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Personalized medicine and direct-to-patient trial models have made the difficult even more challenging.
Manufacturing for clinical trials requires addressing complex packaging, labeling, and logistics issues and maintaining blinds, so that the identity of the drug being administered remains unknown. New patient-centered trial models and the growth of personalized gene and cell therapies have added additional degrees of difficulty to the process. Creative management and use of interactive response technologies (IRTs) solutions are helping sponsors and contract partners improve overall efficiency and reduce waste. In this article, Matt Blume, general manager of global business operations for Catalent Pharma Solutions, shares insights and best practices. In a separate interview, Stefan Dürr, senior director, client delivery, with Cenduit, LLC discusses the use of IRT in optimizaton efforts.
PharmTech: How are you addressing the typical disconnect between chemistry, manufacturing, and control (CMC) and good manufacturing practice (GMP) specialists in your work with clients?
Blume (Catalent): We include clinical project managers in early phase manufacturing discussions with the sponsor. For example, in our San Diego facility, we have co-located clinical project managers in the CMC plant so that they can be included in the earliest possible project discussions. Even though these discussions may not focus on clinical supply issues, the earliest stage of the product is the perfect time to highlight some of the areas that sponsors should consider (e.g., general project timelines as well as packaging configuration options). Early development batch production is a good time to place product down on stability in multiple material configurations. Doing this very early in the process allows meaningful data to be gathered as soon as possible, ensuring that the most patient-friendly package is designed, and allowing for potential savings in Phases II and III if data can be established that allow for higher shipping temperatures.
There is no downside to ensuring that all team members are engaged throughout the process. The interaction of the different specialties not only helps the specific project being discussed, it also builds cross-functional knowledge, strengthening the CMC team’s understanding of clinical concerns and the clinical team members’ knowledge of CMC challenges.
PharmTech: What are the most challenging packaging and logistics issues involved in clinical trial manufacturing, and how (and when) should they be addressed?
Blume (Catalent): One challenging task is the labeling of biologics and gene therapy products prior to freezing. At the point of fill/finish, minimum label content must be determined so that it can be used for many different countries and destinations. This needs to be addressed very early on because many of the facilities that focus on biologics and gene therapy are not clinical supply experts. Co-locating clinical supply team members to focus on label design and clinical challenges within the manufacturing team is extremely helpful, especially since these teams have little clinical trial experience, unlike their peers at traditional solid dosage form manufacturing plants.
With smaller vials and syringes that will be subjected to cold temperatures, it is very important to ensure that the adhesive used for the label is appropriate and that as much of the label text as possible will fit within a small area. For example, many gene therapy treatments are packaged in 3mL vials, minimizing the real estate available for vial labels. Early involvement with clinical specialists is key to thinking through minimum label requirements and design.
Another challenge is the blinding of increasingly complicated therapies including biologics and pre-filled syringes. Many factors must be considered when blinding an injectable or intravenous therapy. With injectable products, the solution’s appearance must be verified before administration, so the matching placebo must match all of the characteristics of the active product.
PharmTech: Where do you see direct-to-patient models having the greatest change on clinical trial manufacturing and logistics?
Blume (Catalent): By delivering directly to the patient from a clinical packaging site, the manufacturing distribution site now becomes a pharmacy dispensing site. In the United States, the regulatory and licensing requirements for establishing a pharmacy and licensure in all 50 states must be met before patients can be supplied. This requires licensure and expertise in areas that have not traditionally been required at clinical supply facilities. In addition, shipping direct-to-patient requires that data privacy procedures be in place to ensure compliance with all data privacy laws. With traditional supplies, materials are shipped by kit number to a clinical site. No patient names or addresses are ever part of the clinical supplier chain. In direct to patient, however, the established pharmacy will have this information and must control it appropriately.
The new models also require flexibility (e.g., the initial patient visit of a trial may be with the investigator, and future shipments will be made directly to the patient’s home). Having the materials co-located in one site with the ability to ship to site or directly to patient is important when the total amount of available supply is low. Direct-to-patient orders will need to be flagged differently through IRT and processed differently through the site. When establishing the trial setup, careful thought must be given as to whether an order should be triggered as a site shipment or as a direct-to-patient shipment.
