The size of clinical trials continues to expand, observers say, creating a ripple effect in pharmaceutical packaging.
Credit: Top: Almac Clinical Services; Bottom: PCI
The size of clinical trials continues to expand, observers say, creating a ripple effect in pharmaceutical packaging. More emphasis is being placed on secondary packaging design to minimize risk of product damage or activation during shipment. Studies are also becoming larger, as regulators encourage the pharmaceutical industry to test a greater number of patients.
The challenge is preparing supplies that prompt compliance, as many clinical studies have complex dosing regimens and require packaging components to be flexible and applicable for all study countries. “We are now seeing more requests to design packaging for injectable investigative drugs, all requiring different packaging from what is typically used for solid dose formats,” observes Ed Bani, technical service manager, Rondo-Pak (Norristown, PA), a manufacturer of cGMP compliant pharmaceutical folding cartons. “But regardless of the medicine form, clinical trials customers want the best of both worlds for their packaging: patient-friendly packaging with clear, concise labeling for patient compliance that still maintains the rigid standards for filling, assembly, storage, stability and containment of the product.”
The most common types of packages for clinical trials are blisters, bottles, pouches, syringes and tubes, industry members say. Each may be assembled in different configurations, so as to drive study compliance. “Since a majority of clinical supplies require a high degree of human interaction with the unique package designs, none pose a particular set of issues over the other types,” says Joe Morris, president, Sharp Clinical Services (Allentown, PA), a provider of clinical trial materials services to the pharmaceutical and biotechnology industries.
Medication adherence is having a substantial impact on the approval criteria for drug candidates, according to published reports. FDA recently provided a draft guidance specifically addressing adherence strategies, including encouraging sponsors to implement adherence practices, such as using smart bottles to monitor medication use. Since pharma companies can control the packaging, as such, it is viewed as a key tool for driving patient adherence.
“MWV’s Aardex Solution uses a ‘smart’ technology called MEMS Caps, which is used to measure adherence patterns of clinical trial subjects,” notes Tom Grinnan, senior director, global patient adherence, MeadWestvaco Healthcare (MWV; Richmond, VA), a designer and producer of integrated primary and secondary packaging solutions for the healthcare and pharmaceutical industry. “The Aardex Solution provides the technology, analytical tools and analysis to monitor patient adherence in a trial and show the impact.” Better understanding of patient adherence during a trial can lead to improved trial efficiencies and optimized trial outcomes, experts say, and boosts the chances of the drugs being commercialized.
To meet study compliance requirements, the use of blister packaging along with CR wallet cards is reportedly common for later phase studies. Generally, blisters are more compliant, especially if titration is involved or the patient needs to take two different products. A blister may also be required due to the stability of a drug.
Wallet-style blister packs are used for solid oral medications and available in child-resistant formats, such as MWV’s Dosepak. The manufacturing and filling processes for wallets and blister packs can be automated, experts say, although handwork usually occurs for portions of these processes. “An increasing number of trial packs are used for injectable and inhaled medications,” Grinnan observes. “These package types tend to be highly customized ‘kit’ packages that require manual fulfillment.”
The same wallet card format may contain different product strengths—including placebo and comparator product—that all look the same to protect product “blinding” for the study. Everything—from the positioning of any printed elements to the color—has to look exactly identical, to ensure no one will be able to spot any differences. By comparison, commercial drugs are packaged one dosage strength/product at a time. “A select group have the knowledge of what is actually contained in the package by virtue of the product identifiers,” says Bob Misher, general manager and senior vice president, clinical services, Packaging Coordinators Inc. (PCI; Philadelphia), a provider of pharma commercial packaging solutions and clinical trial services. As a result, the controls to manage different products that look identical are rigorous.
How clinical packaging, commercial packaging runs differ
On the surface, clinical trials and commercial runs appear to be similar in that each requires a robustly tested match of product and the primary package. However, clinical runs differ in that a package may contain multiple products within the same pack, industry members say. The process can vary widely, depending on the package and run volume.
