Aseptic design considerations for preservative-free medication dispensers

By April 3, 2017Healthcare

By Joe Keenan, Director of Sales and Business Development, Healthcare Dispensing Systems.

Plastic-based dispensers are commonplace for Ear, Nose, Throat (ENT), Ocular and Topical medication delivery. Traditionally, engineering focus for these devices has been primarily on dosage modulation, metered-dose precision, human factors considerations and, of course, unit cost. These dispensing devices are typically designed to protect the integrity of the medication via proper sealing attributes and proper drug contact materials selection. However, drug manufacturers have typically relied on the use of preservatives in the formulation in lieu of the device to protect the medication from bacterial contamination.

Now, consumer preference and brand team desires for differentiation are driving manufacturers, particularly in Europe, to remove preservatives from formulations, because they can create adverse reactions in many patients. The side effects of preservatives often include irritation of the nasal passages, nose bleeds, allergic reactions and tissue thinning or damage – particularly a concern with chronic medication usage. Our quantitative research has shown that 80% of patients prefer preservative-free medications, and they are often willing to pay more for them. The research also found that the vast majority of physicians and pharmacists prefer prescribing/recommending preservative-free medications.1

So, how can drug manufacturers appeal to health care providers and patients with medications that are both preservative-free and protected from contamination?”

Managing bacterial contamination in products for safe patient use is a numbers game. Our own microbiome, the community of microbes that live in each person, is vast. We host a myriad of microbial strains, both good and bad. Our bodies’ health and proper functioning rely heavily on maintaining the proper balance of good microbes versus bad.

Like in our bodies, the ingress of one bad microbe into the formulation with subsequent delivery to the consumer is not of much concern. However, if that microbe is able to take residence in the formulation and colonize unabatedly, subsequent dosing of the medication may inject such a bolus of bad bacteria to the user’s target site, for instance their eye, that it can potentially overwhelm the body’s natural microbiome balance. The bad microbes then become the dominant and flourishing flora, and infection ensues.

Preservatives can effectively prevent this. Fast-kill preservatives such as benzalkonium chloride (BAK) do not give bad microbes a chance to take root. Bacteriostatic formulations also have the same inherent protection. However, if the delivery devices for a preserved or bacteriostatic formulation are not manufactured in proper hygienic conditions, bad microbes can take root in the pre-filled device, as their colonies can take safe harbor via biofilm protection, even when filled with these formulations. The outbreak of infections/deaths in the US caused by contaminated disinfectant products in 2012 is an example of this risk.2

Designing a preservative-free medication dispenser puts a heavy burden on the engineer to ensure that bad microbes cannot infiltrate the drug reservoir and colonize. The following are the most common methods and tools of the trade that are used to achieve a safe and effective preservative-free delivery system.

Single-use vs. Multi-use

Single-use devices are a popular modality for preservative-free medications. They have a distinct advantage over multi-use devices since their drug reservoirs are not subject to repeated exposure. Blow-Fill-Seal (BFS) ampules are popular in ophthalmology, since they are aseptically filled and are discarded after one dose. If proper hygienic and sterile practices are used in their manufacture, filling and patient use of these products, they are a safe choice.

The downsides of single-use devices compared to multi-use devices are their cost and drop delivery precision (i.e. ophthalmic). One example of an offering that combines the best of both worlds is the offering from Mystic Pharmaceuticals, which offers the precision, convenience and better economics of a multi-use device, and also incorporates dosing in individualized blister pockets.

Materials

Pharmaceutical packaging engineers already need to limit their material choices due to pharma grade material requirements, sterilization stability, etc. For developing preservative-free dispensers, engineers will often look for materials that will inhibit the growth of microbes near the dispenser outlet. There are several antimicrobial additives that can be used in the molding process that can impede the colonization of microbes. The engineer must balance this additional cost verses the empirical effectiveness in making the right selection.

Surface modification processes can also be used to change the surface tension of the dispenser outlet. This has the advantage of expediting the wicking of residual formulation from the dispenser tip and reducing microbial surface adherence. Again, cost verses empirical effectiveness needs to be taken into consideration.

A popular material that is employed in some preservative-free dispensers on the market is an inserted silver coil just inside the dispenser tip outlet. This coil releases silver ions within the formulation, which act essentially as a preservative by having an oligodynamic effect on microbes that slip in. While very effective, many drug manufacturers have raised concerns over compatibility of their formulations with silver ions and potential patient allergies and side effects from long-term exposure, such as localized argyria.

Mechanical Elements

Tip seals are commonly used to mitigate bacterial ingress into dispenser tips. These systems typically employ a spring-loaded shut off valve that opens under pump pressure and closes when pump pressure subsides. It is important for engineers to design the tip seal so that it does not create a negative pressure at the tip when pump pressure subsides – doing so may cause lingering microbes at the dispenser tip to be drawn in to the medication reservoir.

Preservative-free dispenser systems are typically coupled with containers that are either standard bottles or airless systems. Standard bottles require air back fill in order for the pump to work effectively. In these cases, a filter will need to be fitted in the air path, typically 0.2μm porosity, in order to effectively block microbial ingress. Airless systems using bag-in-bottle technology do not need air back fill, as their reservoir bag collapses as the medication is drawn out.

Benefitting pharmaceutical brands and consumers

In closing, devices and technology exist today to provide safe and effective delivery of preservative-free medication. These devices can reduce the discomfort typically caused by preservatives, thus providing consumers with a better medication usage experience. Our annual, global Packaging Matters™ study indicates that a positive experience with packaging can lead consumers to repeat purchase, meaning increased sales for brands. Therefore, packaging that enables preservative-free medications offers benefits to both pharmaceutical brands and their consumers.

1 WestRock Quantitative Research. 2009.

2 12-12-12 FDA HHS Public Hearing _Full Transcript_.pdf