Packaging Pharmaceuticals and Medical Devices for Clinical Trials
by Daphne Allen, Managing Editor
It might seem that packaging would be the last thing on the minds of manufacturers preparing healthcare products for clinical trials. After all, isn't it the chemical makeup of a drug or the design of a device that determines its clinical success? Some, however, would argue that the packages around the products are sometimes the most critical element of a clinical trial.
Clinical trial product packaging must not only protect pharmaceuticals or medical devices, but also maintain product sterility and communicate instructions for use to healthcare practitioners and patients participating in the trial. Packaging engineers must not only create packages that meet these needs, but also create them quickly — the sooner a company can get its product packaged and into clinical trials, the sooner it can use clinical data to support a device premarket approval or new drug application. To help manufacturers reach clinical trials quickly, packaging suppliers offer a variety of services ranging from package design and production to labeling and clinical trial product inventory control.
COMPLEXITY OF CLINICAL TRIAL PACKAGING
Clinical trial packaging can be simple or complex, depending on the complexity of the device or pharmaceutical, how close the manufacturer feels the product is to market, and how much time is allotted for package development. Engineers can start developing the packaging materials and components any time from product conception up until the stage at which the product is ready to enter clinical trials.
Tablets are often put into unit-dose packaging for clinical trials. Photo courtesy — Sharp Ivers-Lee.
Clayton Bussey, CEO of Packaging Solutions Inc. (Fremont, CA), explains that 80% of his pharmaceutical manufacturing customers ask him to start developing packaging one to two years before they expect their drugs to be approved. "When designing packages for clinical trials, we ask our clients for their distribution, shipping, and marketing requirements and then design packages for the present stage as well as the ultimate one," Bussey explains. "That way, when the drug is approved, it's an easier transition to final packaging."
Some companies, however, need packages designed and produced on shorter notice. Jim Reimers of Medical Device Manufacturing & Ventures Inc. (Brea, CA), a contract manufacturer of medical products and packaging, explains that customers often need packages within a matter of weeks. But because some products are still in the R&D stage and aren't yet being produced in mass quantities, Reimers explains, there isn't the need or the time to design clinical trial packages to be the same as the packaging used for marketing. "Our main concern when designing packaging for clinical trials is to quickly produce packages that will maintain sterility and hold the device securely during transportation to the clinical site," Reimers says. "Simple packages like peel pouches with die-cut plastic backers usually work well."
Some medical devices, however, need more than just a pouch. Jerry Zimmermann, a packaging design engineer for Guidant Corp.'s Cardiac Rhythm Management Group (St. Paul, MN), explains that the packaging they create for their defibrillators and pacemakers that are entering clinical trials is the same as that for commercial products, save for a label indicating that the device is for investigational use only. "Because we are packaging implantable medical devices, we don't create packaging that is incomplete — products are packaged as we would market them," Zimmermann explains. "Packaging is an integral part of the product life cycle. We wouldn't want to take any shortcuts in clinical trials that could affect the product or the perception of the product."
The Trialpack 600 places a combination of up to four different tablets or capsules into the same blister pack. Photo courtesy — Doyen Medipharm.
Avoiding shortcuts means that clinical trial packaging must be scrutinized just as carefully as commercial packaging. Reimers reports that his firm tests the strength of heat seals as well as performs burst testing for all packages, just as one would perform for commercial packaging.
Tim McBride of Sharp Ivers-Lee (Conshohocken, PA), a contract packaging design firm, explains that the quality of packages can affect the outcome of a trial. "If a clinical blister card is missing a tablet like a placebo or active drug, you could jeopardize the entire study."
MEDICAL VERSUS PHARMACEUTICAL
Because clinical trials for medical devices and for pharmaceuticals are designed differently, the packaging and labeling for each are also quite different. Investigational medical devices are usually used by medical practitioners such as doctors and nurses, whereas pharmaceuticals are usually dispensed by practitioners for patients to use themselves. And medical devices are usually used at the rate of one per patient, whereas pharmaceuticals are often tested along with comparators and placebos as well as at different dosage amounts. Such differences affect packaging requirements.
Tim Brewer of Clinical Trial Services (CTS; Audubon, PA) explains that 95% of the studies for which he prepares packages are blinded trials. A company specializing in clinical trial services such as packaging, labeling, and inventory control, CTS primarily produces blister unit-dose packaging for pharmaceuticals. "Oftentimes we are the only entity that knows which dosing regimens patients are taking. Frequently, the sponsor company wants to remain blinded so it can avoid creating bias in any of the practitioners or patients," Brewer explains. To perform such a task, Brewer explains that sometimes, along with simple instructions, the only identification the packages contain are color-coded labels. "To achieve this blinding, many precautions must be taken. Products must be manufactured to look identical and packages must be produced to eliminate tampering and breaking of the blind."
Packaging Solutions' Bussey says a lot of companies have come to him searching for labels they could use for clinical trials. In response, his firm has developed two-ply labels with a hinge and a blacked-out portion that conceals a random numbering sequence. His son, Bill Bussey, also with Packaging Solutions, says that "if during the trial doctors need to identify a particular treatment, they can peel the hinge away to reveal the number sequence and report the situation to the sponsor, who has the main list."
For most medical devices used in clinical trials, however, healthcare practitioners know what they are using. "Many devices going through clinical trials are technical enhancements and advances of existing device technologies and procedures," Reimers says. "Participating doctors usually aren't concerned with the aesthetics of the packaging, they just want the device to function properly. And many times, company representatives are right there with the doctors as the devices are being used to answer any questions that may come up."
