REALITY CHECK: HOW FDA TESTING FALLS SHORT
Outdated FDA protocols don't account for real-world usage, newer lens materials and virulent organisms. Proposed updates could bring big changes.
February 1, 2019
This course covers current FDA testing reguations and proposed changes.
Dr. Wu is a postdoctoral research fellow at the School of Optometry and Vision Science at the University of New South Wales, Sydney, Australia.
Dr. Truong has been working in clinical practice for a decade. During this time she also gained a BSci and continued on to submit a PhD at the school of Medicine at the University of New South Wales, Sydney, Australia.
Dr. Stapleton is the head of the School of Optometry and Vision Science at the University of New South Wales, Sydney, Australia.
This course is COPE approved for 2 hours of CE credit. COPE ID is 48363-CL. Please check your state licensing board to see if this approval counts toward your CE requirement for relicensure.
Joint Sponsorship Statement:
This contin uing education course is joint-sponsored by the Pennsylvania College of Optometry.
Drs. Wu, Truong and Stapleton have no financial interest in any products mentioned in this article.
|The increase in Acanthamoeba infection risk among contact lens wearers suggests a need for better FDA testing methods.|
There has been a dramatic shift in contact lens disinfection solutions in the last decade, with multipurpose solutions (MPS) largely replacing more traditional multiple-step systems consisting of separate cleaning and disinfecting liquids, or unpreserved saline in conjunction with chlorine-releasing tablets. Currently, over 90% of patients report use of an MPS for lens disinfection; hydrogen peroxide, polyhexam-ethylene biguanide (PHMB)-based and polyquaternium-1 (Polyquad)/myristamidopropyl dimethylamine (Aldox)-based systems are considered the most commonly used.1,2
While use patterns have evolved, regulatory policy has lagged behind. Manufacturers must comply with FDA guidelines to obtain clearance for the sale of contact lenses and lens care products in the United States. The guide documents in question—Premarket Notification 510(k) Guidance Document for Daily Wear Contact Lenses and Guidance for Industry: Premarket Notification 510(k) Guidance Document for Contact Lens Care Products—were published in 1994 and 1997, respectively. Due to subsequent updates in contact lens technology and reports of adverse health incidents, including widespread Acanthamoeba keratitis, these documents have been deemed by many to be out of date.3-5
The Division of Ophthalmic and Ear, Nose and Throat Devices (DOED) has since suggested a number of changes to these documents—namely, the addition of a test protocol to evaluate MPS efficacy against Acanthamoeba keratitis. Other suggestions include the prevention of environmental contamination, particularly as a result of water contact, and the impact of contact composition on MPS efficacy.2 For example, ionic charge, lens material porosity and relative hydrophobicity are markedly altered between traditional hydrogel lenses and newer silicone hydrogel lenses; these properties are known to impact microbial adhesion and the uptake and release of MPS preservatives, which may compromise disinfection efficacy.6-9
This article provides an overview of specific issues identified with current MPS guidelines and standards applicable to MPS products sold in the United States. Proposed modifications raised by various expert bodies in an attempt to address these issues will also be discussed.
CONTACT LENS-RELATED ACANTHAMOEBA
|Table 1. Conventional Hydrophilic Material Groups|
|I||Low Water Content (<50%), Nonionic*|
|II||High Water Content (>50%), Nonionic*|
|III||Low Water Content (<50%), Ionic*|
|IV||High Water Content (>50%), Ionic*|
|*Being ionic in pH = 6.0 - 8.0|
These microorganisms exist commonly in freshwater and soil environments as either an active trophozoite or dormant cyst form, the latter of which is encased in a double-layer cellulose wall that enables it to withstand harsh en vironmental conditions, including exposure to extreme temperature, pH and dryness.3,4 As a result, they exhibit resilience to many forms of disinfection.3-5 Pathogenic organisms known as endosymbionts, which include Pseudomonas and mycobacterium, may also grow and replicate within the cytoplasm of Acanthamoeba, further enhancing its virulence.6,12
Acanthamoeba keratitis (AK) is a rare but serious corneal infection that is often sight-threatening despite medical interventions.
