According to a recent informal poll of Healthcare Packaging (HCP) readers, half the respondents agreed that packaging should enter the stream at the beginning of the clinical trial. An encouraging number, considering the metamorphosis the primary package will likely undergo as the drug formulation continues to change during the course of the trial.
"Whatever the container closure system is, it has to be considered early on," says Kristen DeVito, director of project management for Aptuit (www.aptuit.com), a company that provides research and development services, including clinical supplies manufacturing, packaging, and global distribution. "But the formulation may continue to change during the course of research and development, so as it's refined, the container closure system is also being refined."
Argos Therapeutics, a company that makes immunotherapeutic products, has three ongoing trials in Phase I and II: two for cancer and one for HIV. Fred Miesowicz, chief operating officer, urges drug companies to develop its packages early in the trial and think about its long-range needs for commercialization early on. At the same time, he advises them not to get ahead of themselves when developing the final package: "Most companies won't engage in a high-tech solution to administer a drug until they do the therapy, it's working, and they're advancing to larger clinical studies because of the investment you have to make early on," he says. "You want to understand the drug and its behavior and stability before you start doing mechanical changes to how you administer it."
Stability is a key consideration when choosing the appropriate packaging for your trialand ultimately the commercialization of the final product.
"A clinical package has to protect a product that sometimes has an unknown sensitivity to moisture, oxygen, and light, so sometimes higher barriers are selected than might be needed for commercial rollout," said one HCP survey respondent. Another wrote: "In most cases, millions of dollars are spent on drug discovery, and researchers prefer using packaging that provides the maximum protection. Once a decision has been taken to commercialize after a successful clinical trial, there is a move to review packaging and propose the one with the optimum protection for that formulation. This is done with a view to improve profitability and ensure uninterrupted availability."
Compliance and tracking
When asked what form of tracking patient compliance has proven to be most effective during a clinical trial, approximately one third of survey respondents cited blister packaging. Other methods included pill counts, patient diaries, bar coding, individual follow-up, and RFID.
No doubt, tracking and promoting compliance is a vital function of the clinical trial package. "[Clinical trial packaging] focuses more [than commercial packaging] on extracting a profile of compliance information and patient use," according to a survey respondent. "Clinical trial packages should promote proper usage/dosage while also helping gather rich data on same."
Another respondent noted: "The trial is useful only if those conducting it know what drugs were taken by which patients and at what time. The package is integral to this in providing confirmation of codes to validate the identity of patient/drug match-ups and plays a key role in supporting the documentation of compliance."
Unique to patient
Unlike the final commercial drug, each clinical trial drug is unique to a specific patient; therefore, there is no room for packaging errors. "If you're doing a commercial package, you might reconcile labels to about 2 percent," says Efrem Zaret, a consultant and president of EZ Associates Inc. (www.ezassociates. com), a company that assists with clinical supplies management and packaging development. "If you're reconciling clinical materials, it's zero defect. You can't lose a label. You have to account for every one. Errors are not allowed to happen. You never go to the next step unless reconciliation is perfect. If you find an error after packaging, you have problems because it can wipe out a trial."
Miesowicz is acutely aware of this fact. Each Argos' trial patient's therapy is autologous, meaning it is made from the patient's own tumor and blood, he explains. "A lot of tracking is involved to make sure the right patient gets their own drug." Argos uses a combination of bar coding and multiple visual checks of the packaging before it leaves the facility and at the site when it is received. "The vaccine is made one patient at a time," says Miesowicz, "and one person works on one vaccine, so you have the ability to more easily track labels and patient identifiers."
Some companies are starting to look at technologies, such as RFID, that will not only monitor compliance but help keep track of medication throughout the trial. Percentages are still fairly low: Out of 43 HCP survey respondents, six people cited RFID as an effective means of tracking patient compliance during a clinical trial.
"When you look at a clinical trial, one of the challenges all packagers face is making sure that you have the right items in the right patient kits," says Matt Blume, senior manager of operations, Aptuit. "A lot of companies do 100-percent visual inspection, but you can have operator fatigue or operator error and an incorrect item could be placed in a kit."
Aptuit is working on a pilot project to test the use of short-range UHF (ultra-high-frequency) RFID tags on primary and secondary clinical trial packages. Once the patient kit has been assembled manually, the operator sends it through a reader to verify that all RFID tags in the carton are present and correct. "You're doing 100-percent verification of everything after you've closed the box, so you've eliminated the chance of an assembly error [going undetected]," says Blume.
At what cost?
Half of the survey respondents indicated that products for clinical trials are packaged manually. Because each package is unique, the process is labor-intensive and difficult to automate, says Zaret. When sourcing packaging materials, cost can also be an issue, said one respondent, "due to lower-than-production volumes." According to Zaret, costs for small packaging orders are usually high because suppliers "have to make special runs, and the timelines are long because they don't want to let you into their commercial schedules."
Zaret advises using commercially available components whenever possible. "If you have to use a special component, you're looking at some problems," he says. "For example, I had a study where we needed a cap that was commercially available but needed a special liner. I had to go to the liner company and break into their schedule to make what I needed, and I had to buy more than I needed because of their minimum requirements. Then I had to wait weeks and weeks for the cap company to break me into its schedule to use this special material. We paid a huge up-charge for that."
Packaging placebos for blinded trials also presents costly challenges: "If the innovator has a customized package, blinding will require either a new outer package to mask or a repackaging to a similar-looking standard package," said one HCP survey respondent. In addition to ensuring that the placebo and active drug are indistinguishable from each other, trial personnel must ensure that the two do not become mixed up, which requires an enormous amount of documentation. Also, as one respondent noted, compatibility of the placebo with the packaging material could be an issue: "Actual drugs may be compatible, but placebos may not."
By the final phase of the study, packaging should resemble the commercial package more closely, and factors that weren't at the forefront during the trial come into play, such as marketing."Packaging must also be memorable, in a sense that after the product clears clinicals, the doctors and patients can easily recognize that product a year or two from the date of the trial," wrote a respondent. "In other words, think long term."
Argos' clinical trial drugs are currently packaged in cryovials that maintain the temperature of the cell or tissue at minus 190 C for as long as eight to nine days. But once the drug is ready for commercialization, Miesowicz envisions the package will have undergone some changes. "One of the considerations for commercialization would be ease of thawing and ease of injecting the patient with the drug," he says."Right now, you have to open the vial, insert the needle, aspirate the fluid, and then inject the patient. We envision an enclosure you could attach to a syringe so you could easily inject the patient."
Argos currently has prototypes of the final package, which would be implemented during Phase III of the trial; however, that stage is still two-and-a-half years away. Scaling up for commercialization will involve automating the process and carrying it out in multiple shiftsa considerable financial investment.
"Right now, we have one shift, and it's mostly manual," says Miesowicz. "Any automated packaging requires a long lead time to develop, build, test, validate, and clear with the FDA. If you wait too long to do that, you're going to delay your ultimate commercialization of the drug. We started very early, and some of our investors were critical. They wanted to know why we were spending the money now," he says. "Well, if you don't spend it now on this end, you'll definitely spend it on the other end."