Development of Sterile Ophthalmics

The global ophthalmics market continues to expand and diversify, but quality control remains a major issue.

by Susan Thompson, Technical Director at VxP Pharma

The worldwide market for ophthalmics is growing steadily. Along with prescription drugs administered via the eye, the sector also includes post-surgery eye products, as well as over-the-counter pharmaceuticals, contact lens solutions and eyecare formulations. Experts estimate the ophthalmics market’s current scale at more than $17 billion, with a compound annual growth rate (CAGR) of six percent; most of that taking place outside the U.S.

However, even as new drugs, reformulations, dosing innovations and emerging markets drive growth in this sector, it’s not without its setbacks. In March 2017, the U.S. Food and Drug Administration (FDA) published a warning letter it had sent to the Singapore-based ophthalmic manufacturer Opto-Pharm, noting that inspectors had discovered “numerous leaking containers and other bottle formation defects” at the company’s facility. Furthermore, the FDA also noted that Opto-Pharm markets some of its products as drugs, while “these products are not labeled or formulated in accordance” with their intended uses.

Warnings like these hint at several issues that continue to challenge ophthalmic developers, along with the contract manufacturing organizations (CMOs) that produce their formulations. Even as the sector grows, concerns about quality and accuracy continue to plague the worldwide supply chain, creating a clear demand for manufacturing partners that can provide sterile, expert-run facilities.

A host of new sterile ophthalmics are entering the worldwide market.

In previous decades, the ophthalmics market was mainly composed of common, low-value active pharmaceutical ingredients (APIs). Today, on the other hand, combined formulations and reformulations are becoming more widespread and diverse. Innovative new treatments are also entering the market, driven by demand from an aging population.

In fact, aging demographics continue to serve as some of the biggest drivers for ophthalmic growth and diversification. While the development of pediatric drugs remains a market force, the vast majority of new ophthalmic drug development is driven by the age-related market. In addition to generic volume products with broad targets, several developers and producers are now targeting more niche diseases and symptoms as well. Treatments for diseases like dry eye, diabetic retinopathy, glaucoma and conjunctivitis have pushed the ophthalmics market toward a high degree of segmentation.

Along with these disorders, eye-related complications like post-operative infections have also spurred growth in the ophthalmics market. Many clinical caregivers actively seek out anti-infectives and post-op ophthalmic therapies. Meanwhile, anti-allergy prescriptions now account for more than half of all sales in drop dose ophthalmics. Anti-infectives and artificial tears round out the market, accounting for at least 20 percent of worldwide sales. In all the areas, the market is either stable or growing at a steady rate.

The key area for growth, however, is that of ophthalmics targeting wet age-related macular degeneration (AMD). Several firms have developed anti-vascular endothelial growth factor-A (VEGF-A) injectables in the form of monoclonal antibodies (mAbs), while still others are currently awaiting approval from the FDA and other regulatory bodies. Within the next year, global sales of these AMD drugs are expected to hit $500 million or more.

But even as the sheer number of ophthalmic therapies continues to proliferate, the methods of delivering those therapies have also become more diverse and specialized than ever before.

Proprietary technologies add further complexity to the sterile ophthalmics market.

Along with new APIs and formulations, the ophthalmics sector is currently witnessing massive growth in new techniques for drug delivery and dosing, while improved droppers deliver drops in more consistent shapes and sizes. Increasingly, organizations are improving on the traditional three-piece bottle design, creating bottles specialized for unit-dose or multi-dose applications.

One reason for this is the mounting evidence suggesting that preservatives may be detrimental to ocular hygiene. In view of these findings, a growing number of formulation technologies promise preservative-free containers, which maintain the formulation’s sterility not only during fill but even after the product is opened. For example, many new containers offer tighter closure, while others are designed to be discarded immediately after a single application. Still other systems provide finer filtration within the closure system of the tipping cap itself.

Quality control remains a major concern in sterile ophthalmics.

