Review of Standard for Evaluating the Effectiveness of...

TECHNOLOGY/APPLICATION

Review of Standard for Evaluating the Effectiveness of Contact LensDisinfectants

Ruth A. Rosenthal*, Scott V. W. Sutton, Barry A. Schlech

Alcon Research, Ltd., Fort Worth, Texas

ABSTRACT: A new standard has been developed by the International Organization for Standardization (ISO)for evaluating contact lens disinfectants. This paper reviews the ISO 14729 standard and applies it tomarketed products. The historical significance, justifications, scope, interpretations, application, and worthi-ness are discussed. The standard provides a more consistent procedure and a higher standard for contact lensdisinfectants. As a result, more effective contact lens disinfectants have been marketed.

Keywords: contact lens, disinfectants, antimicrobial, ISO, method, procedure, standards

Introduction

The international regulatory hurdles for approvalof a new contact lens care product were formidablein the 1980s and early 1990s. National bodies wererequiring specific, national tests to be conducted.These requirements were in response to concernsover the contamination of lens care products spurredby reports documenting contamination of lensesduring consumer use (20,30,31,47,54), lens cases(6,11,19,24,27), and solutions (3,5,9,12).

Several countries had specific sets of standardsor guidelines which a contact lens disinfectingproduct (CL disinfectant) had to meet in order forthe governing regulatory body to grant approval tomarket in their country. The Food and Drug Admin-istration (FDA) guidelines were the most extensiveregulations governing the approval of contact lensdisinfectants at that time (49,50) and they had asignificant impact on the development of the newinternational standard. The FDA required that aCL disinfectant be tested by a D-Value test andD-Values be calculated (42), although no specificcriteria were set (43). A D-Value is the calculatedtime required to reduce a population of microor-ganisms by 90% or one-log

10 (log). In addition, the

FDA requi red no surv ivors a f te r a l ens wastreated according to label instructions with the CL

* Author to whom correspondence should be addressed:Alcon Research, Ltd., 6201 S. Free Way, Fort Worth,TX 76134. E-mail: [email protected]

disinfectant and accessory products (e.g., cleaners,rinsing solutions) when tested by the MicrobialChallenge Multi-Item Test (MCMIT) (44). On theother hand, the French guidel ines (15,16,17)required that a CL disinfectant show > 5 log reduc-tion on contaminated lenses without the help of acleaning (rubbing) and rinsing step (similar to hardsurface disinfectants). The British (26) had differ-ent standards, requiring that a CL disinfectant meettheir preservative effectiveness standards (i .e. ,a 2-log reduction at 6 hours and a 3-log reductionat 24 hours for bacteria, and a 2-log reduction offungi by 7 days). The Dutch (13) had yet anotherstandard, mandating a 3-log reduction of bacteriawithin the use period and a 2-log reduction of thefungi at 7 days (Tables 1 and 2). This diversity ofnational standards meant that products had tobe tested by multiple tests that were frequentlyill defined.

Why Was the ISO Standard Developed?

Microbiology methods for testing CL disinfectantsneeded to be harmonized for three reasons. First,accurate es t imat ion of ant imicrobia l efficacyrequired precisely controlled and reproducibleconditions. The different conditions mandated indifferent tests may have affected the apparent effi-cacy of the CL disinfectants. Secondly, the expenseassociated with the multiple testing requirementshampered the in t roduc t ion of new produc ts .Agreement was needed as to how to establish effi-cacy criteria for these products. The third reason isthe consideration that contact lenses are inserted

Vol. 56, No. 1, January/February 2002 37

onto the ocular surface; therefore, a disinfectingsolution can not be required to be so strong as todamage the patient’s eye.

This harmonization effort fell under the ISO um-brella. The United States provided major supportin the development these standards. The ISO 14729procedure, “Microbiological Requirements and TestMethods for Products and Regimens for HygienicManagement of Contact Lenses,” for testing of CLdisinfectants emerged.

Developing the Standard

In the 1980s representat ives f rom several CLdisinfectant manufacturers began to draft potentialstandards and criteria. A group of microbiologistsfrom several of the companies in the United Statesworked together to provide procedural detai lswhich would g ive cons i s ten t r esu l t s . Therecommendations were taken to the ISO committee(22) and regulatory bodies of the world. Commentsf rom the g roups were incorpora ted in to the

Table 1. Historical review of antimicrobial activity standards for contact lens disinfection solutions.

