Sterile Ophthalmic Product Filling: Challenges and How to Address Them

In order to meet the growing requirement for safe, sterile, and secure packaging and delivery of ophthalmic products, a number of innovative pharmaceutical packaging formats are being developed.

Aseptic filling lines must be highly sophisticated and adaptable to address a variety of packaging challenges in this growing market because of the diversity of these sterile ophthalmic medications. Eyes are unquestionably one of the most highly sensitive and vital organs in the human body.

Extreme discomfort can be caused by the slightest irritation, which can lead to swelling, infections, and allergies. Vision could also be affected and could even lead to permanent damage and blindness. Sterile packaging of pharmaceutical products for ophthalmology applications is vital and there is no margin for error during the packaging process.

The eye drops market is split into the categories of eye care eye diseases and others. The ophthalmic/eye care industry is growing fast; it has a projected CAGR (compound annual growth rate) of 5.1 % from 2019 to 2026, when it is projected to reach $ 1.95 billion.

While Europe is growing quickly, North America dominates the global vision care market and Asia-Pacific is an emerging market. Much of this growth is because of the increase in the geriatric part of the market, where deteriorating eyesight is usual.

The larger scope of surgical solutions and a heightened awareness of preventative care for vision loss, together with new topically administered drug developments to treat eye disorders and ophthalmic diseases, will increase the size of the worldwide vision care market dramatically.

Historical overview

A number of eye irritations and ophthalmic diseases are treated with drug products that are topically administered. Yet, where early production environments were unclassified, over the years, the ophthalmic industry has changed massively. Filling operations must be accomplished in cleanrooms with controlled environments as these operations now fall under regulatory scrutiny.

Ophthalmic packaging historically included a glass vial with a separate dropper but the industry moved to plastic containers with a combined drip tip, as the reintroduction of the dropper into the product when dispensing presented a contamination risk.

The minimized risk of user contamination and vastly enhanced containment of the sterile solution brings numerous benefits when compared to glass containers in that they are compressible, unbreakable, and light.

There are also different plastic choices, which possess different features. These must be considered as they can present difficulties when filling products. For instance, as they can tolerate terminal sterilization, polypropylene containers supply increased barrier protection, but they are rigid and hard to squeeze.

Alternative polyethylene components are squeezable and soft but are unable to withstand terminal sterilization and must be pre-sterilized, meaning that for these bottles, the entire filling process must be totally sterile.

Polyethylene is also permeable and can absorb active ingredients as well as preservatives while permitting the ingress of oxygen, which may degrade some products. For each specific product and container combination, stability research must be performed to balance the desired functionality with shelf life.

Today, over 70 % of ophthalmic drug products are simple solutions supplied in multi-dose plastic container closure systems (CCS), which typically contain a supply of the drug for a month or more.

Preservatives like Benzalkonium Chloride help to extend the life of the product, but side effects that have been recently observed have created the market for preservative-free alternatives.

Many new, innovative pharmaceutical packaging formats are being developed because of this and they are regularly introduced to meet the growing need for secure, sterile, and safe packaging and delivery of ophthalmic products.

Regulatory requirements

The FDA’s Centre for Drug Evaluation and Research (CDER) regulates Ophthalmic drug packaging components. These components work together to:

  • Minimize product contamination throughout its utilization
  • Protect the drug product’s quality
  • Aid administration and dosing
  • Maintain product sterility following initial seal breakage by the patient

Ophthalmic drug product packaging is thought to be more critical to product safety and performance than the packaging used for solid oral drug dosage forms because of the extended period of use.

The WHO guidelines for good manufacturing practices (GMP) should be followed for the appropriate system of quality assurance for the manufacture of ophthalmic pharmaceutical products.

As outlined in compendia (pharmacopeias) and standards, e.g., those of the International Organization for Standardization (ISO), the requirements for pharmaceutical packaging and packaging materials must be considered only as a guideline.

The suitability of packaging material or packaging for any particular requirements and conditions can only be established via detailed stability and packaging studies on the particular product.

Quality components are crucial

The quality of ophthalmic pharmaceutical product packaging plays a key role in the overall quality of the product. It must:

  • Carry the correct information and identification
  • Protect against all adverse external influences that can affect the properties of the product, e.g., light, moisture, oxygen, and temperature changes
  • Protect against physical damage
  • Protect against biological contamination

The standard multiple-dose CCS for liquid ophthalmic drug products is made up of a drug-dispensing tip/dropper, a 3-piece eye drop container consisting of a bottle (squeezable plastic container), and cap, as seen in Figure 1. Over seals or other tamper-evident features are frequently incorporated.

Traditional 3-piece eyedrop containers.

