DEVELOPING A NEW SOLUTION
Development of a New Multipurpose Disinfecting Solution: Concept to Clinic
Creating and securing approval of a new MPS is a multifaceted and resource-intensive effort.
By Leslie Napier, PhD, Denise Rodeheaver, PhD, DABT, & Michael Marks, PhD
In the 1960s, Wichterle invented soft hydrogel contact lens materials based on hydroxyethylmethacrylate (HEMA). After receiving FDA approval in 1971, HEMA-based contact lenses resulted in rapid growth of the contact lens market. Over the next three decades, contact lens material innovations were focused primarily on modifications of HEMA soft hydrogels for improved performance and on manufacturing technologies resulting in disposable or frequent replacement lenses. The next major breakthrough in soft lens technology was silicone hydrogel (SiHy) lenses, which were introduced in 1999 and 2001 (Pure Vision from Bausch + Lomb and Focus Night & Day from CibaVision, respectively). Over the past decade, SiHy material evolutions have been focused on adjusting bulk and surface properties to provide high Dks but more wettable lenses. In parallel, continued efforts have concentrated on improving the wettability of non-SiHy daily disposable lenses through the use of migrating marcromolecules, packaging solutions and surface-locked macromolecules. The newest member of the silicone hydrogel family is a daily disposable lens (TrueEyes from Vistakon). Despite the continued innovation and ever-increasing complexity of SiHy materials, the most common reason for patients to drop out of contact lens wear continues to be discomfort. 1
Many contact lenses worn on a daily wear basis must be supported with contact lens care products. Like materials, these products have evolved over the years—from complex, multistep combinations of cleaners and disinfecting agents to multipurpose care solutions (MPSs) containing ingredients to clean, disinfect and wet lenses. The complex nature of multipurpose solutions is often not appreciated. In many ways, these products are even more complex than many ocular pharmaceutical products. For example, multipurpose solutions contain many ingredients that must be combined together to perform multiple functions throughout the lens-wearing day, including providing initial lens comfort, moisturizing the lens to minimize dryness throughout the day, and preventing build-up of tear components on the lens. Contact lens care products must also be compatible, not just with the ocular tissues, but also with the contact lenses and the plastics used in the containers and lens cases.
As with any pharmaceutical product or device, there are many stages of development for a multi-purpose solution. Formulations are initially developed in the laboratory by combining various concentrations of desired ingredients and testing them in preclinical screening models. It can take many years to identify a formulation that meets the preclinical screening criteria. Once a candidate formulation has been identified, additional pre-clinical testing, such as microbiology and toxicology studies, are conducted to ensure that the product is safe for human testing. Clinical studies generally take an additional 1 to 2 years. The clinical results are combined with relevant pre-clinical data for submission to regulatory agencies.
While developing multipurpose solutions has always been a multifaceted and resource-intensive effort, recent events have resulted in additional challenges. New SiHy materials continue to be introduced in the marketplace. Not only are these materials very different from traditional hydrogel materials, they're often very different from each other. In fact, the FDA, along with the International Standards Organization (ISO) and the American National Standards Institute (ANSI), has established a Group V classification for SiHy lenses and is working on sub-classifications within the new category.2 Thus, care solution manufacturers must evaluate potential formulations with many more lenses than in the past. This has added a significant amount of preclinical and clinical testing. The recalls of two popular multipurpose solutions in prior years have resulted in increased scrutiny of this product class. Regulatory agencies are reviewing the current testing requirements and will likely increase these requirements in the future, adding to the resources and time required to develop lens care products. Historically, testing by manufacturers has generally exceeded what is required by regulatory agencies, contributing to the high quality of many products.
This article describes the extensive pre-clinical and clinical testing involved in developing a new contact lens care MPS, Opti-Free PureMoist MPDS and the rigorous testing used by Alcon in exceeding regulatory requirements associated with product development.
Contact lens care solution design and development begins with fundamental research to identify novel ingredients that can improve the contact lens wearing experience. With the introduction of SiHy lenses to the market, Alcon conducted research to identify compounds that could render hydrophobic SiHy lenses more hydrophilic. Initial research studies were conducted with various compounds in simple buffered formulations to understand the interaction of the compounds with these materials. Interactions are assessed by surface wettability, measured with sessile drop and captive bubble techniques, and by bulk moisture,3,4 measured with a lipophilic dye diffusion technique. It is often necessary to modify existing techniques or develop new techniques to better understand compound-material interactions. The captive bubble technique, for example, was modified3 from published methods5,6 to improve reproducibility, and the dye diffusion technique was newly developed. From this initial research, the novel ingredient contained in Opti-Free PureMoist Multi-Purpose Disinfecting Solution (MPDS), poly(ethyleneoxide–butyleneoxide, referred to as HydraGlyde Moisture Matrix, was identified.
Once properties of the novel ingredient are demonstrated, additional studies are conducted to design a suitable formulation. Key considerations in early formulation design include stability under high temperatures, antimicrobial activity and retention of novel ingredient properties. As studies progress, the formulation complexity increases with the addition of antimicrobial agents, buffers and surfactants until a final formulation is identified. Multiple formulation iterations occur during this design phase. Several years of development and testing culminated in the Opti-Free PureMoist MPDS formulation, which was designed to provide optimal moisture, wetting and lubrication for newer generation SiHy lenses.