Table 2. Historical review of lens challenge testing criteria.

38 PDA Journal of Pharmaceutical Science and Technology

standards. This was the basis for the current ISO14729 standards.

Justifications

There were several areas of debate about theprocedure based on d i ffe rences in h is torica lperspective and usage. The United States FDAwanted organic soil to be included in the testing ofCL disinfecting procedures. The United KingdomMedic ines Cont ro l agency (26) thought tha tAcanthamoeba should be included. The inclusionof virucidal testing was included in the olderFDA disinfection procedures but was less of aconcern. These topics were annexed as informativetechnical reports into the resulting ISO 14729procedure as described below.

A laboratory prepared organic soil composed of amixture of killed Saccharomyces cerevisiae andinactivated fetal bovine serum was part of theearlier FDA guidelines (49,50). This procedurerecommended testing lenses coated with microor-ganisms in this organic soil mixtures by the labeldirections for use of the CL disinfection regimen(7,28). Several representatives argued that testingefficacy of the CL disinfectant solution in the pres-ence of organic soil provided useful informationabout whether the product may become neutralizedby organic material that is likely to be present oncontact lenses removed from the eye. The counterargument was that the use of organic soil was notuseful because there was not a consistent methodfor preparing soil and none of the laboratoryprepared soils accurately modeled tear components(2,18). Additionally, even tears themselves variedin composition from person to person (18,51,53). Fi-nally, since the rubbing and rinsing steps removed soil,it was probably of little value in the Regimen Test. Asa compromise, the use of organic soil in the RegimenTest is an option in an informative technical report inan Annex of the procedure. The practical outcome ofthis compromise is that the use of soil is required inthe United States, but is not required in Europe.

Concern about Acanthamoeba infections in the U.K.prompted the debate over the inc lus ion of arequirement to Acanthamoeba activity. However,the incidence of Acanthamoeba is very low (29,41)and there are no standardized methods for testingAcanthamoeba (4). Therefore, this protozoan is notrequired as a challenge organism.

Testing CL disinfectants for virucidal activity wasnot included in the ISO 14729. The procedure isfor testing CL disinfectants for individual use.Viruses are obligate intracellular parasites and donot replicate or proliferate on contact lenses (34).Test ing products with viruses is impor tant inrelation to trial lens procedures. Trial lenses arereused between multiple patients, following properdisinfection. However, spread of HIV, hepatitis, andadenovirus between patients is a concern (8,10,52).

Scope of the ISO 14729 Standard

The ISO 14729 disinfection procedure evaluatesthe relative efficacy of the CL disinfection system.Two basic principles have been accepted. The firstwas that the new procedure would be based onestablishing criteria that are realistic to achieve, withthe understanding that the innate antimicrobia l

Figure 1. Flow Chart for Stand Alone and RegimenTests. This chart diagrams the relationship betweenthe Stand Alone Test and the Regimen Test in theevaluation of a new contact lens disinfectant. Asummary of the criteria is provided in Table 4.


Stand AloneTest

RegimenTest

Stand AloneTest Passed

Test Failed

RegimenTest Passed

Test FailedRegimenCriteria Met

SecondaryCriteria Met

PrimaryCriteria Met

Yes

No No

No

Yes

Yes

activity of the disinfectant would be assisted by thecontact lens rubbing and rinsing regimen (23).Secondly, the new procedure would al low forapproval of a CL disinfectant based on its activitywithin the lens care regimen.

The final procedure consists of two parts (Figure1). The first part evaluates the innate antimicrobialactivity of the disinfecting solution alone (hence,it was named the “Stand Alone Test”). If a productmeets the primary criteria, it is exempted fromfurther testing by the Regimen Test. It is assumedthat when used with the rubbing and rinsing steps(which removes 103 to 104 microorganisms fromthe lens), the disinfectant will be capable of pass-ing a more stringent regimen criteria (21,39,40).The second part (if required) is the Regimen Test.The Regimen Test evaluates the antimicrobialefficacy of the entire regimen described in the pack-age insert (e.g., rubbing, rinsing, and disinfecting)(Table 3).

The secondary criteria required that the concentrationof each bacterial species be reduced by a minimum1.0 log unit, and that the sum of the log reductionsof the three chal lenge bacter ia had to exceed5.0 log units for the disinfectant to be eligible forevaluation by the Regimen Test. This was believedto be the minimal level of activity acceptable for aCL disinfectant, even allowing for the mechanicalcleansing of the lens.

