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Are quality standards being reduced
as eye drops are classed as devices?
PeJo29/Dreamstime.com
Lucy Titcomb takes a look at the anomalies surrounding the classification of ophthalmic preparations
I
n March 2009, the Royal Pharmaceutical
Society published “Practice guidance:
medical devices”.1 In this guidance it advised that pharmacists, when deciding to purchase a medical device for retail sale, should
ensure inter alia that it is CE marked, that it is
suitable for its intended use or purpose and
that instructions for its use are appropriate
and easy to read.
Although not listed among the examples
given in the guidance, there are now many artificial tear eye drops classed as devices rather
than medicines. Pharmacists are now purchasing these CE-marked eye drops not only for
over-the-counter sale but, since April 2008, to
fill NHS prescriptions. The eye-drop devices
Lucy Titcomb, MRPharmS, MCPP, is
lead ophthalmic pharmacist at Birmingham
& Midland Eye Centre, Sandwell & West
Birmingham NHS Trust, Dudley Road,
Birmingham B18 7QH
(e-mail [email protected])
www.pjonline.com
in question are listed in the Drug Tariff in
“part IXA — appliances” and may therefore
be prescribed by GPs, dentists and nonmedical prescribers. Ten new eye-drop devices have been added to this section since
the end of 2008 and the list now contains 18
eye drops.2
Manufacturers wishing to supply appliances and chemical reagents for NHS prescribing must first seek approval from NHS
Prescription Services for inclusion of a product in part IX of the Drug Tariff.3
Applications must meet the following three
criteria for inclusion:
■ The products are safe and are of good
quality
■ They are appropriate for GP and, if relevant, non-medical prescribing
■ They are cost-effective
The eye-drop devices listed in the Drug
Tariff are shown in Panel 1.
Single dose, preservative-free
The Drug Tariff listing for single dose, preservative-free eye drop devices includes the
words “single dose unit”. The instructions for
use of Vismed (TRB Chemedica), Systane
(Alcon), Hydromoor (Moorfields Pharmaceuticals) and Blink Intensive Tears (AMO)
comply with this standard. Lumecare Tear
Drops single dose units are not yet available.
Product literature for these products includes
phrases such as “does not contain preservatives, any solution not used immediately after
opening should be discarded”, “do not reuse,
once opened, discard” and “always use fresh
solution, discard the container and remaining
solution immediately after use”. However, instructions for the other two single dose products are less strict.Those for Clinitas (Altacor)
include the statement “the eye drops do not
contain any preservatives; so after use, dispose
of the container, in an environmentally
friendly manner, even though it may not be
completely empty”. A user wondering
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whether this means after single or multiple
use of the resealable container will find rather
vague guidance on the product website:4
“The individual units of Clinitas lose their
sterility when opened, the individual units
can be resealed by turning the cap upside
down, however as the product contains no
preservative it should be discarded after short
term use.” There is no definition of “short
term use”. Instructions for Ocusan (Agepha)
are more specific: “The ampoule can be resealed and reused for up to 12 hours after 1st
use. Discard ampoule 12 hours after 1st use.”
Is this a safe practice? In a review of the literature on microbiological contamination of
eye drops, Schlech5 includes studies reporting
contamination rates of over 32 per cent in
bottles of unpreserved eye drops.
Although single dose units were not contaminated during a 24-hour evaluation of
spontaneous contamination of ocular medicines in studies by Marchese et al 6 and Su et
al 7 the former authors, who also inoculated a
range of single dose units with bacterial and
fungal pathogens, found only very small reductions in viable counts of Staphylococcus aureus and Pseudomonas aeruginosa over 24 hours
in jaluronic acid (=hyaluronic acid), the only
artificial tear product tested.This was in contrast to single dose units containing ketotifen,
pilocarpine and tetryzoline-feniramine
(=tetryzoline-pheniramine) in which the
number of colony forming units of the bacteria studied were reduced by over 3 log units
within 24 hours. This indicates that these
drugs possess some antibacterial activity while
the artificial tear does not.
Rahman et al 8 found that 60 per cent of
samples of multidose preservative-free bottles
of hypromellose were contaminated following use over three or seven days.The authors
conclude that preservative-free eye drops in
multiple application containers are at risk of
contamination with potentially pathogenic
micro-organisms. They stated that this may
place some patients at increased risk of developing serious ocular infections and that the
prescription of these drops to patients with
compromised ocular surface defences needs
to be considered with caution.
