Sophisticated Packaging for Clinical Trials
Packaging for clinical trials materials is becoming a complex challenge.
Jenevieve Blair Polin, Contributing Editor
Quintiles International provides packaging, labeling, and distribution services for patient administration at investigational sites worldwide.
Jenevieve Blair Polin, Contributing Editor
The scope of clinical trials is vast, with some studies enrolling tens of thousands of patients in 15 or more countries. With so much at stake, clinical trial materials packaging takes on great importance. A well-designed package can increase compliance, reduce wastage, and shorten the study timeline.
Recent decisions by the U.S. Consumer Product Safety Commission (CPSC) to enforce child-resistant (CR) packaging regulations for clinical trial materials have shaken up the industry. On May 23, 2000, CPSC issued a statement mandating CR packaging for all oral-dosage clinical trial drugs dispensed for home use that are toxic enough to harm a young child. Packaging in studies that began after November 23, 2000, must comply. Manufacturers whose primary packaging is not CR temporarily have the option of simply putting the primary package into a CR outer container (15 CFR section 1700.15) as a stop-gap measure. After May 23, 2002, however, the primary packaging in all new clinical trials of these types of drugs must be CR.
While achieving child resistance for a bottle is straightforward, the CPSC mandate challenged contract packagers of blister cards to respond with a variety of innovations. A blister package design may incorporate at least one of the CR features described in ASTM D-3475 or be tested and meet the requirements for child resistance. CR blister cards, including the patented SlidePack and the E-Ztear packages from PCI Services (Philadelphia), have been available for years.
The trick is to design a blister card that is not only CR but also senior friendly. Many designers believe the best way to achieve this goal is to incorporate steps that require cognitive skills rather than brute force. "Children don't do sequential operations very well," notes Efrem Zaret, director of quality assurance for Almedica (Allendale, NJ), "so if you have three separate operations, like a peel, another peel, and a push, that would probably be CR."
The leading approved package that meets these criteria is the Dosepak, developed by Westvaco Corp.'s Mebane Packaging subsidiary (Mebane, NC). The Dosepak consists of an outer carton with a locking feature that is permanently wedded to an inner carton, the traditional blister card, which slides out and unfolds.
Mebane Packaging offers the option of adding a tear-resistant laminate to the outer carton to increase child resistance for highly toxic substances. "We can also work with the substrate to add a tear-resistant additive and other things to make it more difficult for children to tear into the package with their teeth or fingers or anything they may be given during the testing phase," adds Tim Freeze, manager of products, solutions, and systems for Mebane.
The package composition can also incorporate light or moisture barriers if needed. The Dosepak works with blister cards made from a variety of materials including Aclar. "The blister card is overlayed with Printkote EasySeal Plus, Westvaco's patented extrusion coated paperboard, which seals at low temperatures with short dwell times and adheres consistently to foils and films," explains Angela O'Neal, Mebane's marketing services manager.
Many contract packagers are putting their own blister cards in the Dosepak unit. "We have partnered with Westvaco, making slight modifications so the Dosepak works much better for a lot of our specific packaging types," says Mike McNear, vice president, customer services, for Fisher Clinical Services (Allentown, PA), formerly Covance Pharmaceutical Packaging Services.
Most packagers are also developing their own CR blister card designs. McNear says Fisher expects to have approval on some patented solutions within the next six months. Almedica has partnered with their vendors to develop a CR blister card that meets the requirements of the CPSC, according to Hans Engel, Almedica's buyer, and Laura Pedrick, Almedica's graphic designer. Clinical Trial Services (CTS; Audubon, PA) has also developed a CR blister card.
Comar (Vineland, NJ) is working on an innovative CR closure system that is neither a bottle nor a blister pack. "Most of the approaches that are successful are going to be outside of those formats," predicts Phil Waegelin, director of Comar's Contract Packaging Division.
Despite these innovations, many contract packagers are reassuring their customers that the changes required are actually minimal. "Our new design," says Tim Brewer, CEO of CTS, "won't change our process one bit. Strip placement will be the same, and the size of the blister card shouldn't increase much. The cost shouldn't go up, and the timeline shouldn't increase."
Clinical Trials Operations Improved With Robot-based Packaging System
Because clinical trials deal with human health, the accuracy of drug delivery is of utmost importance. "As pharmacists, we must be certain that we're not only delivering the correct drug, but also the correct amount of medicine for every dose the patient takes," says Dan Beechuk, who has worked in the clinical trials area for 35 years and has managed the Clinical Pharmaceutical Operation of Pfizer (Ann Arbor, MI) for the past 20 years. For a long time, though, he was convinced that there was a way to improve packaging speed without sacrificing accuracy, and he even worked with students from an engineering school to look at the possibility of using robots for mechanical placement.
Traditional methods for creating clinical trial packages with multiple substances required several steps and manual assembly. First, each drug was blister packaged in its own tray. If there were three different drugs or three different strengths of the same drug, then three different sets of trays were created, handled separately, inventoried, stored, then cut into strips, and hand assembled into the final configuration on a unit-dose card according to the trial regimen. Besides the time-consuming manual assembly, a substantial amount of handling was involved in this process.