The ISO disinfection test has several roots. TheStand Alone Test is based on pre-existing antimi-crobial activity tests. These procedures include theFDA D-Value Test, the British Pharmacopoeia Testfor Preservative Efficacy, and the Dutch disinfec-tion test (Table 1). The primary criteria of the StandAlone Test are intended for CL disinfection prod-ucts with a higher level of antimicrobial activity. Ifthe CL disinfectant meets the primary criteria, thentesting by the Regimen Test is not required. Theassumption is made that the rubbing and rinsing

Table 3. Summary of performance requirements for ISO 14729 contact lens disinfection procedures. Passageof the Stand Alone criteria allows the disinfecting solution to be marketed as a disinfectant. This requiresreduction of the challenge organism by the stated log unit values at the end of the disinfection period. Lesspotent disinfectants may be tested as part of a regimen if they meet the “Regimen qualification” criteriaoutlined.


Tab

le 4

. S

um

mar

y of

IS

O 1

4729

pro

ced

ure

. I

SO/F

DIA

147

29.

Mic

robi

olog

ical

Req

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men

ts a

nd T

est

Met

hods

for

Pro

duct

s an

d R

egim

ens

for

Hyg

ieni

c M

anag

emen

t of

Con

tact

Len

ses.


steps of a regimen can be relied upon to lower thecontact lens bioburden to levels suffic ient toensure efficacy when used according to labelinstructions. Therefore, further testing of that prod-uct would not be necessary when it is to be used ina standard lens care regimen that includes rubbingand rinsing of the lens. The primary criteria of theStand Alone Test and Regimen Test criteria werereadily agreed upon. However, some other productsmarketed at that time showed weaker antimicrobialactivity. Therefore, the group agreed to add second-ary c r i t e r ia to the S tand Alone Tes t as aqualification for the Regimen Test. Addition of thesecondary criteria allowed weaker CL disinfectionsystems to be marketed as part of a regimen. Theseproducts had proven safe and effective over time.In addition, the secondary criteria were designedto prevent products, such as unpreserved salinesolutions, from being marketed as the disinfectingpart of a regimen. Therefore, if the disinfectantalone exhibits a lower level of activity, then theent i re regimen is tes ted to ensure efficacy. Atwo-part or two-tier approach is not unique. Thecriteria of European Pharmacopoeia preservationefficacy test uses two levels of preservative activ-ity (14). The Regimen Test is based on the FDAMCMIT and the French AFNOR lens challenge test(Table 2). The Regimen Test evaluates the effect ofthe entire regimen, including the rubbing, rinsing,and disinfection steps as a unit. The ISO 14729Regimen Test uses the best of two procedures: TheFDA MCMIT which evaluates the effect of thedisinfection process to eradicate microorganismsand the French AFNOR Test which uses membranefiltration for recovery and has criteria of a greaterthan a 5-log reduction.

The Stand Alone Test

The Stand Alone Test evaluates the innate anti-microbial activity of the CL disinfectant within therecommended disinfection time. With this proce-dure, three lots of product are evaluated. In the test,each lot of product is challenged with a largechallenge (106 CFU/ml) of five different micro-organisms (Table 4). The microorganisms includeGram-negative bacteria (Serratia marcescens andPseudomonas aeruginosa), Gram-positive bacteria(Staphylococcus aureus), yeast (Candida albicans),and mold (Fusarium solani). The product is sampledfor survivors at 25, 50, 75, and 100% of the disin-fection time for bacteria, and then additionally at

400% of the disinfection time for yeast and mold.The additional sample time was included to pro-vide assurance on the reliability of the study. Ifthe disinfectant meets the requirements of the StandAlone Test, the product can be labeled as a CLdisinfectant.

The Stand Alone Test is designed to increase thestringency and the reproducibility of the test with-out sacrificing the disinfecting capability of the lenscare regimen. Several changes were made in thebase FDA document with these goals in mind:

1. Choice of challenge microorganisms

The Stand Alone test is conducted with aspecific set of microorganisms chosen asindex organisms similar in scope to thoseof the previously used regulatory tests. Themost significant change is the use of thefungus Fusarium solani to replace the spoil-age organism Aspergillus fumigatus in thebattery of challenge organisms. This changewas justified on two counts. First, the fun-gus Fusarium is an ocular pathogen (25).Second, an index organism should displayan intermediate spectrum of susceptibilityto disinfecting agents, allowing differentia-tion among solutions. Fusarium solani isclearly preferable to Aspergillus in this re-gard. Finally, efficacy against Aspergillusis demonstrated in the test for preservationefficacy, also required for regulatory ap-proval of a new disinfecting solution. An-other important change was the control oforganism growth conditions. The ISO 14729procedure has specific requirements for thenumber of passes from the original stockculture and specific growth media, tempera-ture and incubation times.

