September 29, 2020 PAP-Q3-20-CL-011
The ideal phase I biologic is simple in formulation and flexible in preparation. It should be easy to manufacture, appropriate for multiple routes of administration, and able to support dose range or escalation studies. However, even with the ideal phase I biologic, there are pitfalls in the development process that can prevent moving the drug into clinical trials as rapidly as possible — the primary goal of the early clinical phase. Achieving this goal efficiently is multifaceted, requiring a range of expertise, as it involves simultaneous execution of the formulation development with preparations for future phases, aligning efforts across multiple organizations, managing resource utilization, and complying with regulatory necessities.
The formulation development process of a biologic drug product is very similar to what a company would use for traditional small molecules. Once the molecular target disease is identified and characterized, drug candidate screening is performed. In the case of biologics, this involves developing a clonal cell line and a reproducible drug substance manufacturing process and performing a number of formulation development steps in the high-throughput environment of a process development lab; further studies include screening for buffers, excipients, surfactants, initial freeze–thaw studies, stability work, and developing analytical methods.
Despite the familiarity of this process, there are commonly overlooked considerations. In-house expertise from an integrated partner can help identify additional key considerations when moving forward. In Catalent’s experience, this includes factors such as container closure compatibility, manufacturing process equipment, filtration processes, need for additional formulation excipients, and compatibility with construction materials specific to manufacturing equipment.
Beyond these early-phase considerations, future development may require lyophilization of the product. An early evaluation at initial liquid formulation stability data will determine if this is necessary and whether cryoprotectant or bulking agents are required. Expert review and due diligence by an integrated supplier early on will provide clarity and speed to the development process by eliminating the need for ad hoc adjustments to these variables during later project phases.
The development process is not only about developing the fastest and most stable formulation, but also about how to get the finished product to the patient.
The development process is not only about developing the fastest and most stable formulation, but also about how to get the finished product to the patient. One area where significant benefit can be leveraged from integrated development is clinical packaging design executed in parallel with early-stage formulation development. (Figure 1)
In the early phases, most biologics are going to be in a liquid or potentially frozen state for shipping and delivery to the clinical sites. Packaging experts will help identify the best way to handle these materials and their specific needs. Since these products are often light-sensitive, they may require protective cartons or sleeves to go over the packaged drug product. Additionally, there are considerations for the product at the clinic. For example, an integrated supplier will be made aware when samples are frozen products. In turn, they will use appropriate cryo-labels to prevent labels from falling off in the freezer — an expensive problem if not preemptively addressed.
While it’s true that many contract manufacturing organizations can support small-scale packaging operations in early phases, as a product moves through the drug development life cycle toward expanded clinical programs, there are additional complexities that integrated suppliers are uniquely qualified to address. For example, many clinical trials have investigational products that require specific packaging or kitting. Using a supplier with integrated formulation development, clinical manufacturing, packaging, and supply chain capabilities would capture significant time savings by eliminating the time-consuming process of identifying and orienting a new supplier for each task. Additionally, an integrated approach would prevent duplicate efforts across formulation, manufacturing, and packaging workflows, shortening all timelines.
There are additional time and budgetary benefits recognized by working with a single integrated supplier for clinical packaging design. An integrated supplier can help prevent the need for multiple service and quality agreements or separate safety assessments, start analytical release testing in parallel with packaging operations, and streamline the transport and regulatory compliance for drug substances and drug products. Finally, an integrated supplier enables relatively easy harmonization of cleaning verification or validation strategies, as a single team handling the method and the sampling requirements will be in charge of designing and testing the process and analyzing the products.
It is important to remember that communication is key to meeting tight project timelines when evaluating suppliers for a biologic development project.
If a clinical trial is conducted in a region or a country requiring QP release, such as the European Union or the United Kingdom, QP review of the entire process, including drug substance and drug product manufacturing, packaging, and any associated labeling when performing a final clinical release, will be required. Having QP input early in the process, not at the end, is critical to streamlining efforts.