However, the issue of whether these systems actually deliver a formulation that’s both preservative-free is another question. While this concept has certainly existed for some time, many attempts at solutions remain unproven. One promising contender is a specialized all-in-one container and delivery system, which allegedly offers a built-in 4.2µ filtration system that pulls sterile air back into the bottle after each drop is dispensed. Rumors abound that other pharma companies are actively developing their own proprietary containers and delivery systems, with this same goal of delivering sterile ophthalmics in a preservative-free formulation.

In addition to innovations in packaging and delivery, many pharma firms are also seeking to profit from their intellectual property in another way: by strategically partnering with other firms to commercialize targeted ophthalmic therapies. Many of these new drugs are biologics such as mAbs, designed to target specific protein receptors and achieve highly specific effects, without the risk of side effects. Like many sterile biologics, however, mAbs are notoriously difficult to develop, challenging to manufacture, and delicate throughout the distribution phase.

Other firms, meanwhile, are developing other proprietary biologic therapies that they claim will combine the benefits of antibody therapeutics and small molecules. Molecular Partners, for example, has been developing a proprietary group of therapies known as DARPins, which (the company claims) combines “the best of both antibody therapeutics and small molecules,” offering powerful, precise therapies with a low development cost. It remains to be seen whether these proprietary technologies will prove commercial viable in this already flooded market.

Meanwhile, novel delivery devices have provided another avenue for technological innovation. One pharma firm, for example, recently developed a system that aims to treat acute anterior uveitis by using iontophoresis to deliver EGP-437, a dexamethasone phosphate ophthalmic solution, to the surface of the eye. This solution sits near the cornea, and promotes the migration of ions across the ocular surface, driving a like-charged API directly into ocular tissue. But this technology, too, remains untrialed and unproven in the market thus far.

In short, while demand for innovative ophthalmic drug containers, delivery systems and therapies continues to rise, the challenges of actually bringing these technologies to market remain significant. And the challenges of development only represent one piece of that puzzle.

Quality control remains a major concern in sterile ophthalmics.

As one might expect in a market as diverse as this one, much of the innovation in ophthalmics is driven not by big pharma firms, but by smaller companies specializing in niche formulations. Some of these companies even focus on a single specific molecule, which they optimize for ophthalmic applications. Others, meanwhile, are developing generics into new branded products.

To an increasing degree, these smaller companies are competing directly against large pharma firms, many of whom are seeking new applications for legacy patents that may be profitable after rebranding. This relatively leveled competitive playing field has given CMOs and CDMOs a broadening range of opportunities to work with firms on a variety of scales, often managing several products for the same customer; and expand their capabilities and expertise along the way.

In fact, because many pharma companies lack the expertise and facilities to manufacture their drugs themselves, they typically partner with a CMO in the manufacturing stage. However, as with any manufacturing partnership, the challenge of maintaining consistency and quality throughout the supply chain can be a major one. In large part, this difficulty derives from the fact that many CMOs are based in non-U.S. locations, and offer their development partners only limited insight in their exact procedures for sourcing, transporting and storing pharmaceutical ingredients.

As the case of Opti-Pharm’s FDA citation amply demonstrates, not every CMO that advertises a sterile manufacturing environment can actually deliver on that claim. As the FDA explained in its report on that case, a successful series of studies on a facility’s performance don’t guarantee that a process is truly quality-controlled. Without a clear understanding of the root causes of defects in container closure and product integrity, sterility shortfalls are likely to reoccur time and again at the same site.

Even so, many ophthalmic developers are now partnering with contract development and manufacturing organizations (CDMOs) earlier-on in the development stage as well. These developers may outsource not only the manufacturing, but the refinement and sourcing of the product to their partners, and even the selecting of the API molecule itself. In following this approach, smaller firms can take advantage of economies of scale that they wouldn’t be able to leverage on their own.

In a sector increasingly defined by aging customers, technological competition and regulatory strictness, ophthalmic development firms are under greater pressure than ever to maintain tight control over their entire supply chain. But in order to achieve this, they need to collaborate closely with their CMO and CDMO partners, from the initial stages all the way through clinical trials and commercialization. For large and small firms alike, a single sterility misstep can spell the abrupt end of a long, costly development process.