OR WAIT null SECS
A brief case study of a facility-fit analysis provides insight into how to adjust capacity when moving from clinical-to commercial-scale production.
In the new millennium, the biopharmaceutical industry has undergone a significant transformation in all areas of business. Blockbuster drugs, the foundation of the biologics revolution, are becoming increasingly rare. Many companies have experienced considerable setbacks within their clinical-trial programs. As a result, biopharmaceutical executives are faced with the ever-present dilemma of optimizing investment opportunities focused on advancing as many clinical prospects as practically and financially feasible. Focusing on medicines for broad patient populations no longer guarantees business success. Therefore, companies are identifying techniques and approaches that give an edge to the potential approval of a clinical candidate. One such approach is the use of translational sciences, particularly biomarker research. One outcome of using this novel approach is the development of more personalized, targeted medicines serving smaller patient populations.
The integration of biomarker data into the development process potentially promises less risky clinical-
trial programs and the opportunity to deliver product portfolios with greater chances of approval. However, the pursuit of multiple, lower-volume biological products represents a challenge to a company's short- and long-range manufacturing strategy. In an industry where competition creates pressure to lower cost, increase efficiency, and avoid capital investment, shifting from fewer, high-volume products to multiple, low-volume products represents a hurdle for companies with existing large-scale commercial facilities. How can a company maximize its current manufacturing capacity to meet a new business model that requires higher utilization rates and the accommodation of multiple product mixes? In other words, how can we get more from what we have?
Meeting this challenge requires collaboration between development and manufacturing functions far earlier in a product's development cycle to ensure manufacturing success. Completing a broad-based "Facility-fit Analysis" is important for providing an organization with an enterprise view of its manufacturing operations. The analysis is an efficient and cost-effective way to address challenges within the existing facility structure and allows a company to meet its changing business requirements in the most flexible, efficient manner.
MedImmune's Frederick Manufacturing Center (FMC), located in Frederick, Maryland, offers one example of how a
facility-fit analysis has helped the company create an operation geared towards greater flexibility. As the flagship manufacturing asset for MedImmune, FMC, in collaboration with its process development partners, is working to tailor production processes to efficiently fit the current infrastructure of the plant. To understand how the facility-fit analysis is improving the company's business operations, below is a brief history.
The first manufacturing building (B636) at FMC was constructed in the mid-1990s and commissioned to manufacture Synagis (palivizumab), a monoclonal antibody. Building 636 has 2 × 2.5k L bioreactors and associated proportional downstream purification capacity. The FMC was expanded in 2006 with the initiation of construction for B633, a large-scale (4 × 15k L bioreactors) mammalian cell culture-based commercial production facility initially designated for the manufacture of a mix of products in the pipeline at the time. As part of the design, MedImmune introduced a degree of flexibility to the facility, enabling it to potentially accommodate a range of product titers.
But one year after groundbreaking, the shape and magnitude of MedImmune's pipeline changed significantly. That same year, AstraZeneca acquired MedImmune and integrated the capabilities of Cambridge Antibody Technology (CAT), which AstraZeneca had acquired in 2006, into MedImmune's existing R&D infrastructure. Seemingly overnight, MedImmune's investigational pipeline jumped from approximately 40 candidates to more than 120 candidates, resulting in a fundamental shift for FMC from a single commercial product facility to a clinical and commercial multiproduct facility.
Addressing this situation required the company to overcome three key challenges as described below.
Although reasonably flexible, B633 had been originally designed to manufacture only one to two commercial products per year. With MedImmune's changing business focus and robust pipeline, the company now had to target multiple late-stage clinical candidates and fixed commercial requirements on an annual basis. By analyzing the long-term clinical and commercial demands on the facility, not just manufacturing capacity but also technical transfer and postmanufacturing support, a team was able to identify immediate areas of opportunity to increase capacity. Additionally, longer-range initiatives were identified.
First, the company modeled the plant and processes to identify potential bottlenecks. Because the manufacturing plant was now required to run multiple products, archetypical processes were developed that reflected the range of titers that could potentially occur with the product portfolio. Large-scale manufacturing plants such as B633 are designed with a certain amount of throughput. The throughput of the plant is a function of run rate. The capacity of the plant is driven by a combination of run rate and plant idle time. The idle time of the plant basically resides in two areas, one being the time to evaluate and characterize products that have been first introduced to the plant and scaled to 15k bioreactor scale and the other being plant changeover from one product to the next. In case of product evaluation, most commercial manufacturing facilities do not require the time to evaluate products between batches; therefore, this switch is not a significant factor influencing capacity. However, this element represents greater influence in a late-phase clinical program where scaling the process beyond the pilot plant level is common practice.
