Child-Resistant, Unit-Dose Packaging for Clinical Trials
Clinical trials management firms are helping to design clinical trial, unit-dose packaging that is stable, compliant, cost-effective, and quick to produce.
Jenevieve Blair Polin, Contributing Editor
|For its Pick and Peel system, ProClinical seals a child-resistant overlay to the back of the blister card.|
In May 2002, the phase-in period for child-resistant (CR) packaging for clinical trial drugs will be over. From this point on in U.S. studies, Consumer Product Safety Commission (CPSC) guidelines dictate that the primary packages for all clinical trial drugs toxic enough to harm a small child and distributed for outpatient use must have CR features. The greatest challenge posed by these requirements is their application to blister packaging, considered essential for many complex crossover and titration studies.
REGULATIONS AND TESTING
CR blister packaging has been available for years for commercial products, but the same approaches were not directly transferable to clinical trial packaging. "Typically when you develop tooling and dies for a commercial blister package, those particular tools are used for years to package millions of units of a product that generates income," points out Frank Tiano, vice president, U.S. operations, of PCI Clinical Services (Philadelphia). In contrast, he says, "More times than not, Phase III clinical blister packages are unique presentations that will never see the light of market."
Performing a child test protocol for every clinical trial blister package would also have been a major obstacle. Tiano was instrumental in forging an agreement between CPSC and the packaging industry. CPSC agreed that as long as a package design incorporates a CR feature described in ASTM D3475, the manufacturer may forgo the child test protocol. "That was a major break for us," Tiano emphasizes. "You can imagine with 500 companies out there lining up at three or four testing sites, for every clinical trial presentation, and sometimes waiting two or three months to get the results, it would have just shut us down from an industry perspective."
|This design tree by PCI Clinical Services' Frank Tiano can help companies determine whether CR packaging is needed for a trial.|
Some pharmaceutical companies nevertheless choose to have their clinical trial packages protocol tested, regardless of CPSC's exception. "This decision rests to a great extent on the toxicity of the drug," says Sandy Richwalski, vice president of operations, Clinical Supplies Group, Quintiles Clinical Supplies Inc. (Mount Laurel, NJ). "People are asking, 'If I have seven tablets inside this blister card,' for instance, 'would the toxicity of those seven tablets be such that they could poison someone?' If not, then they're not as worried about making sure they have the protocol and the certificate," she adds. Tiano has developed a decision tree to aid pharmaceutical clients in making this assessment. (See the decision tree)
"Each client must make an informed choice about the type of CR package to employ," points out Robert Misher, president of BlisTech Corp. (Fairfield, NJ). "When you do protocol testing, each package has a different failure rate. One package that has a low failure rate may at the same time be a little more difficult for seniors to use. Another CR package has a higher access rate by children—although it still passes the protocol—and it is much easier for seniors to use. We must leave that decision up to our clients, based upon their knowledge of their product and its toxicity levels, and the nature and the population of the people they are going to enroll in the clinical study," he emphasizes.
One sticky question pharmaceutical companies must address is whether to employ CR packaging for all clinical trials materials distributed globally, or to do so only in countries that require it. Europe has a patchwork of regulations. Germany has some CR requirements, but most countries on the continent do not. The UK in November 2001 released a British standard for CR packaging. It's a design and test standard that has yet to have the force of law, but industry insiders expect that a British law requiring CR packaging may be only a few years away.
"I've had one large pharmaceutical client say, 'There's no way we would do two different packaging forms. If we're concerned about children here in the United States, it would be irresponsible for us to put that product in a package that wasn't CR overseas.' I've seen other equally large Fortune 100 companies taking a totally different view: 'If it's not required, we're not going to do it in Europe,'" says PCI's Tiano.