For example, in a previous project, a customer supplied label text for the drug product in the early stages of a phase I open label study. Their non-integrated contract manufacturer designed, printed, and applied the labels to the drug product. However, when a QP was later engaged, they questioned some of the information included in the label. Catalent stepped in with an integrated project team including manufacturing, clinical supply, and QP to resolve the issue. This team was able to collaborate and quickly generate a short-term solution acceptable to the customer. In addition, the clinical supply team and QP provided the customer guidance regarding how to revise the label text for future labeling activities, so that updated label, text, and label proofs would meet the EU Good Manufacturing Practices (GMP) requirements (Figure 2).
Another challenge encountered involves a common production-related issue, an unexpected observation causing a batch production to stop. In this case, there were two potential paths presented by Catalent experts and the customer. Since Catalent had engaged in a productive relationship with the QP early on, Catalent set up a meeting with all partners. The two pathways were discussed, and the QP identified potential delays that may have resulted from one of the paths moving forward. This QP input was extremely helpful, as it defined what would be an acceptable path towards continuation of the trials in both the United States and the EU.
Clinical packaging, labeling, and kitting become increasingly difficult as the product moves forward in the drug development life cycle. With an integrated supplier, the relationship between the customer, manufacturer, and clinical supplier has already been established, allowing the team to proactively collaborate in a forward-looking fashion.
For example, a former client required a very small quantity of drug product to be packaged and labeled to support an early-phase trial. Given the limited scope, the packaging activities could be performed at the manufacturing site. However, the labeling requirements were more complex than what the contract manufacturer could support. The Catalent product manufacturing team reached out to the integrated clinical supply team to assist in label design and printing. The labels were then shipped to the contract manufacturing site for application. The integrated clinical supply team was able to be leveraged by the client and clinical manufacturer to enable the completion of labeling within the client’s timeline. Since the clinical supply team and customer had a relationship earlier in the clinical life cycle, the team was poised to support this client’s complex labeling during future clinical phases.
It is important not to overlook the benefits of an integrated supplier to clinical distribution, storage, and resupplies. Although these activities are at the end of the development process, in Catalent’s experience, it’s still very important for final delivery of the product to patients. In a previous project, both formulation development and clinical manufacturing needed to be completed on a tight timeline with complexities in the supply chain. This included the parallel filing of regulatory documents with formulation development activities, resulting in import difficulties. However, the manufacturing and clinical supply project managers were connected with the customer and internal project teams from the start of the development process. Because of the integrated project team, the client was able to leverage the wide array of services offered within Catalent to quickly overcome supply chain challenges. The clinical supply project manager was able to collaborate with the customer to identify a solution utilizing a third-party depot, allowing the final finished product to be shipped to the clinical site to enroll their first patient on schedule.
It is important to remember that communication is key to meeting tight project timelines when evaluating suppliers for a biologic development project. A supplier with a comprehensive catalog of integrated services has the experience and perspective to communicate more efficiently and clearly with external partners. Furthermore, internal communication at an integrated supplier can lessen or even eliminate the burden of having to provide project information multiple times.
Utilizing a partner that can leverage a wide network of subject matter experts also eases the client burden by seamlessly drawing on a broad network of experience as opposed to seeking out expertise in a piecemeal fashion. These cross-functional teams have a personally vested interest to ensure the success of the entire program. An integrated project team has cross-discipline visibility on every component of a development process, from formulation through the supply chain logistics. This makes integrated suppliers ideal for efficient planning and robust execution of the development program to ensure it progresses in its clinical life cycle to regulatory approval, launch, and eventual commercial release.
Ann McMahon is Program Director, Clinical Supply Services & Drug Product Technologies Integrations for Catalent and has over 17 years of experience in the pharmaceutical industry. Prior to Catalent, Ann was a Manager, New Product Launch at West-Ward Pharmaceuticals and Boehringer Ingelheim. Ann’s areas of expertise include project management, packaging and labelling, technical transfer, scale up and commercialization, supply chain management, operational and supplier management, and analytical services. Ann holds a B.S. in Biology/Biochemistry from Ohio Northern University and a M.S. in Clinical Pharmacology from the Ohio State University.