When the Process Becomes the Product: Single-Use Technology and the Next Biomanufacturing Paradigm

The modern biopharmaceutical industry has developed and grown over the past 35 years to a mature industry. From its starting point, marked by the generation of the first hybridoma cell line in 1975, followed by the development of molecular biology methods for the manipulation of DNA between 1980 and 2000, it is now common practice to manipulate the genome of cell lines to produce specific antibodies or therapeutic proteins and to manipulate the genome of viruses to produce safe vaccines (1, 2).

These new technologies have formed the basis for the development of new drugs produced by biotechnological methods, which have brought unprecedented economical success to the rising biopharmaceutical industry. This success is illustrated by the fact that it is forecasted that in 2014, eight out of the ten top-selling drugs (more than $1 billion cash flow) will be biopharmaceuticals (3). Today, some of these biopharmaceuticals are manufactured at the ton scale.

This success was made possible not only by new technologies, but also by the fact the engineers were able to design and build specialized equipment and facilities that fulfill the specific biopharmaceutical industry requirements for sterility, containment, and segregation at large volumes

At the beginning, traditional stainless-steel equipment stemming from chemical engineering was successfully adapted to biotechnology. The equipment was continuously improved and fine-tuned. The major improvements of chemical engineering were, however, achieved in automation and control as a consequence of the digital revolution.

The low yields achieved with the first biopharmaceutical manufacturing processes primed the construction of ever-larger equipment and facilities to achieve economy of scale while satisfying increasing demand. The largest bioreactor used for mammalian-cell cultivation has a working volume of 25,000 L. In bacterial fermentation, even larger bioreactors up to working volumes of 100,000 L have been developed.

The combination of large liquid volumes stemming from the low-yield production step with low-capacity purification methods, such as chromatography, resulted in large manufacturing facilities that integrated huge liquid-handling capabilities to operate bioreactor production and multiple purification steps. The advent of monoclonal antibodies also enabled a standardization of the process architecture and steps, further enabling the concept of standardization of distributed manufacturing facilities.

Furthermore, the cleaning and sterilization of all liquid-handling capabilities, which has to be executed with the equipment in place, requires huge capacity for the generation of water for injection (WFI) and clean steam, as well as a highly complex piping system to and from the points of use at the equipment. Table I lists key parameters of systems and facility elements for a traditional stainless-steel manufacturing facility and their single-use counterparts.

Table I: Key parameters of systems and facility elements of traditional stainless-steel and single-use facilities. Data from references 9 and 10.

It is, therefore, not surprising that the construction of a manufacturing facility consisting of six bioreactors of 10,000 L or more and two entire purification trains requires four to five years. This estimate excludes the embedding and validation of the manufacturing process in the new facility, for a total capital expenditure (CAPEX) of more than $450 million.

Four to five years in biotech can be an eternity: by the time the facility is ready for use, there is a significant chance that the product has failed in the clinic or the process has changed dramatically, rendering the finished facility obsolete.

The routine operation of such a facility requires approximately 250 full-time employees (FTEs) for production, maintenance, and quality control (QC) because of the complicated equipment and layout, the significant number of utilities, the quality control of the facility and the utilities, and the utilization of low-capacity manufacturing technologies.

Hence, the combination of traditional stainless-steel-based technologies, complicated facility layouts, and low-yield manufacturing processes have resulted in high depreciation and operation expenditures (OPEX), which have a significant effect on the economics of business cases for new drugs and on competitiveness in general.

In the past, this cost structure was the reason why only large biopharmaceutical companies were able to build large traditional biopharmaceutical manufacturing facilities and maintain the required staff to operate these facilities. Furthermore, the economics of manufacturing in these traditional facilities were biased by the fact the biopharmaceutical drugs were, and are, sold with a significant upside (up to 90% margin), leaving the cost of goods sold (COGS) as negligible.

With the first biopharmaceutical drugs losing patent protection, the advent of biosimilar drugs, the rarefication of obvious new blockbuster drugs, and smaller markets and revenue, the biopharmaceutical industry is currently undergoing a major paradigm shift. This shift is accelerated by the development of alternative technologies to traditional chemical engineering and the rethinking of process architecture, technologies, and manufacturing facility layouts.

PARADIGM SHIFT

The major adoption drivers for the biopharmaceutical industry were the availability of manufacturing-grade and scaled-up single-use systems, the opportunity to reduce CAPEX and OPEX costs, the acceleration of construction projects, and the reduction of the overall qualification and validation effort. Multiple publications comparing traditional with single-use technology have calculated a CAPEX saving of up to 60–70% and an OPEX saving up to 20–25% (4–6).

The flexibility of the disposable options available on the market makes their implementation seamless since they can easily be customized to meet the requirements of an already designed facility. In addition, the high number of different disposable options in various functional areas allows the Pilot Plant to be a very flexible production unit and to respond to different project requirements (7).

The evolution of single-use technology was developed in parallel with new modular facility construction concepts made up of pre-assembled modules. The main advantage of modular construction is the significant reduction of construction time compared with traditional construction techniques.

Interestingly, despite adopting new single-use technologies, the biopharmaceutical industry has maintained the basic facility layout stemming from the traditional stainless-steel facilities. This statement holds true even for facilities built out of pre-assembled modules. The drivers for choosing the traditional layout are based on regulatory requirements, risk mitigation in hybrid approaches between single-use and traditional technologies, and simply following past behaviors (8).

This traditional approach still results in complex facility layouts, which require multiple heating, ventilation, and air conditioning (HVAC) systems and elaborate flows of goods and personnel. Hence, the benefits offered by single-use systems and modular facility construction techniques were and are only partially realized.