One approach is to disassociate the studies. "The U.S. researchers do the U.S. studies, and the Europeans do the European studies, so you don't have to have the same package on both sides of the ocean to do the clinical testing," Tiano adds.
|CTS has a system in place to automatically label and compile millions of blisters for clinical trials.|
Environmental concerns may also complicate the choice of packaging materials for global studies. While PVC-based materials are commonly used for blisters in the United States, says Philip Diamond, vice president of business development for Clinical Trial Services (CTS; Audubon, PA), some European countries prefer other materials. The material of choice in Europe is typically polyethylene, says Diamond. However, "the polyethylene blister is more difficult to form. It goes through the machine more slowly, and from that point of view, it is more expensive to make because of the longer processing time," he explains.
PICK A CARD
Every clinical trial is unique, so the packaging is not "one size fits all." Most contract packagers offer a choice of about six CR blister package approaches. Demand for CR blister packaging for clinical trials has grown astronomically. "The amount of cards that we've been asked to produce within the first six weeks of this year surpassed the entire amount that we did last year," says Joseph J. Urban, RPh, senior director of technology for ProClinical Pharmaceutical Services (Phoenixville, PA).
A new client, who hasn't worked with a CR blister card, may not realize the lead time required for developing one. Lead times far exceed those required for bottles. The best time to contact the contract packager is when the protocol is in draft, Richwalski says. "The earlier the better. We like to start discussions when the clinical team is identifying the protocol and just start being part of the solution. The more we're up front, the more we can assist them. We can start doing things in parallel, helping them expedite and be successful in their trial."
The contract packager develops the design for the client, then transmits the file to the maker of the blister card. The pharmaceutical company must approve a blueline of the card design before it is printed. The blister card manufacturer then prints and cuts the card, with the custom punches, notches, and other cuts that the contract packager has specified. The cards are then shipped to the contract packager, where they are wedded to the blisters.
The choice of a specific packaging option may also dictate further testing. Some blister cards require use of specific foils or other materials. "A customer may request a certain card, but they need to ask themselves if they have the stability data to support this choice, if the choice dictates a change in materials," warns Quintiles' Richwalski. In such a situation, the pharmaceutical company should ask the packager to pull additional samples so that they may set up this configuration for stability testing.
LOSE THE CARD?
The first-generation CR blister solutions were ingenious but also labor intensive. PCI's SlidePack, as well as the Dosepak from MeadWestvaco Corp.'s Mebane Packaging subsidiary (Mebane, NC), for example, are elegant, but they can be costly for some clinical trials. "Some of these solutions are incredibly expensive, particularly if you are only doing a small run of 3000 or 4000 packs, because of the setup costs," explains Martin Noblet, director of marketing for Almedica International Inc. (Allendale, NJ)
Still, MeadWestvaco has sold 2.6 million Dosepak units since CPSC regulations mandating CR packaging for clinical trial drugs went into effect. One-third of the orders it has received have been for trials requiring 4000 units or less. Keshav Sharma, MeadWestvaco's business development manager–clinical trials, explains that faster speed to market and other efficiencies make Dosepak cost-competitive. "Dosepak increases patient compliance, which helps ensure the integrity of trial data and streamline the approval process," he says. "It also migrates from clinical trials to commercial distribution with a simple change in packaging graphics, all of which preserve patent protection time and increase revenue for the product manufacturer."
The next-generation approach is more streamlined. PCI's Tiano says the company is seeing more growth in demand for a simpler package. "We're getting a lot of our products packaged into the break-tab, peel-back, and push-out design. It's a Type VIII ASTM classification. That's getting us out to the market a lot quicker, and the cost is moderate, comparable to the cost of a non-CR blister."
The key to this innovation is the ability to form all the required blister cavities on a single blister sheet. The blisters are then filled with as many as three or four different products— each tablet or capsule in its own cavity—either by hand or by automated filling equipment. This system replaces the traditional method of packaging each different solid-dosage form in a strip, then gluing the strips into place within the blister card. When multiple products are filled on one blister sheet, the card itself becomes superfluous. "We add up to four drugs onto one blister footprint, then just add the CR feature as part of the lidding stock in the back. Using this approach, we can do away with the cards," Tiano explains.
