Leah Tufts and Leroy Anderson, Bellwyck Pharma Services
Highly sensitive drugs are a growing sector of the clinical trial environment and require specialized environmental controls, elevated shipping provisions, and customized label identification. They are especially at-risk during transport, and the first real test of their stability is during the journey to clinical trial sites. As we look for solutions to reduce risks associated with these products, special planning and care is required. This article outlines key supply chain planning considerations for highly sensitive drugs and provides guidance to prevent losing valuable time and money.
Highly sensitive drugs, early in their development cycle, may not have ample stability data to support their journey to trial sites without temperature controls. Because of this, proper planning is required to create contingencies and mitigate supply chain risks to ensure that products are within acceptable temperature ranges throughout the entire supply chain. Without proper supply chain planning, highly sensitive drugs can be compromised, even completely lost, costing a company valuable time and money compared to a well-managed clinical trial.
Most often, delicate drugs are very temperature-sensitive, requiring specific conditions to remain stable and maintain their shelf life. Packaging temperatures, conditions, and handling instructions must be closely adhered to in both refrigerated and frozen environments to maintain product integrity.
Adding to the challenge of maintaining those handling and storage conditions are the blinding requirements of the study — ensuring both the drug and its placebo are packaged, stored, shipped, and distributed in the same way and have similar properties in every stage of the supply chain. This includes all documentation and labeling of the study. The packaging aspect of blinding a study can become particularly challenging in multicountry, multilanguage studies. To keep the study blinded, common product descriptions (i.e., “Patient Kits” or “Active” and “Placebo”) and sequence ranges are used, but no patient numbers should be used on any paperwork or documentation.
Labeling can also present big challenges in highly sensitive drugs. Any mistakes in labeling operations have the potential to compromise or even ruin a study. Proper label generating systems are validated to separate randomization numbers by treatment arm. This also ensures that when packaging placebo, the label numbers correspond with the random code for placebo drug product, and the same with active drugs. Intricate detail, including specific label placement and carton orientation, is required when packaging the different treatment arms of the study to ensure that blindness is maintained throughout the entire packaging campaign. For example, if one person packaged all the active drug with the opening of the carton facing them, and another person packaged the placebo with the opening of the carton facing away from them, that could unblind the study as it becomes clear to the investigators and the patients that these two products are different.
Sometimes, highly sensitive drugs are classified as dangerous goods — perhaps containing a high percentage of ethanol or another toxic substance. When this occurs, additional regulations from federal transport agencies apply to the shipments, adding challenges and significant documentation to packaging, shipping, storing, and distributing.
Storage and warehousing also pose significant challenges for highly sensitive drugs. Warehouses and cold storage units must be controlled-temperature environments with built-in backups and redundancies to ensure they are maintained at the proper temperature range. For instance, if a condenser or evaporator unit goes down, the secondary unit in that controlled space would maintain temperature while the malfunctioning unit could be repaired. Additionally, any GMP spaces or storage spaces within facilities should be backed up by generators in case of power loss. All of this is part of a larger preventive maintenance program. If issues can be prevented, it’s best to have a program in place to do so rather than react to problems as they occur. Lastly, all equipment essential to maintaining temperature and environmental conditions should be tested frequently to ensure it will function in an adverse event.
The distribution phase presents many challenges: maintaining temperature throughout the process, crossing borders, clearing customs, and mitigating possible delays. ERP systems, and other internal tools, can provide specific instructions to operators when preparing an order for shipment. These resources help to properly train the staff to avoid issues that could jeopardize the product, and, consequently, the study.
Very rarely will a drug company have the ability to execute a highly sensitive drug supply chain on their own; therefore, they look for third-party contractors to assist. However, it is important that the chosen supply chain partner has the necessary capabilities, facilities, procedures, and personnel to be successful. The contracted partner must have standard procedures, adhere to each product’s proper storage conditions, and maintain GMP compliance for the specified conditions. A vast infrastructure is required to maintain an environment capable of packaging, storing, and transporting highly sensitive drugs for complex studies.
Personnel also play a big role. The contracted partner must have people who are thoughtful and creative in their approach toward every project due to the many and differing intricacies of each clinical protocol. Personnel must be highly educated about processes and cognizant of their responsibilities at every step.
If any of the above controls and protocols are overlooked, there are a host of potential consequences. Studies can suffer delays, which postpones the results and stalls time to market. All of these have significant financial repercussions for drug companies. In worst-case scenarios, studies can be completely ruined from compromised drugs, which can have devastating ramifications, especially for small companies.
Small drug companies do not typically have the resources of Big Pharma. In fact, some small drug companies have one opportunity to perfectly execute their study and ensure that their highly sensitive drug reaches its destination unscathed. Failing to do so could result in the company defaulting.
To prevent studies from going awry and creating catastrophic scenarios, proper supply chain planning for highly sensitive products is critical. The first step in executing this is understanding the study implicitly. Project managers review the study protocol, ensuring they can interpret the protocol requirements and translate those to our internal team, which will implement requirements for the drug to be packaged, shipped, stored, and distributed properly.
This deep understanding of the drug requirements and the development of internal requirements leads to the development of a supply chain strategy. However, that strategy hinges on many variables: How will products be packaged? What is the best packaging and labeling strategy? Is this a single- or multiple-run campaign? Will it be a one-month supply or multiple-months’ supply? What are the economic and budget limitations? Will depots be required or can product be shipped directly to sites? There’s a lot to be considered and, as 5 Critical Steps In Developing Your Clinical Supply Chain discusses, the strategy must be laid out as soon as possible.
