Originally Published PMPN July 2001
Functional Packages Protect and Deliver
From prefilled syringes to inhalers, drug-delivery systems can handle the most sensitive of drugs.
Erik Swain, Senior Editor
Many of today's new drugs can't be constituted into a solid dosage, or even a stable liquid one. In addition, they may need a special method of dispensing to ensure maximum effectiveness.
These and other factors explain why the development of drug-delivery systems is almost as active an endeavor as the development of the drugs themselves. Some of these systems, from prefilled syringes to inhalers, also serve as container-closure systems that protect the product in some way and are considered functional packaging. Such systems represent some of the most cutting-edge packaging developments of today.
"Most products being developed today are very dependent on their ability to be delivered in a patient-friendly fashion," says Michael Goldberg, MD, chairman and chief executive officer of Emisphere Technologies Inc. (Tarrytown, NY). "That means a successful drug-delivery system is tremendously important."
INNOVATION SPURS INNOVATION
Most of the trends in special delivery systems have roots in the biotechnology industry. By their very nature, biotech products are less stable and more atmospherically sensitive than conventional drugs. They also require a complex route of administration, whether through injection or even through the pulmonary system.
"A slew of drugs have come out or are coming out in the biotech area, and they need drug-delivery forms better than a simple vial," says Gerhard Mayer, PhD, BD Pharmaceutical Systems (Franklin Lakes, NJ). "Many of them are being launched in prefilled syringes."
"There seems to be a pretty definite move to nasal and/or pulmonary applications for a lot of drugs that are now in injection or oral forms," notes William F. O'Dell, vice president of global marketing, West Pharmaceutical Services (Lionville, PA).
For instance, reports say that inhaled insulin is showing some promise in clinical trials for treating Type II diabetes, and some experts say patients suffering from the condition may one day be able to eliminate needle use.
"The reason [for nasal or pulmonary delivery] is to get the drug into the system more rapidly and produce a more rapid onset of the therapy," O'Dell continues. "We have seen a tremendous increase in the number of lyophilized or freeze-dried drugs available. A lot of the newer biotech or genomic drugs are unsustainable in liquid form and the only way to create stability is to freeze-dry them. A lot of new drugs come to market in that state."
The delivery forms used to dispense these drugs usually have moving parts, and the combination of moving parts and volatile drugs can present challenges with drug-package interaction if the system is not developed carefully enough.
"The biggest problem is shelf life," says Paul Oberdorfer, vice president of Air Tite Products Co. (Virginia Beach, VA). "A lot of drugs are prepackaged and then sit on a shelf, and some [materials] in a regular syringe, such as synthetic rubber or silicone oil, can cause problems with interaction. That is why we are working on an all-plastic syringe with no rubber or oil."
Steve Dilts, director of sales and marketing for Unicep Packaging Inc. (Sandpoint, ID), agrees that careful consideration must be given to material selection. "As specialty drugs with more fragile formulations are developed, shelf-life issues are very important," he says. "We have to be flexible in offering solutions to those issues. Our primary material is LDPE, but often we find ourselves using secondary packaging to enhance shelf life. We have also explored using different coatings."
Another material innovation, says Jim Lucas, business development manager, Rexam Sofab (Purchase, NY), is the use of "an aluminum pouch welded onto a dose-monitoring pump. It is an airless pack that provides 100% barrier. Because it provides an airless environment, it has a lot of applications with proteins or peptides, which are light-sensitive or easily oxidized. And there are no rubber gaskets at all, making for a very clean pump. It can dispense highly viscous products in a metering format and can be filled on a conventional system."
CHALLENGES AND RESPONSES
Drug-delivery systems are often unit-dose devices, which Mayer says is not surprising considering that "there is a switch away from vaccines that contain preservatives. The main reason is to get thimerosal, the preservative that has been commonly used in multidose vials, out of the product. This produces a need for single-dose systems."
One concern when using unit-dose devices, Mayer says, is avoiding overfill. "For single-dose systems, prefilled syringes make a lot more sense than a single-dose vial. If you are filling a vial, USP tells the pharmaceutical company to overfill the vial by 25%. Many companies, in fact, overfill by a lot more," he explains. "That translates to lost product and lost profits. But not with a prefilled syringe, where the overfill is typically only 2 or 3%."
West is attempting to reduce the risk of overfilling unit-dose devices for lyophilized and dry-powder injectable drugs with a system called Clip 'n Ject, which features a plastic transfer device that links to a standard vial and uses a prefilled syringe containing a diluent to allow a closed reconstitution of the drug.
