Medical Device Link.

Originally Published PMPN March 2004

Clinical Trials

Daphne Allen

In the last five years, clinical trials have increased in scale and complexity. “Today’s blockbuster drug trials often involve 30,000 or more patients around the world taking medicines for many years,” reports Philip Diamond. He serves as vice president of marketing for Clinical Trial Services (CTS; Audubon, PA, and Craigavon, UK). “Such trials can be a logistical nightmare to control. You’ve got to guarantee no mistakes for 10 million or more patient labels.” 

Frank Lis suspects that the need to go global and to involve so many patients is because of FDA. “The agency is requiring more patients for more data on drug safety and efficacy,” explains Lis, who is Cardinal Health’s senior vice president and general manager for global clinical supply services. “The patient population is only so big here in the United States, so many trials are held in multiple countries. In the future, I expect to see more studies in Asia and China, too.”

Martin Noblet, director of marketing for Almedica International Inc. (Chester, UK), adds that Eastern Europe is emerging as another location for clinical research.

To help sponsors prepare for such global trials, clinical trial supply providers have expanded their services to more than just packaging and labeling. Routine offerings include packaging and labeling, storage or ware- housing, study-specific randomization, distribution, reconciliation, and destruction. Some offer drug development and manufacturing and analytical chemistry.

Packaging is also evolving. A trial with patients in several countries requires packaging and labeling that can be supplied quickly with the necessary languages and compliance-enhancing features.

Services Multiplying

“It’s more than just packaging these days,” says Lis. “Companies are coming to us to manage the whole clinical drug supply chain, so that’s where we are investing. Pharmaceutical companies used to deal with the CROs [clinical research organizations] themselves, but now we are.”

Clinical packaging operations therefore are often managing distribution. They might not even call themselves packagers anymore, given their new roles as supply chain managers. 

“We see the value of offering a full range of services—preclinical, formulation, clinical supplies, and distribution,” says Scott Houlton, vice president of Quintiles Clinical Supplies (Mount Laurel, NJ, and Kansas City, MO). By getting involved with the drug product early, he says that “we can develop a better understanding of the compound, offer suggestions on manufacturing demands, and suggest appropriate means of packaging and distribution.”

Lis also sees a benefit to cradle-to-grave services. “Cardinal Health offers drug discovery, dosage form development, and clinical manufacturing services and can examine the compound to design the study and clinical profile.”

Many of the services being used today, though, involve supply fulfillment. “We help firms make just enough product to avoid overages,” says Lis. “With expensive drugs, manufacturers no longer want to package 20-30% more than what they need. Now it is just 5%. So we start dealing with the investigator sites to look at patient enrollment to predict what supplies they’ll need. We then put together a distribution profile.”

Jeff Hallquist, director of sales for Fisher Clinical Services Inc. (Allentown, PA), says that he has seen clinical supply services requests evolve from tactical project management to more of a strategic program management. “We look closely at the sponsor’s goal for the trial. Also, for a global trial, for instance, we ask such questions as, What countries will enroll first? How many common languages will there be or will we need? How many campaigns will there be? Will the core group of patients be expanded based on initial trial results? Answers to these questions will help us plan production of supplies and label accordingly to provide for the greatest flexibility.”

Cardinal Health’s new warehouse in the United States, with 92,000 sq ft of space, has been a “phenomenal business,” Lis reports. The firm is now breaking ground on a new storage and distribution facility in Schorndorf, Germany, near its clinical operations
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Fisher has a new facility in Horsham, West Sussex, UK. “The location facilitates bringing products into the European Union (EU),” says Hallquist. “When it comes to the new EU Clinical Directive, which takes effect in May 2004, it helps to have a center in the EU with a qualified person (QP) to review all documents and to guarantee that the products are packaged according to EU requirements.”

Quintiles also has a new sterile suite in Kansas City, MO, for the development of sterile-fill and lyophilized products. “It is part of our attempt to bundle attractions and link services throughout our company to help drug companies with development,” says Houlton. “With manufacturing and packaging in one suite, you don’t have to hand it off to another vendor.”

When to Outsource?

Houlton says that “clinical supplies should no longer be about who can blister the cheapest. We are interested in developing long-term relationships so the sponsor can rely on just one vendor. Sponsors shouldn’t have to hire internal managers just to handle six different vendors.”

He continues to say that dealing with multiple vendors can raise questions about accountability. “Hand-offs from one vendor to another or from vendor to manufacturer can be challenging. There are opportunities to drop the baton. Figuring out who did is a gray area. If you have the same vendor handle task A and task B, that vendor will take responsibility for any mistakes.” He adds that the bidding that manufacturers must go through to find the best prices for individual projects may cost more in the end.

David Bernstein, though, believes that outsourcing projects to many different manufacturing, packaging, and testing vendors has its benefits. Bernstein is vice president of pharmaceutical sciences and regulatory compliance for Cato Research West (Oakland, CA), a contract research and development organization. “One-stop shopping does not always translate into speedier drug development. Companies should use the best contractor for the project at the time,” he says. “Best” doesn’t always mean cheapest, though. “You have to look at the project needs, packaging, and the clinical sites. My role is to translate the clinical drug protocol into an overall CMC [chemistry and manufacturing controls] program and specifically a clinical supply program. Manufacturing and packaging are often interlinked and firms need a skilled orchestra leader to coordinate multiple vendors.”