Figure 1. Traditional 3-piece eyedrop containers. Image Credit: SP Scientific Products

The 2-piece eye drop for preservative-free products, seen in Figure 2, has been a more recent development. This cap dispenser and container are gaining market acceptance as it stops the requirement for preservatives, which could have detrimental effects on patients.

The product is dispensed through a 0.2-micron filter once the cap has been opened; this prevents the backflow of bacteria. The container sidewalls are very soft, so special consideration is needed to support the neck of the vial during cap closure.

Newer 2-piece eye drop container for preservative-free products.

Figure 2. Newer 2-piece eye drop container for preservative-free products. Image Credit: SP Scientific Products

Depending on the product being packaged, the filling requirements for both types of containers present unique challenges as the product must be accommodated within the sterile filling line.

Addressing filling challenges

Since ophthalmic pharmaceutical product packaging can bring about a number of challenges throughout the filling process, the system which is utilized for filling and capping must be designed specifically to combat these challenges.

The MI-O is one such system. It is developed specially by SP i-Dositecno to handle these extremely light and small plastic eye drop containers, in a number of formats, including aero pump, preservative-free and standard drop caps. The MI-O efficiently orients, fills, places the drip tip, and applies the threaded cap, all in a sterile environment at high speeds.

The MI-O houses multiple key components within its linear layout. This makes it totally adaptable to the specific characteristics of each individual ophthalmic product, allowing the efficient packaging of eye drops in a range of formats, including aero pump, preservative-free, and standard drop caps.

The first main challenge that a system like the MI-O must solve is the fact that the smaller plastic containers are light with a relatively high center of gravity, so they may easily fall over during the filling process.

Vacuum belts may be needed to keep an upright position during the linear transfer process. These plastic containers must be controlled positively from the beginning of the filling process at the unscrambler through to the final cap closure.

Key filling system components

Unscrambler

The plastic containers must be oriented as they all come in bulk. Slower speed applications (less than 100 vials per minute) can be handled by utilizing vibratory sorting bowls and this type of unscrambler is utilized in the MI-O, which can handle up to 6000 vials per hour, as seen in Figure 3 a & b.

A vibratory unscrambler used by the MI-O ensures easy sterile sorting of plastic containers.

Figure 3 a & b. A vibratory unscrambler used by the MI-O ensures easy sterile sorting of plastic containers. Image Credit: SP Scientific Products

This solution is sanitized easily and is perfect for cleanroom applications with laminar airflow. All elements of the equipment can be reached through the Restricted Access Barrier System (RABs) enclosure with gloves.

A mechanical unscrambler is usually employed for higher speed applications (up to 200 vials per minute), as seen in Figure 4. These units are typically larger and more challenging to access through RABs enclosures. The mechanical movements of the unscrambler produce particles and air jets are commonly utilized to help move the vials, which may also introduce contamination.

A mechanical unscrambler used for higher speed filling can prove challenging to clean.

Figure 4. A mechanical unscrambler used for higher speed filling can prove challenging to clean. Image Credit: SP Scientific Products

As it is harder to reach all parts of the machine with RABs enclosures, the mechanical unscrambler is hard to sanitize and clean. So this technique is not ideal from a GMP perspective, but that is often overlooked to gain a higher throughput.

Filling

For a filler, key requirements are that it must accommodate unobstructed laminar airflow over the vial path with minimal shadowing and be designed to GMP standards. The machine should be linear so that all areas can be accessed through RABS gloves for cleaning and sanitization.

The SP i-Dositecno MI-O filling and capping machine has been designed specifically to combat a number of filling challenges and as ophthalmic product characteristics differ greatly, it is vital to have this flexibility built into the filler so that it can handle a number of different filling requirements.

Options can include peristaltic pumps, which use rollers to squeeze a charge of fluid through a tube, although they are not quite as accurate as positive displacement pumps for small volumes. There is no need for a validated cleaning procedure because after a batch is finished, the tubing can be disposed of.

Some customers prefer a peristaltic pump to accommodate a single-use disposable product path. Alternatively, two-piece ceramic piston pumps supply better filling accuracy and cleaning-in-place/sterilization-in-place (CIP/ SIP) capabilities.

In order to withdraw fluid from the tank and then dispense a specific volume into the vial, the piston within a cylinder moves up and down. The piston has a slot on the side and rotates from the inlet to the outlet, which acts as a valve, as well as the cylinder for volume displacement.

This type of system must be cleaned and sterilized between batches. Some ophthalmic products are very expensive and it is vital to include 100% in-process control of the filling weight and to minimize product loss, it must supply a net weight solution during start-up and end of the batch.

Some product families have suspensions that need continuous mixing of the product and to prevent precipitation; they have a subroutine to keep the product moving during machine stops.