Kim et al 9 studied the microbial contamination of preservative-free artificial tears in
reclosable containers over a period of 10
hours and concluded that they are at risk of
contamination in a daily and multiple use setting, especially in patients with a poor administering technique, which is associated with
fingertip touch and advanced age.
Schlech10 evaluated microbiological contamination of preservative-free eye drops following proper and improper administration
techniques and found contamination rates of
over 80 per cent on multiple use when the
dropper tip touched the conjunctiva, cheek
or hand during twice daily administration for
five consecutive days.
While the in-use period studied by
Rahman et al 8 is greater than the in-use shelf
life proposed by the manufacturers of
Ocusan, Kim’s study over 10 hours9 shows
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The Pharmaceutical Journal (Vol 284) 26 June 2010
Panel 1: Eye drop devices listed in the Drug Tarriff,
part IXA — appliances
Product
Active ingredients
Preservative system
Discard instructions
Single dose, preservative-free eye drops
Blink Intensive Tears
Polyethylene glycol 400 0.25%
Sodium hyaluronate 0.2%
None
Single use only
Hydromoor
Hypromellose 0.3%
Borax and boric acid
Single use only
Systane
Hydroxypropyl guar*
Polyethylene glycol 400 0.4%
Propylene glycol 0.3%
None
Single use only
Vismed
Sodium hyaluronate 0.18%
None
Single use only
Clinitas
Sodium hyaluronate 0.4%
None
Short-term use
Ocusan
Sodium hyaluronate 0.2%
None
12h after opening
Lumecare Tear Drops
Hypromellose 0.3%
None
Not known yet
0.2micron nylon
fibre membrane
8 weeks after
opening
Multidose, preservative-free eye drops
Hyabak
Sodium hyaluronate 0.15%
Hylo-Care
Sodium hyaluronate 0.1%
Dexpanthenol 2%
Non-return bottle
3 months after
opening
Hylo-Forte
Sodium hyaluronate 0.2%
Non-return bottle
3 months after
opening
Hylo-Tear
Sodium hyaluronate 0.1%
Non-return bottle
3 months after
opening
Vismed Multi
Sodium hyaluronate 0.18%
Non-return bottle
3 months after
opening
Cetrimide 0.01%
4 weeks after opening
Multidose, preserved eye drops
Lumecare Long Lasting Carbomer 980 0.2%
PVA 1.4% Tubilux
Polyvinyl alcohol 1.4%
Oxyd (stabilised
oxychloro complex)
0.06%
4 weeks after opening
Blink Intensive Tears
Polyethylene glycol 400 0.25%
Sodium hyaluronate 0.2%
Ocupure (sodium
chlorite) 0.01357%
45 days after
opening
Oxyal
Sodium hyaluronate 0.15%
Oxyd (stabilised
oxychloro complex)
0.06%
60 days after
opening
Optive
Carmellose 0.5%
Glycerin 0.9%
Purite (stabilised
oxychloro complex)
0.01%
6 months after
opening
Systane
Hydroxypropyl guar*
Polyethylene glycol 400 0.4%
Prolylene glycol 0.3%
PolyQuad (polidronium 6 months after
chloride) 0.001%
opening
*Concentration not specified
that the potential for contamination is a real
one.Although this could be dangerous in certain patients the product’s instructions do not
contain any warning against multiple use in
patients with compromised eyes who are at
risk of ocular surface infection.
Multidose, preservative-free
Some of the eye drop devices included in the
Drug Tariff — Hyabak (SpectrumThea),
Hylo-Care, Hylo-Forte, Hylo-Tear (Scope
Ophthalmics) and Vismed Multi (TRB
Chemedica) — are multidose, preservative-
free preparations in which the contents of the
bottle are protected from contamination by
the innovative design of the delivery device.