2. Description of efficacy

A second major change is in the abandonmentof the calculated D-Values to descr ibeefficacy. A D-Value is the calculated timeto reduce a population of microorganismsby 90% or by one-log unit. D-Values areusually applied to thermal disinfectionwhere the kill rate is linear (32). Since thek i l l r a tes o f CL d is in fec tan ts a re no tlinear, D-Values are neither predictive of


antimicrobial activity nor are they reproduc-ible for CL disinfectants. The method fordetermining acceptability in the ISO 14729procedure is a requirement for a specificlog reduction of each challenge species inorder to demonstrate efficacy. This methodis desirable because it is simple and repro-ducible. It has been used as a method to showpreservative efficacy for many years.

3. Required validation

A detailed method is provided for validat-ing the assay. The val ida t ion requiresdemonstration of the ability of the testsystem to recover survivors (33,46,45).

4. Number of lots tested

Data from three lots are required and eachlot is tested with separate inoculum. Thisprovides more information on the perfor-mance of the product.

5. Low level disinfectants may qualify for the“Regimen” test

It was recognized that CL disinfectantsmust have low toxicity because of use inthe eye. The benefits to the patient fromthese sys tems con ta in ing less tox icchemicals outweigh any increased hazarddue to lower bacterial efficacy. A provisionwas made to allow solutions to be marketedas part of a recognized regimen if thedisinfecting solution alone showed a mini-mum standard of efficacy. If a productmeets these minimal standards, then itqual i fies to be tes ted by the RegimenTest. This minimal entry standard is in theISO 14729 procedure to assure that anycandidate CL disinfectant has at least aminimal level of antimicrobial activity. Itwas wel l known that the contac t lensrubbing and rinsing steps are capable ofreducing the microbial load from an initialinocu lum of 10 6 CFU/ lens to about103 CFU/lens (21,39,44). Thus, the combi-nation of preliminary regimen steps, suchrubbing and r ins ing , and the ac t ivedisinfection step provide excellent removaland kill of microorganisms.

The Regimen Test

The Regimen Test was designed to evaluate theefficacy of a disinfecting solution in a regimen(Table 4). The contact lens care regimen as awhole i s eva lua ted , inc lud ing the rubbing ,r insing, disinfecting, and any other identifiedmanipulations. After treating each lens by thesteps outlined in the contact lens care regimen, thenumber of surviving organisms on the lens andin the so lu t ion i s de te rmined by membranefiltration.

The Regimen Test is a carrier test, loosely basedupon the MCMIT. A carrier test is a test whereobjects, such as contact lenses, are inoculated withmicroorganisms and tested according label instructions for use. There are several important pointsof differentiation from the MCMIT, however, as de-tailed below:

1. Choice of challenge microorganisms

The Regimen Test uses the same challengeorganisms as the Stand Alone Test. Again,the major change is the use of Fusariumsolan i a s the cha l lenge organ ism inplace of the spoi lage organism Asper-gillus fumigatus.

2. Organic load

The organic load is optional in this test,in contrast to the requirements of the FDAand the French lens challenge tests. Theorgan ic load cons i s t s o f inac t iva tedbovine serum and killed Saccharomycescerevisiae. I t is a laboratory model fordeposits accumulated during wear, suchas pro te ins , l ip ids , mucins , and o therorgan ic components (53) . However, alaboratory prepared organic load is notthe same as that found in tear deposits.(2,18).

3. Three lots

The efficacy of the regimen against eachorganism must be demonstrated with threedifferent manufactured batches of product.Previously, the FDA allowed testing of onlya single lot of product.