Zimmermann's experience is similar. "Because we have electronics and programs that go with our implantable devices, I couldn't imagine hiding the identity of the product."
Ray Johnson, vice chairman of Doyen Medipharm Inc. (Morris Plains, NJ), a company that provides packaging equipment, says that when testing medical devices, companies don't have to prove efficacy based on how someone feels, as they do when testing pharmaceuticals. "Durability and effectiveness can be measured when testing a device. For example, did the stent open the artery or not?" Johnson says.
MORE THAN A PACKAGE
Because patients play such an important role in pharmaceutical trials, packaging engineers need to find a way to ensure patient compliance. This can be quite a challenge especially because, according to Jann Keenan, president of the Keenan Group (Ellicott City, MD), the 1993 National Adult Literacy Survey sponsored by the federal government showed that nearly 50% of Americans "read too poorly to understand most printed health information (see news story on page 11). That means instructions have to be clear enough for patients to understand and follow. Otherwise, a missed or doubled dose could affect the trial outcome.
CCL Labeling Equipment's model 6105 — CTL applies fan-folded labels to bottles for clinical trials.
The most popular way to increase patient compliance is to package pharmaceuticals in unit-dose blister packs. "Previously, patients would be given four or more bottles and a chart that said something like, 'Take two tablets from the first bottle and three from the second on the first day.' You could never be sure people were taking the pharmaceuticals correctly," explains Johnson.
As easy as blister packaging makes the clinical patient's role, it can complicate the packager's. Johnson explains that many packagers end up using strips of blister packaging containing just one row of the same product and then manually assembling several strips containing either different dosages of the same drug or different drugs such as the test drug and a competing drug or a placebo.
To automate the blister packaging of different pharmaceuticals tested during a trial, Doyen Medipharm manufactures a robotics-based machine that packages a combination of up to four different tablets or capsules into the same blister pack. According to Doyen, Parke-Davis's Clinical Pharmacy Group (Ann Arbor, MI) will use the Trialpack 600 to package a range of pharmaceuticals into blister packs for phase one through phase four clinical trials.
MORE THAN A PACKAGE SUPPLIER
Several contract packaging design firms report that in recent years their business has grown. "Eight years ago, no one was outsourcing their clinical trial packaging," says CTS's Brewer. "Now business is kicking up — even the larger companies are using outside firms."
Reimers explains that he works with a lot of start-up medical device manufacturers. "A lot of start-ups don't have the necessary resources like facilities, cleanrooms, and staff," he says. The firm also can manufacture, assemble, and sterilize products as well as ensure that all regulatory requirements are met.
Capsules in unit-dose blister packs. Photo courtesy — Sharp Ivers-Lee.
Sharp Ivers-Lee's McBride also sees an increase in the use of outside firms during the last 10 years. "Contract packagers have become a mainstay," he says. "Companies are requesting broad-based services and support."
That means many companies are looking for more than just a package. Along with designing and producing packaging and labeling, Reimers' Medical Device Manufacturing & Ventures maintains device history files for its clients. Sharp Ivers-Lee can ship products directly to study sites and can also repackage, relabel, inspect, and assemble products.
In addition to offering packaging and labeling, CTS offers the manufacturing of tablets and capsules as well as the distribution of clinical pharmaceuticals to investigator sites. It also has been packaging clinical supplies in Europe for the past nine years. The next challenge for CTS, Brewer explains, is to "get people to use technology" for clinical trial packaging. "Every job is small, and no one seems to want to improve the process," Brewer says. CTS is working toward implementing electronic verification of labeling, something that recent FDA regulations are encouraging. (See "OTC Labeling Reform: What's on the Horizon," PMP News, January 1998.) "We want to use this so we don't have to perform 200% inspection of labels, which means that one operator applies labels, and two operators double-check the labels," says Brewer. "We are currently devising a way to code products so they could be inspected electronically yet still disguise the information so patients or doctors can't understand it. Unfortunately, doctors often try to break the blind trial."
For those companies that prefer to design and manufacture their own packaging, some equipment suppliers offer units specifically designed for clinical trial packaging.
CCL Labeling Equipment (Monrovia, CA) offers fully automatic and semiautomatic labeling systems for clinical trials. Developed for small-batch production, the 6105-CTL can accommodate fan-folded labels. To meet tight schedules, the system can generate 25 to 45 products per minute with a label placement accuracy of 1/32 in.
Mentioned earlier, Doyen's Trialpack 600 employs a machine vision system to inspect the placement of different tablets and capsules. It also uses a graphical user interface to safeguard against operator errors. Doyen's Johnson expects to sell a number of the units, despite a price tag of $400,000. "We see many manufacturers bringing their packaging operations back in-house — they can save millions of dollars by doing so," Johnson says.
Even though it may consist of only a few layers of plastic or paper, clinical trial packaging can be as important as the pharmaceuticals or medical devices housed within. It must protect its contents and successfully communicate instructions to users while meeting the requirements of the clinical trial protocol.
To help device and pharmaceutical manufacturers produce quality packaging for clinical trials, packaging and equipment suppliers offer a variety of products, services, and machinery that meet specific needs. These needs include the quick and accurate production of small product volumes and the disguising of product for blinded studies. Some suppliers are even offering additional services such as distribution and study monitoring. So, whether a manufacturer is shopping for equipment to produce its own packaging or working with an outside firm, it should have no problem finding the necessary support.