“The items typically being packaged and labeled are managed at a serialized level, where each package is often intended to be unique, as opposed to commercial packaging, where the batch sizes are notably larger and all packages are intended to be identical to each other,” Sharp’s Morris says.
Setting up the clinical packaging run tends to be much smaller in scale, experts say, but balanced by highly variable requirements imposing hazards on standardization. “It must relate to all rules for investigational products,” notes Jonathan Calderwood, global marketing manager, Almac Clinical Services (Craigavon, UK), which specializes in packaging, distributing and delivering supplies for clinical protocols.
Packaging runs can be “one shot deals”—such as early phase studies with fewer supply requirements—and are typically impacted by several factors, such as length of the trial, duration of dosing, availability of study drugs, expiration date of the study drugs and/or comparator product. Based on these variables, some studies may require multiple time-phased campaigns to ensure continuity of drug supply for the duration of the clinical trial.
“As drug development models change, we must match packaging to new trial realities—such as adaptive studies—and build as flexible of an approach as we can,” Calderwood says. “Companies are not strictly outsourcing packaging, but component aspects of the IMP supply chain, and rely on expertise to manage getting investigational products from clinical bulk production to finished product available across the globe.”
Late-phase studies require a greater number of subjects over a longer period of time, so multiple packaging campaigns are common. “Reasons for multiple packaging campaigns include limited product availability from the sponsor company and limited expiry data,” PCI’s Misher points out. “In most cases ‘just-in-time’ (JIT) packaging is not required.”
JIT concepts apply less to the manufacturing and packaging of the clinical supplies, experts say, but are more relevant in labeling operations and distribution of clinical materials. PCI offers a “rapid response” program that addresses the needs for projects requiring completion in less than four weeks from award. “Timelines in the CT world are very aggressive, as pharmaceutical companies look to expedite commercialization of drugs in their pipeline,” Misher reports. “So opportunities to expedite supplies for studies are critical.”
For example, a sponsor company may have several studies running concurrently using the same packaging format. “To maintain a flexible supply and have drugs available for all studies,” Misher says, “the protocol number is not included on the original supply labeling. It is added at the time of distribution with a supplemental protocol number label.”
From a regulatory standpoint, manufacturing and packaging of all pharmaceutical products must comply with cGMP requirements, regardless of clinical or commercial applications. The guidelines to perform a function such as kitting are the same for the warehousing and distribution of finished goods in healthcare, observers say. All such activities must be done under the guidance of a compliant quality system that would include general inventory-control aspects, such as cycle counting, traceability and product identification.
Although regulatory requirements are similar for packaging implemented for commercial uses vs. clinical trials, there are differences. For instance, “there are some unique regulatory differences that apply to clinical label requirements and additional regulatory requirements for products being used outside of the United States in global trials,” Sharp’s Morris says, noting these can vary by region and country.
The labeling and kitting processes are different from commercial packaging as well. For example, the double-blinding of clinical packs requires using more barcode labeling and database management on the line. “Clinical runs tend to be short, with extensive documentation and audit trail requirements, so line set-ups can be long,” MWV’s Grinnan observes. “The longer runs of commercial packaging require investment in automated quality control, such as scanners for visual inspection.”
Meeting client needs for trial drug, kit with comparator
Larger and more complex Phase III clinical trials typically involve a study drug, comparator product, and placebo. Additional ancillary supplies or rescue medications may be included in the kits. “It’s important to consider that each component relates to the ease of use for the patient balanced alongside manufacturing efficiencies and supply chain considerations,” Almac’s Calderwood points out.
Clinical trials are highly dependent on kitting. In this instance, several components are bundled together into one package—such as medication, supplies and directions—and then shipped to patients involved in the trial. The self-contained package offers all of the necessary components for drug administration.
