Clinical Trials Packaging: A Few Issues Companies Can't Afford to Miss
Some missteps in packaging and labeling could disrupt your clinical trials supply.
By Christina Elston
Diamond Contract Manufacturing can turn kits around in 24 hours.
While the focus of a clinical trial would seem to be the supplies—the drug under study—this isn’t always the case. Industry experts say that clinical trial supplies are often almost an afterthought. Not taking this crucial part of the study into account early on can cost pharmaceutical companies in the long run.
“Clinical supplies are often of little concern, but they are key for clinical trial success,” says Steve Jacobs, president of Bilcare Inc. (Phoenixville, PA). “If clinical supplies are not handled well, it could cost a company tens of millions of dollars if a study is invalidated.” Designing patient compliance packages can greatly improve a company’s ability to show in a “statistically significant way” that a product works.
To give your clinical trial the best chance for success, we’ve asked several professionals for advice on developing packaging and labeling appropriate for your clinical supplies.
Short-term stinginess could mean long-term costs. “What is the overall goal of the trial?” This is a question that Jeff Hallquist, director of sales at Fisher Clinical Services Inc. (Allentown, PA), says companies need to take into consideration when designing their packaging. Using this as a guideline for appropriate spending in the right places could save money down the road. “Some companies focus on the cost of packaging the clinical supply materials, as opposed to managing the drug supply and considering the enrollment challenges and their impact on the overall cost of the trial,” says Hallquist.
A company that fails to take into account that a particular patient population for a trial has Parkinson’s disease, for instance, and therefore doesn’t employ a senior-friendly design, could call patient compliance into question. If FDA then calls for an expanded patient population for the study, those increased costs would likely eclipse the expense of packaging the product more suitably, say in senior-friendly blister packs, in the first place. Such packaging could have also demonstrated patient compliance.
Careful control of the packaging and labeling process is absolutely necessary. “Controls need to be in place so that there is no question as to what is an active drug, what is a placebo, or what is a comparator,” says Jacobs. “You have to be able to track back to know with 100% accuracy what product the patient took. If there is any question about the study results, clinical operations goes back to the clinical supplies unit to make sure that the right product is in the right package and that the right label is on the right package.”
If a company doing a multinational study chooses to label supplies for use only in a single country as opposed to using a booklet label for many countries, they limit their flexibility and risk additional expense, Hallquist says. Labeling the drug for use in multiple countries might cost more, but would allow flexibility if enrollment patterns are different than predicted. This could help avoid the need for relabeling. “You can keep the supplies in a central depot and ship them as needed,” Hallquist says. “It gives you more flexibility with those supplies.”
Software Helps Users Manage Supplies
Software may help drug companies plan their clinical studies, generate labeling, and record warehousing and shipping activities. With trials often expanding their scope to include global populations, such support could ease preparation.
Prisym ID Inc. (Charlotte, NC) offers two such programs. Prisym ClinTrial handles trial management, such as tracking randomized patient lists, stratification of patients and study groups, patient visits, and treatment codes. All data from the ClinTrial module can be printed on packaging labels using Prisym Medica labeling software.
Specials Clinical Manufacturing is using Prisym Medica to print labels for patient packaging and to secure its recordkeeping. Elaine Mackie, packaging manager at Specials Clinical Manufacturing, says, “Many of the other systems we considered did not provide the correct level of service and security, which is an especially important factor in our industry. Plus, the Prisym Medica software is user-friendly and has a very useful reminder mechanism.”
Supplied as a server-based application or as a single workstation version, the software encrypts data and records critical activities, electronically linking them to individual users and providing time and date stamping.
Werum Software & Systems (Towaco, NJ) is offering PAS-X CT. The system offers a structured intuitive user interface that facilitates interaction among those involved in producing and delivering patient kits. PAS-X CT supports the management and definition of clinical studies as well as the production of packaging and labeling, such as on-demand multilanguage labeling. Warehousing and shipping operations are also considered. It can be used along with bar code readers, wireless technology, and RFID tags.
Aptuit has recently announced the acquisition of InfoPro Solutions, developers of the Clinicopia information system. It encompasses planning and forecasting, clinical supplies management, inventory management, clinical manufacturing and packaging, resource management, and clinical label creation and approval. Aptuit will leverage InfoPro’s IT expertise and products, implementing the system internally and developing a range of integrated informatics solutions.
Not allowing enough lead time can cost you money. Many companies fail to account for the time it can take to package and distribute clinical supplies, says Frank Lis, senior vice president and general manager for global clinical supply services at Cardinal Health. “People tend to look at the clinical packaging group kind of like a pharmacy,” he says. They come with their order and expect that it can be filled promptly. “But there’s a lot that goes into filling these orders.”
