May 1, 2017 (Vol. 37, No. 9)
Jeffery Odum CPIP Global Technology Partner, Strategic Manufacturing Concept Group NNE
Platforms Advance Significantly to Reduce Space Required to Manufacture Drugs
Recently there has been a significant amount of attention and narrative given and written around modular facility design for biomanufacturing facilities. To understand why organizations investigate this delivery option and in recent years have become enamored with its potential, you have to understand the primary drivers behind the “modular decision.” For many companies, flexibility, scheduling, and facility-size reduction are the key drivers.
As companies seek viable options to increase manufacturing capacity for expanding pipelines and the implementation of new enabling technologies, flexibility becomes a key concern. Figure 1 represents the “utopia” of facility operation that most companies would like to achieve: a facility designed in a manner that will allow them to perform a wide array of manufacturing activities within the same infrastructure to meet manufacturing demand while achieving a level of cost control that ultimately has a positive impact on overall cost-of-goods.
Such a “fit-to-purpose” design approach requires:
- High-level understanding of product-process attributes
- Well-defined operational approach
- Well-defined risk identification
- Robust process definition
- Synergistic scale-up/scale-out methodologies
Flexibility will likely involve the need to manufacture multiple products. These may take the form of similar product types (monoclonal antibodies, bacterial, and cell therapy) or related process unit operations and platforms (single-use technology, skid-based). From the model presented, scalability will also be a factor. As the product(s) move through the pipeline, their target needs to support the patient population will increase. The robustness of the process will become a key factor as the manufacturing lifecycle approaches commercial launch quantities. Efficiency and utilization will be critical factors in the design approach.
Often the main business case driver for investigating a modular design/delivery approach is the need to reduce the time required to complete physical construction of the facility in order to meet market demands for the product(s). Some of the first examples of modular construction driven by schedule needs came from the Walt Disney Company and the design and delivery of the Contemporary Resort Hotel, and a significant number of projects from the oil and gas industry.
The Modular Building Institute estimates that construction schedules can be reduced from 30–50% by implementing a modular design/
Facility Size Reduction
A modular design approach inherently requires that standardization and the ability to replicate key design elements of the facility be key attributes of the overall design. With the advent of single-use equipment platforms and improvements in process efficiency (titers and yield) there has been a
visible, often significant reduction in space required to manufacture a given quantity of drug substance/API material. This reduction in physical size translates to reduced total installed costs for manufacturing assets and improvements in cost of goods equations.
Design Strategy for Modularity
The key to modular facility design begins with recognizing that biomanufacturing is an enterprise that has three components: process, facility, and infrastructure (Figure 2). These three elements must be in synergy with the business and operational drivers of the organization in order to be successful. The process elements would include items like the product(s) being produced and their logical operating units, the equipment platform (steel or single-use), and the input materials. In the enterprise model, infrastructure refers to attributes such as the various control systems, procedures/SOPs, and people-related aspects such as personnel qualifications and training.
The facility element then focuses on segregation strategy, flows, environmental classification/segregation, cleaning, and utility support systems. These facility elements become critical aspects of the modular design approach and must be addressed as part of the greater risk-assessment aspects related to the overall operational philosophy of the facility.
These facility elements will have a significant impact on layout and segregation strategy for biomanufacturing facilities. This will translate into how the definition of the “module” will be identified and how the operational aspects of the process will be aligned with the overall facility design. Without this alignment between the process, infrastructure, and facility, any modular approach will likely fail.
A modular design strategy must answer the question, “why?” There will be many drivers around why to have a modular approach, as we discussed. The design strategy must also have a clear focus on the manufacturing platform attributes, scale, equipment platform, process closure, and product protection.
The optimum design strategy should provide for:
- Fast decisions around investment, cost-of-goods, and time-to-market
- Reduced investment in initial TIC and consistent expansion cost models
- Fastest to the market delivery option
- Maximized future outcome based on new products/new technology
The optimal design strategy should result in a well-defined fit to purpose. Addressing product, process, and facility attributes to optimize the functionality of the facility is critical. These attributes would include:
- Open process architecture where process equipment from the full range of potential suppliers that could be used to build the optimal process train(s)
- Multiproduct capability that promotes fast changeover between products, addressing product portfolios
- Full facility lifecycle capability to address clinical, launch, and market supply requirements
- Standardization to support upstream and downstream operations with the necessary utility and support capabilities
- Optimized workflow to support high utilization, efficient operations, and a sound GMP design strategy
- The appropriate GMP attributes to support the manufacturing enterprise
Today there are a number of modular delivery options from which companies may choose. These should be evaluated around the purpose of the facility and what attributes best fulfil that purpose.
Panel and walkable ceiling systems are a pre-engineered, modular cleanroom system designed for integration into pharmaceutical, biotechnology, and other critical manufacturing environments to achieve the goals of a cleanroom operation that can be validated.
- PVC cold-welded panel to panel seams
- PVC ceiling coves
- UL-rated raceway for electrical service
- Impact resistant
This option has a number of attributes including:
- Good for unique geometries
- Good product industry standards.
- Assembly fast and straight forward—in theory can be disassembled (compared to stick built)
- AHU’s are separate and all utilities are excluded/separate.
- Need protecting from heavy objects (tanks!)
- VHP and IHP resistance.
Prefabricated, autonomous cleanroom Pod units are unique from traditional cleanroom structures, due to their ease of scalability, mobility, and the ability to repurpose the units once the production process reaches the end of its lifecycle. These units are highly flexible, can be arranged in many configurations, and are often placed in open-air conditioned shell spaces for ease of future flexibility. Evaluation of unit attributes is important to maximize utilization and assess unit costs.
These products are based on an intermodal container platform and are designed to fit inside new or existing warehouse spaces. They are based on a very well-defined standard template that can be configured into cleanroom spaces. The containers are strong and since they already exist, this makes construction faster. Their delivery time is a nominal 8–12 weeks and flexible. Scale is potentially an issue—height could be a problem if we have process equipment above 1,500 L scale.
Bio on Demand
Bio on Demand is a flexible, modular-adaptable facility design approach that allows for implementation of any or all of the various modular approaches presented. The open-architecture approach is based on a library of standard functional modules that can be adapted to specific process and facility situations. Such an approach provides for implementation of not only modular approaches but also combinations of modular and traditional “stick-built” construction delivery.
1. “Biopharmaceutical Manufacturing in the Twenty-First Century—the Next Generation Manufacturing Facility” Witcher and Odum, Pharmaceutical Engineering, volume 32, No. 2, March 2012.
2. “Product-Process-Facility Relationship”, Jeff Odum, Encyclopedia of Industrial Biotechnology, Wiley & Sons, pending publication 2017.
3. Walt Disney World Info website.
4. “Improving Oil and Gas Well Performance with Modular Facility Design” Halker Consulting, March 2015.
5. “Why Build Modular?” Modular Building Institute website, February 2017.
6. “Modularity Creates Flexible Manufacturing Systems” Jennifer Markarian, Pharmaceutical Technology, Volume 38, Issue 9, September 2014.
7. “Impact of Facility Layout on Developing and Validating Segregation Strategies in the Next Generation of Multi-product, Multi-phase Biopharmaceutical Manufacturing Facilities” Mark Witcher, Pharmaceutical Engineering Supplement, December 2013.