After the formulation is identified, a lengthy battery of tests is conducted to evaluate the disinfection profile, compatibility with contact lens materials, stability, preclinical safety, and clinical safety and efficacy. These tests are conducted in accordance with recognized national and international standards.
Any new MPS formulation must show disinfection efficacy as defined by FDA and ISO standards.7-9
Opti-Free PureMoist MPDS contains the same patented disinfection platform used in previous generations of Opti-Free products, Polyquad and Aldox disinfectants, that have been safely used by millions of contact lens wearers and thus was anticipated to have the same proven disinfecting capabilities.
Manufacturers can use two different procedures to qualify their care solutions as contact lens disinfectants. The Stand Alone test measures the inherent disinfection capability without the presence of contact lenses. In this procedure, microorganisms are added to the care solution based on the manufacturer's recommended soaking time. The care solution must provide sufficient antimicrobial activity to reduce the required bacteria by 3 logs and the required yeast and fungi by 1 log each in order to meet the primary criterion of the stand-alone test and to be labeled as a contact lens disinfecting care solution. Using this test, Opti-Free PureMoist MPDS reduced bacterial load by at least 4.2 log units, fungi load by 3.9 units and yeast load by 4.8 units, exceeding the requirements.10
If the care solution does not pass the primary criteria of the Stand Alone Test, it must pass the secondary criteria and then proceed with regimen testing that may include rubbing, rinsing and soaking in an effort to qualify the care solution as part of a disinfection regimen. In this test, contact lenses are inoculated with microorganisms and subjected to the regimen recommended by the manufacturer. To pass the regimen test, there must be no more than 10 organisms recovered from the combination of each lens type and lens care solution. If the regimen eliminates the rub, rinse or soaking steps, it must be tested in the Stand Alone Test and Regimen Test using inoculums prepared in organic soil.
In addition to these required tests, manufacturers often conduct tests to further evaluate the disinfecting capability of MPSs. These include testing against clinical isolates from recently occurring ocular infections, testing at elevated temperatures, and evaluating the disinfection capability of the care solution during long-term storage. Opti-Free PureMoist MPDS has demonstrated activity against multiple, relevant clinical isolates and allows storage of contact lenses for up to 30 days.11
The toxicology evaluations required to establish the preclinical safety of a MPS are well defined and are based on a risk assessment approach as outlined in various regulatory guidelines.7,12 Existing literature, studies with similar formulations, and/or de novo testing may be used to satisfy these requirements. Globally, the expected or required toxicology analyses focus on: 1) ocular biocompatibility of the care solution with all lens types; 2) cytotoxicity, 3) sensitization potential, 4) acute oral toxicity, and 5) mutagenic potential. Sensitization, acute oral toxicity and mutagenicity assays evaluate the care solution alone to ensure that the care solution itself does not pose an allergic reaction risk, is not acutely toxic if accidentally ingested, and does not present a long-term mutagenicity risk. Novel ingredients, new lens materials or changes in patient use can significantly influence ocular irritation and cytotoxicity, so the design of these studies must consider: 1) contact lens material types, 2) biocide uptake into and release from lenses, and 3) the proposed clinical regimen.
For Opti-Free PureMoist MPDS, representative traditional hydrogel (Group I and Group IV) and four SiHy (Group V) contact lenses were used in preclinical safety evaluations to assess different polymers, surface treatments and biocide uptake/release properties. These lenses were used in cytotoxicity and ocular irritation evaluations. Two cytotoxicity tests were conducted with the care solution itself and two tests with lenses soaked in Opti-Free PureMoist MPDS to evaluate in vitro cell viability and cellular metabolism. Based on differences in lens properties and biocide uptake-release kinetics, six lens types were used in the pivotal 21-day rabbit lens wear studies for Opti-Free PureMoist MPDS. These studies provided a comprehensive evaluation of repeated daily use of the product in the recommended clinical regimen. An additional, short-term ocular study evaluated the misuse of direct instillation of the multipurpose care solution in the eye during lens wear. Table 1 outlines a standard toxicology strategy to evaluate safety of a new MPS.
Once toxicology testing has shown a product to be safe for human testing, clinical studies can begin. Interestingly, contact lens care products are classified as devices in some countries (for example, Europe and the United States) and as drugs in other countries (for example, Canada). The requirements for clinical testing of contact lens care products in order to obtain a CE Mark for Europe are described in ISO regulations including 11980 and 14155.13,14 The FDA describes their clinical requirements for clearance of contact lens care products in the 1997 510(k) Guidance Document.7 These documents describe the parameters that must be measured, the lenses that must be tested, the study duration required and the minimum required sample sizes. As noted in Table 2, the 510(k) guidelines only require 60 subjects wearing Groups I and IV traditional hydrogel lens types. Thus, many care solutions on the market may have been initially tested on less than 100 subjects. While the 510(k) Guidance is still in effect, the FDA has communicated additional testing requirements to manufacturers, primarily due to the introduction of SiHy lenses and because the ISO guidelines have been updated. This has resulted in a substantial increase in the number of subjects required for clinical testing. As can be seen in Table 2, the subject numbers included in our clinical studies of Opti-Free PureMoist MPDS exceed minimum FDA and ISO requirements.
