Unique Manufacturing Challenges Associated with Sterile Eye Ointments

The manufacture of ophthalmic ointments is much more complex than the production of ocular liquid therapies and presents several unique challenges. It is essential for drug developers to choose outsourcing partners with extensive manufacturing experience with these specialized capabilities in the aseptic processing of these unique products.

The Advantages of Ophthalmic Ointments

With several eye disease treatments reaching blockbuster status and the incidence of chronic eye diseases continuing to rise, drug development activity in this field is increasing. In early 2020, there were more than 400 ophthalmic candidates targeting approximately 1,000 chronic eye disorders advancing through the clinic.¹

Owing to the unique anatomy and physiology of the eye, however, treating eye diseases can be challenging.^2,3 The eye is designed to protect the cornea and retina, which are often target tissues. It is therefore difficult to deliver the correct dose to the appropriate area of the eye. For instance, the bioavailability of traditional eye drops is limited by numerous defense mechanisms in the eye, including lachrymation (tearing), the ophthalmic inner and outer blood–retinal barrier, and the ophthalmic impermeability of the cornea, among others.³ These mechanisms are designed to prevent the entry of harmful foreign substances, but they create significant barriers to ocular drug delivery.

Despite these issues, administration directly to the eye is necessary in many cases, because the active drug substance would be degraded in the intestinal tract if delivered orally.⁴ Of the various options for direct ocular delivery, when possible (treatment of the different layers of the cornea, conjunctiva, sclera, and other tissues of the anterior segment of the eye), topical application is preferred owing to the ease and convenience for patients, as well as lower cost.³

It is known that increasing the viscosity of ophthalmic drugs can reduce nonproductive absorption and drainage and increase the precorneal residence time, leading to productive ocular absorption.3 The contact time for ophthalmic ointments has also been shown to be longer than that for many ophthalmic solutions.

Complex Products

Ophthalmic ointments are complex products with a wide range of aspects that must be considered with regard to their formulation and production. In addition, for many of these products, complex manufacturing processes are involved, and extensive regulatory requirements must be met.

Some of the factors that must be considered when developing a manufacturing process for ophthalmic ointments are the tonicity, pH and buffering, solubility, stability, viscosity, inherent drug substance toxicity, and need for preservatives, as well as the filling, packaging, and storage of the final drug product.⁴  

Ophthalmic ointments have traditionally been packaged in collapsible tin or aluminum tubes. These presentations can be a potential source of metal particles and therefore must be controlled through the component manufacturing process, which may include cleaning before sterilization and filling.³ Plastic tubes are not typically used, because they allow air to enter the tube after the administration of each dose, creating the potential for contamination. Collapsible tubes made from laminates of plastic, aluminum foil, and paper have been developed that can be sterilized by autoclaving, ethylene oxide, or gamma irradiation, depending on the type of material and cap used (polypropylene or polyethylene, respectively).

Requirements for the testing of ophthalmic preparations fall into two categories and are covered in two U.S. Pharmacopeia guidelines: USP <771> Ophthalmic Preparations—Quality Tests⁵ and USP <1771> Ophthalmic Preparations—Performance Tests.⁶ The former addresses the assessment of general quality attributes (e.g., identification, potency, purity, sterility, particulate matter) and the latter addresses the determination of in vitro product performance (e.g., dissolution or drug release of the active drug substance from the drug).³

Sterility is Crucial

The sterility of ocular therapies, including those formulated as ointments, is crucial given the delicate nature of the eye and the fact that these products are applied to the conjunctiva, the conjunctival sac, or the eyelids.⁴ Microbial contamination of ophthalmic ointments creates risks for the patient ranging from serious infection to loss of vision and even death.³ Particulate contamination can also cause irritation and potentially temporary or permanent eye damage.

Assuring sterility of ophthalmic products is not a simple matter, however. It requires the development and implementation of extensive quality management and quality assurance controls within the manufacturing facility. For ointments packaged as multiple doses, antimicrobial agents must be included in the formulation, unless the formulation without antimicrobial agents is sufficiently microbicidal, as outlined in USP <51> Antimicrobial Effectiveness Testing. All ophthalmic dosage forms must be subjected to sterility testing.

A lack of sterility assurance creates the potential for contamination and risk to patients, and it can lead regulatory authorities to recall products and shut down manufacturing facilities until the issues are resolved. A recent example occurred in 2019, when the U.S. FDA recalled hundreds of lots of eye ointments sold under the CVS, Walmart, and Walgreens brands due to sterility concerns.⁷

The Need for Aseptic Processing

While terminal sterilization of filled drug products is preferred by regulatory agencies, for many ophthalmic ointments such a process would degrade the drug substance. Aseptic processing is thus necessary and requires that both the final formulated product and the container used for the ophthalmic preparation are sterile before filling and closing, which must be performed under aseptic conditions.

Options for sterilization of the drug product include filtration, treatment with heat or gamma radiation, or a combination of these processes. The optimum method is determined by the stability and solubility of the drug substance.⁸ While heat and radiation treatment may be applicable for some ophthalmic ointments, sterile filtration is the most commonly employed technique, as it has the least amount of impact on the drug substance.⁴ The formulated product is passed through a sterilizing filter. Filters with ~0.2-μm pores will remove bacteria and fungi and some viruses. The filtered product is filled into the sterile final product container under aseptic conditions.

