Drivers, Risks, and Enablers in Next-Generation Biomanufacturing Environments

“Next-generation” biomanufacturing—what is it specifically and how does it differ from past and current installations?

David M. Marks, President and Principal Consultant, DME Engineering, explains it this way: “Next-generation biologics facilities are an alternate approach to biomanufacturing, but they are not appropriate for every production scenario. Most large-volume biotherapeutics will continue to be manufactured in traditional stainless steel facilities.” [1]

Marks says that most next-generation facilities contain some, but not all, of the following elements: [2]

  • Smaller process scale (continuous, scale-out versus scale-up)
  • Emphasis on flexibility—multiproduct, multiphase
  • Consolidation of manufacturing space
  • Reduction in classified space
  • More closed processing
  • More continuous (versus batch) processing
  • Expanded use of single use/disposables
  • Expanded use of modular construction

A key benefit to “next-gen” facilities is the flexibility that they offer in conjunction with traditional biomanufacturing approaches. Marks states, “Many facilities today could be considered hybrid traditional/next-gen technologies because they implement some of the new disruptive technologies where it provides the greatest benefit.” [1]

Defining and understanding the drivers, uncertainties, and risks associated with building and operating biomanufacturing facilities is a key first step to the development of future generation facilities. [4]

Opportunity Drivers

Business drivers—the effect of property, plant, and equipment on the bottom line—are numerous, interrelated, and complex: [4,5]

  • Operational excellence
  • Throughput
  • Flexibility
  • Facility utilization
  • Sustainability
  • Emerging markets
  • Competition
  • Return on investment/cost of goods sold

In a real-time, multiple-choice next-generation technologies survey conducted by Marks at the 2014 ISPE annual meeting, biomanufacturing professionals were asked what they felt was the strongest driver for building next-generation facilities; 49% chose “Need for flexibility.” [3]

Flexibility is crucial for facilities of the future, Marks explains: “Facilities for emerging markets, small-volume therapeutics, and personalized medicine will require less capacity and more flexibility in order to be fully utilized.” [5] High utilization rates almost always translate into cost-effective facilities. [4]

Future facility design success must be measured in terms of utilization, flexibility, and efficiency, while providing a platform that facilitates the operational excellence required to produce high-quality product reliably and meet ever-evolving regulatory compliance guidance. [4]

Risk Drivers

Some of the manufacturing risks that drive modernization [5] include:

  • Product quality
  • Regulatory compliance
  • Obsolescence
  • Safety
  • Reliability

Survey respondents were asked to select the biggest challenge associated with implementing a next generation facility; 30% chose “risk management.” [3]

Technology Enablers

A common theme across all the drivers is the influence of new technology. New enabling technologies can provide manufacturing platforms that are flexible, have low capital unit operations changeovers, efficient movement to new markets, and a scale-out approach with smaller capacity increments. [4]

New technologies and facilities of the future can positively influence cost by allowing: [4]

  • Lower cost capital solutions and equipment
  • Lower operating costs
  • Improved process performance
  • Better utilization of raw materials and personnel
  • Increased productivity and product quality
  • Accelerated schedules with shorter lead time process systems
  • Transition from fixed to variable cost structures that can flex with demand

Technology enablers include: [2]

  • Process improvement (higher yield)
  • Single use
  • Continuous processing
  • Better analytical capabilities
  • Improved process knowledge
  • Process closure
  • Modular construction methods

Survey respondents were asked to select the most significant next-generation technology enabler; 47% chose “Single-use/disposables.” [3]

Marks explains, “Process improvement is an enabler because higher yield allows for production with smaller batch sizes. Single-use technology has size limitations, so driving down processing scale allows for expanded use of the technology. Continuous bioprocessing offers the same advantage, so there is a certain synergy between single-use and continuous technologies.” [1]

Single-use systems (SUS) provide significant opportunities to isolate the process from the surrounding environment, enabling a wide variety of process implementations and facility designs. [6] Single-use equipment and components are notable examples of a technology that can significantly reduce startup and operating costs in some applications. [4]

Strategies and Methodologies

Key strategies for next-generation facilities include: [2]

  • Quality risk management (QRM)
  • Continuous, scale-out versus scale-up
  • Segregated facility versus ballroom
  • Hybrid technologies
  • Closed processing
  • Automation
  • Process analytical technology (PAT)
  • Manufacturing execution system (MES)