Likewise, product changeover can be fairly influential in determining overall plant capacity. For example, if a changeover process requires 10 days, then one has to consider the impact on available overall plant capacity if it has two products going through the facility per year versus five products. In the former case, one could attribute plant changeover to a 20-day reduction in plant capacity. In the latter case, 50 days of capacity are lost to changeover time. Some key questions emerge: What does capacity look like in the current state versus the optimized state? And how aggressively can changeover time be improved to increase throughput?
MedImmune examined ways to reduce the second component of idle time—that is, product evaluation. In this case, a team developed a risk-based approach to evaluate and characterize products with the goal of minimizing the time between batches. The ability to model and demonstrate consistency of scalability from bench to commercial scale for the bioreactors provided a high degree of assurance that product quality would not be impacted as the process is scaled.
During the processing of the initial batch from a campaign at scale, the team gathered further evidence by conducting laboratory scale purification studies to evaluate harvested material from the production reactor for product compared with material produced earlier in the development cycle at the pilot scale. This analysis typically occurs simultaneously with the large-scale purification process and data from the "scouting study" is available prior to the end of the large-scale purification.
Lastly, the team looked at ways to minimize differences in the overall production process required for multiple products. Rather than investing time and money focusing on changing the facility itself because the manufacturing processes are different, the team evaluated the option of approaching each new product candidate employing a common process that can be broadly used for a range of products in the development portfolio. The use of this platform-process approach by process development enables the site to meet the goal of minimizing changes to the facility to accommodate new products.
The shifting product mix for building B633, including products aimed at large patient populations, high doses, and chronic indications, to a blend of high and low clinical and commercial demand, necessitated an overall evaluation of MedImmune's assets within its manufacturing network. Because B636 was configured to lower product requirements, appropriate product candidates had to be shifted from the B633 facility to another facility, or initially manufactured in that facility in the future. B636 contains shell space suitable for installation of additional upstream and downstream manufacturing capabilities. The company is therefore evaluating the use of disposable technology to fit out this shell space, thus offering greater flexibility in terms of rapid installation of required capacity to meet ever-changing product demand.
Although the industry has been slow to adopt disposable technology, recent advances in consistency of manufacturing, increased reliability of equipment, and expanded use in early-phase clinical manufacturing makes the use of disposables a viable alternate to fixed stainless steel bioreactors.
Outsourcing is another option for meeting clinical product demand without major capital investment for facility modifications. Most products in the development portfolio at MedImmune are antibody-based and expressed using mammalian cell culture. As a result, the manufacturing process is generally consistent from product to product and well suited for FMC. But if a product that is expressed in a microbial based system or that has low clinical/commercial demand is introduced to the facility, then the nature of the process will necessitate significant capital investment into the facility to manufacture the product at commercial scale. The production process for that product may require additional steps that do not fit within the facility's current design. Such a change requires reassessing the plant's fit. What modifications are needed to make the new clinical process fit within the facility? Is this a cost-effective investment for the company?
To answer that question, a company also needs to look at the future demand for the product, stage of clinical manufacture and projected capacity utilization if the product is successful. Let's say, for example, a facility has the capacity to produce 80 batches of product a year, and a new product candidate requires only two batches a year to service the commercial market, yet a capital investment of $15 million is required to alter the facility for process fit. In this case, outsourcing at a minimum clinical supply may be a better option until further certainty of success for the product is understood.
Because the FMC facility services both internal and external partners for the scale-up and manufacture of late-phase clinical and commercial supply, the company had to establish and maintain a common approach to technology transfer, build knowledge and understanding of the facility constraints with all stakeholders, and drive towards platform technologies. The key was bringing everyone into the development process at the earliest stage. With this approach, FMC management was able to provide feedback on direction and impact to the site.
In addition, all stakeholders needed to be instructed on the capability and operating aspects of FMC so that they could develop standardized models (i.e., columns size, flow rates, buffer amounts) and ensure that their processes worked within the boundaries of the existing facility. Today, the company is creating a better working relationship between process development and the manufacturing organization; they are sharing knowledge and information, and building back that data into the established parameters. The goal is to create processes that seamlessly fit FMC rather than making costly capital investments that may risk the product timeline.
FMC is still in a state of transition. For some products, MedImmune is receiving late-stage clinical material with processes designed years before the facility was commissioned in 2010. In some cases, the team may have to adapt the facility slightly to meet the process. Overall, putting together a facility-fit analysis earlier in the lifecycle of the process ensures that it is ready for the facility, and allows for a more seamless flow from late-stage clinical to validation and commercialization.
GREG LIPOSKY is general manager/vice-president of the Frederick Manufacturing Site at MedImmune.