Bilcare’s Jacobs agrees that there is a late start. “Some companies wait until Phase IIIB before they start developing their commercial packaging,” he says. “At that point, they go for the highest barrier packaging, like Aclar or coldformable foil, which can be overkill. Instead, they should start stability studies using specific film and foil combinations when the formula is locked down at the end of Phase II.” Bilcare can offer a program to take a small amount of product and, through sensitivity testing, identify the best film-and-foil combination for the commercial package. “This can save the commercial packaging side a lot of money and should be started earlier in the development process from where it is now,” he says.
Lis adds that if a company doesn’t choose materials that give enough shelf life for the duration of its study, or doesn’t dedicate the time and money to thorough stability testing, it may end up having to produce additional drugs to finish.
Supplies, Lis continues, are often an afterthought, garnering just two to three pages of a 70-page trial protocol document. Companies fail to account for import and export license timelines—which can sometimes take four to six weeks—as well as for lead times for tooling and even time requirements to order label supplies. “One of the biggest things that people underestimate is the lead time it takes to get materials,” he says. If label content is in multiple languages, translation time is also a factor.
Companies that find themselves in a time crunch often demand flexibility from their contractors, but this flexibility adds to labor and materials costs. Smaller companies, and increasingly larger ones as well, are developing an eye toward cost. “I think that the large pharmas are starting to notice it,” says Lis. “It definitely adds to the cost of development.”
Putting together your own kits might not be the best use of your resources. Labs that use contract packagers to build kits for clinical trials can realize cost savings, improve flexibility and turnaround time, and not have to reinvent the wheel with regard to industry knowledge and regulations, according to Jason Aymerich, sales manager at Diamond Contract Manufacturing LLC (Rochester, NY). “More companies are using [contract] companies as a resource, but there is still a lack of awareness that these things can be done,” Aymerich says. “They can speed up the process and get their drugs to market faster.”
Contract packagers have a more-stable volume of work and so are able to maintain a consistent workforce and stable relationships with materials suppliers. Labs, on the other hand, generally experience tremendous fluctuation in demand for clinical trial kits. “Their kit production is very volatile,” says Aymerich. “They may produce 10,000 kits one day, and 10 kits the next.” When contract packagers are vertically integrated, as Diamond is, says Aymerich, they can offer labs tremendous flexibility and turnaround times that they couldn’t possibly realize on their own. A university lab without the in-house staff that undertakes a clinical trial might spend a month putting together kits. “We turn around all of our kits in less than 24 hours,” Aymerich says. “This broadens your ability to meet your customers’ lead times and volumes.”
Working with a company experienced in the building of kits can also help firms navigate regulations. Many companies are not knowledgeable regarding International Air Transport Association (IATA) regulations, which include guidelines for packaging and labeling of diagnostic specimens, according to Aymerich. It is ultimately the responsibility of participating doctors to prepare specimens for safe transport back to the lab. Diamond prepares kits that make it easy for labs to educate the doctors they are working with about proper protocol. “We try to make that packaging as user-friendly as possible,” Aymerich says.
Clinical Trials Packaging Mishaps
Despite the best efforts of suppliers, packagers, and clinicians, problems in clinical trials do happen, says Allen Cato, MD, PhD, cofounder of Cato Research West (Oakland, CA). Cato recalls several incidents from his 25 years of clinical trial experience. “There is mispackaging in clinical trials, and people don’t even realize it,” he says.
One of the oldest incidents involved a study of nitroglycerin. Following the study, clinicians reviewing the data noted that none of the patients receiving the drug reported the usual side effects. Many patients taking nitroglycerin report headaches. Upon investigation, they discovered that the supplies for the trial had been repackaged. The nitroglycerin, which is sensitive to light, had been moved from brown bottles to clear bottles, rendering it completely ineffective.
In another study—a six-way crossover study to test a bronchodilator—supplies were packaged with the wrong sequence, so that patients did not receive the appropriate medications. Fortunately, one group of patients was scheduled to report for airway tests, but to receive no medications, not even a placebo. When supplies turned up labeled for this patient group, the error became apparent. “The only way we found it was that we had patients receiving nothing,” Cato says.
In a third study, the mix-up was not accidental. The trial was of an antidepressant, but several patients scheduled to receive the drug showed no trace of it in blood tests. Meanwhile, there were detectable levels of the drug in the blood of patients in the placebo group. Apparently, a disgruntled employee had decided to juggle the supplies. “You just would not think about that,” says Cato, “but it has happened.”
Cold-chain custody is too hot an issue to ignore. One of the biggest changes in pharmaceuticals in recent years has been a shift from small-molecule drugs to large-molecule therapies that require cold-chain custody, according to Hallquist. More often, companies need to qualify not just the drug package, but the insulated shipping container as well as the supply-chain pipeline.