Hyabak is presented in the ABAK system,
which contains a 0.2micron nylon fibre
membrane that filters the solution. Pressure
exerted on the bottle causes the solution to
pass through the antibacterial filter in the
ABAK system, forming a drop that falls from
the tip of the dispenser. When pressure is released, the solution is reabsorbed and filtered
from bacteria and air, ensuring the protection
of the solution throughout its use.11 The effi-
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Panel 2: Eye drops available in the COMOD and ABAK systems
Drug
Trade name
Available in:
Carteolol
Diclofenac
Povidone
Carteabak
Dicloabak
Filmabak
France, French overseas territories, Netherlands, Portugal, Italy
Belgium, Netherlands, Spain
Belgium, Italy, Netherlands, Poland, Portugal, Spain,
Switzerland
France, French overseas territories
Russia
Germany, Italy
Netherlands
Austria, Czech Republic, Germany, Monaco, Netherlands,
Poland, Switzerland, Turkey
Belgium, Brazil, Burkina Faso, Chile, France, French overseas
territories, Greece, Hong Kong, Italy, Korea, Morocco,
Phillippines, Portugal, Senegal, Singapore, South Africa,
Switzerland
Israel
France, Germany, Israel, Italy, Portugal*, Russia, Switzerland
UK
UK
Argentina, Belgium, France, Germany, Italy, Netherlands,
Poland, Portugal, Spain, Mexico, UK
UK
Russia
Austria, Belgium, Brazil, Burkina Faso, Cameroon, Congo,
France, French overseas territories, Gabon, Guinea, Hong Kong,
Korea, Morocco, Phillippines, Portugal, Senegal, Singapore,
Spain, Togo
Italy
Austria, Czech Republic, Germany, Malaysia*, Monaco,
Netherlands, Poland, Switzerland, Turkey
Germany*
Austria, Czech Republic, Germany, Netherlands, Turkey
Sodium cromoglicate
Fluidabak
Vid-COMOD
Wet-COMOD
Allerg-abak
Allergo-COMOD
Cromabak
Sodium hyaluronate
Sodium hyalouronate
with dexpanthenol
Timolol maleate
Cromo-COMOD
Hylo-COMOD
Hylo-Forte
Hylo-Tear
Hyabak
Hylo-Care
Hylozar-COMOD
Timabak
Timolabak
Timo-COMOD
Xylometazoline HCl
Timopos-COMOD
Xylo-COMOD
* Discontinued or no longer marketed in this country
cacy of the filtering system has been demonstrated by Kim et al,12 who passed a solution
contaminated with 105 and 107cfu/ml of
Staphylococcus epidermidis through the filter in
each direction; from contaminated contents
and into the sterile contents from a contaminated external source.
The Hylo- range eye drops are delivered
via the Continuous MonoDose (COMOD)
system, an airless, preservative-free multidose
container.13 The COMOD system is also used
for CE-marked and medicinal products with
a wide range of products available in many
countries14 (Panel 2).
Vismed Multi is a preparation with a similar non-return bottle maintaining sterility of
the contents. The dose of eye drops is delivered to the eye at a 45 degree angle from the
aperture of the dosage system; a traditional
bottle tip is not present.
Although pharmacists may be reassured
that the solution inside the bottle remains
sterile, once expressed from the bottle remnants of solution in or on the bottle tip containing no preservative may be open to
contamination in use and enter the eye at the
delivery of the next dose. Høvding and
Sjursen15 found that swabbings from 38 of
180 dropper tips (21.1 per cent) yielded bac-
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teria. Recent research has shown that a large
majority of patients touch the eye with the
bottle tip when administering eye drops.
Stone et al found that the proportions of patients who were able to instil a single drop
into the eye without touching the bottle to
the eye were 14 of 64 (21.9 per cent) with a
15ml bottle and 36 of 117 (30.8 per cent)
with a 2.5ml bottle, ie, 78.1 and 69.2 per
cent, respectively, do touch the eye.16 The
clinical relevance of this in a system in which
the contents of the bottle are protected
against contamination is not known.
Multidose, preserved eye drop devices
The other eye drop devices listed are multidose, preserved eye drops, a presentation that
pharmacists have traditionally been taught
should be discarded four weeks after opening,
a limit introduced by the British Pharmacopoeia Commission in 1966 and which still
applies to all multidose, preserved eye drops
licensed as medicines in the UK.17
The Royal Pharmaceutical Society’s guidance for use of ophthalmic preparations in
hospitals and care homes includes the statement:“If a fresh container of eye drops is supplied on discharge from hospital this may be
apportioned a ‘user life’ of 28 days.”18 The
British National Formulary states:“Eye drops
in multiple-application containers for domiciliary use should not be used for more than
four weeks after first opening (unless otherwise stated).”19 The BNF does not enlarge
upon the words “unless otherwise stated” but
this may relate to the European
Pharmacopoeia’s reference to labelling of
multidose containers stating that the label
must include the following:“The period after
opening the container after which the contents must not be used. This period does not
exceed four weeks, unless otherwise justified
and authorised.”20
This advice appears to be prudent when
one considers the results of a study by
Geyer et al in which 19 per cent of multidose
bottles used by glaucoma patients for up to
eight weeks were contaminated while those
used for periods of more than eight
weeks were contaminated in 40 per cent of
cases.21
One multidose, preserved eye drop device
listed in the appliances section of the Drug
Tariff, Lumecare Long Lasting, contains carbomer 0.2 per cent with cetrimide as the preservative and is, therefore, similar to the
medicinal products Liposic and Viscotears.