Packages utilized for bundling drugs and relevant components together range from plastic trays and bags to corrugated boxes and totes. Many sponsor companies will request vendors to perform primary and secondary packaging to complete the final clinical supply ready for sites and patients. “The use of commercial comparator products is determined by the sponsor company when it designs the clinical trial and identifies their primary and secondary end points,” PCI’s Misher says. “We do commonly help provide comparator products for investigational studies and ensure discrete supply for the study.”
Cold chain shipping of clinical study drugs
Clinical packaging for temperature-controlled pharmaceuticals may also include insulation to maintain temperature standards. Some clinical study drugs are required to be stored and shipped in either a refrigerated or frozen state. These requirements are usually defined early in the process and the appropriate packaging materials and label stock are specified to ensure proper performance throughout the life of the clinical study.
“It is common with both oral solids and injectables to use cold chain storage and shipping, which requires some expertise to ensure product integrity during transit,” Misher says. “We work with clients to identify the optimal solution for their product and provide confidence it is delivered to the patient within the parameters it was designated for.”
For refrigerated and frozen products with established excursion times, packaging and labeling can be conducted at room temperature, and are carefully monitored and documented. “Refrigerated products with no allowable excursion time can be labeled within the refrigerated environment,” Sharp’s Morris says. “Frozen products with no allowable excursion time may be labeled over dry ice to maintain the required temperature.”
Shipping containers used in transporting clinical materials are highly dependent on the temperature condition, experts say, which must be maintained during transit, the environment in which the material is being delivered to, and duration of the shipment. “The overall selection of these finished shipping containers should also be made with the understanding of the required payload that can be supported,” Morris advises.
As third-party logistic providers (3PLs) move into value-add services like kitting, contract packagers are expanding their shipping and fulfillment capabilities. For example, some offer primary and secondary packaging as well as 3PL standard services. By combining these services, contract packagers can partner with customers and assist them with minimizing their working capital requirements.
MWV supplies packaging used in clinical trials, a service complemented with logistics to customers’ clinical packaging facilities. Almac utilizes a global network of partners as its core competency lies specifically in clinical supply chain management. “Where appropriate, we develop partners to complete the ‘to site’ aspect across the large geographical spread of clinical sites,” Calderwood says. “No one company can cover everything, but we act as the controller.”
For logistics between the storage depot and investigator sites, PCI’s clinical supplies are shipped overnight, predominantly via FedEx in the US and UPS in the UK. “Shipment of bulk supplies from the packaging center to a regional depot are generally managed through World Courier due to the shipment volume and cost of the supplies,” Misher explains.
Sharp works with a number of 3PL providers for distribution. “We have selected this approach since we are required to distribute clinical supplies very quickly and efficiently around the globe,” Morris says. “Each 3PL partner that we use has specific strengths and areas of expertise, as well as scale of operations which can be effectively leveraged.”
Contract clinical packaging providers say they are well positioned to sourcing the necessary medical components and delivering them in a suitable pack for end users. They represent a valuable resource for clients to outsource traditional in-house activities, or companies who have a limited packaging and distribution infrastructure. All claim to provide effectively the same global services.
For example, Almac claims its IRT solution positions it as the top global player in clinical supply chain management. Rondo-Pak reports having an experienced and professional design team to assist clients in the critical secondary packaging selection process. “We work closely with the client’s process engineers to ensure the packaging will run efficiently on their designated filling equipment,” Bani says. “In addition, we can offer traditional printed packaging components as well as fully assembled cartons for ease of use and (the) speed to market aspects of the trial process.”
PCI offers “seamless support” from clinical to commercial. “Our ability to support clients in taking a compound from clinical development to commercial launch within the same organization and on a global platform provides substantial value to our clients,” Misher says. “We add value by bringing commercial considerations, insight and expertise much earlier in the development process, while at the same time providing a single provider and continuity of services for bringing drug candidates to successful commercialization.”
Sharp reports it is positioned to provide all of the key services that comprise the clinical supply chain. “By fully integrating these services, we are able to satisfy a wide range of customers who are looking to consolidate vendors,” Morris says. “We are also more able to effectively reduce inherent risks in clinical timelines by reducing the interactions which can be created by a complex network of service providers.” These services include, among others, comparator sourcing, clinical label design/printing, package design, clinical packaging, global storage and distribution.