The Trialpack robot-based blister packaging system from Zurich-based Fleximation—represented in the U.S. exclusively by Klöckner Medipak (Clearwater, FL)—was the solution for Pfizer. Installed at the end of 1999, the Trialpack system incorporates a Klöckner Medipak EAS unit-dose blister packager and a robot- based filling system, capable of accurately placing up to four different products in complex, double-blind, randomized clinical trials.
The idea for the Trialpack system was the feasible solution to a common problem. "While I was working for another robotic company," explains Matthias Vogelsanger, founder and president of Fleximation, "I worked on a custom robotic filling system for clinical trial blister packs for a Swiss pharmaceutical company. I realized there was a real need for an even better, commercially available system." And so he created the Trialpack system. Exceptional flexibility, safety, on-line quality control, and fast and easy setup for the small batch sizes typical of clinical trials were his design parameters, along with keeping special tooling at a minimum to make the system more affordable.
"Klöckner Medipak's EAS unit-dose blister packager was already the preferred machine for clinical trial packaging operations," notes Vogelsanger. "The EAS machine also offered inexpensive tooling and the ability to configure packs via software." And so, Klöckner Medipak became the exclusive North American representative of the Trialpack system in March 2000.
Currently, Pfizer's Clinical Pharmacy Operation's blisters are standardized on Pentapharm alfoil PVdC- coated vinyl film from Klöckner Barrier Films. The Packaging Development division of the company selected Klöckner materials more than 10 years ago, when the first Medipak EAS machine was acquired there. "We wanted to take the conservative route and pull all of our clinical trial products in high-barrier materials," explains Monica Schiksnis, manager of package development.
While clinical trials have varying complexities and therefore distinctive packages, Pfizer's Clinical Pharmaceutical Operation's packaging engineer Rick Klepek estimates that for a package with a medium complexity level it generally takes a total of 3 days and 2–3 people to produce, handle, inventory, and cut up the trays, and another 2 people to hand assemble the final unit-dose packages. This compares to the approximately 6 hours that Trialpack requires to do the same job. "Up until now we've had two operators on the new robotic system, one to watch the machine and keep the product and material levels full, the other to inspect every blister," says Klepek. "But the truth is the machine is totally automatic, and we can cut down to one operator."
"The new robotic Trialpack system actually takes more time to create each unit-dose package with multiple drugs than a conventional blister packaging machine takes to create a tray of one type of drug," says Beechuk. "But it is eliminating all those subsequent steps and handling, as well as the manual assembly of cards that gives us the big time savings. With the robotic system, we can work with the different drugs simultaneously and create the final package in one step." In addition, the unit-dose package also helps ensure compliance with the trial regimen, explains Beechuk.
Instead of allocating, inspecting, and cutting apart trays of single product, the preparation process before a production run using the Trialpack system includes half an hour of designing the packing pattern on PC-based software. This consists of defining the pattern of tablets and capsules and the wording to be printed (such as morning, noon, evening, and day 1, day 2, etc.). The production file is then loaded onto the Trialpack system. Using system prompts, the operator can load up to four different tablets and capsules into safety-locked feeders. The feeders require no change parts to accommodate different types of products, so setup time is less than 20 minutes.
The product travels on conveyors from the feeders to the robot with a vacuum-operated gripper, which locates each tablet or capsule on the conveyor using information from the integrated vision system and places it in the appropriate blister cavity. The robotic feeder can handle up to 54 products per minute; however, the complexity of the pattern and the number of days of the particular clinical trial govern the speed of the machine at any point in time. Each blister cavity is checked before placing product inside, and correct placement is verified with the vision system using data from the production file. If the system detects an error, it automatically rejects the blister package. All errors and other quality-related events are automatically logged to provide full documentation for every batch. The system can also print information on the foil-lidding material on the back of the blister.
Not only is the system saving time and labor costs, but "we're also running at 98% and higher efficiencies, some days 100%," says Klepek. "On two production runs this past week, one of 300 packages, the other of 240, we had zero scrap. The only time we've had any waste was during QA tests when we tore apart packages to check them."
"Now that we're part of Pfizer, we're going to get even busier," predicts Klepek. "With the efficiency of the Trialpack system, we'll be able to bring Pfizer's clinical trials in-house." Klepek estimates this will cut the cost of packaging Pfizer's trials in half.
As for Beechuk, who had the vision to pursue a more efficient, robotic solution: "We always thought robotics were the way to go. We're pleased that we finally have a machine that allows us to have a very sophisticated model for handling as complicated a study as we can design, one that lets us handle more than one drug at a time and one that can do it accurately and reliably."
BOTTLES AND BLISTER CARDS
Cost can be a sensitive issue and may affect the choice between bottles and blister cards. "We have gotten cost estimates ranging from $7.50 to $10.00 for a CR card," points out Sandy Richwalski, Almedica's director of operations, "whereas a bottling job can be done for far less."