Product documentation for Lumecare Long
Lasting includes the instruction to discard the
contents 28 days after first opening.
Another, PVA 1.4% Tubilux, contains
polyvinyl alcohol 1.4 per cent with Oxyd
0.06 per cent.Although it contains a different
preservative from the medicinal products
Liquifilm Tears and SNO Tears, which each
contain benzalkonium chloride and disodium
edetate, it is also given an in-use shelf life of
28 days.
Conversely, other multidose, preserved eye
drop devices listed in the Drug Tariff have
longer “user lives” ranging from 45 days to
six months (see Panel 1). All these products
contain preservatives, but not ones with
which most pharmacists are familiar.The current BNF does not list the preservatives in
Optive, Oxyal or Systane.19 Martindale does
not list the preservative Oxyd (in Oxyal and
PVA 1.4% Tubilux).
Polidronium chloride (PolyQuad) the preservative in Systane is only listed as an ingredient of a contact lens product marketed in
Mexico for wetting, disinfecting and storage
of gas-permeable and hard contact lenses and
Ocupure (in Blink Intensive Tears) as an ingredient of Blink products marketed in
Argentina and Australia.
Purite (in Optive) can only be found in
Martindale in the title of a reference for a
study comparing efficacy and safety of brimonidine and brimonidine-purite, an
Allergan product not licensed in the UK.14
Oxyd and Purite are brands of stabilised oxychloro complex, a “disappearing” oxidative
preservative that breaks down into sodium
chloride and water when exposed to light.
Purite consists of an equilibrium mixture of
oxychloro species: 99.5 per cent sodium chlorite, 0.5 per cent sodium chlorate and trace
amounts of chlorine dioxide, which have bac26 June 2010 The Pharmaceutical Journal (Vol 284) 635
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Panel 3: Comparison of preservative efficiacy tests for eye drops
British Pharmacopoeia
1980
Sampling
time
Bacteria
Fungi
European Pharmacopoeia 2008
A criteria
B criteria
Bacteria
6h
Log 3
reduction
Log 2
reduction
24h
No organism
recovered
Log 3
reduction
7 days
Log 2
reduction
14 days
Fungi
Bacteria
Fungi
United States
Pharmacopeia 2009
BS EN ISO 14730:2000
Bacteria
Bacteria
Fungi
Log 1
reduction
No increase
from day 0
Log 3
reduction
No increased Log 3
from day 0
reduction
Fungi
Log 1
reduction
Log 2
reduction
Log 3
reduction
Log 1
reduction
No increase
from day 0
Reinoculation to
give 104 to 105
21 days
28 days
No increase No recovery No increase No increase No increase No increase No increase Log 3
from count at from count at from count at from count at from count at from count at from count at reduction
day 0
14 days
7 days
24h
7 days
7 days
14 days
tericidal, fungicidal and virucidal activity.
Polidronium chloride (Polyquad) is an ammonium surfactant preservative widely used
in contact lens solutions.
Are such extended user lives justified for
these products? How are pharmacists able to
ensure that these eye drops are suitable for
their intended use and that instructions for
use are appropriate?
Preservative efficacy testing
The European Pharmacopeia (PhEur) specifies that ophthalmic preparations should be
sterile. Formulations of multidose eye drops
include one or more antimicrobial preservatives to reduce the number of organisms in
the eye drops should contamination occur
during their period of use.
Preservatives used in eye drops licensed as
medicines in the UK are required to meet the
test for efficacy of antimicrobial preservation
as specified in the PhEur. For parenteral and
ophthalmic preparations, the standard A criteria are that the reduction in the count of bacteria (specified strains of Pseudomonas
aeruginosa and Staphylococcus aureus) with
which a sample has been inoculated to a concentration of 105 to 106cfu/ml must be log
2.0 at six hours, log 3.0 at 24 hours, and there
must be no recovery at 28 days.The reduction
in the count of fungi (specified strains of
Candida albicans and Aspergillus niger) must be
log 2.0 within seven days and “no increase” at
28 days.