Bernstein’s experience with vendors has been mostly positive. “Most are pretty responsive and GMP compliant. Some have exceptional staffs. They offer overlapping services, though, so I look for the best for my client’s job.”

The EU Clinical Directive may prompt virtual biotechnology and pharmaceutical firms to seek the help of a qualified vendor. “The directive has some U.S. firms very concerned with the release of clinical materials within the EU,” says Hallquist. “Having one entry point and therefore one set of requirements to follow, instead of trying to meet the regulations of each country, is definitely better. But there is still a lot of interpretation going on because of the regional differences that remain within the EU. A QP must certify that materials are manufactured and packaged according to acceptable standards, such as GMPs, and that these standards are maintained throughout the supply chain. These QPs must review and approve the documentation sent with clinical drug batches. Some QPs, however, won’t certify shipments without first having inspected the manufacturing or packaging facility.” Fisher offers what it calls EU Gateway services that include QP release to ensure compliance.

Another challenge will be when 10 new states join the EU in 2004, adds Noblet.

Packaging

The complexity of clinical trials has mushroomed in the last 10 years, reports Bernstein. “Sponsors are trying to get more information from fewer trials, so drugs often need to be packaged in complex configurations.”

Products, comparators, placebos, escalating doses, and others, therefore, must be at the ready for quick and accurate assembly of individual patient kits. “We are using electronic verification to ensure that we are assembling the correct treatment kits for patients,” explains Diamond at CTS. “We rely on electronic code scanning technologies on the packaging line. Our Transmark line, for instance, is a fully automated line that applies bar codes with ink-jet technology to blisters and scans those blisters down the line to ensure that the correct sequence of products has been assembled.” He adds that CTS has employed Transmark for some “mega” studies. CTS also uses automation to print, verify, and apply random codes to booklet labels and to verify that the right labels have been placed on the right products. It then compiles these products into patient kits.
Noblet also says that information systems are increasingly becoming important to clinical manufacturing, packaging, supply, and returns. He points to a wider use of interactive voice response (IVR) systems throughout the clinical supply chain. 

Diamond and others agree. “IVR use has magnified in the last few years. It tells the CRO what pack to give to the patient, and it tells us that a pack has been used and that we need to replace it. We are then able to select the right pack from our stock and ship it to the site.”

Joe Saccomanno, currently director of study planning and development for BlisTech Corp., says that he is seeing a lot of interest in novel packaging technologies. “I am seeing less bottles, more blisters. Interest in the Med-ic Smart Package, for instance, is big.” The developer is Information Mediary Corp. (For more information about Med-ic, see our March 2003 feature, “Blisters for Clinical Trials.”)

The Med-ic Smart Package uses an electronic tag built in to the blister to record each time a product is removed. Saccomanno says that there is also interest in another product from Information Mediary, Log-ic, to record temperature exposure. “Drug makers know that FDA is concerned about temperature control, especially for biologicals with large protein molecules, which are very sensitive to temperature spikes. Companies want to do whatever it takes to get a $500 vial of medicine to the clinical site intact.” 

Fisher’s Hallquist has also seen interest in blisters grow. “Our choices include Dosepak and Surepak from MeadWestvaco and KeyPack from Keystone Packaging.”

Joseph Urban, senior director of ProClinical Pharmaceutical Services (Phoenixville, PA), says that for the last three years, his firm has provided Pick and Peel child-resistant blister cards to more than 40 pharmaceutical companies for use in clinical trials. “We’ve seen an increase in demand, especially for larger studies.” Some of these pharmaceutical firms are also using Pick and Peel for commercial packages. “If you begin to prepare for commercial packaging during Phase III studies, there is a cost savings when you go to market in the same package. All you need to do is change labeling.”

Urban also adds that ProClinical has applied for patents on new blister card laminates that should allow a company to choose what F rating of child resistance and senior friendliness rating they want. Clinical quantities of Pick and Peel Cards can be obtained from ProClincal, while commercial and larger clinical quantities may be obtained directly from Graphic Packaging International (Yardley, PA). 

ProClinical has also expanded its clinical and commercial packaging offerings through the acquisition of Vital Pharma Inc. Vital Pharma develops and produces aseptic packaging for liquid pharmaceuticals. Vital Pharma’s former president William Stringer, has joined ProClinical as the president of its new subsidiary, ProClinical Aseptic Manufacturing LLC. 

“We believe there is a niche for blow-fill-seal packaging, especially for ophthalmics and topicals. We are drafting patents for new uses for blow-fill-seal and expect these will be in clinicals shortly,” says Urban.

Clinical supply firms are just waiting for the go ahead from manufacturers. Says CTS’s Diamond: “Sponsor companies hold off until the last possible moment before confirming the design and quantity of clinial supplies. They expect us to turn somersaults, so we need flexible systems to be able to adapt to their needs in a short time.” 

Copyright ©2004 Pharmaceutical & Medical Packaging News