Survey respondents were asked to select the most promising long-term next-generation strategy for large-volume biologics; 47% chose “Continuous biomanufacturing.” [3]

Continuous bioprocessing technology addresses the scale limitations inherent in SUS; increases throughput by extending process time, not scale-up or scale-out; and enables manufacturing of large-volume therapeutics at smaller scale. [2]

Survey respondents were asked to select the most promising long-term next-generation strategy for biomanufacturing product segregation; 43% chose “Mix of traditional and next-gen strategies”; in a close second, 41% selected “Closed processing in ballroom suites.” [3]

Closed processing improves facility cost, flexibility, and adaptability by allowing room environment parameters to be non-CPP (critical process parameters) and considered a controlled non-classified environment. [2]

Key Considerations When Planning for Facility Modernization

“The age of a facility does not necessarily mean it’s ‘old’ or ‘outdated,’” states Younok Dumortier Shin, Director–Global Technical Operation, Janssen. “There must be a clear understanding of the current state versus the desired future state.” [7]

Deciding whether to modernize traditional facilities versus building new should be determined by manufacturing needs.

Marks explains, “It’s not easy to change a traditional facility to next generation. The facility-design philosophy and space program are radically different. Most manufacturers just end up building a new facility.” [1]

He continues, “Products that are currently manufactured in traditional facilities will continue to be manufactured that way because leveraging some of the newer single-use and continuous bioprocessing technologies requires significant process development. So
these next-gen facilities will likely see products that were specifically developed to take advantage of these manufacturing methods.” [1]

As organizations begin to think about bringing their facilities up to next-generation conditions, they need to consider a number of key issues [5]:

  • Facility unknowns: Develop contingencies for encountering undocumented or inaccurately documented existing conditions, unknown utility capacity to support new equipment, inadequate structural support for new equipment, etc. Detailed construction documents are frequently inaccurate, especially after multiple renovations within the same space. In older facilities, it is not unusual to have incomplete documentation of the existing mechanical/electrical/plumbing systems.
  • Good manufacturing practice (GMP) and technology gaps: GMP standards evolve over time, so manufacturing standards that were common 20 years ago are no longer acceptable.
  • Facility segregation/flows: Develop rational circulation patterns, cleanroom transitions, and heating, ventilation, and air-conditioning zones.
  • Regulatory considerations
  • Complex process systems
  • Process validation
  • Construction activities adjacent to ongoing GMP operations: Develop an execution approach with minimal disruption.
  • Optimal upgrade timing: Can you piggyback on the next process change?
  • Facility master plan: Ensure a process technology fit and update the plan proactively to keep the facility up-to-date. [7]

Marks concludes, “In most cases, facility modernization means a renovation of existing stainless steel systems, such as more robust cleaning-in-place/sterilization-in-place technology, better process instrumentation to facilitate PAT and QRM, and improvement in cleanroom design or facility flows.” [1]

—————

[1] Marks, David M., President and Principal Consultant, DME Engineering, interview 3 September 2015.

[2] Marks, David M. “ADM Concepts as a Model for Next Generation Biomanufacturing,” ISPE Annual Meeting, Las Vegas, Nevada, USA, 12–15 October 2014.

[3] Survey. ISPE Annual Meeting, Las Vegas, Nevada, USA, 12–15 October 2014.

[4] Witcher, Mark, et al. “Facility of the Future: Next Generation Biomanufacturing Forum; Part I: Why We Cannot Stay Here—The Challenges, Risks, and Business Drivers for Changing the Paradigm.” Pharmaceutical Engineering 33, no. 1 (Jan/Feb) 2013.

[5] Marks, David M. “Manufacturing Modernization: Old Facilities + New Tech,” ISPE/FDA/PQRI Quality Manufacturing Conference, Washington, DC, 1–3 June 2015.

[6] Witcher, Mark, et al. “Facility of the Future: Next Generation Biomanufacturing Forum; Part II: Tools for Change—Enabling Technologies and Business and Regulatory Approaches,” Pharmaceutical Engineering 33, no. 1 (Jan/Feb) 2013.

[7] Dumortier Shin, Younok. “Maintaining Your Manufacturing Facilities in ‘Current State’,” ISPE/FDA/PQRI Quality Manufacturing Conference, Washington, DC, 1–3 June 2015

 

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