Critical Aspects of Clinical Trial Packaging
By Marie Redding
Not much changes very often, or very quickly, in the world of pharmaceuticals—or in regards to packaging for clinical trials—but there are a few trends.
“In the past, we were mainly focused on clinical trials for solid-dose drugs,” says Manfred Zurkirch, CEO, Körber Medipak/Dividella. “In recent years, however, more injectable liquids are being tested,” he says.
Jonathan Calderwood, global head of marketing, Almac Group, agrees that there are many new biotech products being made now. “There is a distinct trend for different presentations of investigational drugs, such as syringes, ampoules and vials—requiring specific clinical packaging, different from what is typically used for tablets or capsules,” he says.
Trials are also becoming larger, since regulators are pushing the Pharma industry to test a greater number of patients, according to Zurkirch’s recent experiences.
Some suppliers have been discussing the efficiency of automation—but, are more Pharma companies moving towards it yet?
“Although automation provides many benefits, at the end of the day it is dependent on how large the study is, and how many studies you can fit into one machine. Clinical trials are still a pretty fragmented market,” says Zurkirch. “Typically, a larger Pharma company will utilize all the benefits of automation by investing in the equipment.”
Calderwood says that automation is key. “Automation provides many efficiencies. We always strive to deliver the right approach to meet the specific needs of each project—and when we can automate, or semi-automate, we will.”
Protecting ‘The Blind,’ Maintaining Consistency
Although clinical trial packaging may seem simpler to produce because it is designed to look generic, certain aspects can be more difficult.
“It is critical for a clinical trial package to ‘protect the blind.’ Everything —from the positioning of any printed elements to the color—has to look exactly identical. Even slight variations are unacceptable,” says Ward Smith, director of marketing, Keystone Folding Box Co. (Newark, NJ).
Smith points out the importance of making sure a clinical trial package doesn’t contribute to the ‘placebo’ effect. “Our job, as suppliers, is to ensure that the packaging doesn’t influence a trial, in any way,” says Smith. “If an investigator or research staff sees a slightly lighter blue on some packages, for example, they may think they figured out which boxes contain the study drug and which contain placebo. It’s a natural instinct to try to guess,” he adds.
That kind of “guessing” could potentially influence the staff’s interaction with the patient. A researcher or physician may unintentionally ask a patient a leading question, which may influence the answer. “The way a trial is conducted can certainly affect its outcome,” Smith explains.
Keystone prides itself on being able to maintain color consistency; both within an initial production run and with re-supply orders.
How do they do it? “We have a complex QA system, experienced press operators, and a few trade secrets I can’t reveal,” Smith says.
Consistency is largely dependent upon the expertise of the printing press operator, and how color is adjusted, according to Smith. “The printing challenges for us include identifying a standard, so that color is perceived [as] the same on all future runs,” he adds.
Slight variations in color during the printing process can be caused by many factors. Unless a supplier is skilled in color management, variations can easily occur with resupply orders, when a supplier prints a different batch. Minor variations that might be acceptable in a commercial package can create problems in a clinical trial package.
“It’s not unusual for a sponsor to expand a trial after study start-up, and then need additional clinical supplies. A resupply batch can be mixed with the first, sometimes stacked side-by-side on shelves at research sites—and any slight differences may be noticeable by the research staff,” says Smith.
Christine Wenner, director of project management, CTM and Specialty Products, Sharp Corp. (Allentown, PA), agrees with the importance of packaging maintaining a consistent look. She says that sometimes she needs to stress this to her customers.
“Many of our customers are from small companies, and it may be their first clinical trial. We often offer advice about how to maintain a consistent look, and we explain what we do to help ensure this,” she explains.
For instance, sometimes a first-time customer will mistakenly believe that the package needs to have a lot number. “That would ‘break the blind,’ so we recommend a traceable code instead,” says Wenner.
Wenner prevents color issues by securing all the necessary packaging materials in advance, so there is no variation when each new batch is ordered.
“When a trial goes on for years, sometimes color issues can’t be avoided,” says Wenner. “In that case we will advise our customers to reorder a full supply of packaging, to ensure that any shift in color will be across the entire resupply,” she says.
In addition to concerns over maintaining color consistency on packaging, color variations can occur on the product itself. In a tablet, for instance, the active drug and the placebo may look slightly different, according to Wenner.
“Sometimes our customers aren’t aware of any color differences, because the product was sent straight to us from a contract manufacturer,” she says. “If the customer specified a clear blister package for a tablet, then it’s an issue,” adds Wenner.
The ‘Blinding’ Process
Wenner also has the task of “blinding” existing packages.
Typically, customers will send the supplier the products that will be used in a trial, and Wenner works with customers to find design solutions. The packaging is “blinded” by being redesigned and altered, to ensure that no one will be able to spot any
This is necessary when a trial is comparing the effectiveness of two different drugs. “Often, a drug that is already approved and on the market is being compared to a new one,” explains Wenner.
“A branded drug that is going to be used for a trial will sometimes be packaged in a vial, for example, and it may have distinguishing features that we may not be able to duplicate exactly,” says Wenner. These features might be unique colors or a specific stopper shape.
“The solution is to create a method of blinding the packaging, which will ensure that all the vials are masked, and users won’t see any color differences,” Wenner explains.
During one of Wenner’s recent projects that included “blinding” a vial, the supplier came up with a way to hide the shape of the vial and stopper from users.
What exactly was done? “We can’t reveal every detail,” Wenner says.
Utilizing Technology to Increase Productivity
Bar codes, when used on clinical trial packaging, can be another way to “protect the blind.” Suppliers say they also help make the randomization process more efficient.
Körber Medipak/Dividella, often incorporates bar code printers, as well as track and trace capabilities, into machinery lines for customers using its automated equipment.