The goal of clinical testing as described in the 510(k) Guidance is “substantial equivalence.” This means that a manufacturer has to show only that a new care solution performs similarly to one that is currently on the market. It is not required that a care solution be an improvement over one or more products on the market. While substantial equivalence is the regulatory requirement, Alcon believes that a new product should have demonstrable clinical benefits to contact lens wearers that can be communicated to practitioners and patients. In order to do this, Alcon develops a clinical study plan for each product that includes relevant clinical endpoints, multiple patient samples and a variety of contact lens types. In addition, careful consideration of study design factors such as the particular subjective and objective measurements and the time of clinical assessments are taken. Extensive and thorough site training ensures that investigators carry out the study in a manner consistent with the regulatory guidelines and the clinical protocol. Due to these considerations, Alcon was able to demonstrate the benefits of Opti-Free PureMoist MPDS in our clinical studies as described in the clinical summary article included in this Special Edition of Contact Lens Spectrum.
As described above, the development of a new MPS is a long and rigorous process. These care solutions are complex formulations with multiple ingredients having specific functions. They must be evaluated with ever-increasing numbers of different lens materials. Preclinical testing includes stability, microbiology, and toxicology, each governed by specific regulations. Clinical testing involves carefully designed, large, multisite studies incorporating a variety of lens material types and a multitude of subjective and objective assessments.
Opti-Free PureMoist MPDS was in development for 5 years and has undergone extensive testing to evaluate the mechanism of action and the safety and efficacy of the product. Results of this testing indicate that Opti-Free PureMoist MPDS is an advanced entry into the contact lens care sector. Opti-Free PureMoist MPDS is expected to provide contact lens wearers comfort and moisture from insertion to removal, improving the lens-wearing experience and reducing the likelihood of patient drop outs. CLS
1. Richdale K, Sinnott LT, Skadahl E, Nichols JJ. Frequency of and factors associated with contact lens dissatisfaction and discontinuation. Cornea 2007;26(2):168-174.
2. International Standards Organization Systematic Review of 18369-1:2006: Ophthalmic optics–Contact lenses Part 1: Vocabulary, classification system and recommendations for labeling specifications, July 22, 2010; ISO/TC 172/SC 7 N, N 1126.
3. J. Davis, H.A. Ketelson, A. Shows, D.L. Meadows. A lens care solution designed for wetting silicone hydrogel materials. Poster presented during ARVO 2010, Ft. Lauderdale, Fla.
4. Ketelson HA, Dassanayake N, Lyon H, Carey C, Meadows D. In vitro and ex vivo lipophilic dye uptake into silicone hydrogel lenses. Poster presented during ARVO meeting 2007 in Ft. Lauderdale, Fla.
5. Davis J, Baier RE, Meyer AE, Ketelson HA. A new mechanism for facilitated rewetting of silicone hydrogel contact lenses. Poster presented during ARVO meeting, 2011 in Ft. Lauderdale, Fla.
6. Cheng L, Muller S, Radke CJ. Wettability of silicone-hydrogel contact lenses in the presence of tear-film components. Curr Eye Res 2004;28(2):93-108.
7. U.S. FDA Premarket Notification 510(k) Guidance Document for Contact Lens Care Products, May 1, 1997.
8. International Standards Organization 14729: Ophthalmic optics-Contact lens care products-Microbiological requirements and test methods for products and regimens for hygienic management of contact lenses.
9. International Standards Organization 14730: Ophthalmic optics-Contact lens care products-Antimicrobial preservative efficacy testing and guidance on determining discard date.
10. Borazjani RN, McAnally C, Callan M et al. Antibacterial, antifungal, and antiamoebal properties of a novel multi-purpose solution. Invest Ophthalmol Vis Sci 2010; 51: E-Abstract 3414.
11. Data on File, Alcon Research, Ltd.
12. International Standards Organization 10993-1 Biological evaluation of medical devices-Part 1: Evaluation and testing within a risk management process.
13. International Standards Organization 11980: Ophthalmic optics–contact lenses and contact lens care products-Guidance for clinical investigations.
14. International Standards Organization 14155: Clinical investigation of medical devices for human subjects-Good clinical practice.
|Dr. Napier is director and clinical trial management head for Vision Care at Alcon Research. Her team is responsible for global clinical trials on contact lens care and over-the-counter dry eye products. Dr. Napier holds her doctoral degree in biomedical sciences. She has held positions of increasing responsibility during her 13 years at Alcon.
Dr. Rodeheaver is a project toxicologist fellow, responsible for developing preclinical safety strategies, overseeing toxicology evaluations and supporting registration approvals of new contact lens care and OTC dry eye products at Alcon.
Dr. Marks is assistant director of Vision Care R&D for Alcon Laboratories, Inc. He holds a doctoral degree in biomedical engineering and has held several positions in research and development during his 11 years at Alcon.