Beginning in June 2003, investigators identified increased outbreaks of the disease in the Chicago-Gary-Kenosha metropolitan area; consequentially, Complete Moisture Plus (AMO) was recalled in 2007 after a national inquiry found it resulted in an increased risk of Acanthamoeba keratitis.13,14 An elevated level of the disease continued to persist following the recall, however, suggesting the recalled MPS may not have been the sole culprit.7
Several subsequent studies have endeavored to elucidate the persistence of the Acanthamoeba infections post-recall.5,7-9,11,15 Additionally, a microbiology workshop involving the FDA, eye care professionals, microbiologists and members of industry convened in 2009 to discuss testing protocols for Acanthoamoeba disinfection efficacy.16 Below is a general overview of the testing parameters proposed at this meeting:
- What should be the challenge size for testing MPS in the absence of a contact lens?
- Which Acanthamoeba strains should be tested?
- How should the cells be grown in order to obtain cells in the tro-phozoite stage of growth?
- How should cells in the cyst stage be produced?
- How should the number of survivors of trophozoites or cysts be measured?
- What should be the protocol to use when testing for MPS efficacy in the presence of a contact lens?
- What should the overall performance criteria be for the different possible test scenarios?
- Should the MPS's ability to cause the Acanthamoeba cells to encyst be measured?
|Table 2. Silicone Hydrophilic Material Groups|
|V-A||No Water Specification, Ionic*|
|V-B||High Water Content (>50%), Nonionic*|
|V-C||Low Water Content (<50%), Nonionic*, Hydrophilic-monomer Only|
|V-Cm||Low Water Content (<50%), Nonionic*, Surface Treated (ST)|
|V-Cr||Low Water Content (<50%), Nonionic*, Non-ST, Semi-interpenetrating Network|
|*Being ionic in pH = 6.0 - 8.0.|
Other microbiological test method workshops (one in May 2014; the latest in November 2014) have been held by the FDA following the 2009 meeting to accommodate further discussion of test parameters—namely, what strain of organism to cover, life cycle (both trophozoite and cyst stage), growth method and how to encyst Acanthamoeba?18-20,37
No consensus has been reached thus far regarding an appropriate microbiological test method for Acanthamoeba; however, suggestions of critical test parameters include the use of least two different Acanthamoeba strains in cyst form and use of an inoculum size no greater than 1,000 to 10,000 cysts or trophozoites.
Research also indicated Acanthamoeba grown in the presence of bacteria demonstrate less variability in their susceptibility to the MPS tested, as opposed to when grown axenically (i.e., in the absence of other microorganisms).21 Acanthamoeba cysts produced from growth on non-nutrient agar (known as the starvation method) are significantly more resistant to disinfection by PHMB-based MPS compared with cysts induced by Neff's encystment medium.21,22 Therefore, the microbiological and nutritional environment are both significant factors in modifying cyst resistance, and the susceptibility of Acanthamoeba to biocides may vary depending on the experimental conditions.
As manufacturers continue to evaluate MPS efficacy against the test organisms, precise standardized experimental protocols and conditions still need to be defined in order to obtain valid results from multiple sites. Further research is also still warranted to finalize a testing guideline for solution efficacy against the forms of Acanthamoeba likely to be encountered in real world conditions.
Preservative uptake—the absorption of preservative from the solution within the lens case into the lens matrix—is evaluated based on the amount of preservative absorbed from the solution in question at different points in time until a concentration plateau is obtained. Release describes the sequestration of preservative from the lens into an aqueous solution, such as the tear film. Distinct factors that affect uptake and release include water content, charge, relative hydropho-bicity, surface treatment and poros ity of lens material, in conjunction with the concentration, charge, iconicity in the product matrix, molecular weight and hydrophobicity of the care component.22 Variations in the adsorption of the solution components by lenses can lead to differences in the amount and rate of release onto the ocular surface; both can compromise disinfection efficacy of the solution (Silicone Takes Over).8,9
Silicone Takes OverSilicone hydrogel lenses (the first generation: balafilcon A and lotrafilcon A) were first introduced to the market in the late 1990s, when manufacturers began to inject silicone polymers into the original hydrogel monomers to improve material performance (i.e., oxygen permeability, ion transport, deposit resistance and mechanical properties).70 However, while silicone polymers allow high oxygen transmission, they are hydrophobic and thus require the hydrogel polymer water phase to allow transport of gases like oxygen and carbon dioxide, ions and tear film components across the lens.
