Small-molecule drug development has drastically advanced over the past three decades. Drug substances are more complex, manufacturing processes have become increasingly specialized, drug-delivery solutions are ever more sophisticated, and regulatory requirements have tightened to deliver a higher level of quality and efficacy to patients. Still, demand for safer, more efficacious, and cost-effective drug products continues to grow leading drug developers to increasingly outsource projects from early stage development through to clinical manufacture and commercial production.

The emergence of the COVID-19 pandemic is further accelerating this trend. The depth of the role contract development and manufacturing organizations (CDMOs) play in supporting complex drug development challenges with sustainable solutions for the lifecycle of new drug development has evolved. Regardless of whether a drug manufacturer is a larger international industry leader or a small emerging specialty firm, ensuring business continuity throughout the entire lifetime of their small-molecule drug products is essential.

The pathways for moving through development stages with a CDMO are not always intuitive, however. For the best possibility of success, drug developers should partner with a CDMO that has experience implementing a well-defined, phase-based approach to project execution beginning anywhere in the development cycle from early to later stages. This strategy allows for integrated, seamless progress via the development of processes that scale and transfer smoothly while maintaining project timelines.

What is a phase-based approach?
In a phase-based approach to small-molecule drug development, phases of a project are well-defined, documented, and understood by both the CDMO and the client. The goal is to ensure that projects only advance once all requirements of each phase are met. Taking this approach makes possible the integration of activities that support the progression of a new drug candidate from early stage to commercial launch and beyond, starting from the very beginning when a project is first evaluated to when it is “completed,” whatever form that might take.

At Cambrex, small-molecule development projects are divided into the following phases:

• Evaluation and Decision Phase
• Planning Phase
• Preparation Phase
• Execution Phase
• Assessment Phase
• Post-execution Phase

Going through the phases
One of the first benefits of a phase-based approach, particularly for virtual companies with little if any knowledge of the drug-development process, is having a clear understanding of where/how a project begins. The Evaluation and Decision Phase provides the needed clarity and is initiated with a request for proposal from the potential client.

During this phase, there is extensive contact with the client, including in-depth discussion about the project objectives. It begins at Cambrex with information gathering and the performance of a feasibility check. This process is followed by a site-selection process, during which the optimum location within Cambrex’s international network of R&D and production facilities is identified. The ultimate outcome of this phase is the development and acceptance of a work proposal.

In the Planning Phase, the signed proposal is in hand and movement on the project begins with the establishment of a project team and development of the initial project plan. Knowing the objectives and scope of the project, a proposed timeline and initial execution strategy are agreed upon with the client at the project kick-off meeting. The project plan is outlined based on the team and resources and is finalized into a scope of work once all key issues have been addressed.

With the initial plan in hand, the Preparation Phase can begin. The key goal during this phase is to achieve risk mitigation. All documentation needed to support the project is initiated, particularly documents that support GMP-related requirements, such as management of change, and other project governance materials such as development reports.

Governing processes are also established, raw materials procured, and initial analytical methods and any existing manufacturing process and chemistry/formulation development information transferred to Cambrex from the client. As appropriate based on the phase of development, a quality risk matrix is developed to establish a risk-mitigation strategy.

Process development and manufacturing work begins in the Execution Phase. All information is recorded in the appropriate notebooks depending on the phase of development—lab; pilot plant; clinical manufacturing for phase 1, 2 or 3 trials; formulation development; validation production batches; etc.

The Assessment Phase, which comes next, often takes the longest time to complete. Once all the batches have been produced and all the data generated, it is essential to determine the meaning of those results which guides next steps and decisions. This goal is achieved through generation of documents necessary to close out the project, such as regulatory documentation (e.g. demonstration of successful validation and to support relevant filing requirements) and tech transfer reports.

Equally important is the evaluation of the risk-mitigation strategy, including identification of any realized risks. It must be determined if any issues have arisen that would require a project to be sent back to an earlier phase due to quality or other technical concerns.