The packaging costs, however, account for a very small percentage of the costs of a clinical trial. "Most of our clients don't want to skimp on the cost of packaging if it might have any chance of affecting the validity of the clinical trial," notes Tom Jeatran, director of clinical trial materials for Cook Pharmaceutical Solutions (Bloomington, IN). In general, the use of blister cards over bottles can increase compliance.
Chances are that the packaging format may change as the product itself evolves in the development process. Companies may conduct Phase I studies with the powder form of an active substance before they develop it into a capsule or tablet. "With some components, it's a lot easier to then go into a capsule formulation for Phase II studies and develop a tablet formulation later," explains Martin Page, director of operations for PCI UK Clinical Services facility (Manchester, England). The package may follow suit, changing from a bottle for the powder to a blister for Phase II studies, and then back to a bottle for Phase III if the company's intention is to market the final product in bottles. "During the clinical phase, a company will often go for the more protective materials, but when it comes to commercialization it will look for the cheapest possible material that provides the required barrier properties," Page adds.
The choice "can also be driven by what is convenient, what is quick, and of course what you have stability in," says Sean Smith, COO of clinical supplies at Quintiles International (Glasgow, Scotland).
|The E-Ztear package from PCI Services meets child-resistance requirements.|
Blister cards are de rigueur for studies with multiple drugs and complicated dosage regimens. "The more dosage forms the patient is expected to take in a given period, the more you need a blister card so that you can visually represent how the dosing should be done," says Fisher's McNear. "The multiproduct blister card not only reduces the number of steps that you have to take in packaging, but also in some cases, it decreases the lead time needed for some complex components," he adds.
"Almedica in Europe is able to package at least three products in the same blister," says Martin Noblet, director of marketing for Almedica. "With good blister-card design and multiple product filling, we are able to meet customers' requirements in about 90% of study protocols."
Bottles and blister cards are the mainstays of clinical trial materials packaging, but some new drugs demand alternative packaging. Many biotech drugs, explains Cook's Jeatran, are peptides or proteins that must be injected rather than administered orally.
Far more important than the cost of the package is the cost of the investigational drug itself, which may also be in short supply. "Flexibility in clinical supply is very much the buzzword at the moment," says Quintiles's Smith. "I want to be able to produce 15,000 kits and send them anywhere in the world."
Interactive voice-response systems (IVRS) and medical identity numbers reduce material wastage and improve supply. Quintiles, Covance, Almedica, and CTS all offer IVRS. Cook's Jeatran holds a patent on IVRS, which he developed when he was working for Eli Lilly and Co. (Indianapolis). Jeatran explains, "By using IVRS, you can cut the amount of material you need for a clinical study by at least a quarter, but sometimes as much as two-thirds."
Sometimes, however, a company saves money by not using an IVRS. "We have a manual call randomization center, so if it's a small study and the drug is very expensive, we may save the client money by doing the randomization manually," reveals CTS's Brewer.
Last year CTS bought Applied Clinical Concepts Inc. (Durham, NC), which is now known as CTS Durham. This division tightly manages drug supplies for studies. "They'll package a study with 5% overage. Most studies are packaging 20–50% overage," Brewer boasts.
Booklet labels are another way to minimize the inventory required. By attaching a booklet label containing 15 languages, for instance, explains Smith, "you've got one single stand-alone inventory item as opposed to 15."
Richwalski estimates that Almedica has provided labels in at least 35 languages, using its proprietary Almedica Drug Labeling System software. "We were the first label software company out there in clinical trials, so this is second nature to us," she says.
Multilingual booklet labeling has its pitfalls, though. "You may have approvals on five or six of the 13 languages you want to put on a label," warns Brewer, "but without the rest, you can't start the label. We've seen those things delay studies by months." In such cases, he suggests that a client group the approved languages on a smaller booklet label and proceed with the study in those countries. When the rest of the languages are approved, the client may print a second booklet label.
For even greater flexibility and control over clinical supply, Quintiles has opened a series of 13 global depots. By June of this year, each will be fully audited as a GMP facility. The company may then send study drugs to a depot, where they will be held under controlled conditions. "If recruitment in that country isn't running as we wanted, we can bring that drug back and allocate it to another part of the world because we've documented and guaranteed its control," Smith says.
EARLY CONSULTATION PAYS OFF
Contract packagers stress the importance of coming onboard early in the design process. "A lot of clients tend to think of clinical trial materials management as just a packaging operation," says Almedica's Noblet, "but the reality is we're increasingly a professional service organization, providing overall project management."
If these professionals look at the protocol, with their expertise they can suggest the best packaging design for that trial. "Then you're going to get the best compliance and have the best chance of getting it packaged on time," says Fisher's McNear.
With advance notice, packagers can secure components or provide additional designs. "The sooner we get involved in the process," McNear sums up, "the more elegant and the more technical the solution can be."