If these A criteria cannot be met, for example, for reasons of adverse reactions to the
preservative, the reduction for bacteria must
be log 1.0 at 24 hours, log 3.0 at seven days
and “no increase” at 28 days, and for fungi a
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The Pharmaceutical Journal (Vol 284) 26 June 2010
reduction of log 1.0 at 14 days and “no increase” at 28 days (B criteria).
Although the A criteria standards for fungal organisms have not changed since the days
of an independent British Pharmacopoeia
(BP), those for bacteria are less stringent than
those specified in the past. For example, the
1980 edition of the BP required that the
number of bacteria recovered reduced by a
factor of no less than 103 within six hours of
challenge and no organism is recovered at 24
hours and thereafter.22
However, the PhEur criteria are more
stringent than those applied by the United
States Pharmacopoeia (USP) in which organisms are introduced into a sample of the preserved solution to be tested to give a final
concentration of 105 to 106cfu/ml of specified strains of Pseudomonas aeruginosa,
Staphylococcus aureus, Escherichia coli, Candida
albicans and Aspergillus niger.The reduction in
bacteria must be log 1.0 by day 7 and log 3.0
by day 14 with no increase in survivors by
day 28. The test for fungi does not specify a
reduction; rather there should be no increase
in survivors from day 0.23
These less testing standards for eye drop
preservatives have led to use of a wider range
of preservatives in ophthalmic products in the
US than in Europe.
A third test, BS EN ISO 14730,24 now encompassed in the British Standard for contact
lens care products25 has been designed to determine discard dates for these products, including lubricant solutions, which have
historically been used to wet and aid the
comfort of contact lenses.This standard’s preservative effectiveness test involves an inoculation of at least a 10ml sample of the product
No increase
from count at
day 14
with the same bacteria and fungi as used in
the USP test to give a concentration of 105 to
106cfu/ml organisms on day 0 and a second
inoculation to give concentrations of 104 to
105cfu/ml of the same organisms at two
weeks.The reduction in bacteria must be log
3.0 by day 14 and, after reinoculation at this
time, by log 3.0 by day 28. For fungi, there
must be no increase in survivors at day 14 and
no increase in survivors after rechallenge at
day 28. Compliance with these criteria allows
the allocation of a 28-day in-use shelf life.
The required reduction in cfu/ml for bacteria and fungi for the different tests is compared in Panel 3.
The vast majority of eye drops classed as
medicines in the UK contain the preservative
benzalkonium chloride or a combination of
benzalkonium chloride and adjuncts such as
disodium edetate, borax or boric acid.
Charnock tested a range of artificial tears according to the PhEur standard and, as one
would expect, that containing benzalkonium
chloride and disodium edetate met the A criteria for both fungal and bacterial contaminants.26
Although the eye drop containing Purite
0.005 per cent was free of Candida albicans at
seven and 28 days, thus meeting the A criteria for that potential contaminant, it failed to
meet the A criteria for Pseudomonas aeruginosa
and Staphylococcus aureus. The eye drop containing Purite did meet the B criteria for
both bacteria, being free of these organisms at
24 hours after inoculation. The preservatives
used in the other eye drop devices listed in
Panel 1 were not included in this study and
preservative efficacy against two of the organisms usually included in the PhEur test,
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Panel 4: Comparison of ophthalmic preparations, contact lens
care products and artificial tears
Ophthalmic preparations
■ Typically used for short
periods (there are exceptions,
eg, glaucoma, dry eye)
■ Packaged in small volume
containers (up to 15ml)
■ Used on compromised eyes
■ Used once daily or more
frequently
Contact lens care products
■ Used with contact lenses on a
long term basis
■ Distributed in larger volume
containers
■ Used with contact lenses in
healthy eyes
■ Typically used once daily
Artificial tears
■ May be used for for short or
long periods
■ Packaged in small volume
containers (up to 15ml)
■ May be used on compromised
eyes (eg, following surgery)
■ Used once daily or more
frequently
tions are packaged in small-volume containers and are for use for short periods on compromised eyes. Contact lens care products are
distributed in larger volume containers and
are used with contact lenses on a long-term
basis on healthy eyes. The potential risks for
contact lens care products are the
solution/lens interaction causing ocular irritation and the risks of the solution contamination by the repeated (daily) use of the
product.”
