As clinical trials grow in size and duration, suppliers are aiming for packaging and labeling efficiencies.
By David Vaczek
|For blinding tablets in clinical trials, Almac Clinical Services uses an automated over-encapsulation system. At facilities in Craigavon, Ireland and Audubon, PA, tablets are vacuum picked and deposited into shells that may then be back filled with excipient.
Clinical trials have grown larger and more complex as pharmaceutical companies look to generate more data from them. With growing package volumes, clinical trial packaging automation is rendered more cost-effective and useful.
“Pharma firms are expanding trials to larger patient populations to get better patient data,” says Frank Lis, vice president, general manager, Catalent Clinical Supply Services, Catalent Pharma Solutions (Philadelphia). “Phase 3 trials that used to be 1000 or 2000 are now 5000 to 10,000 patients.”
“During the different phases of developing a compound, they will often change the packaging, if they find they can achieve better stability data and a longer shelf life,” Lis adds.
“Larger multicountry trials are growing as clients respond to FDA’s requirements for more patient data as well as to the competitive nature of trials seeking new patient populations abroad,” says Eric Deschamps, vice president of marketing, ClinTrak (Bohemia, NY), a standalone business within Fisher BioClinical Services.
“Companies have the option of running trials longer, or adapting the trials,” says Deschamps. “In adaptive clinical trials, clients are looking to grab more data, quicker. Labeling processes have to provide patient group-specific dosing information in a just-in-time scenario.”
Almac Clinical Services (Craigavon, Ireland) has improved service levels with the adoption of an automated label verification system.
“We are no longer allocating resources for manual tasks,” says Jonathan Calderwood, global marketing manager, Almac Clinical Services. “Besides seeing improvements in project time lines, we have increased capacity by 80–90%.”
The system avoids process bottle necks that occurred with 200% manual checking.
“Clinical label generation is quite complex in itself, so this system keeps up with production demand. Labels are available and approved for production in a much shorter time frame,” Calderwood adds.
The system checks and verifies variable content including randomization details as well as industry-standard fixed text.
“Catalent is in the process of implementing an automatic label verification solution to replace manual checking,” Lis says.
ClinTrak uses inspection software from Global Vision (Montreal) to verify label content before going to press. The pharmaceutical client sends a Word document; it is transferred to a PDF format used to create the printing plates; and then the software checks for anomalies, says Deschamps.
“This way, we ensure that what we produce on the label specification side matches the pharmacy firm’s master spec,” Deschamps says. “Then we send the label spec document back to the client for verification.”
Static content such as dosing information is flexo printed on labels and booklets. Labels are sampled for inspection by a Global Vision camera system. Before shipping to Fisher Clinical or third-party packagers, or before going into storage, a secondary printing event occurs for adding variable data to make the labels specific to different patient treatment groups.
A module of Aptuit Inc.’s (Greenwich, CT) Clinicopia clinical trial supply management software, the Clinicopia Labeling System, manages label creation. Text and randomization schedules are imported into the system for automatically populating label designs, says Gerry Hepburn, president of clinical operations, Aptuit.
|Child resistance is provided via the peel-and-push function of the lid stock in an Aptuit multifill blister.
Label creation is coordinated with inventory management. As jobs are scheduled in a packaging suite, the system identifies them and brings up the approved label design.
Hepburn says automated inspection of the labels is not cost-effective for Aptuit, as the company typically produces smaller runs of several thousand labels.
Operators in manual inspection compare the labels against master labels printed on clear acetate overlays.
AUTO PACKAGE ASSEMBLY
For clinical trial packaging in blisters, automated processes address clients’ different blister packaging requirements. Customers may favor wallet formats for their billboarding features, or look to reduce packaging costs with uncarded blisters.
Packagers will either assemble cards with blister strips, or stamp multiproduct blisters that replicate the package in one step.
Catalent Clinical Supply Services assembles strips in its HingePak, RX Barrier, and SlidePak proprietary compliance formats. The Key-Pak from Keystone Folding Box Co. is another alternative employed.
“In most cases, you can’t put these formats on a blister carding line off-the-shelf,” Lis says. “Because there is wide variability in the clinical protocols, we usually have to make modifications so the package design supports the dosing regimen.”
Strip assembly is fully automated. A shuttle, or inline style, blister sealer from Zed Industries (see sidebar), and a rotary style unit from Algus Packaging Inc. (DeKalb, IL) are employed.
Automated package assembly with the inline sealer produces four to five times the amount of units per shift compared with manual assembly, depending on the size of the card and number of tablets, Lis says.
“Some clients like the strip method with the card because you can put directions on the card,” he says. “The choice of strip or multifill package will depend on the clinical trial protocol. When we are multifilling blisters, we leave head space on the blister for the label.