4. Quantitative recovery

The microorganisms from all solutions andlenses are recovered by membrane filtrationand plated onto an agar surface. Passing thetest is determined by recovery of a mini-mal number of microorganisms. The ISO14729 Regimen Test requires that for eachmicrobial species, the average count for alllots tested be no more than (NMT) 10survivors for each lens-solution combina-tion per species. A total of 24 lenses permicrobial species are tested. This is animprovement over the MCMIT because theISO 14729 procedure quantitates the survi-vors, whereas the MCMIT was based onturbidity (indicating microbial growth),which could have resulted from only a fewmicroorganisms, or several million.

5. Validation requirements

The quantitative recovery allows a far moreprec i se va l ida t ion pro toco l than wi thliquid recovery. The Regimen Test is vali-dated to detect low numbers of viablemicroorganisms from the test solution.

The design of CL disinfecting solutions should takeinto consideration the event of non-compliance. Forexample, the disinfection time should be appropri-ate for contact lens wear. Likewise, if the rubbingstep is eliminated, the product should be testedunder stress conditions (23). Although outside thescope of the ISO standard, additional testing of theCL disinfectant, such as other microorganisms, highlevels of organisms, and organic soil , may beconsidered depending on the particular patientinstructions for use of the product.

Interpretation of the ISO Standard

The ISO 14729 standard has two tiers of criteria(Figure 1). The first tier is the Stand Alone Testand the second tier is the Regimen Test. The StandAlone test gives insight into the performance of theCL disinfecting solution without the aid of theproven regimen steps, such as rubbing, rinsing, anddisinfection.

The Stand Alone Test has two sets of cr iteria,the primary and secondary. If the CL disinfectingsolution reduces the level of bacteria by an averagegreater than or equal to 3.0 log units and the levelof fungi by an average greater than or equal to 1.0

Table 5. Comparison of ISO 14729 performance criteria for bacteria at disinfection time.


log units within the recommended soaking period,then the CL disinfectant meets the primary criteriaof the Stand Alone Test (Table 3). Meeting thepr imary c r i t e r ia s imply means tha t the CLdis infectant i s expected to pass the Regimencriteria, if it should be tested. Therefore, if the CLdisinfecting solution meets the primary criteria, itis exempted from further testing and can be labeledas a disinfectant.

If the CL disinfectant fails to meet the primarycriteria, but passes the secondary criteria, then itqualifies to be tested by the second-tier RegimenTest. The secondary criteria are met if the sum ofthe average log reductions for the three challengebacteria is at least 5.0 log units within the recom-mended soaking period with a minimum of a 1.0log reduction for any single bacteria (Table 3). Theproduct cannot be classified as a CL disinfectingsolution or as part of a CL disinfecting regimenaccording to the ISO 14729 standard unless it meetsthe both the secondary criteria of the Stand Alonetest and the Regimen Test (Figure 1).

If the CL disinfectant meets this minimal level ofactivity, it qualifies to be tested by the Regimen Test.The Regimen Test evaluates the label instructions inthe package insert for the entire disinfecting systemor regimen. The Regimen Test requires that the popu-lation of microorganisms be brought to an average levelof NMT 10 CFU/lens (Table 3). If the CL disinfectingregimen meets the Regimen criteria, it can be labeledas part of a CL disinfecting system.

Table 6. Comparison of regimens of marketed products.a

aDescriptions are summarized from marketed product labels.

The Regimen Test actually has more stringentcriteria than the Stand Alone Test, because thesecriteria include the contribution of mechanicalcleaning of the contact lens. A level of NMT10 CFU/lens (Regimen Test) is approximately a5 to 6-log reduction per microbial species, dependingon the inoculum size. In comparison, the log re-duction required to pass the primary criteria of theStand Alone tes t i s a 3 .0 - log reduc t ion fo rbacteria and 1.0-log reduction for fungi. Whereas,the Regimen allows no more than an average of 10survivors (CFU/lens), the primary criteria of theStand Alone test allows up to 1 X 105 (100,000)survivors of some species (CFU/lens) (Table 5).However, the CL disinfecting solutions that passesthe primary criteria are expected to also pass theRegimen criteria because of the contribution ofthe rubbing and rinsing steps to the removal ofmicroorganisms.

The Difference a Regimen Makes

A regimen is any process by which a lens isdisinfected. It is the use directions on the label ofeach CL disinfecting product. Examples of labelins t ruc t ions f rom severa l d i ffe ren t marke tedproducts are summarized in Table 6.