The final Post-Execution Phase is critical because conclusions are drawn about performance throughout the other phases of the project. The entire team participates in a discussion of the lessons learned that can be applied to future projects. Depending on the phase of development, a full risk-mitigation summary is completed to document the process. Projects in the early stage of drug development can still assess challenges that may have occurred, and the team can present suggested next steps in final development reports.

At this point, the project is “completed” and ready to pass to new ownership, whether that means progression to the supply of clinical materials or transfer to another production site within Cambrex for commercial production. There is, therefore, also a future-oriented aspect to this phase, in which the strategy for moving on is identified.

Mitigating challenges
Even with a well-defined, phase-based approach to small-molecule drug development, challenges can still arise. Most often these occur in the Preparation and Assessment Phases, and knowing this, the Cambrex team pays special attention to mitigating challenges in these phases.

For later stage projects, during the Preparation Phase, it is essential to identify all relevant risks and develop adequate mitigation strategies to minimize those risks. Development of appropriate documentation and testing is also essential to ensure that all the information needed to make the right decisions with respect to the risk mitigation strategy has been provided. The likelihood that quality or other problems will arise and be identified in the Assessment Phase increases dramatically if the Preparation Phase is not properly implemented. As a result, a project can be kicked back to the Preparation Phase rather than moving on to the Post-Execution Phase.

In the Assessment Phase, inappropriate or incomplete evaluation of what occurred in the Execution Phase can also hinder or stall a project. Improper assessment of outstanding risks is particularly problematic. During later stage projects, it is essential to determine if risks were adequately addressed and if not, why not, and whether there are any remaining risks going forward.
Quality risks such as degradation/stability and dissolution issues that are realized can, for instance, require a project to return to the Preparation Phase where steps will be taken to recover from the problem.

The value of Quality Risk Management
For customers progressing to later stage of drug development, Cambrex can assist in applying a quality risk management process in the Preparation Phase where all relevant potential risks across the entire project—not just the process or formulation—are identified and a comprehensive risk management strategy developed in collaboration with our customers. In addition to the more traditional technical risk matrix that looks at the process, equipment, etc., an administrative quality risk matrix is developed that considers all other project-related risks, such as difficult-to-find raw materials and other supply chain, logistics and support-team-related issues.

Risks are identified as low, medium, or high. Most tend to be low, but there are typically some that are classified as medium or high. All risks are recommended to be evaluated, rated, and mitigated, as appropriate.

In the Assessment Phase, Cambrex focuses on closing out the technical and administrative quality risk matrices. Both are rescored based on the data collected in the Execution Phase. Regardless of the scoring level, Cambrex collaborates with its customers to ensure risks are not overlooked.  In addition, Cambrex ensures that all reports and regulatory documentation are closed out with the risk matrix in support of moving to the Post-Execution Phase.

Cyclical process
Indeed, Cambrex’s phase-based approach to small-molecule drug development project execution is a cyclical process. At any given time, a project can be evaluated with respect to achieving its objectives and deliverables. This affords Cambrex the ability to support customers with a well-defined process, and pivot at any point, whether for the purpose of improving efficiency/productivity or due to the need to meet new regulatory requirements.

This well-defined and cyclical phase-based approach makes it possible for Cambrex and our customers to clearly identify the status of each every small-molecule drug-development project and what needs to be done next. Every project manager can tell the customer exactly what phase the project is in at any point so that customers are always fully integrated into the project.
Outcomes and completion criteria are reliable with this detail-oriented approach. Cambrex understands the drug development cycle and has years of expertise at every stage, allowing us to efficiently recognize opportunities to benefit our customers. 

Built on a foundation of trust
Transparency and communication are critical to the success of Cambrex’s phase-based approach to small-molecule drug development. Team-wide discussions take place at routine project team meetings where customers have a consistent project manager serving as the main contact. Direct communication lines are also established to technical experts at Cambrex to ensure that critical information can be shared in real time.

Given the current travel restrictions and social-distancing requirements resulting from the COVID-19 pandemic, Cambrex is offering extensive virtual communication systems, from basic online meetings to virtual viewing of in-plant operations. An emphasis on collaboration through established communication pathways with a commitment to transparency solidifies partnerships and builds customer trust.