So are artificial tear eye drops ophthalmic
preparations or contact lens care preparations?
This question is addressed in Panel 4.
Conclusion
Escherichia coli and Aspergillus niger, was not
tested.26
Preservatives in four artificial tears available in the US were compared by Rosenthal
et al,27 who tested Systane Free, Genteal,
Refresh Tears and Soothe Emollient eye drops
against the preservative effectiveness tests of
the USP. Refresh Tears lubricant eye drops,
which contain Purite 0.005 per cent, complied with the USP preservative effectiveness
test for fungi and for bacteria. The preservatives used in the other eye drop devices listed
in Panel 1 were not included in this study.27
Can UK pharmacists be reassured by the
fact that the brand of artificial tears containing Purite 0.005 per cent complied with
pharmacopoeial tests for preservative efficacy?
The USP test is less stringent than that in
the PhEur and compliance with the PhEur
test was only for the B criteria (those used
when compliance with the A criteria is not
achievable because of adverse effects of a preservative or preservative concentration which
meets the more exacting A criteria). No studies including eye drops containing Purite
0.01 per cent, the concentration used in
Optive the product marketed in the UK,
were identified.
Karageszian et al determined the antimicrobial preservative effectiveness of Oxyd in
accordance with the methodology of the
USP.28 The ophthalmic tear solution tested
complied with both the USP and PhEur tests
for preservative effectiveness against bacteria
and fungi but the formulation of the solution
tested is not specified and the relevance of
this study to the product Oxyal marketed in
the UK is not known.
The new “disappearing” preservatives have
been introduced because of the adverse effect
profile of commonly used eye drop preservatives. López Bernal et al found Polyquad and
thimerosal (=thiomersal) less toxic to the
corneal epithelium than benzalkonium chloride29 and Noecker showed less epithelial toxicity with stabilised oxychloro complex and
with sodium perborate than with Polyquad
and with benzalkonium chloride.30 Ingram et
al found sodium chlorite less toxic to ocular
cells than benzalkonium chloride or hydrogen peroxide and described it as having the
best balance of high antibacterial toxicity
with low ocular toxicity.31 Labbé et al compared the ocular toxicity of benzalkonium
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chloride and polyquaternium-1 and found
that even high doses of polyquaternium-1
were much less toxic than benzalkonium
chloride.32
The lower toxicity of these preservatives
may be a valid reason for accepting their
lower preservative efficacy in the PhEur test,
a test in which a 28-day shelf life is to be allocated, but is this preservative efficacy valid
for an extended in-use shelf life?
If a manufacturer wants to validate a discard date longer than 28 days, annexes to the
standard BS EN ISO 14730 annotated “informative” describe tests to determine extended expiry dates using a variety of
methods. For example, one of the prescribable eye drop devices allocated a six-month
in-use life is tested against discard date procedure I in which the product is rechallenged
with an inoculation of 103 test organisms at
25, 50, 75 and 100 per cent of the proposed
discard date and at 14 days after the proposed
discard date (personal communication).
Although this appears to be a fairly stringent
test and one which reflects the “real life” situation of contamination in use compared
with the pharmacopoeial test, which only
confirms rapid destruction of contaminating
organisms inoculated at the start of the in-use
period, is this efficacy suitable for an artificial
tear device when it would not be applicable
to an artificial tear medicine? Other companies may use other “informative” discard date
procedures.
Discard date procedure II includes a section relating to simulated use in which a 1ml
aliquot is dispensed every three days for three
months, a scenario which does not simulate
use as an artificial tear drop that, when used
for the treatment of dry eye disease, would be
used much more frequently. Pharmacists cannot always determine whether the discard
date procedure applied to a product is applicable to the use of the product in practice because the part IX application process is
treated as “commercial in confidence”.
The standard with which artificial tear eye
drops classed as devices must comply, BS EN
ISO 14730, clearly states which eye preparations it is intended to cover: “There are differences between ophthalmic preparations
and contact lens care products and some of
these are significant in relation to preservative
efficacy testing.Typically, ophthalmic prepara-
In conclusion, what do we have in these new
eye drop devices included in the Drug Tariff?
