Formulations intended for ocular delivery must comply with a wide range of guidelines, both physiological and regulatory.
Ophthalmics remain one of the most successful categories of pharmaceuticals worldwide, with a market cap of at least $17 billion, and a compound annual growth rate (CAGR) of six percent. In contrast with drugs in other high-growth sectors like biologics, many conventional ophthalmic drugs are relatively straightforward to develop and manufacture; a fact that draws an ever-growing number of pharma developers to this space.
But the world of ophthalmics is not without its challenges. Ophthalmic formulations must be carefully balanced to ensure adequate bioavailability and minimal irritation, while maintaining sufficient quality control to gain regulatory approval.
The following sections outline several key considerations in ophthalmic formulation development, and discuss the measures some developers are taking to address these issues.
An ophthalmic formulation may take the form of a solution, a suspension, an ointment or an emulsion.
One of the most popular forms of opthalmic formulation is the topical instillation: a solution that enables the active pharmaceutical ingredient (API) to be administered directly onto the surface of the eye. But while topical instillations are easy and safe, they tend to offer low bioavailability, since reflex blinking and nasolachrymal drainage tend to wash much of the fluid away from the cornea.
To address this challenge, pharmaceutical developers have created a number of innovative alternative formulations. For example, a suspension causes the API to remain in contact with the cornea for a longer period. By varying the size of drug particles within a suspension, the manufacturer can even create a formulation in which some particles are absorbed immediately, while others come to rest in the precorneal pocket for longer-term release.
Another option is to suspend the API in a hydrocarbon that melts at the eye’s surface temperature, creating an ointment that can be applied directly to the cornea. As the ointment melts, the API can be released at a sustained rate over an extended period. However, it’s crucial to note that ointments are known to cause irritation, inflammation, and even impaired vision. Thus, this type of formulation should only be used when necessary.
For a combination of high bioavailability and excellent solubility, some ophthalmic manufacturers are turning to emulsions, in which the API is dissolved in oil, which is then dispersed in water. Emulsions can deliver high concentrations of API over extended periods, with minimal irritation. But there’s a drawback: research on ophthalmic emulsions still in the experimental stages. Manufacturers are currently testing a wide range of emulsion additives, from mucoadhesive polymers to lipid additives; and a set of clear best practices still remain to be established.
The ophthalmic formulation’s pH should be close to that of tear fluid.
One unique challenge of ophthalmic formulation development is that of pH. While all drug formulations must be pH-balanced in ways that optimize the stability and bioavailability of their API, ophthalmic formulations must also avoid causing irritation to the highly sensitive cornea and precorneal tissue. In order to avoid irritation, the pH of ophthalmic formulations should be kept as close as possible to 7.4, the pH of tear fluid.
Of course, this presents some development challenges, as many drugs are chemically unstable at this pH. For this reason, many ophthalmic manufacturers add pH buffers to their formulations, in order to delicately adjust the pH into a range that preserves the API, while also causing a minimum of eye irritation. This can require a significant amount of trial and error; and the help of a contract manufacturing organization (CMO) experienced in ophthalmic development can greatly streamline this stage of formulation development.
All properties of the ophthalmic formulation must be aligned with FDA guidelines.
One of the greatest disasters that can befall a drug is to meet with regulatory disapproval in the final testing stages; or, worse yet, after manufacturing has already begun. Drugs that fail to obtain approval from the U.S. Food and Drug Administration (FDA) and other regulatory bodies may face restrictions and even outright bans in some countries. Thus, it’s critical to align all properties of an ophthalmic formulation with regulatory guidelines, right from the start.
For example, the FDA is likely to deny approval to ophthalmic formulations that include coloring agents. Formulations that cause excessive irritation are also likely to meet with disapproval. But these guidelines are only the beginning. The most effective way to avoid regulatory trouble is to partner with a CMO who knows how to navigate the ophthalmic space, and can help design the entire testing and manufacturing pipeline with regulatory approval in mind.
An ophthalmic formulation must remain both sterile and microbe-resistant.
Sterility is essential for ophthalmic formulations, because they come into direct contact not only with the surface of the cornea, but also with precorneal tissue. The easier it is for these tissues to absorb the API, the more easily they can absorb bacteria and other contaminants, creating serious health risks for patients, not to mention legal risks for manufacturers.
These risks are very real, and demand great caution on the part of any ophthalmic developer in search of a trustworthy contract manufacturing partner. In March 2017, for example, the FDA sent a warning letter to Singapore-based ophthalmic manufacturer Opto-Pharm, sternly reprimanding them for allowing containers in their facility to leak and become contaminated.
The case of Opti-Pharm provides an important case-in-point about the development of sterile ophthalmics: the sterility and microbe resistance of an ophthalmic formulation depend not only on the formulation itself, but equally on the contract manufacturer’s ability to follow good laboratory practices (GLP) and good manufacturing practices (GMP), and maintain a sterile environment and packaging pipeline until the formulation is sealed in its final containers.
In short, an ideal formulation is only one component of a successful ophthalmic drug. Good laboratory practices are equally crucial for regulatory approval. For this reason, many ophthalmic developers are choosing to partner with experienced CMOs early-on in the development process, in order to optimize formulations, testing procedures, and manufacturing pipelines toward the release of a successful ophthalmic drug.