Some choices to overcome these issues include the utilization of recirculation and magnetic mixer technology. Some products oxidize quickly and so need nitrogen purging before, during, and after filling to decrease the residual oxygen content within the container headspace.

Cap insertion

Similar to the dropper tips, domed caps must also be handled very accurately by utilizing a pick and place system. Components are fed into a supply hopper, which feeds a vibratory bowl on demand.

The vibratory bowl will move the caps to flow down a chute to a pick and place station where they will be picked up by vacuum and placed onto the top of the container and tip accurately.

Some bottle designs have a recessed thread, which also needs the pick and place station to rotate and start thread engagement. This will stop cross-threading in the final torque station.

Dropper tip insertion

Dropper tips come in many sizes and must have a reliable system to orient them properly so they can be picked up and accurately placed within the neck of the bottle. The vertical force that is required for the final tip placement can also differ depending on the designed tolerances between the bottle and tip.

Some bottles have extremely thin walls for squeeze ability and unless the bottleneck is supported properly by the filling and capping system, they will collapse during the tip placement process.

For instance, two-piece eyedrop packaging for preservative-free products is highly susceptible to collapse and must be supported extremely carefully to stop issues. By utilizing a specially designed pick and place system, as seen in Figure 5, the MI-O can achieve this.

The two-piece eyedrop package for preservative free products is very susceptible to collapse and must be supported carefully to prevent issues

Figure 5. The two-piece eyedrop package for preservative-free products is very susceptible to collapse and must be supported carefully to prevent issues. Image Credit: SP Scientific Products

Cap closing

In order to ensure the container has been fully sealed, the final station on the ophthalmic product filler line captures the cap and rotates the threaded component. As plastic threads will relax over time, precise application torque is crucial and it is vital that a container stays fully sealed throughout its shelf life.

This torquing station is servo driven and so the pre-defined closing torque level will be met consistently. Some advanced filling machines, like SP i-Dositecno’s MI-O, also provide a torque meter system option to monitor and record 100 % of the application torques, as seen in Figure 6.

This is accomplished by utilizing strain gauge instruments to measure the resistance torque of the container directly; the data can then be utilized to readjust application torque settings as needed.

Sophisticated filling machines such as the MI-O can offer a screw torque monitoring system using strain gauges to provide application torque data for all products.

Figure 6. Sophisticated filling machines such as the MI-O can offer a screw torque monitoring system using strain gauges to provide application torque data for all products. Image Credit: SP Scientific Products

Conclusion

The ophthalmic market is growing quickly because of advancements in cures for previously untreatable conditions and an increasingly aging population. Filling lines must be highly sophisticated to handle the wide range of requirements, as the applications and formats of ophthalmic pharmaceutical products are diverse. Advancements have to keep pace with market demands.

Having identified the extremely specific requirements of the ophthalmic market for flexible, advanced, and reliable filling systems as far back as 2005, SP i-Dositecno can meet these technological challenges with its MI-O filling equipment, which has been designed especially for ophthalmic products.

The company has continually evolved its advanced filling lines to accommodate the requirements of the new pharmaceutical packaging formats. SP i-Dositecno can fully support the growing global requirement for sterile, safe, and secure packaging and delivery of ophthalmic products with this constant innovation.

Acknowledgments

Produced from materials originally authored by John Erdner, Portfolio Manager from Fill-Finish, SP Industries, and Alex Armengol, International Senior Sales director from SP i-Dositecno

About SP Scientific Products

SP is a synergistic collection of well-known, well-established, and highly regarded scientific equipment brands — SP VirTis, SP FTS, SP Hotpack, SP Hull, SP Genevac, SP PennTech, and most recently SP i-Dositecno — joined to create one of the largest and most experienced companies in freeze-drying/lyophilization, complete aseptic fill-finish production lines, centrifugal evaporation and concentration, temperature control/thermal management, glassware washers and controlled environments.

SP is part of SP Industries, Inc., a leading designer, and manufacturer of state-of-the-art laboratory equipment, pharmaceutical manufacturing solutions, laboratory supplies and instruments, and specialty glassware. SP's products support research and production across diverse end-user markets including pharmaceutical, scientific research, industrial, aeronautic, semiconductor, and healthcare. In December 2015, SP Industries was acquired by Harbour Group, a private investment firm founded in 1976. Harbour Group is a privately owned, operations focused company based in St. Louis, Missouri. Headquartered in Warminster, Pennsylvania, SP has production facilities in the USA and in Spain and the UK in Europe and offers a world-wide sales and service network with full product support including training and technical assistance.


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Last updated: Dec 15, 2020 at 10:48 AM

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