From a package design standpoint, companies now must consider how product packages will fit together into an insulated shipper that will maintain the correct temperature throughout distribution. Hallquist recalls a recent incident in which one pharmaceutical company—not a customer of Fisher—had to discard an entire shipment of vaccine that arrived in Eastern Europe frozen. The shipper had been qualified to maintain refrigeration in the face of temperature changes, but not to prevent freezing.
It can pay to have someone else manage your drug supply. Companies working with partners on long-term studies might want to consider whether it’s practical to contract out the management of their drug supply plan, says Scott Houlton, president of clinical packaging and logistics at Aptuit (Kansas City, MO). If there is resupply needed in a multiyear study, who will make sure supplies are available at the right time? “We do that, but I think we’re one of the few contract packagers that offer this service,” Houlton says. Aptuit got involved in study-drug management about two years ago, in response to requests from key customers. “It’s a topic that comes up a lot, Houlton says. “Some of the small biotech and virtual companies are the ones that can most benefit.”
If Aptuit is handling packaging, storage, and global distribution for a trial, some customers have decided it makes sense for them to handle drug management as well. “It just takes one more middle person out of the way,” Houlton says. “The more you can avoid handoffs, the fewer opportunities you have for things to fall through the cracks. The worst thing you can do is have a study that’s enrolling really well, but you have to slow down because you don’t have the supplies.”
The issue also speaks to the need for good management of partner relationships—such as those between the trial sponsor, the drug manufacturer, and the packager—in a trial. “Are the roles and responsibilities well defined across those parties?” asks Houlton. Making sure that they are, especially in trials involving controlled substances or comparators that are in short supply, can save time and cost and also allow you to benefit from your partners’ experience in the industry.
“View your contract packager as a partner rather than a pair of hands,” Houlton advises.
Even clinical trial packaging makes an impression. Patient recruitment and retention are big factors in clinical trials, and packaging can have an impact. If patients are presented with a package that appears flimsy or of low quality, or a package that makes the medication difficult to dispense, they might lose confidence in participating in the trial. “The patient population that is recruited into the clinical trial market today is a pretty sophisticated consumer,” says Ward Smith, clinical trial specialist at MeadWestvaco Healthcare Packaging (New York City). “The last thing you want to do is have anything add an element of confidence removal.”
Tom McDonald, also a MeadWestvaco clinical trial specialist, says that packagers in clinical trials are often forced to consider timeline first and the quality of design second, potentially creating a negative patient interaction with the package and subsequently the compound. “You’re often looking at what is the most expeditious route for product packaging,” he says. Because the sponsor company’s name appears on the supplied packaging, the package bears the image of the supplier, so companies should give it a bit more thought.
“What can a package deliver over and above its appearance and functionality?” asks John Smit, MeadWestvaco Northern regional sales manager. He suggests the company’s Surepak, for instance, a tool for promoting patient compliance and an F=1 container, similar to that of a bottle, for highly toxic compounds. Surepak can also be used for packaging delicate or friable medications. These medications can be damaged by dispensing, so the use of Surepak and a peel-and-drop blister allows the medication to be accessed without being damaged. “I would say that we’re poised for a paradigm shift,” he says. “This package is a powerful tool for the sponsor company.”
Inspecting clinical supplies labeling remains a challenge. Photo courtesy Complete Inspection Systems.
Automation could be a worthwhile investment. Though it is still rare in clinical trials packaging, employing automation and automated package inspection can help companies realize greater speed (minutes versus hours), consistency, accuracy, and repeatability in their processes, says Gary Parish, president of Complete Inspection Systems Inc. (CIS; Indiatlantic, FL). But while “every other aspect” of the pharma market has embraced automation, Parish says that clinical trials have lagged behind.
Production requirements for clinical trials can be substantially different from regular manufacturing and packaging lines for several reasons. The number of products produced is substantially lower, each product must be identified with unique product and patient information for tracking during the study, and it is important for doctors and patients not to be able to tell the difference between product and placebo during the study. “All together, you have a unique scenario of short manufacturing runs with each product being different,” Parish says.
The lag in automating clinical trials packaging is partly because of the amount of time and effort required to validate new processes, but also because of the use of older equipment, such as dot-matrix printers and the corresponding custom software created to work with them.
Parish says technology that would make CIS systems more practical for use in clinical trials packaging is workable and becoming more available, and that many exhibitors at the recent WestPack show in Anaheim, CA, were showcasing such systems. “I saw a whole bunch of new setups designed for the smaller runs,” he says.
But even for companies not ready to delve into the latest in robotic automation to package their drug study supplies, not having an eye toward the future can cost you in the present.