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Since the arrival of the human insulin injection in the 1970s, significant innovation and progress have been made in biological therapeutic product development, manufacturing and drug delivery. Today, drug product development is tailored to the clinical phase and follows a defined trajectory guided by the target product profile. Hence, in early clinical development (gene to first in human), the focus is on fast progression into clinical trials by utilizing platform expertise to establish the safety and efficacy of the product. On the other hand, in the late phases of clinical development (Clinical Phase 2/3 to Launch), significant efforts focus on scale-up, establishing a robust manufacturing process and technology transfer into commercial facilities.
Despite the significant progress made over the past years, late phase product development remains a complex and challenging step for several reasons:
1. New therapeutic targets have pushed biologics to expand from monoclonal antibodies into a “zoo” of new mAb-like formats such as bispecific antibodies, nanobodies, fragments, and even further into viral vector areas and mRNA, all with distinct properties and specificities.
2. The trend towards the point of care at the patient’s home and personalized medicine have led to a growing number of drug delivery presentations, from pens to autoinjectors and on-body devices. This adds another layer of complexity to the development but also to the manufacturing of these products.
3. The late phase of development remains the lengthiest phase (almost double the time of the early phase), the costliest part of drug development (multiple times the cost of reaching first in human), and may require a multitude of partners from specialized labs to device manufacturers.
Due to these challenges, only mega and large-cap companies traditionally had the resources, expertise and infrastructure to undertake late phase development and obtain a license application. However, a shift in this trend appears to be underway. Of the 50 new biological entities approved by the FDA in 2021, several sponsors were mid-size companies.
The increasing number of medium and small companies making a commercial debut is only possible with contract development manufacturing organizations (CDMOs) that can drive down cost-of-goods by using platforms and bringing in the needed expertise to support regulatory requirements.
But finding a CDMO who can support late phase activities can be a challenge since not all contract organizations can provide these services.
To support a program from gene to license application and launch, a CDMO must have versatile competencies. Early clinical development requires tailored platforms for different molecule groups, rapid and high throughput methods, as well as an agile development environment. As clinical development progresses to the later phases, different capabilities are required, such as building product and process understanding through in-depth analytical characterization and the development of commercial drug formulations and manufacturing processes. Furthermore, robust analytical methods which can be transferred into a global quality control (QC) network are needed. Finally, pivotal clinical trials are typically performed in the final market presentation, which may include a medical device drug delivery solution. Together, this diverse and expansive set of requirements makes it difficult for a CDMO to provide end-to-end support services for a customer program and difficult for a sponsor to find one partner that can do it all. Therefore, a CDMO with a track record of approval rates and proven experience in the launch and commercial activities is an ideal partner for a company in late phase clinical development.
During late phase clinical development, there are several activities required to help execute a successful product launch. The following sections provide an overview of these phases and discuss some key points to consider if partnering with a CDMO:
Late phase formulation and analytical development
Late phase development requires a holistic development strategy driven by a well-defined target product profile while keeping the patient and final market presentation in mind. For example, a weekly chronic medication of a biologic drug typically requires the development of a high concentration protein formulation and a combination product to enable home use.
Developing effective formulations includes screening broader pH, surfactant and excipients, utilizes the design of experiments (DoE) study designs to interrogate the formulation design space and sets limits by measuring impact on key critical quality attributes. Defining critical quality attributes requires appropriate analytical methods.
Analytical development and quality control establish robust analytical methods for the global QC network. A quality control system should be set up with appropriate release and stability specifications to ensure a safe and efficacious product while addressing all expectations of relevant regulatory authorities.
In order to support these activities, the CDMO partner needs to be experienced in protein formulation, analytical characterization, development and validation.
Additionally, for a combination product, the following additional aspects need to be considered:
• The combination product development needs to be an integrated part of a holistic development strategy as early on as possible. For example, formulation development and product viscosity can show strong interdependencies with product stability and usability of a combination product and, therefore, should be given special consideration.
• A risk assessment strategy is critical during the complete design control process and roles and responsibilities for post-marketing surveillance activities need to be defined.
• Clear alignment is especially key when the CDMO and the component supplier define the design verification and testing strategy due to the complexity of the panel and the source of the data. For example, extractables/biocompatibility data, a part of the initial characterization as well as product-independent design verification data, can be supported by the medical device company. In contrast, product-specific data and QC release testing are typically performed by the CDMO.
“Independent of the in-house capabilities of the product sponsor, it is crucial that the CDMO partner brings extensive experience and competencies to develop and launch a product to market”
• Within the design control process, roles and responsibilities need to be defined. For example, the pharmaceutical sponsor typically owns the design history file, while component suppliers and the CDMO support the pharmaceutical sponsor with the necessary data and information.
Process characterization and validation
The process characterization phase aims at building product understanding with respect to the drug product manufacturing process. These activities follow a quality risk management approach using risk management tools. Potential critical process parameters are defined, and operating ranges are proven through small-scale studies using small-scale -freeze-thaw, -filtration, and -filling models.
The process validation follows the characterization phase and demonstrates consistency in the manufacturing process by running consecutive batches at target operating ranges, which are used to generate registration stability data. In addition, process design studies are required as part of the combination product design control process.
A CDMO should have small-scale models in place representative of the commercial manufacturing site and extensive experience transferring processes from development into manufacturing while leveraging platform data. For example, CDMOs can supply generic data for mixing homogeneity or extractables as well as studies from single-use system manufacturing materials if the sponsor process fits the CDMO platform.
For combination products, the primary container (e.g. pre-filled syringe) and the components of the device (e.g. needle safety device) add complexity to the process characterization and validation phase compared with a drug product in a vial. The combination product components are susceptible to preparation and processing, which may trigger adaptations of the manufacturing or the assembly line. Today, ready-to-use components (e.g. nested ready-to-use pre-filled syringes) have facilitated the standardization of the filling process and avoided complex steps like in-line siliconization, therefore allowing faster technical transfer into CDMO networks.
The launch phase is focused on receiving the market authorization and preparing the commercial supply to the drug markets of interest. In this phase, the market authorization holder must work with the CDMO to draft and submit the Common Technical Document Dossier Module 3 chapters, prepare and host the pre-approval inspection and respond to regulatory inquiries by competent authorities.
Traditionally, small companies have partnered with CDMOs to help ensure successful product launches, but recent trends in outsourcing have shown that larger companies are also partnering with CDMOs to ensure manufacturing resilience in today’s unpredictable supply chain. Independent of the in-house capabilities of the product sponsor, it is crucial that the CDMO partner brings extensive experience and competencies to develop and launch a product to market.
In summary, there are a number of critical steps during late phase drug product development where a strategic partner can work with companies of all sizes, and they can be categorized into three main areas:
• Gathering and identifying appropriate resources: This phase requires the collaboration and coordination of the whole network (formulation, analytical development, process development, QC and manufacturing) for at least 2.5 years.
• Executing during a fast-paced process: In case of a positive clinical readout of pivotal studies, speed and pressure increase CMC activities towards a successful product launch.
• Developing a detailed plan: A successful validation campaign requires strong project governance, effective quality oversight and integration of regulatory activities.