For ophthalmic products, the quality of the container closure system (CCS) is critical to the efficacy and safety of the product inside. An inappropriate CCS can have a number of ramifications for pharmaceutical brands – all the way from disrupting the customer experience to compromising patient safety.

We recommend evaluating a container closure system against the seven key criteria outlined below.

Primary containers can potentially leach components into your product. Extractables are chemical compounds that migrate from container into model solvent solutions under controlled and exaggerated conditions depending on temperature, pH, polarity, and time. Leachables are chemical compounds that migrate from container into the final drug product formulation. For the most part, leachables are a subset of extractables, although interaction with product components may produce leachables not seen as extractables.

When evaluating a CCS, it is critical to identify potential extractables and leachables to ensure CCS is a safe choice for your product. Work with a partner that has existing extractable and leachable data available for their containers and can produce new data for innovator products.Ideally, select a CCS that is already in use in the market. AbbVie Contract Manufacturing has fully characterized our CCS, and we possess the requisite data and understanding to leverage this experience for new products.

Any ophthalmic CCS must be developed using particular materials and specifications to ensure chemical compatibility with ophthalmic products. For example, an eyedropper bottle will need to fall within typical ranges for pH, osmolarity, and viscosity. Although you are unlikely to encounter a CCS in the traditional pharmaceutical world that is not designed to meet these specifications, it is nonetheless important to keep in mind when evaluating a CCS. Working with an experienced provider whose experts understand the complex science behind compatibility (and whose containers are already in use in the market) is one way to ensure chemical compatibility.

Ophthalmic containers are semi-permeable, which creates dual risk, allowing external materials to migrate in, and internal materials to migrate out. External materials, such as volatile material from secondary packaging (cartons, package inserts, promotional stickers, and even promotional displays) can out-gas and permeate through a CCS and potentially into the product. It is critical to understand which of these external materials can permeate your product. If the external packaging is provided with the product, the product owner is responsible for providing a thorough data-based evaluation to demonstrate permeability.

Internal materials – primarily water – can also migrate out of the product, even though a sealed bottle. This is problematic because it can affect the stability and potency of the product. The rate at which water leaves the product is referred to as the water-vapor transmission rate (WTVR), and if the rate is too high, it could negatively impact the concentration of the main ingredient and degradants as they are formed.

To combat the risks of semi-permeability, we recommend choosing a primary CCS that is already in use to ensure that the WVTR is already well understood. AbbVie’s knowledge of our CCS and the various components of our secondary packaging, including inks and dyes, reduces the testing burden on our customers, because much of the data they require is already in place.

Whether you are selecting a CCS for a new product or changing the CCS of an existing product, you must ensure you have all the data to prove the CCS is safe and compatible with your product (for example, that there are no extractables or leachables of concern).

For prescription products, this data must be provided upfront to the FDA and/or other global regulatory agencies. For over the counter (OTC) products, this data only needs to be provided if your company is audited. However, the data must be on-hand regardless, so the initial data needs, and the scientific rigor required to assess the data, are the same across prescription and OTC products.

We recommend selecting a partner, such as AbbVie CMO, that fully understands the differences in regulatory expectations for your ophthalmic formula and can align with American Academy of Ophthalmology (AOO) guidelines for color-coding of caps and labels. For example, data requirements differ between preserved and non-preserved ophthalmic presentations, and unit dose and multidose presentations. Experienced providers like AbbVie offer primary containers that are already in use in the market, which means much of the necessary data is already available. Working with an experienced provider can ensure your CCS or product transition is much smoother.

Every ophthalmic container requires a certain amount of overfill to ensure the end user can receive the labeled dosage. This overfill is referred to as the necessary overage required to achieve your volume claims on the label, and it is a particularly important consideration for prescription products taken for a short duration.

For multidose preservative-free formulas, depending on cost and yield, you may want to select a CCS that offers a more efficient extractable volume. It’s important that your supplier knows how to ensure the delivered volume meets patient expectations or requirements – for example, that a 14-day supply provides enough available drops to cover the prescribed doses throughout the treatment course.

Additionally, as the product is used and ages, dispensing tip design and size can impact the CCS’s ability to consistently deliver the proper dose. It’s important to work with an experienced provider who understands these nuances and can help your company select the right CCS for your product and patients.

When changing CCS, it’s important to consider not just what happens inside the bottle, but also how the new CCS may affect secondary and tertiary labeling and packaging. This may not be a major concern from a safety or efficacy perspective, but a bottle that does not fit into existing packaging sizes creates a knock-on effect throughout the packaging supply chain. If a new CCS is slightly larger or smaller, this may require changing the size of the carton or even the shipper, or redesigning the label and package insert.

Packaging concerns may be less consequential when evaluating a CCS for a new product, but for companies looking for a new CCS for an existing product, selecting a similar-sized CCS can save many headaches down the line.

A major consideration when changing the CCS of an existing product is how a change may affect the patient’s experience. Patients rely on consistency from their pharmaceutical brands, and any slight change, such as an adjustment in diameter, color, the effort required to squeeze a bottle, or the ease of delivering the drop onto the eye, can give patients cause for concern.

Products designed to be used in short-course prescriptions may not need to consider these elements, as patients may not notice a difference. But packaging changes to products designed to treat chronic conditions can cause long-time users to worry. An improvement in CCS, however, would likely be welcomed by patients.

Another important part of the patient ‘experience’ and relationship to a brand is a product’s sustainability claims. Consumers increasingly want to understand the environmental impact of the products they use, and regularly used pharmaceutical products, material impact, and recyclability are top of mind for consumers.

We recommend working with an experienced partner that understands the effect a CCS has on the patient experience, and work to either minimize the perceived change or improve the overall experience and sustainability so that a change in CCS is perceived positively by patients.

Ultimately, choosing a CCS is a balancing act: it’s important to make sure any system you consider is chemically compatible and checks the right boxes, while also taking softer considerations such as brand identity, packaging, and patient experience, into consideration. The right CCS is critical to the safety and overall experience of your customers, and therefore, not a decision any company should rush.

For products competing in already crowded markets, the right CCS can be a critical differentiator for your brand. We recommend working with an experienced partner that knows their CCS and packaging well, can provide the right data, and can advise you on the best CCS for your product and brand.

At AbbVie CMO, we deliver millions of doses of leading ophthalmic brands annually. Our expertise in ophthalmic drug manufacturing and fill-finish and the positive track record of our established CCS design and testing program make AbbVie an excellent choice for outsourcing eyecare products.