Flexibility in Manufacturing Is Fundamental to Production Success

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Flexibility in all aspects of plant operations, including outsourcing relationships, will be crucial for meeting changing market and regulatory expectations.

Traditional manufacturing strategies won’t allow drug makers to respond quickly enough to increased competition from generics or the entry of new market players, nor reduce development times and costs. With the shift in demand; growth from mature to emerging markets; emerging expectations for local production; a renewed focus on targeted, highly potent therapies; and the ever-greater complexity of new drug substances, fixed, single-product batch manufacturing facilities are no longer relevant for most candidate drugs in the pipeline. Multi-product sites — designed to allow rapid switching between smaller-volume processes for the production of high-quality, high-purity, highly potent, cytotoxic or otherwise challenging and specialized APIs and biologic substances — will be the new norm.

Configurable, adaptable

State-of-the-art flexible facilities are designed to be configurable and adaptable with more open architecture (facility-wise and equipment-wise to avoid dependence on single suppliers) and extensive automation systems.¹ Continuous manufacturing strategies are typically incorporated at some level, and for biopharmaceutical plants, single-use technologies are widely used, although hybrid setups consisting of both disposable and stainless-steel equipment remain common to achieve optimum performance.

For biologics manufacturing, NNE Pharmaplan refers to this approach as the “bio-on-demand” standard.¹ Such flexible facilities allow production of different product volumes to meet the needs for both clinical and commercial manufacturing and to rapidly respond to changes in expected market demand (a recent survey of 50 pharmaceutical industry leaders conducted by ORC International, and sponsored by Patheon, revealed that many drug companies over- or underestimate new product demand by up to 25%). ² They also are typically designed to enable rapid switching between different products and product packaging (i.e., vials, cartridges or syringes for parenterals). ³

Many Aspects to Flexibility

Multi-product manufacturing and scalability are key features of flexible facilities, as are mobility and replication. Segregation of heating/ventilation/airconditioning (HVAC) systems for each production area allows for the manufacture of multiple compounds in a single plant. Continuous manufacturing provides ready scalability from the development lab to the clinic, and on to commercial production. Modular systems provide both mobility and duplicability.

Modular and Flexible

It is important not to confuse modularity with flexibility. Stick-built facilities constructed of modular panels are no more flexible than traditional sites, nor are modular units physically connected in a permanent arrangement that rely on a single HVAC system. Only modular units with individual HVAC systems (autonomous cleanroom POD solutions as referred to by G-CON Manufacturing) that can be readily decontaminated and sanitized for reuse are truly flexible and designed for multi-product processing. ⁴ They are also mobile and can be easily replicated. In addition, because modules are pre-engineered, they can be constructed, installed and commissioned much more rapidly than traditional facilities.

The full benefits of flexible facility designs are only realized with the implementation of appropriately flexible process designs. Modular processing systems and “plug-and-play” equipment provide easy scalability as well as customization for specialized manufacturing and rapid switching of production solutions. ⁵ In bioprocessing, the ability to reconfigure downstream process trains using flexible, portable, disposable units is preferred in multi-product manufacturing sites because often these operations vary significantly for different types of biologics. ⁶

Advances in Automation

When effectively implemented, automation can increase efficiency, productivity and quality while reducing costs. The reason: effective automation requires high-level process understanding in order to identify key areas for both control and optimization. ⁷ Automation is being employed in a variety of applications ranging from batch and recipe management to individual processes to whole-facility automation, including integration of production scheduling and purchasing operations. Connectivity and integration of control systems with different aspects of plant operations allows remote access for monitoring of processes and, when combined with simulation/modeling tools and extensive data collection and analysis, manufacturers are afforded the ability to respond rapidly to process excursions. This also allows for proactive management and exploration of trends for both process optimization and early identification of potential issues.⁷

Automation is also fundamental to the integration of individual unit operations based on disposable technologies for flexible and continuous manufacturing. In lieu of this need, GE Healthcare’s Life Sciences business and Emerson Process Management announced in late 2015 that Emerson’s DeltaV distributed control system would be incorporated in GE’s Flex-Factory integrated biomanufacturing platform based on single-use technologies. Senior Vice President of Industry Solutions for Emerson Process Management, Jerry Brown, expects that “the collaboration will support more predictable processes that eliminate unnecessary work, which translates into a reduced time to market for our customers.” ⁸