Additionally, the contrasting properties of the constituent materials of a silicone hydrogel lens result in significantly different lens surface characteristics compared to conventional hydrogel materials, including wettability, deposition of proteins and lipids and lens/solution interactions (e.g., uptake and release of preservative by the lens or biocide sequestration).71-74
A decades-old grouping system developed over 20 years ago, based on contact lens water content and charge, has proved effective for predicting potential solution incompatibilities with the varied range of poly(HEMA) lenses available on the market; however, similar incompatibilities could not be predicted when silicone hydrogel lenses were added to this conventional grouping system (Table 1). For example, the multipurpose solution preservative Aldox, which features a positive charge and hydrophobic tail, demonstrates strong interactions with silicone hydrogel materials—that is, all silicone hydrogel lenses, regardless of ionic charge and/or water content, uptake a greater amount of Aldox compared to poly(HEMA) contact lenses.15,30,75 A silicone hydrogel material group was added to the classification upon identification of this issue and subdivided into five subgroups to account for differences in poly(HEMA) content (Table 2).
Preservative uptake and release are assessed for new solutions according to ISO11986, "Ophthalmic Optics—Contact Lenses and Contact Care Products—Determination of Preservative Uptake and Release,â€ which guides testing to determine if ocular irritation is likely to occur from preservative uptake and subsequent release.
At this time, preservative uptake is assessed by the International Standards Organization and is not currently required for FDA premarket testing of contact lenses and lens care products (see, "Going Global,â€ page 34). However, the FDA has proposed updates to its guidelines advising that manufacturers demonstrate that representative lenses do not decrease the concentration of preservative below the specified concentration range when incubated in a care product solution. The proposed acceptance criterion is that preservative concentration in the lens case should remain within the manufacturer specifications after the recommended soak time. Lenses that do not pass should be labeled as such on the product and packaging or subjected to additional disinfection efficacy testing prior to approval for the US market. This is the first time an acceptance criterion for preservative uptake will be introduced into the guidance.
In addition to concerns regarding compromised disinfection efficacy, preservative uptake and release are critical determinants for solution-induced corneal toxicity. Despite being asymptomatic, a significant proportion of contact lens wearers (i.e., 37% of subjects) that used a PHMB-based system displayed a level of staining consistent with the classic solution-based toxicity reaction.24 Studies have also reported an increased rate of corneal staining associated with several care systems in combination with silicone hydrogel materials.25,26 Several MPS systems were reformulated in an attempt to improve their compatibility with the newest lens materials in order to minimize staining potential. A clinical test matrix for silicone hydrogel lenses was also proposed by the FDA to address clinical performance.
However, some researchers have questioned whether staining has significant clinical relevance, casting doubt on whether the FDA's clinical test matrix is appropriately set up with adequate consideration of these clinical parameters.
LENS WEAR PATTERNS
Research groups continue to investigate if lens wear noncompliance may have contributed to a Fusarium outbreak in the United States and Singapore.27,28 The major noncompliant behaviors identified thus far are: reuse of solutions, especially after lens storage; lack of a manual-rub cleaning step; overnight use of daily wear contact lenses; and the use of lenses past their recommended replacement date.28-30 Other research indicates poor hand washing and lack of understanding regarding proper use of lens care products are other significant noncompliance behaviors, among others.31-39
It has been suggested that solution testing should take into account such behaviors; however, many researchers agree testing for such an array of noncompliant behaviors and situations is nearly-impossible.
Artificial tear use may also have an impact on disinfection efficacy.40 Certain artificial tear components may be used by infective microbes as a source of energy or to enhance the growth of biofilm on the contact lens surface.41-43 Handling a contact lens may also contaminate its surface with organic material, which can neutralize certain disinfectants.44 ISO14729 does not require organic soil to be used when evaluating MPS disinfection; however, the September 2014 microbiology workshop yielded the suggestions of adding an organic soil test (i.e., 1x107 to 1x108 CFU/ mL heat-killed Saccharomyces cere-visiae yeast cells in heat-inactivated bovine serum) and an artificial tear component test (0.5% hen egg lysozyme, 0.1% porcine stomach mucin, human serum, 0.2% bovine serum albumin, 1% albumin, 0.1% mucin and 0.2% mucin) to the standard testing protocol. Additionally, recent research has found that conditioning bacteria to human tear fluid or corneal epithelial cells may upregulate virulence gene expression in bacteria, including those genes resistant to killing.45,46 Therefore, the antimicrobial efficacy of MPS against host-conditioned microbes may be reduced when compared with non-conditioned laboratory standard strains. Use of conditioned bacteria for ISO testing may better reflect the actual MPS biocidal activity against bacteria likely to be encountered in situ.