Ideally, these conversations between the supply chain partner and drug company should happen well in advance of execution. Depending on the packaging type and strategy, there could be extended lead times encountered. For example, tooling is needed if blister packs and wallet cards are being used, which can take six to eight weeks to acquire. In addition to the package type, labeling strategy can also play a role in extended planning time. For instance, booklet labels are often utilized for global studies, and these types of labels have wait times for translations, proofing, and printing of multiple pages. Regardless of packaging and labeling type, lead times for chosen applications will determine how early planning should begin.
Typically, a project manager from both the drug company — someone with a deep understanding of the project and its requirements — and the contracted partner will lead planning. The project manager from the drug company will provide the contractor’s project manager with the overview and details of the project. From there, the contractor begins looking at the plan through a QA lens to get a perspective on special occasions, doc reviews, and other circumstances unique to the study. The contractor will then bring in the operations team to evaluate and review in-house packaging processes. Next, the contractor’s logistics team reviews the distribution plan, asking questions such as: What depots need to be set up? What will packing configurations be? How many shipments will be required? Finally, regulatory requirements of each country involved are examined by both the drug company and the contractor.
Fast and robust traffic lanes also help highly sensitive drugs remain stable and maintain their shelf life. This is especially true for multiple global regions; ideally, products will ship, clear customs, and arrive at their destinations as quickly as possible. Fast shipping lanes reduce the risk of temperature-sensitive products becoming compromised. However, the traffic lane used must not only be fast, but it must also be robust. The courier must be capable of handling temperature-sensitive packages and have the capability of maintaining controlled temperatures throughout its transit. Not all carriers may be able to offer this type of robust traffic lane.
Interactive Response Technology (IRT) also plays a major role in keeping studies blinded. Drug companies hire software companies to create programs that allow the drug company visibility to where their product is in the supply chain. This software also allows sponsors to track patient dosing, including each patient’s assigned treatment arm, and provide the outcome to physicians in a blinded manner.
Packaging is the first line of defense to protect highly sensitive drugs from environments that could put them at risk. Primary packaging isolates the product from its environment and is done, in most cases, for solid dosage form in HDPE bottles, PVC, and foil blister strips. Secondary packaging is used to blind the drug product. This includes cartons, randomized labels, and tamper-resistant packaging. Tertiary packaging includes insulated shippers and enables the drug to be maintained within particular conditions to keep it viable and maximize its shelf life and to be continuously monitored during shipping, storing, and distributing (more on this in a moment).
Environmentally controlled chambers rely on HVACs, freezers, and refrigerators with the ability to regulate and control environmental variables as needed. A contracted warehousing organization should also have previously mentioned redundancies of protection built into them to ensure warehouse drugs maintain their integrity in the event of emergency. Often, freezer- and/or refrigerator-enabled warehousing space comes at a higher price-point than traditional or general warehouse space because of the redundancies needed to maintain the required temperature in any situation.
Real-time monitoring is also a vital tool to protect highly sensitive drugs, both in warehouses and in transit. Contracted packaging, shipping, storing, and distributing organizations should have real-time monitoring in all their storage and warehousing depots. These facilities should be closely watched and tracked via a remote-sensor system — a centralized dataset that captures temperature and humidity in all the different storage conditions across every location. This monitoring is done 24/7 and is accompanied by a temperature monitoring system that alerts key personnel prior to an actual temperature/humidity outage occurring within these critical spaces. Waiting for the storage areas to breach the acceptable storage condition ranges only allows for reactive and not proactive measures to be taken. Once appropriate personnel are notified, actions can be taken to correct and mitigate the issue moving forward.
All warehousing sites with real-time monitoring are required to perform seasonal temperature mapping. Monitors are strategically located within the storage areas to identify any potential dead spots, in terms of keeping the temperature within specified ranges. The entire warehouse space, including refrigerators and freezers, are mapped for best- and worst-case locations, so in-spec temps can be achieved throughout the warehouse. While there are few regulatory guidelines that specify the requirements for temperature mapping, a contracted warehouse organization must be able to defend the logic used to ensure that temperature throughout the warehouse or cold storage unit is maintained.
Single-use, real-time monitors can also be placed inside shipments. Depending on storage conditions, there are several different versions of the technology that can monitor different temperature ranges. These units can run for close to two months, capturing data, recording it, and giving the receiving side the ability to plug it into any computer and download a graph. That graph will show the actual temperature within the shipment in 5-minute increments. The graph shows the trial site whether the product stayed within specifications, so it can determine whether it is safe to move ahead and use the product.
Often, small and midsize companies do not receive the close, intimate, detail-oriented attention they deserve from supply chain partners. Regardless of company size and dollars spent, supply chain partners should provide the same high-quality service to every client. That service should be based around the following factors:
The conditions necessary to pack, transport, store, and distribute highly sensitive drugs can create big challenges, and if they are not properly addressed, can cost drug companies valuable time and money. However, understanding risks and properly planning for them will minimize risk for these expensive, highly sensitive, and crucial clinical drug products.
About the Authors
Leroy Anderson is a senior manager of operations at Bellwyck Pharma Services. In this capacity, Leroy is responsible for distribution and warehousing, packaging, and facility management of clinical supplies. Leroy has been in this position for 10 years, servicing hundreds of studies for multiple clients. He has 26 years’ experience with Pharmacia/Pfizer in commercial/clinical packaging and distribution and three years’ experience with a biotech company in Toronto, responsible for logistics/planning.
Leah Tufts is VP of U.S. operations at Bellwyck Pharma Services. Leah oversees the entire U.S. operation, including distribution, warehousing, and packaging activities. Her role includes managing the growth of the site, both in personnel and facility capacity and capabilities. She has been with Bellwyck for six years, previously overseeing the clinical QA team. Leah’s experience prior to Bellwyck ranges from commercial manufacturing and packaging to clinical R&D.
Leroy Anderson and Leah Tufts, Bellwyck Pharma Services