Today, the evolution of single-use technologies offers the possibility to close the entire upstream process and downstream process up to the isolation of the drug substance. Hence, no open handling steps are required in facilities operating either with traditional stainless-steel technology or with hybrid approaches using traditional and single-use technologies. The only remaining open handling step is the thawing of a cell vial at the start of the process, although some researchers are already investigating the possibility of storing cells in bags.

The possibility of isolating the entire manufacturing process from the environment primes a major paradigm shift in the biopharmaceutical industry. While in the past, individual groups developed their processes for the unit operation they were responsible for (i.e., a silo approach), today, the new approach is to integrate all unit operations into one end-to-end manufacturing process (i.e., a holistic approach). The holistic approach enables the architecture of the manufacturing process and the integrated single-use technologies to be installed such that risks to the process stemming from operator interaction can be minimized. This is a major breakthrough when taking into consideration that the operator is the primary source for contamination and process deviations. In that sense, the process itself becomes the product.

This paradigm shift should prompt a review of the traditional facility layout to translate the benefits stemming from entirely closing the manufacturing process and the reduction of operator-linked risks into major CAPEX and OPEX reductions, which will dramatically affect the COGS of a drug.

CONCLUSION

In the past, biopharmaceutical manufacturing was extremely CAPEX and OPEX intensive. The high gross margins and benefits achieved with the produced drugs made it possible to neglect the COGS, because the main objective was securing drug supply. The objective of future developments must, however, be the design of purification processes without chromatography steps, which will result in a further simplification and significant reduction of the average CoGs for manufacturing of mAbs (9). Today, with the advent of biosimilars, smaller market shares, and difficulties in finding new drugs, the biopharmaceutical industry — especially in the developed world—faces difficult times that demand swift adaptation to increase productivity, maintain market share, and remain competitive with new entrants from the East.

New technologies such as single-use components offer new ways to approach and resolve the challenges of the biopharmaceutical industry and resolve the paradox between low cost and high quality.

The evolution and maturation of single-use technologies over the past two decades has now reached a scale feasible to support market manufacturing.

Today, the entire manufacturing processes can be closed and isolated from the operator. To design efficient closed processes, a holistic approach is required that integrates all unit operations from upstream processing through downstream processing to the isolated drug substance.

This prerequisite marks a major paradigm shift within the biopharmaceutical industry as the manufacturing process becomes for the first time the product, while in the past only end-product testing was applied, disregarding the manufacturing process itself.

This holistic approach also prompts a review of the current manufacturing facility layout. The closing of the manufacturing process allows the application of new facility concepts resolving the paradox between regulatory requirements for segregation and process simplification.

Modular facility concepts allow manufacturing facilities to be built even faster and at lower CAPEX costs. The new concepts also make qualification, validation, maintenance, and operation simpler, lowering the OPEX further.

Today's new technologies and concepts resolve the paradox between low cost and high quality in biopharmaceutical manufacturing. The key is to think in a holistic way, to be bold, and to translate the new regulatory requirements such as QbD and PAT into new operating models that are sustainable in the future competitive environment (11, 12). Taken together, new technologies based on disposability continue to redraw the economic landscapes of biopharmaceutical companies. An assessment of the fullest value of these technologies requires the broader context of the variables of facility design, QbD, and risk assessments as outlined in ICH Q8/9/10 [8-10], and the established pathways of lead development in order to capture all the benefits stemming from these new technologies (10).

PARRISH GALLIHER is founder and chief technology officer of Xcellerex, a GE Healthcare Life Sciences company, Marlborough, MA, Parrish.Galliher@ge.comALAIN PRALONG* is vice-president of New Product Introduction & Technical Life Cycle Management, GlaxoSmithKline Vaccines Wavre, Belgium, alain.x.pralong@gsk.com

REFERENCES

1. G. Köhler and C. Milstein, Nature 256, 495-497 (1975).

2. J.M. Walker, Methods in Molecular Biology, (Springer).

3. FACTBOX-World's Top-Selling Drugs in 2014 vs 2010, www.reuters.com/article/2010/04/13/roche-avastin-drugs-idUSLDE63C0BC20100413, accessed March 11, 2013.

4. A. Sinclair, BioPharm Intl. 21 (6), 26-30 (2008).

5. A. Foulon et al., BioProcess Intl. 6 (6), 12-17 (2008).

6. A. Ravisé et al., Biochem. Eng.Biotechnol. 115, 185-219 (2010).

7. A. Koch, et al., American Pharmaceutical Review, Nov-Dec issue (2006).

8. Code of Federal Regulations, Title 211, Current Good Manufacturing Practice for Finished Pharmaceuticals, Part 42 (Govern-ment Printing Office, Washington, DC).

9. A. Luitjens and A. Pralong (2011). Going Fully Disposable – Current Possibilities: A Case Study from Crucell, Single-use Technology, in Biopharmaceutical Manufacturing (Wiley, 2009) pp. 341-349.

10. A. Luitjens, J.Lewis, and A. Pralong (2012). Single-Use Biotechnologies and Modular Manufacturing Environments Invite Paradigm Shifts, in Bioprocess Development and Biopharmaceutical Manufacturing, Biopharmaceutical Production Technology, (Wiley, 2012) pp. 817-857.

11. FDA, Guidance for Industry: Process Validation: General Principles and Practices (Rockville, MD, 2011)

12. FDA, Guidance for Industry: PAT —A Framework for Innovative Pharmaceutical Development, Manufacturing and Quality Assurance (Rockville, MD, 2004).