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Volume 32, Issue 1
For rapid scale-up of biomanufacturing under expedited review status, facility design must better integrate product development and manufacturing lifecycle activities.
Consider this situation: data coming out of your Phase II trial is better than expected. An application for Expedited Review has been submitted and accepted by FDA. Exciting times, no doubt, but what does this mean for planning and executing a facility design program moving forward?
In 2014, FDA defined four programs to facilitate and expedite development and review of new drugs that show significant promise in addressing and treating serious or life-threating conditions (1):
These programs provide a number of advantages during the clinical trial phase of drug development that include:
Once a drug has been granted any of these designations a number of actions will be set in motion that will eventually have an impact on the planning and execution of facility design.
In a traditional approach to drug development, a manufacturing process is defined for early-stage clinical materials, and those materials are often manufactured, at small scale, in pilot or development facilities or by contract manufacturing organizations (CMOs) that are set up specifically for that type of manufacturing program. Quite often these facilities have some of the following attributes:
Figure 1 represents a visual overview of the relationship between development and commercial manufacturing activities that highlights the challenge that must be addressed by the manufacturing enterprise when expedited review status becomes a time-driven reality.
In Figure 1, the integration points between clinical and commercial manufacturing become easy to see. But why are these integration points important?
For the example of Accelerated Approval, FDA may focus on evidence of the drug’s impact on a surrogate endpoint (1). Here, the surrogate endpoint is defined as “a marker, such as a laboratory measurement … that is thought to predict clinical benefit …” (1). Thus, a potential to accelerate advancement of the product into later-stage clinical manufacturing at a more rapid pace becomes the new driver for process development that would lead to potential product launch upon final FDA approval.
When a company receives expedited drug development designation from FDA, the guidance sets in motion numerous requirements around process and facility attributes that would support the eventual commercial launch of the product to meet the anticipated market demand (1). The guidance is clear on the information that is expected to support manufacturing development. This information includes timelines for manufacturing capabilities and validation approach, as well as relative information from the chemistry, manufacturing, and controls (CMC) section.
For a biopharmaceutical, the biologics license application (BLA) identifies the information that will drive facility design planning and execution. From the specific instructions for completion of Form 356h submission as part of the BLA (2), the CMC section addresses manufacturer information that includes:
The establishment description goes on to identify specifics such as:
Once expedited review designation becomes reality, the details of process and facility design for the commercial product, whether by the manufacturer or a designated third-party CMO, should be in place.
Under expedited review, timelines for the development of key design documents will become a crucial factor. Planning for commercial launch capabilities will need to begin earlier. Development focus must be on achieving synergy between clinical and commercial manufacturing sooner rather than later.
Manufacturing output is crucial, driving design decisions on equipment platforms, influencing physical size and adjacencies in facility architecture, driving the selection of technology platforms, and affecting the overall segregation strategy of the manufacturing layout. The facility design challenge becomes apparent when one considers the need for a strategic approach to the product manufacturing lifecycle, shown in Figure 2, that results in a facility that can support expedited review and provide the capability to manufacture clinical, launch, and commercial materials (3). This manufacturing lifecycle can include both large-scale pilot runs and preclinical materials up to commercial launch quantities coming out of the same asset (i.e., establishment).
Some basic goals of the project design execution process should include:
Project execution strategy to support expedited review must use an integrated approach to optimize timelines. This strategy has five key focus elements:
Expedited review also encourages frequent communication with FDA during development and supports enhanced efforts to ensure that manufacturing equipment and facilities are ready for inspection during review of the clinical section of the application (1). As a result, process and facility design must take on an expedited execution approach. For example, under breakthrough therapy designation, FDA promotes many interactions that include type B and C meetings, critical milestone meetings, and advisory committee meetings (4).
During the planning for conceptual design of a new product launch facility, one of a company’s monoclonal antibody (mAb)-based products in early-stage clinical trials received breakthrough designation, and an expedited review approach was implemented. The design project changed its focus to move the planned development facility into a development and launch-capable asset.
Using the lifecycle framework described in Figure 1, the new project scope and focus were defined.
For this project, the following design themes were identified:
The following were the key design assumptions and considerations for the project:
To meet expedited review scenarios as a “future-case” solution, the developed design solution included:
The proposed facility design solution includes:
One of the key challenges in this effort was to address how to support the rapid execution of product development timelines, when the product development function has a large number of potential integration points associated with accessing important manufacturing assets necessary for product launch. The number of integration points can increase significantly as the launch effort requires access to larger-scale manufacturing assets. Although a great deal of process characterization and optimization is done at small scale, product launch support will require rapid scale-up to support downstream development as well as assure upstream operations perform as required in larger bioreactor systems. The optimized solution allowed performing process scale-up within the “launch” facility to eliminate tech transfer issues for rapidly moving from process development and preclinical manufacturing into early clinical manufacturing and again into the commercial launch manufacturing phases. Early understanding and resolution of scale-up and equipment problems can facilitate producing clinical material on an accelerated schedule as required for supporting clinical trials and product licensure.
Expedited review designation brings with it challenges to facility planning, design, and project execution. The traditional timelines and methodology will require a new approach to conceptual planning, process-facility attribute definition, and design implementation and execution. With the high level of activity around new advanced therapy medicinal products, planning for the challenges presented by expedited review designation is becoming a crucial need for manufacturing organizations.
1. FDA, Guidance for Industry, Expedited Programs for Serious Conditions-Drugs and Biologics (Rockville, MD, May 2014).
2. FDA, Form 356h, Application to Market a New or Abbreviated New Drug or Biologic for Human Use(Aug. 2018).
3. J. Odum, “The Key Design Drivers for Developing Flexible Manufacturing Assets,” LinkedIn (2017).
4. M. Raggio, “Overview of FDA Expedited Programs with a focus on Breakthrough Therapy,” Presentation at FDA Small Business and Industry Assistance Regulatory Education for Industry (REdI) Conference (Fall 2015).
Vol. 32, No. 1
When referring to this article, please cite it as J. Odum, “The Impact of Expedited Review Status on Biomanufacturing Facility Design," BioPharm International 32 (1) 2019.