The Impact of Expedited Review Status on Biomanufacturing Facility Design

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?

What is Expedited Review?

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): 

• Fast-track designation

• Breakthrough therapy designation

• Accelerated approval

• Priority review designation.

These programs provide a number of advantages during the clinical trial phase of drug development that include:

• More frequent meetings with FDA to define the clinical trial program to ensure proper data collection

• Acting on drug applications in a shorter time frame than the standard review

• Increasing FDA review/guidance as early as Phase I

• Basing approval on an agreed surrogate marker instead of a defined clinical endpoint.

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. 

Regulatory requirements of expedited review

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:

• Small-scale manufacturing equipment, often at a bench-scale level

• Open process characteristics

• Significant reliance on procedural controls in lieu of facility controls

• Less restrictive implementation of GMP protocols; often a focus on good laboratory practice (GLP)

• More manual-driven operations instead of automated approaches.

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:

• Method of manufacture; visual representation of the manufacturing process

• Detailed process description

• Process controls

• General layouts and floor diagrams

• Contamination precautions

• Bioburden control

• Container and closure systems.

The establishment description goes on to identify specifics such as:

• General information that includes product, personnel, equipment, waste, air flows

• Water system design basis

• Heating, ventilation, and air conditioning (HVAC) system design basis

• Contamination control measures such as cleaning and cleaning validation

• Computer systems for manufacturing.

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.

Planning for expedited review

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:

• Ensuring operational continuity as the process design evolves

• Maximizing product comparability over the product lifecycle

• To the greatest extent possible, eliminating the traditional approach to tech transfer and focus on process evolution

• Keeping design off the critical path.  

Project execution strategy to support expedited review must use an integrated approach to optimize timelines. This strategy has five key focus elements:

• Risk management: Early in the development phase, risk identification and mitigation strategies (assumptions) must be implemented. Strategies should include a clear understanding of the quality-by-design aspect of the product–process relationships.

• Seamless process and automation: Move quickly to define control strategy to enhance quality engineering design and productivity.

• Integrated project delivery: Produce deliverables in a timely manner to support rapid review and implementation.

• Innovation tools: Enhance early reviews for operations, maintenance, constructability, and key drivers around regulatory compliance (e.g., layouts, segregation, validation strategy) using tools such as building information modeling, virtual reality, and process modeling.

• Lean project delivery: Focus on “right the first time” execution; time is of the essence.

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).

Case study 

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:

• Eliminate tech transfer when transitioning from clinical to commercial manufacturing

• Develop synergy between operational execution of late-stage clinical and commercial launch capabilities

• Optimize site material suppy-chain management to support manufacturing

• Perform risk mitigation focused on clinical/commercial success

• Optimize key in-process manufacturing operations to remove bottlenecks and improve efficiency.

The following were the key design assumptions and considerations for the project:

• Designed specifically for the defined mAb-based platform at 2000-L scale

• Ability to address clinical uncertainty (success/failure)

• Facility to be used for clinical supply and commercial launch

• Incorporate a strategy for transition to long-term commercial manufacturing

• Provide expansion flexibility (2X) within the facility without building modifications.

To meet expedited review scenarios as a “future-case” solution, the developed design solution included:

• Multi-product capability beyond the defined mAb platform with scale-out 

• Incorporated product development capability (minimizing development facility cost) 

• Faster product development timeline

• Minimization of development investment and operational cost

• Full operational modularity.

The proposed facility design solution includes:

• Flexibility to address rapid scale up/down depending on clinical uncertainty via a high level of segregation 

• Adaptability to different process configurations (e.g., multiple 2x2000-L configurations)

• Simple process transfer in/out.

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.

Conclusion

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.

References

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). 

Article Details

BioPharm International
Vol. 32, No. 1
January 2019
Pages: 37–40

Citation 

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.