Avoiding Recalls: How to Ensure Sterility in Ophthalmic Products


In the wake of several high-profile eye drop recalls, we look at the challenges of achieving sterility in ophthalmic products, the consequences of failing to do so, and how AbbVie Contract Manufacturing ensures product sterility and safety.

Millions of patients worldwide rely on ophthalmic drops for treatment of eye conditions. And as the incidence of eye diseases rises, eye medications are set to become a constant presence in the home medicine cabinet. As of 2020, some 1,000 chronic eye disorders were treatable through the more than 400 ophthalmic medications available on the market.

But without adequate sterility measures, ophthalmic medications can quickly become harmful — and even fatal, as recent events have illustrated.

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Recent ophthalmic recalls

A handful of ophthalmic product recalls recently set off alarm bells for consumers, retailers, and manufacturers around the world.

EzriCare and Delsam Pharma Artificial Tears - This eye drop product was voluntarily recalled on February 2, 2023, by manufacturer Global Pharma Healthcare Ltd. The CDC had previously identified an extensively antibiotic-resistant strain of Pseudomonas aeruginosa in open bottles of the product, leading to 81 reports of adverse reactions in 18 states. Patient reports included eye infections, permanent vision loss, and a bloodstream infection that resulted in four deaths.

Apotex Brimonidine Tartrate Ophthalmic Solution, 0.15% - On March 1, 2023, Apotex recalled several lots of glaucoma drops designed to treat open-angle glaucoma and ocular hypertension. The recall was issued as a result of cracks that developed in several bottle caps and led to sterility concerns. No health reports have been received.

Pharmedia Purely Soothing 15% MSM Drops - On March 3, 2023, Pharmedica announced a recall of two lots of its Purely Soothing drops due to sterility concerns. No negative health reports have been received.

Consequences of inadequate sterility controls

Many eye conditions must be treated topically, as oral delivery can degrade active substances.

Topical solutions are typically applied directly to the conjunctiva, coniunctival sac, or eyelids. With the eye being a particularly delicate and vulnerable organ, total sterility of ophthalmic treatments is critical to ensure patient safety and well-being.

When unsafe eye products make it to pharmacy shelves, patients suffer the consequences — from irritation and infections to permanent loss of vision and, rarely, death. Beyond patient health, the businesses involved in a product recall — the retailers, the brand names, and the contract manufacturers — are exposed to a wide range of risks with damaging consequences. These include financial and reputational repercussions, facilities being shut down, production being held up, and legal ramifications.

How AbbVie CMO ensures sterility in ophthalmic manufacturing

Brands looking to meet rising consumer demand for these complex medications should look to partner with a contract manufacturing organization (CMO) with deep expertise and a strong history of success in manufacturing ophthalmic products. An experienced CMO will ensure that your ophthalmic solutions are produced in a sterile manner and maintain their sterility throughout their shelf life, ensuring patient safety and a strong brand reputation.

Making it sterile: Sterility controls used in manufacturing

Sterile filtration

For most ophthalmic products, sterilization occurs as part of fill/finish. The exact process by which ophthalmic liquids are sterilized depends on what the API and formulation can tolerate. Filterable APIs and formulas are sterilized during the filling process using a sterilizing filter. This is the most frequently used technique for eyecare products.

Bulk heat sterilization

Non-filterable formulas, such as those that are too viscous or have active ingredients that can't be filtered, typically undergo bulk heat sterilization.

Aseptic compounding

Sterile compounding is used when materials in the formulation are not suitable for sterile filtration or heat sterilization. This involves the sterile combination of subparts that have been sterilized independently into a sterile vessel/container.

Aseptic compounding is used in conjunction with sterile filtration or bulk heat sterilization. This process combines sterile filtration and introduces sterile container components aseptically, combining the two under sterile conditions.

Manufacturing process controls

A number of additional controls and systems must be implemented during fill/finish to ensure the safety and sterility of ophthalmic products. These manufacturing controls include process controls for bulking, filling, fill volume controls, tip placement, and initial container closure.

These manufacturing controls require validaton to ensure reproducablbity and the overall aseptic filling process is confirmed through aseptic process simulations (media fills) that demonstrate the process consistently provides sterile product.

All container closures must also be confirmed and validated. Unit dose configurations are leaktested.

Engineering controls and utility systems

Beyond direct sterilization, it's important to maintain a clean, controlled environment to minimize chances of contamination during manufacturing and fill/finish. A number of engineering controls in rooms and on and utility systems ensure that contaminants do not enter the product during manufacturing, including air handlers and high-efficiency particulate air (HEPA) filters; purification of water, steam, and compressed gases; room classification and cleanliness controls; differential room pressures; and other cleaning and sterilization processes for these spaces.

Additionally, personnel controls ensure that operators wear sterile gowning and that there are minimal to no operator interventions into the closed fill zone. Continuous environmental monitoring, including viable and particulate monitoring, ensures water, steam, and compressed gases remain uncontaminated.

Keeping it sterile: Ensuring container closure integrity Container Closure systems

Container closures systems must be validated to ensure sterility is maintained through the shelf life of the product.

Many liquid ophthalmic therapies are available in preservative-free multi-dose formulations and containers, which poses challenges due to airborne contaminants that can easily make their way into wrongly selected containers, compromising the sterility of the product. Containers must be appropriately designed or selected to be both compatible with the drug in question and capable of maintianing sterility.

Shelf life and in use considerations:

The risk of contamination is not limited to the manufacturing stage; products can also be exposed to contaminants when in use by patients. Several crucial considerations ensure that the downstream life of an ophthalmic product, particularly preservative-free solutions, remains stable and sterile.

Firstly, the design and selection of appropriate container closures is a critical step for preventing in-use contamination. Single-use configuration offers an inherent level of sterility assurance, but for multi-dose formulations there are two options:

  • Multi-dose, preservative-free (MDPF) presentations offer sterile filtering of air returning to the bottle, ensuring that airborne contaminants do not enter the bottle with each use. 
  • Multi-dose products that require anti-microbial agents. For these products, the design and stability of the preservative and preservative systems must ensure a safe product over the shelf life of the product.

Stability testing throughout the shelf life confirms the drug is effective through the expiry date. This testing includes microbial limits testing or anti-microbial effectiveness testing (AET), which ensures that the preservative remains functional throughout the product's life.

Conclusion: The right partners make all the difference

Ultimately, safe and sterile ophthalmic products are the result of a careful series of quality controls and design choices from formulation to fill finish. For pharmaceutical brands concerned about potential ophthalmic quality issues, the best prevention involves working with an experienced CMO — one that will guide your organization through the numerous smaller decisions required to produce a high-quality, shelf-stable ophthalmic solution. To learn more about AbbVie Contract Manufacturing services for ophthalmic products, visit our Eye Care page or contact us.


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