Inside the BottleTraditional multipurpose disinfection solutions consist of different components that combine to achieve various tasks required for contact lens care. Most MPS products are marketed as single solutions for cleaning, disinfection and storage purposes; each has a specific formulation, though the primary components typically remain the same. These include:
• Preservatives. These substances are responsible for killing microbes residing in and on the contact lenses and also inhibiting contamination of the MPS solution itself for prolonged use after opening.21
Preservative uptake and release profiles vary depending on the kind used in the MPS formulation, which can lead to differing disinfection efficacies.15 Too much of a preservative released from the lens into the tear film can also result in corneal toxicity.22 Common preservatives include polyhexamethylene biguanide hydrochloride (PHMB), polyquaternium-1 (PQ-1), myristamidopropyl dimethylamine, hydrogen peroxide and polyaminopropyl biguanide.
• Surfactants. These are amphiphilic chemicals similar in nature to a detergent that aid in removal of loosely bound protein deposits of an inorganic or lipid nature.41 Due to the amphiphilic nature of surfactants, they may potentially act as lubricants by reducing surface tension.23 This increased wettability buffers interacting ocular tissues from hydrophobic areas on the surface of the contact lens.42 Typical MPS surfactants include isopropyl alcohol, sodium citrate, sodium phosphate, polyvinyl alcohol and sodium borate.
• Chelating Agents. These substances bind proteins and metals like calcium to prevent deposition on the contact lens surface.25 Ethylenediaminetetraacetic acid (EDTA) is the most common MPS chelating agent. EDTA has been shown to be an adjuvant that can enhance biocidal activity.69
• Buffers. Buffers help maintain the pH of the MPS to ensure biocompatibility a enhance comfort and reliability of the component agents. Common MPS buffers include borate, phosphate, bicarbonate, citrate and nitrate.21
• Wetting Agents and Lubricants. These decrease surface tension to increase the wetting angle of the contact lens surface, which leads to improved comfort of the contact lens via reduced friction between the contact lens and ocular surface and eyelids.21 Common wetting agents and lubricants include Tetronic 304, poly(oxyethylene)-poly(oxybutylene), hydroxypropyl methylcellulose, hyaluronic acid, carboxymethylcellulose and propylene glycol.
While the inclusion of these parameters is expected to simulate a more realistic portrayal of daily lens wear and the factors that might complicate it, the obstacle once again becomes how to standardize such parameters, including how to ensure uniformity of human tear conditioning fluid or appropriate incubation times for artificial tear interference testing. Thus, establishing standard testing parameters and setting passing criteria requires further evaluation to adequately replicate real life conditions.
|Fig. 1. Flow chart for Stand-alone and Regimen Tests specified by ISO 18259.18|
Given the controversies, recommendations encourage manufacturers to make evaluating MPS in the presence of contact lenses a standard, at least with respect to biocompatibility. Additionally, lens/solution incompatibilities should be labeled on the product and packaging to help contact lens wearers make an informed decision about their choice of lens care product. The FDA has also proposed incorporating other specific parameters, including the addition of two new strains of Pseudomonas to the test panel and use of organic soil to reflect real-life scenarios.
GP LENS CLEANING
In some cases, contact lenses and lens cases act as vectors for microbes derived from the environment, delivering these microorganisms to the ocular surface where complications may arise. Studies have identified exposure of contact lenses to sources of water, including tap water, as risk factors for Acanthamoeba keratitis.47-53 However, while rinsing with tap water has long been advised against as part of the soft lens care regimen, many GP lens care regimens continue to include use tap water for rinsing as part of their care process.15
The Centers for Disease Control (CDC) revised its Consumer Updates website in 2010 to convey the elimination of water for GP lens care, and the FDA published an addendum to the 510(K) contact lens care labeling guidance; However, some GP lens solutions continue to recommend its use, and many consumers remain unaware of the change.54,55 Potential alternatives to tap water with GP lenses do exist—for example, sterile saline rinses—but the uptake of such options seems to be low.
The group also discussed a related issue regarding scleral contact lenses, which are typically inserted with a fluid reservoir. Often, unpreserved saline is used, but tap water may also be used in some cases. While this may present several problems, it is not clear how common this practice is.