“These are useful additions to a line that will help in a clinical trial environment” says Zurkirch.
Catalent Pharma Solutions (Somerset, NJ) often prints 2-D bar codes on labels for products that will be sent to a trial. The codes contain randomization and blinding information.
“We’ve been using bar codes for clinical trials quite a bit,” says Frank Lis, vice president of strategic accounts & innovation, clinical supply service, Catalent Pharma Solutions Catalent Pharma Solutions. “Bar codes turn the randomization process into a paperless system, so there’s no need to bring complicated lists of randomization numbers into the room,” he explains.
Another advantage is that there’s no way to tell by looking at a package with a bar code if it’s the placebo or drug. “The bar code also contains information about the clinical study,” says Lis. “And, when bar codes are used on products in a kit, all the parts can be scanned to ensure that each patient is receiving the proper items,” says Lis.
Very few suppliers offer these types of bar coded labels for clinical trial kits, according to Lis. “Eliminating the manual process of checking randomized lists—and all the paperwork involved—increases productivity and eliminates errors,” says Lis.
“This leads to shorter production times, quality improvement, and cost reduction. There is an initial investment in hardware and software, but the long-term savings can be well worth it, especially for larger trials,” he adds.
Utilizing the Blister to Increase Patient Compliance
Some suppliers say calendarized blisters have become much more popular for clinical trials.
Missed doses can affect the outcome of a trial, so these blisters help ensure the patient adheres to a specific dosing regimen.
“Generally, yes, blisters are more compliant, especially if titration is involved or the patient needs to take two different products. A blister may also be dictated due to the stability of a drug,” says Calderwood.
MeadWestVaco often supplies blister packs for clinical trials. “Our most popular clinical trial package is our Dosepak, because it allows us to print patient instructions on the inner card, in a consistent manner,” says John Musaus, global director, healthcare product marketing, MWV. MWV’s Shellpak, with built-in child-resistant features, is another popular option.
MWV also offers a new type of injectables package for clinical trials that was designed after a series of
customer site visits. “We saw the incredible amount of manual labor during the assembly process and pack-out of clinical trial kits and brainstormed a package that would reduce the total delivered cost—TDC—of the process,” says Musaus.
Packages that electronically monitor patients’ dosing regimens have been around for more than 10 years and are only now slowly increasing in popularity. “We’re just seeing the market beginning to develop. Clinical trial designers are realizing that for certain trial designs, patient adherence data is integral to the overall study analysis,” says Musaus.
Why has it taken so long for the idea of electronic packages to catch on? “Cost has always been an issue, and still is. For the subset of clinical trials where adherence data is required, the added expense of electronic packages is being included in budgets early on, when clinical trials are in the planning stage,” says Musaus.
Electronic adherence packages are now being considered by drug developers as a tool to collect data, according to Musaus. “In most cases, the data captured is the date and time patients remove medicine from the package. This data can be integrated with other data collected during the trial,” says Musaus. “Clinical trial designers are starting to measure and link patient adherence rates with other data measured during the trial like pharmacokinetics (PK) and pharmacodynamics (Pd). This is especially true for drugs that have a short duration half-life and are sensitive to patients taking their medicine within specific time windows,” Musaus says.
A bottle cap, with a built-in timer, is one type of electronic monitoring system.
MWV offers two types of electronic monitoring systems that can be used with its blister packages. One uses a printed electronic circuit that is placed behind the blister card and measures the removal of the pill from the blister cavity. The other is a sensor that tracks the removal and replacement of a blister card from its carton. “These options precisely measure the exact time a drug was taken and offload the data to a system where drug developers can perform their analysis,” says Musaus.
One of MWV’s electronic blister solutions will soon be used by a major Pharma company for the first large-scale Phase III clinical trial.
Responsibilities Shift in the Future
Pharma companies are outsourcing many new types of jobs lately, which have traditionally been done internally. Catalent is one supplier that has been taking on additional responsibilities that have included managing the entire supply chain.
“Our customers have been asking us to work more closely with their clinical operations team. We’re becoming more involved in forecasting—for instance, determining how much drug is needed and managing inventory at clinical trial sites,” says Lis.
Almac has also been more involved in providing supply chain management services. “We have been providing services that include forecasting and monitoring product usage, to make sure resupply orders effectively reach trial sites,” says Calderwood.
“Taking on these additional responsibilities allows our customers to focus more on the core areas of their business,” he adds.
Lis also says Catalent’s customers are also under an increasing amount of pressure to increase production speed and reduce costs. “We will keep investing in the technologies that are helping to achieve these goals,” he adds.
The Bottom Line
Keystone’s Smith advises that Pharma companies choose suppliers carefully, because partnering with one for a study is like a marriage.
“Studies can last multiple years. No one wants to risk changing supplier’s mid-way through,” Lis explains. “There is great value in choosing the right vendor for your study supplies. In a Phase III study, the average cost-per-patient is $40,000. In comparison, the cost-per-patient of packaging drug supply is a small factor in a study budget…it’s worth procuring the right package from the right vendors.”
Since acquiring Aptuit in early 2012, which includes the company’s clinical trial supplies and formulation development businesses, Catalent has doubled in size.
“The acquisition has expanded our capacity and geographic reach—giving us a stronger position in the marketplace,” says Frank Lis. “Aptuit’s strengths were in storage and distribution, so now we have that capability —as well as many new customers,” he says.
In March, Catalent Pharma Solutions announced the completion of extended warehousing facilities in Schorndorf, Germany, for its Clinical Supply Services business. This has further increased its capacity for the storage and distribution of Investigational Medicinal Products (IMPs)—and incorporates dedicated storage for controlled, highly potent, or cytotoxic drugs.