■ A range of preservative-free, single dose
eye drops that are safe to use as long as
they are used as single doses
■ A range of multidose, preservative-free eye
drops that appear to be safe to use as long
as the patient does not contaminate the
dropper tip in use
■ A preserved eye drop gel that is similar in
composition to licensed medicinal products and, like medicinal products, should
be discarded four weeks after opening
■ A range of multidose, preserved eye drops,
preserved with widely differing concentrations of new preservatives not used
in medicinal products or a preservative
frequently used in contact lens solutions,
with in-use shelf lives ranging from 28
days to six months
An introduction to Part IX of the Drug
Tariff states: “NHS Prescription Services will
normally consider all products which carry a
CE marking to be safe and of an acceptable
quality.”3 However on the limited published
data, pharmacists do not know whether the
multidose, preserved artificial tear eye drops
classed as devices meet the standards required
for an in-use shelf life of four weeks let alone
one in excess of that allocated to those classed
as medicines.
Dry eye is a complex medical condition
defined as a multifactorial disease of the tears
and ocular surface that results in symptoms of
discomfort, visual disturbance and tear film
instability with potential damage to the ocular surface. It is accompanied by increased osmolarity of the tear film and inflammation of
the ocular surface.33 These eye drops, while
complying with the stipulation that “prescribed items allowable on FP10 should be
for the treatment of a medical condition”,3
are tested against a standard for preservative
efficacy for contact lens care products rather
than ophthalmic preparations, a standard not
designed to be applied to prescribable artificial tear eye drops.
Pharmacists will not have forgotten the
withdrawal of several contact lens care products in the past few years. Bausch & Lomb’s
ReNu with MoistureLoc was withdrawn in
May 2006 because it was linked to an increase
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in fusarium keratitis; later that year Advanced
Medical Optics (AMO) withdrew Complete
MoisturePLUS multipurpose contact lens solution and Complete MoisturePLUS Active
because of possible bacterial contamination.
In May 2007 AMO recalled its Complete
MoisturePlus multipurpose solution after reports of Acanthamoeba keratitis associated with
its use.These withdrawals have not been confined to contact lens cleaning and storing solutions. In December 2006, Alcon recalled
Systane Free LIQUID GEL lubricant eye
drops (a product not marketed in the UK)
due to the presence of mould in the solution.
How can we be sure that eye drops using
preservatives other than those used in medicinal products are efficacious in preserving the
product for the recommended in-use shelf
life?
Although fully supporting the search for
less toxic preservatives for patients requiring
artificial tears, ophthalmic pharmacists are
concerned that efficacy tests for preservatives
in multidose ophthalmic preparations are becoming less stringent as time goes on.
Pharmacists require further guidance before they recommend that these eye drops be
used for periods exceeding four weeks in patients with a medical condition, eg, dry eye,
requiring an ophthalmic preparation, eg, an
Panel 5: CHMP conclusions
■ Ophthalmic preparations without preservatives are needed for those patients who do not tolerate eye
drops with preservatives. For long-term treatment, formulations without preservatives are considered to
be valuable alternatives. Ophthalmic preparations without preservatives are strongly recommended for
use in paediatric patients. Therefore, pharmaceutical companies should develop preparations without
preservatives wherever possible in order to cater for the diversity of patients’ needs. Nevertheless, based
on a review of available safety evidence, a general recommendation not to use preservatives in eye drops
cannot be supported.
■ When preservatives are required, the concentration should be at the minimum level consistent with
satisfactory antimicrobial function in each individual preparation and a thorough justification for the
choice of the preservative should be provided.
■ Non-clinical and clinical studies of appropriate design and duration are needed to give reassurance that
the proposed formulations are optimal in term of benefit/risk balance.
■ When preservatives are required, the CHMP considers that it would be prudent to promote new
ophthalmic preparations without any mercury-containing preservatives, eg, thiomersal. This advice is
also in line with the global goal of reducing environmental exposure to mercury.
artificial tear used at a therapeutic dose rather
than for daily wetting of a contact lens.
In December 2009 the European
Medicines Agency reported on discussions by
the Committee for Medicinal Products for
Human Use (CHMP) on antimicrobial
preservatives in ophthalmic preparations for
human use.34 A CHMP ad-hoc group of experts came to several conclusions (Panel 5).
The UK Ophthalmic Pharmacy Group be-
lieves that these statements are equally valid
for eye drops classed as devices rather than
medicines and, with this in mind, has initiated
discussions with the clinical devices section of
the Medicines and Healthcare Products
Regulatory Agency and the professional standards committee of the Royal College of
Ophthalmologists to try to resolve the anomalies and inconsistencies in the regulations applied to artificial tear eye drops.
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