most countries model an inverse relationship
between regulatory function and medicine life-cycle with more
stringent upstream controls (e.g., registration, inspection of
manufacturers) and relatively weaker regulation towards the
lower end of the supply chain (e.g., reassessment of quality)
(WHO, 2017). If a regulatory agency’s upstream investments in
preventing sub-standard medicines are not monitored downstream
for the desired outputs (e.g., quality medicine) and outcomes
(e.g., undetectable viral loads), then the monitoring and evaluation
loop is incomplete and performance cannot be adequately gauged.
This study, together with a recent assessment on post-market quality
of antibiotics and analgesics on the private sector South African
market (Lehmann et al., 2018b) provides evidence that stringency
in medicine registration and manufacturer auditing processes does
not guarantee on-going integrity of pharmaceutical products and
in the absence of routine surveillance, these may go undetected.
South Africa, like other lower and middle-income countries, lacks
the regulatory capacity to fully enforce existing quality monitoring
legislation and strategies to combine surveillance efforts with non-
prot, regional, and global organizations should be more actively
pursued. Furthermore, a risk-based approach to post-marketing
surveillance which prioritizes the on-going reassessment of
“high-risk” products (Nkansah et al., 2017) like ARV FDCs that
have complex production methods, stability concerns, and forms
the therapeutic basis of an extensive health program should be
considered to optimize the use of restricted resources.
We conrmed the quality of three generic versions
of Atripla® tablets and found one to be substandard. This study
underscores the need for routine post-market surveillance of
combination ARV regimens in South Africa to support and
strengthen its large-scale ARV program. We recommend an
independent verication of our ndings by a WHO prequalied or
SAHPRA-recognized quality control laboratory.
The authors would like to thank the Provincial
Department of Health for permission to source medicine samples
from their ARV depot.
There are no conicts of interest.
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OaG1bG2cG3dG4ep < 0.002
(SD% )
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How to cite this article:
Kim Ward, Reem Suleiman, Yunus Kippie, Admire Dube.
A post-market quality assessment of rst-line, xed dose
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ResearchGate has not been able to resolve any citations for this publication.
Full-text available
Pharmacovigilance (PV) data are crucial for ensuring safety and effectiveness of medicines after drugs have been granted marketing approval. This paper describes the PV systems of India, Uganda and South Africa based on literature and Key Informant (KI) interviews and compares them with the World Health Organization's (WHO's) minimum PV requirements for a Functional National PV System. A documentary analysis of academic literature and policy reports was undertaken to assess the medicines regulatory systems and policies in the three countries. A gap analysis from the document review indicated a need for further research in PV. KI interviews covered topics on PV: structure and practices of the system; current regulatory policy; capacity limitations, staffing, funding and training; availability and reporting of data; and awareness and usage of the systems. Twenty interviews were conducted in India, 8 in Uganda and 11 in South Africa with government officials from the ministries of health, national regulatory authorities, pharmaceutical producers, Non-Governmental Organizations (NGOs), members of professional associations and academia. The findings from the literature and KI interviews were compared with WHO's minimum requirements. All three countries were confronted with similar barriers: lack of sufficient funding, limited number of trained staff, inadequate training programs, unclear roles and poor coordination of activities. Although KI interviews represented viewpoints of the respondents, the findings confirmed the documentary analysis of the literature. Although South Africa has a legal requirement for PV, we found that the three countries uniformly lacked adequate capacity to monitor medicines and evaluate risks according to the minimum standards of the WHO. A strong PV system is an important part of the overall medicine regulatory system and reflects on the stringency and competence of the regulatory bodies in regulating the market ensuring the safety and effectiveness of medications. National PV systems in the study countries needed strengthening. Greater attention to funding is needed to coordinate and sustain PV activities. Our study highlights a need for developing more systematic approaches to regularly monitoring and evaluating PV policy and practices. © 2015 by Kerman University of Medical Sciences.
Full-text available
Generic medicines are promoted in many countries as an essential part of the healthcare system. However, in Yemen, there are many challenges to the utilisation of generic medicines. Currently, there is no national level policy to enhance or promote generic medicines use. In addition, other challenges to the use of generic medicines in Yemen including negative perceptions and availability of counterfeit medicines are highlighted in this brief report.
Full-text available
There is considerable interest in optimizing the therapy for important infections in developing countries and in making the best treatments readily available and inexpensive. There is also great concern that resistance to anti-infective drugs is worsening, putting affordable treatments at risk. We argue that an important, but usually neglected aspect of these problems is drug quality. Drugs may be of poor quality if they are counterfeit, substandard or degraded. Few objective data on the prevalence of poor-quality drugs exist but surveys suggest that an alarming proportion of antimalarials and antibiotics in much of the developing world are of poor quality. For individual patients these will increase mortality and morbidity and lead to loss of faith in medicines and health systems. Counterfeit, substandard or degraded drugs with sub-therapeutic concentrations of the active ingredient or the wrong active ingredient are likely to engender the emergence and spread of resistance to these anti-infectives. Although modelling suggests that poor-quality drug should worsen drug resistance, there is sparse evidence from the field, as there has been little research. It will be very difficult to distinguish the effects of poor-drug quality and reduced patient adherence and incorrect health worker prescribing on the spread of resistance. Strengthening drug regulatory authorities, improving quality of drug production and facilitating the availability of relatively inexpensive, good-quality anti-infectives are likely to be key factors in improving drug quality.