Microbial phenotype and gene expression can also affect a microbe's susceptibility to disinfectants and thus the efficacy of a solution. As mentioned previously, the physical form(s) of the organism have differing biocide resistances. Bacteria conditioned with human tear fluid or with epithelial cells may secrete factors that hinder biocidal activity. The low metabolism of bacteria residing in biofilms may also increase their resistance to antibiotics and disinfectants.13,56,57
Many studies have reported that while some disinfecting solutions perform better than others in reducing planktonic bioburden, most were not effective in reducing biofilm.17,58-61 One study shows that while planktonic organisms may be susceptible to PHMB-and Polyquad-based disinfecting solutions, the susceptibility of these same strains of bacteria contained in a biofilm is considerably reduced.62
Additionally, microbial adhesion and biofilm formation is enhanced in silicone hydrogel lenses compared with conventional hydrogel lenses.14 Researchers hypothesize this observation is due to the increased hydrophobic phases, increased protein/lipid deposits on silicone hydrogel lens and higher oxygen transmissibility/availability.63-66 Even though these observations are mostly in vitro, further study regarding MPS efficacy against biofilm should be considered to warrant safe lens wear.
|Table 3. Criteria for the Stand-alone and Regimen Tests for Contact Lens Disinfecting Solutions|
|Test||Fusarium solani (ATCC 36301)||Candida albicans (ATCC 10231)||Pseudomonas aeruginosa (ATCC 9027)||Staphylocloccus aureus (ATCC 6538)|
|Stand-alone Test (Primary Criteria)||1.0 log unit||1.0 log unit||3.0 log unit||3.0 log unit|
|Stand-alone Test (Secondary Criteria)||Stasis at the soaking time||Stasis at the soaking time||Minimum 1.0 log unit||Minimum 1.0 log unit|
|Sum of the log reductions of the three challenge bacteria must exceed 5.0 log units|
|Regimen Test (includes all mfg. recommended procedures, including rub/rinse.)||<10 CFU on lens||<10 CFU on lens||<10 CFU on lens||<10 CFU on lens|
| ATCC: American Type Culture Collection; CFU: colony-forming units
*Based on average reduction at manufacturer's recommended disinfection time.
COMFORT AND CONVENIENCE
Several MPS systems have been reformulated to improve their compatibility with silicone hydrogel lens materials in an attempt to decrease corneal staining potential. In addition, manufacturers have tried to improve comfort for lens wearers by adding wetting agents. However, while wettability is related to improved lens wear comfort, the recalls of two MPS systems (Complete Moisture Plus and Renu with MoistureLoc) has been hypothesized to be the result of a combination of effects, including the addition of moisturizing agents for comfort.19,20 No isolated MPS component appears to be singularly responsible for enhanced rates of Acanthamoeba encystment and thus increased resistance to biocidal activity.67,68 The interaction of components within a formulation—biocide, buffer and moisturizing agent—appear to interplay, in a so-far unpredictable manner, to affect the eventual biocidal activity.67,68
It is difficult to find the critical balance between improved wettability and solution disinfection efficacy without compromising either. Further research is needed to carefully evaluate the balance between these factors for successful lens wear.
Going GlobalIn most countries, an MPS must meet the International Organization for Standardization (ISO) disinfection criteria before it can obtain licensing, prior to any specific country requirements. There are two pathways to obtain ISO classification, specified by ISO 18259 (Figure 1).26 The first is for a solution to satisfy the primary criteria of a stand-alone test; that is, the solution must have a greater than or equal to 3-log reduction (i.e., 1,000 times smaller than the original amount) in each of the three test bacteria and a greater than or equal to 1-log kill (i.e., 10 times smaller than the original amount) in each of the test fungi. The secondary criteria for the stand-alone test is that the solution must demonstrate the concentration of each of the three bacterial species is reduced by 1 log unit at minimum, and that the sum of the log reductions of the three bacteria exceeds 5 log units.
Supplementing the less stringent secondary criteria of the stand-alone test is the regimen test, which requires the solution reduce microbe numbers to a certain level after a lens rubbing and rinsing process. The specific standards for antimicrobial activity and test microbes specified by ISO18259 are detailed in Table 3.27
Members of the DOED plan to revise the 1994 guidance document for daily wear contact lenses and the 1997 guidance document for lens care products to reflect advancements in contact lens materials, microbial outbreak incidents and increased understanding of the pathogenesis of certain microbes such as Acanthamoeba.
Key issues include consideration of new organisms and lens materials in the test panel, lens/solution incompatibility concerns, real-world factors and clearer labeling for GP lens products.
Additionally, future emphasis is expected to be placed on whether MPS manufacturers should account for noncompliance in their premar-ket testing. Clear and consistent instructions for contact lens and lens case hygiene also remain a critical measure that should be considered. Overall, it is anticipated that revision of the ISO18259 standard will have a significant impact on MPS safety and the contact lens market; the specific repercussions remain to be seen.
Editor's note: Thank you to Dr. Nicole Carnt of the Save Sight Institute, University of Sydney, for peer reviewing this article.
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