Quintiles is also moving away from blister strips. Scott Houlton, vice president of clinical supplies, explains. "In our facility in Kansas City, MO, we use several approaches to blistering. Depending on the size of the project, there are still instances in which we create single-product blister strips and assemble the multiple products into cards for sealing. This approach is quickly being replaced with multiple-product blister sheets and cards. We have a fully validated blistering machine from Uhlmann Packaging (Towaco, NJ) that we use to create blister sheets using approved CR peel-and-push components. This process allows us to completely avoid the carding step and to automate the process." Quintiles has strict product segmentation standard operating procedures in place to protect against product crossover in the filling areas, and each area is physically separated from the other. "Additionally, the firm has installed a vision and near-infrared (NIR) detection system from Uhlmann, called VisioNir, to ensure that each individual blister contains a product, and the NIR system verifies that the correct product is in the correct blister by checking the unique NIR fingerprint for that chemical compound.
A cardless blister will not suffice for a lot of clinical trials, however. "Typically the blister has to be trapped and placed into a heat-sealed card that contains a variety of information and graphics to help the patient with the dosing regimen and also to accommodate the clinical labeling for those dosage forms," says BlisTech's Misher. BlisTech is currently protocol testing a new CR blister card design using unique internal barrier properties.
Most other clinical trial management vendors, including Almedica, also have the ability to fill one blister sheet with multiple products. Almedica at its European plants offers the option of attaching a card to the front of the blister sheet to produce what they call the CombiCard. The card makes it possible to include more information than is possible on a cardless blister. Almedica can print dosage information in more than six languages on the card. The CombiCard is not yet available in the United States, Noblet explains, because Almedica is still determining the final CR version.
Almedica, ProClinical, Fisher Clinical Services (Allentown, PA), Quintiles, and CTS at some of their facilities have automated feeding equipment that can add multiple products to one blister sheet at once. "We've done five products on one blister card, 72 tablets," says ProClinical's Urban. "That was a seven-day supply, plus two extras," he adds. "We've automated the entire system, and our output is approximately 100 per minute."
Contract packagers have invested considerable time and money to engineer these multiproduct feeders. Almedica has customized a standard filling machine from a supplier in the UK, whom Noblet prefers not to reveal, to create its multifeeder system. Fisher Clinical Services has developed its own form-fill-seal equipment that can fill up to four products into one blister pack. "Globally, we have 12 multiproduct filling machines, largely represented by our trademarked ClinPacker. Each generation of the machine is improved as we use the latest technologies available to generate new machine specifications," says Michael Buss, manager, creative services, for Fisher.
These customized multiproduct feeders are designed specifically for clinical trials. "There are companies that have very expensive machines that require tooling for change parts that are both cost and time prohibitive for clinical trials. We continue to streamline our process. We design and manufacture our change parts in-house. We can literally be up and running on our multiproduct form-fill-seal machines in a few days," Buss says.
Contract packagers often have to engineer sophisticated tooling at lightning speed. CTS, says Diamond, has recently set up a system for a randomized study with three treatment groups that will incorporate in excess of 30,000 patients taking medication for five years. It will involve the labeling of about 10 million mixed-product blisters—one of the largest global studies ever, says Diamond. The pharmaceutical company chose to outsource this study, he adds, "because of our speed in developing a line for automatically labeling and compiling the patient kits. They would not be able to set it up in the short time frame. From our receipt of a letter of intent to our having the line set up and validated was approximately six months."
Change parts on an automated multiproduct filler must be customized for each new clinical trial, Buss points out, because they are dedicated to the size and configuration of the products filled. These parts are built to very close tolerances. "We have such a diverse range of configurations that we're dealing with for clients, we have just not found a good, universal, automated method yet to adapt to all of those different configurations," BlisTech's Misher summarizes.