Before filtration, the integrity of the sterilized filter must be verified. The compatibility of the formulation and any preservatives present must also be evaluated, because they can bind to or be adsorbed onto the filter surface, particularly with membrane filters.

It is also essential, as with any aseptic manufacturing process, to ensure that the facility is designed appropriately and assures a controlled environment that minimizes contact with airborne contaminants, such as through the use of appropriately designed and qualified processes, one-way air flow, high-efficiency particulate air (HEPA) filters, isolators or restricted access barrier systems (RABS), automated handling systems, effectively trained and experienced personnel, and ongoing monitoring of performance.^4,8

Aseptic filling, in particular, is a complex process that poses the greatest risk for contamination and requires careful coordination. There are, in fact, numerous regulations and guidances relating to aseptic manufacturing from various regulatory bodies: USP, the European Pharmacopeia, the International Society for Pharmaceutical Engineers, the International Organization for Standardization, and the World Health Organization (WHO), among others.⁴

Viscous Materials Present Processing Challenges

Ophthalmic ointments, while providing advantages in terms of improved bioavailability and the opportunity to achieve sustained delivery of ocular treatments, present unique manufacturing challenges in an aseptic environment owing to their higher viscosity.

The first challenge is achieving appropriate mixing, which is crucial to ensure a homogeneous product that does not contain variations in drug substance concentrations or pH and is free of large particulates that can cause irritation and damage to the eyes.⁹ Choosing the appropriate mixing equipment is therefore important. Multi-shaft mixers equipped with two or more independently driven agitators working in tandem provide the best combination of bioavailability, high-shear agitation, and laminar bulk flow needed when mixing more viscous materials.⁹ Vacuum/over pressure process systems also allow for gentle mixing at constant pressure.¹⁰ Concentration gradients can be avoided with such an approach.

Filtration of viscous formulations is the second hurdle when producing ophthalmic ointments. Typically, heating the ointment is necessary to reduce the viscosity to the point where it can pass through the sterile filter.⁸ When the drug substance can withstand the higher temperature needed to reduce the viscosity, the final formulation is heated and passed through the sterilizing filter. If the API cannot be heated, it is dissolved in an appropriate solvent and passed through a separate filter. The ointment base is heated, subjected to sterile filtration, and collected in a pre-sterilized, appropriately designed mixing tank, where it is cooled. The ointment base and drug substance are then combined. The transfer of the drug substance to the tank must take place in such a manner as to ensure continued sterility, such as within a closed system.

Aseptic filling of ophthalmic ointments into tubes is the third obstacle that must be overcome. Here again, it is generally necessary to warm the product to get it to flow. While much less heating is required than for sterile filtration, the entire process must still be performed under aseptic conditions. Specialized equipment is also required for filling into tubes rather than more common plastic bottles, vials, or ampoules. Overall, the manufacture of ophthalmic ointments is much more complex than the production of ophthalmic liquids.⁸

Selecting the Right Manufacturing Partner

The growing demand for ophthalmic treatments — combined with the manufacturing complexity and need for specialized equipment and expertise — is driving greater outsourcing of ophthalmic drug development and production operations to contract service providers.¹

Choosing the right outsourcing partner for projects involving ophthalmic ointments is essential to ensure the development and manufacture of high-quality ocular therapies that meet expectations for safety and efficacy. The ideal contract manufacturing organization (CMO) will have an established track record of success in this area and clearly demonstrated capabilities in aseptic processing and sterile fill-finish of ointments.

AbbVie Contract Manufacturing is one CMO with clearly demonstrated capabilities for bringing complex ophthalmic ointment products to market. In addition, as a CMO embedded within AbbVie Inc., AbbVie CMO has access to the experience and assets of a global pharmaceutical company. As a result, we not only have robust quality processes to ensure compliance with global regulatory requirements but are in a position to provide our customers with supply chain integrity and unparalleled support throughout clinical development, technology transfer, scale-up, manufacturing, and packaging.

References

1. Ophthalmic Drugs Contract Manufacturing Industry 2020-2030 by Product, FDF Manufactured, Primary Packaging, Scale of Manufacturing, Company Size, Key Disease Indications, Key Geographical Regions. Research and Markets. 20 Feb. 2020.  
2. Patere, Shilpa et al. “Influence of Manufacturing Process Variables on the Properties of Ophthalmic Ointments of Tobramycin.” Pharm. Res. 35:179 (2018). 
3. Aldrich, Dale S. et al. “Ophthalmic Preparations.” Stimuli. 39(5) (Sep.–Oct. 2013).
4. Sandle, Tim. “Sterile Ophthalmic Preparations and Contamination Control.” Institute of Validation Technology. 29 Aug. 2014.  
5. USP <771>  Ophthalmic Preparations—Quality Tests
6. USP <1771>  Ophthalmic Preparations—Performance Tests
7. Neal, David J. “Another major chain’s over-the-counter eye ointments recalled. They might not be sterile,” Miami Herald. 11 Jul. 2019. 
8. “Aseptic Manufacturing: A Roadmap to Excellence” Special Report. Pharmaceutical Manufacturing. n.d. 
9. Banaszek, Christine. “Recommended Mixing Equipment For Ophthalmic Preparations.” Pharmaceutical Online. n.d.   
10. “Product application for sterile technology: Production line for eye ointment.” Gemu Group. n.d