Progress With Pat

Truly flexible manufacturing requires continual access to real-time process data for greater understanding, ongoing optimization and the ability to rapidly respond when upsets or other unexpected events occur. Process analytical technology (PAT) is essential for achieving true consistency, given the variability always present in pharmaceutical raw materials, equipment and processing conditions. ⁹ Advances in portable, nondestructive analytical technologies (e.g., particle imaging, near-infrared, Raman, mass and Fourier transform infrared spectroscopies, focused-beam reflectance) with applications like PAT are making their way into pharmaceutical manufacturing. Effective PAT implementations can result in increased quality, faster product release, reduced cycle times and lower labor and energy costs. ¹⁰

PAT, combined with automated control platforms, is also key to successfully implementing fully integrated continuous manufacturing operations. ⁹ Companies like Siemens and Rockwell Automation are focused on developing comprehensive solutions that incorporate both. Rockwell, for instance, has been working with G-Con under a grant from the Defense Advanced Research Projects Agency (DARPA) to build a modular facility for flu vaccine manufacturing that can be rapidly installed and up and running in third-world countries.⁹

Top Drivers When Selecting a Cro Partner

Continual Development of Continuous Solutions

Continuous processes provide the scalability needed for flexible manufacturing. The amount of product produced can be increased or decreased simply by running the processes for longer or shorter periods of time. When microreactors are used, numbering up with parallel systems is another solution for increasing production volumes. There are also additional benefits, including a smaller operating footprint, reduced material and resource consumption, reduced quality control needs, more consistent product quality and reduced out-of-spec material.

In fact, in April 2016, the U.S. National Science and Technology Council (NSTC) listed continuous manufacturing of pharmaceuticals and biopharmaceuticals as manufacturing technology areas of emerging priority. ¹¹ Several other U.S. government agencies are involved in projects related to continuous pharmaceutical processing. ¹² In its December 2015 guidance document, Advancement of Emerging Technology Applications to Modernize the Pharmaceutical Manufacturing Base , FDA outlined the work its Emerging Technology Team (ETT) is doing with companies to increase the understanding of continuous manufacturing. ¹³

FDA has also recently approved drugs manufactured via continuous processing, including Jannsen’s Prezista, which previously was produced in a batch manner in April 2016.¹⁴ The process was developed in collaboration with researchers at Rutgers University, the University of Puerto Rico and the Engineering Research Center for Structured Organic Particulate Systems (C-SOPS), an academic-industry partnership. ¹⁴ Janssen Supply Chain (JSC), a subsidiary of Johnson & Johnson, is currently investigating applications of other continuous manufacturing techniques for the production of other products that may provide reduced scale-up times and decreased time to market. In addition, Janssen and Johnson & Johnson aim to “manufacture 70% of highest-volume products using continuous manufacturing within eight years, increase yield by reducing waste by 33%, and reduce manufacturing and testing cycle time by 80%.” ¹⁵

New approaches to continuous process development are also being evaluated. Rather than focus on pharmacokinetics, researchers at C-SOPS look “at material characterization and how minor changes affect manufacturability as part of a system,” according to Associate Director for Industrial Relations and Business Development Doug Hausner. ¹⁶ Biopharmaceutical manufacturers are also making significant investments in continuous manufacturing technologies and facilities. Eli Lilly, for instance, is investing €35 million to build a continuous API manufacturing facility at its existing manufacturing site in Kinsale, Cork Country, Ireland. The facility will be used for development and commercialization of Lilly’s late-stage pipeline. ¹⁷

References

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3. Stauffer, Rebecca. “Pharma Seeks Long Tail Of Flexible Manufacturing.” Bioprocess Online. 18 May 2016. Web.
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8. GE Healthcare Life Sciences and Emerson Team Up to Drive Biopharma Manufacturing Efficiency . Emerson. 16 Nov. 2015. Web.
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15. Advances in Pharmaceutical Supply Chain: Continuous Manufacturing (CM). Apr. 2016. Web.
16. Markarian, Jennifer. “Continuous Manufacturing Eases Scale Up for Solid Dosage.” Pharmaceutical Technology . 2 Apr. 2016. Web.
17. Lilly Invests $40 Million in Irish Continuous Manufacturing Facility . BioPharmaDive. 7 Apr. 2016. Web.