The ISO 14729 infers that, if a CL disinfectantmeets the pr imary cr i ter ia for dis infect ion ofcontact lenses, then the CL disinfectant is exemptfrom conducting the Regimen Test, because it isassumed that if the CL disinfectant were tested


Table 7. Comparison of Stand Alone Test results to Regimen Test results with and without Rubbing andRinsing steps for a 3% hydrogen peroxide system utilizing simultaneous neutralization of the active.a

Table 8. Effect of soil on Regimen Test.

aData originally presented in poster (36).bThe primary criteria of the Stand Alone Test is an average of a 3.0-log reduction of the three bacteria and an average of a 1.0-log reduction of the two fungi.cThe criteria are an average of NMT 10 CFU/lens, which is equivalent to approximately a 5-log reduction.

according to the label instructions, then it wouldpass the Regimen Test criteria. This does not meanthat a CL disinfectant can be marketed without theappropriate rubbing and rinsing steps. For example,a 3% hydrogen peroxide system that meets theprimary criteria of the ISO 14729 Stand Alone Testwill also meet the Regimen Test criteria whentested with the appropriate rubbing and rinsing steps(Table 7). However, when the 3% hydrogen peroxidesystem is used without the aid of the rubbing and rins-ing lenses, it will fail the Regimen Test (36).

Does Soil Make a Difference in the Regimen Test?

I t has been documented in the l i terature thatlaboratory prepared soil can neutralize the effec-tiveness of some hospital disinfectants, such asiodophors, quaternary ammonium compounds (28),and chlorine (38). Similar findings were found fora PHMB preserved contact lens disinfectant whenhigh loads of microorganisms were introduced intothe product (48). However, the effect of soil is notseen when a rubbing or rinsing step is used prior to


disinfection, since most of the soil is removed priorto the disinfection step. Bell et.al., showed that therewas no difference between tests conducted with lensescoated with soil and clean lenses (with no soil) (1).The results are summarized in Table 8.

Easy Regimen to Meet Patient Needs

What the contact lens user frequently requests is aneasy to use regimen; a regimen where the lens doesnot have to be rubbed or cleaned prior to disinfec-t ion . As shown prev ious ly in the case o fhydrogen peroxide systems, a lens cannot simplybe dropped into a CL disinfectant and be expectedto be disinfected. The ISO 14729 standard was withthe assumption that CL disinfectants would be usedwith the standard rub, rinse, and disinfect steps. Thelens must be treated according to label instructions,whatever that is. Products not using the standardregimen steps should prove their claim under stressconditions. One CL disinfectant regimen with norubbing step reported i ts efficacy under stresscondit ions, such as efficacy against numerousclinical and environmental isolates other than thestandard challenge organisms, using high loads oforganisms, in the presence of soil, after storage ate leva ted tempera tures , and dur ing ex tendedstorage. This product was shown to meet both theprimary criteria of the Stand Alone Test and thestringent Regimen Test requirements using a “norub” regimen (35,36,37).

Worthiness of the ISO Disinfection Standard

The ISO 14729 CL disinfection standard will be avery important standard. For the first time in thecontact lens industry, there is consensus on the stan-dard by which CL disinfectants must perform to bemarketed within the U.S., Europe, and several othercountries. There has been intense review, debate,and revisions from all parties. The standard for CLdisinfectants is much higher than the past. Theimplementation of the standard will result in a moreconsistent quality between products. Today, what-ever the regimen may be, CL disinfectants are testedby a standardized test procedure prior to approvalor certification for marketing. The standard givesthe consumer a better assurance of the performanceof the products that they purchase.

Conclusions

The ISO 14729 procedure provides a more consistentprocedure and a higher standard for CL disinfec-tants. The standard has influenced manufacturersto provide CL disinfectants that are now safer andmore effective than ever. In addition, simpler to usedis infectants wi th good performance are nowmarketed. All are benefits to the consumer.


References

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13. Dutch Food and Drug Adminis t r a t ion(Warenwet) “Appendix to the regulation of con-tact lens fluids and eye-washings,” (1979).

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22. International Committee on Contact Lenses,“Contact lens maintenance systems,” ICLC, 19,153-156 (1992).

23. ISO 14729, “Ophthalmic optics – Contact lenscare products – Microbiological requirementsand test methods for products and regimens forhygienic management of contac t lenses ,”(2001).

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27. Midelfart, J., A. Midelfart, and L. Bevanger,“Microbia l contaminat ion of contact lenscases among medical students,” CLAO J., 22,21-24 (1996).

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