Clinical trials from a logistics perspective
World Courier, generally regarded as the global leader in this space, is now a business unit of AmerisourceBergen, one of the Big Three wholesalers that has distinguished itself not only for developing a large network of specialty-pharmaceutical distribution and services, but also as a global distribution player through its months-old relationship with Walgreens and with Alliance Boots, a UK distributor and retailer.
On paper, the World Courier acquisition offers several potential growth areas: to go “up the pipeline” and operate more in drug development; to combine World Courier’s global scope with ABC’s budding international business; and to enable World Courier to function as a commercial distributor (something it does infrequently today) nationally or internationally.
Since the acquisition, ABC has appointed Doug Cooke, president of ABC Specialty Group’s ICS business unit (a 3PL, primarily for oncologic products) as president of global specialty logistics, with both World Courier and ICS reporting to him.
For the time being, Cooke tells Pharmaceutical Commerce, both units will maintain more or less their own areas of activity, but he adds that “one of the things that made this acquisition attractive to us during the due diligence phase was how similar the operations and culture were. Both companies have a strong service focus, and the World Courier depots (for storing clinical trial materials locally around the world) look like, and are operated to the same GDP standards, as the larger ICS distribution centers.” He adds that biopharma companies have asked him why the same services they obtain from ICS can’t be offered in Europe or elsewhere; “they tell us they wish we were there already.”
Meanwhile, another CTM logistics provider, Marken (RTP, NC) plans to give World Courier a run for its money. The company (which went through several rounds of privateequity ownership in recent years) continues to open new depots around the world, and is also positioning itself as a service provider for both API logistics and for commercial distribution, although Ariette van Strien, senior VP, commercial operations, for the firm, says that “Shipping APIs or finished goods is good business for us in the emerging markets that we’re strong in, and also in the case of having an integrated product launch strategy (to station inventory where it will be most needed), but we’re not about to become a global commercial distributor.”
Van Strien says that an internal project management team looks intensely at investments in new depot construction, as well as investment in new IT platforms or other advanced technologies. These questions around these decisions become even more intensive when partnerships with either CROs or CMOs come up—Marken has working relationships with several leading CROs—and in at least one other case, there is such a heavy volume of samples being returned to a central laboratory that Marken has a fleet of trucks in that city to expedite deliveries.
World Courier’s Cooke says that his company entertains proposals from CMOs and CROs, but the ultimate decision resides with the trial sponsor or drug manufacturer. “Some CROs and CMOs essentially want to ‘private label’ our services under their name in dealing with sponsors,” he says. “That could make sense in some instances, but in general we prefer to work directly with the sponsors.”
Meanwhile, DHL Express (Bonn, Germany) is bidding aggressively on a substantial part of routine clinical trial logistics projects, and is growing at double-digit rates, especially where cold-chain deliveries are involved, says Marco Hogenboom, global head, life sciences and logistics. The company can substantially undercut the other players, he says, by making use of its existing network of express deliveries, which span most major capitals across the world. “Other, courier-based services can serve niche markets or highly specialized shipments as well, but when significant volumes are being sent to places like Latin America, the US or the Far East, we can be very cost-effective,” he says. The business unit also taps into DHL Global Forwarding, which handles bulk freight, when backup storage or other resources are needed.
Other leading players in this space include FedEx, TNT Express (Amsterdam), QuickStat (New York), Sentry BioPharma (Indianapolis), Quest Diagnostics (Madison, NJ) and PRA (Raleigh, NC).
Following the publication of this article, World Courier has gone on the record to say that their position described herein was inaccurately stated. The company’s position is that it maintains a position of neutrality in regard to relationships between study sponsors, CMOs and CROs, and strives to provide the best value proposition to all involved parties in executing a trial logistics plan. Also, for the record, Mr. Cook’s last name is misspelled, for which Pharmaceutical Commerce apologizes.