In addition, at this point, care must be taken not to include patient names or addresses in the IRT request. The shipping site must have processes in place that will allow orders to be split based on their intended destinations, and the site must also maintain patient record privacy standards.
Interactive response technologies (IRTs) and e-clinical tools have become indispensable in ensuring that protocols and followed and in optimizing clinical trial manufacturing, logistics, and other operations. Stefan Dürr, senior director of client delivery and head of Cenduit LLC’s Drug Supply Center of Excellence shares insights into how IRTs are being used in the clinical trial materials supply chain.
PharmTech: What do you see as the most challenging aspects of clinical trial manufacturing and supply today, from each participant’s perspective?
Dürr (Cenduit): The most challenging aspects in the clinical trial supply chain are to reduce costs through reduction of wastage, and at the same time to ensure that clinical trial supplies are never on the critical path for completion of the clinical trial by always having the needed clinical supplies available across the depots and sites in the study. From a sponsor perspective, the challenge is to decide what part of the clinical supply chain is managed in-house and what part is outsourced. The sponsor must ensure that the different internal and external stakeholders work together efficiently to achieve a lean clinical supply chain that achieves the above goals. From a contract development and manufacturing organization’s (CDMO’s) perspective, the challenge is to reduce timelines and increase flexibility to react quickly to changing demands in the clinical supply chain. The faster the needed comparator can be sourced, the next packaging run planned and executed, and the quicker we can ship between the different depots, the less uncertainty you will need to accommodate in your clinical supply plans. From a contract research organization’s (CRO’s) viewpoint, the biggest impact on the clinical supply chain is the ability to predict the recruitment and execution as accurately and as close to the plan as possible. From an IRT perspective, the challenge is to have a resupply algorithm that can adapt to the study needs and minimize wastage through using real time data to determine the lowest buffer stock level at the site that will allow for the treatment of all the patients.
PharmTech: How can IRT solutions help address the following challenges: chemistry, manufacturing, and control (CMC) requirements (i.e., stability requirements, risk of contamination, labeling, overall quality); distribution and logistics; randomization; and comparator sourcing?
Dürr (Cenduit): IRT can help manage some CMC-related actions during the trial (e.g., blocking kits or managing recalls in case of quality issues or management of expiry date following new stability data). Additionally, it can be used to manage temperature excursions during shipments and storage at sites, and to work with temperature stability data from CMC to determine whether an excursion exceeded the allowed temperature stability range. In distribution and logistics, IRT solutions can help users evaluate the distribution service level agreements (SLAs) to best manage the depot and site shipments. Based on how long shipments take, the right moment to schedule a shipment can be determined in IRT to ensure that the shipment arrives in time at the required destination. IRT can also be used to reduce the number of shipments in clinical trials to save costs and reduce the burden on sites to manage many incoming shipments. Of course, IRT is central to managing randomization and can support any requirements. From a drug supply perspective, certain randomization models would allow the reduction of site buffer stocks. Therefore, a close collaboration between clinical supplies and biostatistics can have a positive impact on clinical supply budgets. For comparator drug sourcing, the challenge is getting the right amount of comparator at the right time with minimum waste. IRT can help manage studies with high comparator costs with minimum buffer stocks to keep the wastage as low as possible. IRT can also track and manage all drug-related interactions, allowing users to manage returns or on-site destruction of the drug after conclusion of a trial. In addition, the IRT ensures that all the relevant data are available for inspection readiness.
PharmTech: Are pharmaceutical clients sharing more information upfront to help improve the overall process?
Dürr (Cenduit): We see more companies use clinical supply forecasting solutions and services to plan their clinical supply chains. It is very important that such planning and execution efforts be closely aligned in IRT, and that real-time data are used regularly to re-forecast different future scenarios to ensure that there are no surprises.
Vol. 43, No. 8
When referring to this article, please cite it as A. Shanley, “Orchestrating Success in Clinical Trial Manufacturing," Pharmaceutical Technology 43 (8) 30–31 (2019).