Full-text available
Background The use of cheaper generic medicines is a strategy promotedin many countries to reduce rising health care costs. The aimof this study was to explore factors affecting generic medicineprescribing by physicians in Basrah, Iraq.MethodologyA purposive sample of ten physicians practicing in Basrahwas interviewed using a semi-structured interview guide.ResultsAnalysis of the interviews identified seven major themes:medicine prescribing practice, knowledge of therapeuticequivalency of generic medicine, patients’ acceptance ofgeneric medicine, counterfeit medicine, drug informationsource and effect of drug advertising on medicines choice,brand substitution practice by community pharmacists, and,finally strategies to improve generic medicine usefulness.Participants identified helpful strategies to increase genericprescribing including; physician and patient education ongeneric medicine; persuading physicians about the safety andefficacy of generic medicines; and finally educating seniormedical students on generic prescribing.Conclusion The data suggest that participants were enthusiasticabout prescribing generic medicines. However physiciansinsist that pharmacists should not be allowed tosubstitute generic drugs without prior approval ofdoctors.
Objectives To examine differences in drug product quality between products marketed in developed countries and in developing countries. Methods The quality of drug products marketed in both Germany and South Africa by the same pharmaceutical company was compared. A fixed‐dose combination tablet containing amoxicillin/clavulanic acid, and mometasone furoate nasal spray were selected to represent generic medicines requiring prescriptions, while skin lightening products (legally obtained and/or confiscated) were selected to represent pharmaceutical products that are available without a prescription. Pharmacopoeial tests included assay, content uniformity, and where applicable, dissolution in addition to a visual examination of the packaging. Key findings Some differences between the product marketed in Germany and in South Africa were detected for the amoxicillin tablet formulations, although all samples still complied with regulatory requirements. The mometasone nasal spray product marketed in South Africa delivered a higher dose than was declared on the label. The composition of the skin lightening products conformed qualitatively with labelling, but in some South African samples alarmingly high amounts of hydroquinone were found. Conclusions Important differences in quality were detected between some German and South African products. To preclude drug products of poor or doubtful quality from entering the market in South Africa, countermeasures are needed.
To assess drug quality and pharmaceutical care in South Africa, "mystery" (i.e. anonymous) customers collected 316 samples from July to September 2016. Solid dosage forms containing amoxicillin alone or in combination with clavulanic acid as well as analgesics containing paracetamol alone or in combination were sampled in a randomized fashion from the formal market (pharmacies) and by convenient sampling from the informal market. Visual inspection, uniformity of dosage units and dissolution testing were performed using validated methods to evaluate adherence to pharmacopoeial quality standards and to identify counterfeit, degraded or substandard drugs. Although no counterfeited products were identified, only 55.4 % (173/312) of samples were able to fulfill all pharmacopeial requirements for quality. Most of the 139 samples that failed were unable to pass the visual inspection due to inappropriate labeling and packaging. Additionally, several substandard products were identified: 17 (5.4 %) samples failed dissolution testing and 15 (4.8 %) failed the content uniformity test. To improve drug quality and the quality of pharmaceutical care, better education of pharmaceutical professionals and monitoring of the pharmaceutical supply chain in South Africa are needed. Further field studies are necessary to evaluate risks and quality issues for other drug classes and distribution channels.
The purpose of this study was to evaluate the postmarket pharmaceutical equivalence, stability and bioequivalence of generic and innovator fixed dose combination products of lamivudine (3TC) and zidovudine (AZT) 150/300 mg tablets available in Nigeria. An isocratic HPLC-UV method was developed and validated for the quantitative determination of 3TC and AZT in human plasma and pharmaceutical samples. The model independent f(2) similarity factor was used to compare the dissolution profiles of the two products stored at accelerated and long-term stability conditions for 6 months. The f(2) values for 3TC and AZT in both products were found to be greater than 51. Also, the tablets were stable according to the USP potency and drug dissolution criteria with more than 80% of drug dissolution in 30 min indicating the pharmaceutical equivalence of the two products. The 90% confidence interval for the ratios of generic/innovator pharmacokinetic parameters for 3TC/AZT were 73.5-112.6/63.4-95.8 (C(max)); 68.5-105.6/68.0-114.8 (AUC(0-t)); and 64.2-106.2/80.1-120.3 (AUC(0-infinity)) respectively. The pharmacokinetic parameters failed to fully demonstrate bioequivalence between the products. The results underscored the importance of assessing the quality of the combination drug products that would ensure the safety and efficacy of the generic drug products available in the market.
Generic products reduce healthcare expenditure and create market competition, and it is broadly assumed that these drugs are identical to the original branded reference drug product. In practice, despite legislation demanding demonstration of pharmaceutical equivalence and bioequivalence, thereby ensuring the safety and efficacy of the product, generic products can differ significantly from the reference drug and amongst themselves, particularly in terms of pharmacokinetic properties. These differences most often relate to pharmaceutical technical differences in production of the active principle ingredient (e.g. different crystalline forms or particle size), to use of excipients (such as sugars) or to the manufacturing process itself (such as tablet manufacture). Furthermore, from the patient's perspective, changing from branded to generic drugs can give rise to concerns about switching. Although sufficient safeguards exist to ensure patient safety and generic drug efficacy, it should not be assumed that all generics are entirely identical.
The differences between the branded and generic medicines using solid dosage forms: In-vitro dissolution testing
  • Al Ameri
  • M N Nayuni
  • N Kumar
  • Kga Perret
  • D Tucker
  • A Johnston
Al Ameri MN, Nayuni N, Kumar KGA, Perret D, Tucker A, Johnston A. The differences between the branded and generic medicines using solid dosage forms: In-vitro dissolution testing. Results Pharma Sci, 2012; 1-8; doi:10.1016/j.rinphs.2011.12.001