Packagers have to respond flexibly to the diverse packaging requirements presented by clinical trials. The multifill versus strip approach depends on the protocol design, the sequence of the fill, the size and shape of the input units, and the blister materials to be used among other factors, says Calderwood.
“Some companies prefer mixfill blister cards rather than individual blisters, and vice versa,” says Calderwood. “Some combinations are so complex that the cards are built best by mixed compilation of blisters.”
“On other occasions, for instance, titration cards, it often works well to combine products in a single blister,” he adds.
Hepburn says clients are often requiring extended card space. “We have seen that more customers are looking for more card space to accommodate larger labels. This can weaken the package, creating blister ingress issues. If we don’t reduce the label size, we can include strengthening bars to make the package more robust.”
At Aptuit facilities in the United States, Europe, India, and Singapore, strip packaging is used for about two-thirds of clinical trial packaging.
“Clients have very diverse format needs which we have to support. We primarily use MWV’s Dosepak and variations on the Dosepak, such as when customers require bill-boarding space and child resistant features,” he says.
|The HingePak from Catalent imparts to clinical packaging child resistance and space for compliance features and instructions.
In strip packaging into these formats, “strips are singulated on a conveyor where they are cut and stacked. Strips and base cards are then fed to a rotating table for manual operator assembly, then top sealed at a carding machine,” Hepburn says.
At its newest clinical packaging facility in Kansas City, MO, Aptuit has deployed multifill loading of multiple products into the blister sheet.
Two Model UPS 1030 Uhlmann blister machines automate the process.
“We don’t have a proprietary [compliance] format [for strip packaging],” Hepburn says. “But we have developed some basic compliance designs using double-backing on the blister that requires added effort by the patient to expose the pill.” In multifill processes, CR functionality is typically provided by the lid stock. ”
Aptuit deploys a standard peel-and-push design, and a puncture-access format.
“We have designed tooling that makes it easier for seniors to get hold of the corner of the peel tab,” says Matt Blume, director of operations, packaging and logistics.
Puncture access provides a higher level of CR, with minimal required opening effort. Tablets are egressed from a secondary adjoining cavity after the patient punches through the lid with a pen or key, Blume says.
Uhlmann (Towaco, NJ) provides a modular tool set for producing different blister configurations. “With a much smaller range of tooling, we can create the diverse package formats that we have found is required to meet the very diverse needs of our clients,” Hepburn says.
Feeding is performed manually for smaller runs. For larger runs, Uhlmann Simtap dedicated feeders orient and present the tablets to each blister cavity.
Aptuit is configuring a system for printing static and variable label information on blisters inline. The line includes a CSAT laser printer, with an Uhlmann VisioSafe solution including VisioRead for print inspection. “This will replace the need for printing labels in the label room,” says Blume. “For larger Phase 2 and Phase 3 trials, customers will realize shorter time lines and lower costs.”
For strip and card assembly, the plant uses formats including the Dosepak and Key-Pak. An Uhlmann blister unit modified for clinical use produces and slits the blisters. “On a large index in one stroke we can make up to eight one-cavity-by-eight-cavity strips, or 30 strips a minute,” Blume says.
Standardizing packaging is one way to reduce clinical trial costs.
Hepburn says pharma firms are pressing clinical trial operations to restrict the range of tablet and capsule sizes, to use fewer package formats.
“When clients standardize on formats, this reduces the inventory we have to store for just-in-time labeling,” he adds. “Working from bright stock, we are able to reduce cycle times. You don’t do any secondary packaging [and labeling] until you are ready to ship product.”
Clinical supply kit designs are similarly being reassessed.
“The trial groups have historically had a free hand in the design of the kits,” Hepburn says. “Increasingly, customers are realizing this is adding to their costs. So, they are driving for standardization in kit design, to achieve higher-quality, repeatable solutions that will be more cost-effective.”
Clients by the same token want to ensure that packaging is effectively targeted to the needs of trial participants.
“We think trials are getting more and more bespoke in nature,” says Calderwood. “Rather than impose a standard, we try to tailor the packaging to the trial. Patient compliance is driving [the emphasis on tailored packaging].”
For longer-term open-label trials or post marketing studies, Almac will leverage data from IVRS systems to identify and improve upon inefficient packaging, he adds.
Adaptive trials are another trend that requires flexible responses from suppliers.
“These trials move you to an on-demand scenario,” says ClinTrak’s Deschamps. “We have not really labeled in accordance with this methodology up to this point.”
In adaptive trials, patient dosing may be adjusted, requiring new label instructions. If booklet labels are being used, they might require last-minute revision based on site enrollment.
“A client will not want to pay for 15-page booklet, if a five-page label meets the needs based on enrollment,” says Deschamps. “As patients are being added or dropped to a particular treatment arm, patient-specific information has to be printed at the last moment. This limits the flexibility of the booklet label.”
“We have to create another labeling event to make a non-patient-specific package patient-specific, based on data coming in from an IVR or IWR system,” he says.