"Pharmaceutical manufacturers occasionally do a 20% overfill. That is a huge expense for them, and they do it because of all the problems with reconstitution and variability," says Paul H. Norton, West's program director for the product. "This system has a huge potential to reduce the amount of overfill. Usually when you are doing a reconstitution, you don't know if you are doing it right. This enables you to use the existing drug package in a few easy steps. In addition, because of the way the system is designed, it does not require the pharmaceutical manufacturer to change their package. It reduces their regulatory burden to repeat container-closure integrity or stability studies for their product."
Drug-delivery systems can be used to reduce the potential for medication errors, says Leigh Stewart, director of marketing for Baxter Healthcare Corp. (Round Lake, IL). "One way is providing drugs in a ready-to-infuse package, so that the amount of work a clinician must do to prepare the drug dose is reduced," she says. "Most medication errors occur during administration, so to reduce the number of steps, most of our products are ready to use or at least ready to mix."
Sometimes subtle innovations pay off in drug-delivery development, as Baxa Corp. (Englewood, CO) found out. "We take a standard syringe interface and adapt it for a specific drug, changing the infusion rate to be customized for that particular drug," says Marian Robinson, vice president of marketing. "In one case, after we researched the particular delivery method, we found there was a small market for continuous infusion rather than intermittent infusion. This way you can maintain the blood level and have better efficacy than when you have peaks and valleys dictating how to deliver the drug."
One drug-delivery system was considered so innovative that it received a Gold Award in the Finished Packaging category of the 2001 Medical Design Excellence Awards. The Kabiven multichamber parenteral nutrition packaging system, designed and manufactured by Fresenius Kabi (Uppsala, Sweden), holds a total nutrient admixture in a single container of three chambers separated by inner seals. Not only does this make preparation easier, decreasing the amount of time nurses need to administer the solution, but it allows room-temperature storage for up to 24 months prior to mixing.
"Nurses were asking for a more convenient system," says Lena Soderstrom, Fresenius Kabi's director of project management and strategic marketing, who came to New York City to receive the award at the Medical Design & Manufacturing East conference and exhibition in June. "When you have the ingredients separate, they are easier to handle, because if you mix the product, it has a short shelf life. It is very easy to open because it has three peel- able seals, and it can be used with or without an infusion pump. And the plastic is very easy to handle compared to glass, which is heavy and brittle."
NEEDLESTICK SAFETY
A lot of development activity for drug-delivery systems has been spurred by the passage of the federal Needlestick and Safety Prevention Act in November 2000. With heavy procedural controls now in place for those who administer pharmaceuticals in delivery systems with needles, both industry and hospital end-users see a need to develop systems that provide injury protection or that don't use needles at all.
"The needlestick safety issue is affecting our business in a big way," Mayer of BD says. "When you put a new type of safety system on a delivery device, you have a chance of changing the medical practice at the end-user level. Now that it is the law, our customers understand the need for it, but they also need to understand a wide range of issues that now come up. Safety is 70 to 80% of what we deal with these days."
"Drug-delivery system suppliers can help their customers ensure that this will be a positive and not a negative," he notes. "This is getting far away from what the drug industry knows about. Once you start talking about safety syringes, you have to consider what works, what is the established medical procedure being used, and how to implement a safety system without having to redo stability studies."
BD's own response has been to develop "detachable needles such as the BD SafetyGlide with built-in safety features for luer or luer-lock syringes," Mayer says. (In June, GlaxoSmithKline received FDA approval to market pediatric vaccines in delivery systems using the BD SafetyGlide needles with prefilled syringes.) "For syringes with preattached needles, we also have the BD Preventis, an automatic one-handed safety device that the pharmaceutical company clips over the syringe and therefore does not affect the aseptic processing or stability of the drug. In addition, BD has developed a range of drug-delivery products that eliminate the need for a needle such as the AccuSpray nasal drug-delivery system or the Monovial needleless system for dry drug reconstitution."
Baxter has seen an increased interest in systems that "use a luer-activated device or a blunt plastic cannula to enhance the safety of drug delivery," says Stewart.
But, notes Jeff Turns, senior vice president of Vetter Pharma Turm (Yardley, PA), "there is no universal standard yet" on how these safety systems should be manufactured. "As long as we can do the filling and accommodate the drug company's need for safety, that's what it comes down to."
Ensuring drug-delivery system safety may have other consequences, notes Oberdorfer. "There is a lot of pressure to develop oral dosing for drugs that are now being injected. We are working with a company that is developing special emulsions that can carry drugs that before could not be carried as an oral dose," he says.
There should be even more regulatory developments in this area coming soon, Mayer says. "Self-injection is not covered by the law, but we see that changing sooner rather than later, either through legislative measures or voluntarily by pharmaceutical companies. If you stick yourself, the risk of contamination is not the same, but what happens once the needle goes into the garbage and who has potential exposure thereafter?"
Copyright ©2001 Pharmaceutical & Medical Packaging News
