Future Manufacturing Constraints

• BioPlan Associates, Inc.

Innovative Technologies the Solution: Single-Use Devices, Higher Titer, Continuous

Around 2003 was a peak crunch-time or period of concern that severe bioprocessing capacity shortages would develop, with utilization rates peaking then at 76% for mammalian systems and many potential blockbusters in the pipeline. The subsequent expansion of capacity, with many new facilities coming online, brought utilization rates down, so that by 2006 a rather stable and healthier capacity utilization rate in the 60% - 67% range was attained.

Biopharmaceutical manufacturers avoid unanticipated high production demands, and this generally requires having some excess, ‘flex’ or buffer capacity. But the cost of idle biomanufacturing facility capacity is best avoided. And current utilization rates (at least for mammalian cell culture) appear to be in a healthy equilibrium.

Today, even how we measure capacity and utilization may be changing dramatically. In the past, company and industry-wide capacity and utilization calculations have involved unit operations including fixed stainless steel bioreactor-anchored facilities used for most commercial manufacture, with most of this now decades old.

Yet, as single-use/disposable bioprocessing systems begin to dominate clinical scale manufacture, and creep into commercial scale, even our ability to define capacity utilization is being challenged. Capacity analyses in the future will need to use other metrics than simple liters of bioreactor space.

Figure 1. Average Mab Titre 2008-2016, Commercial Scale

Figure 2. Expected Future Capacity Constraints, by 2021; Biotherapeutic Developers vs. CMOs

Capacity and utilization rates will become increasingly harder to estimate and may even become an irrelevant industry indicator in coming years, particularly as single-use equipment and modular facilities become adopted for commercial product manufacture.

How does one calculate existing and underutilized capacity, when users order and rapidly install single-use systems and even whole facilities on an as-needed basis? Singleuse equipment is simply meant to be used and then trashed. Is an empty room/suite that has been used or has been set aside for installation of single-use bioprocessing systems to be considered under-utilized capacity, or only underutilized when fully-ready for use but sitting idle? Will availability of operations staff become a measure of capacity?

Will capacity utilization even be a concern in the future as single-use systems and modular systems improve and are increasingly used for commercial-scale manufacture?

A number of companies, such as G-Con and GE, are starting to introduce fully modular, e.g., connectable trailer- or shipping containerbased, bioprocessing systems, taking the current trend for increased single-use plugand-play to a new extreme. For example, Pfizer joined with GE for rapid construction of a large modular manufacturing facility for biosimilars manufacture in China. Modular facilities will further confound estimation and interpretation of company and industry capacity and utilization. How does one calculate capacity utilization when whole integrated singleuse-based modular factories can be custom ordered and delivered anywhere in the world within a matter of months?

CMOs, including CMC in Copenhagen, and FujiFilm Diosynth in North Carolina, are using multiple 2000L bioreactors run in parallel, to create single batches that meet the demands of many, even blockbuster biologics. This is especially true as productivity out of the bioreactors increase, and titers increase; in some cases titers have doubled over the past 10 years. This means bioreactors can be substantially smaller for the required production.

Impact of Technology on Capacity

Capacity and productivity are some of the most important trends this year, in our 13th Annual Report and Survey of Biopharmaceutical Manufacturing Capacity and Production. 1 And our data show that neither CMOs nor biotherapeutic developers predict any “significant” or “severe” capacity constraints over the next 5 years.

In fact, fewer than 1 in 4 bioprocessing professionals surveyed this year report that they believe their facility will experience either “significant” or “severe” capacity constraints over the next 5 years, by 2021. This is about the same as last year.

CMOs overall express more capacity constraint concerns than product developers. This could simply be that CMOs are getting more fully booked-up with projects. Also, to unknown extents, future capacity constraints may be foreseen due to companies now expanding their R&D, companies’ product pipelines seeing success and progressing to larger-scale, and/ or respondents presuming that some current equipment and facilities will be obsolete 5 years from now.

Figure 3. Factors Creating Future, 5-Year Capacity Constraints; Biotherapeutic Developers vs. CMOs (Select Data)

Figure 4. Key Areas to Address to Avoid Capacity Constraints; Biotherapeutic Developers vs. CMOs (Select Data)

What’s Causing Constraints – And How Can CMOs Avoid Them?

As part of our analysis of capacity constraints, we asked CMOs to evaluate the factors likely to create production capacity constraints at their facility over the next five years. We found that 70% of CMOs expect to outgrow their facility in five years, compared with 58.5% of biotherapeutic developers. Other critical capacity problems involve hiring and retaining staff. And this brings us back to the issue of measuring capacity utilization - will human factors like staff-hiring backlogs become a more accurate measure of capacity constraint?

Avoiding Capacity Problems

Figuring out how to avoid these problems today, however, seem to center more around innovative equipment, than hiring better. For example, 58.8% of CMOs reported that to avoid capacity constraints in future production, key areas that need to be addressed includes developing more cost-effective disposable, single-use products. Other important key areas CMOs believe should be addressed included betterperforming disposable, single-use products and better continuous bioprocessing-downstream technologies (both tied at 52.9%) CMOs tend to be somewhat more forward thinking in terms of addressing capacity issues. They are, for example, also more likely to seek the development of better performing and more cost-effective downstream purification technologies, in order to avoid future constraints.

Conclusion

Capacity utilization and overall capacity in bioprocessing are rapidly becoming questionable measures of a facility’s ability to avoid capacity constraints. Technology adoption, and improved manufacturing productivity are taking a more critical role as facilities invest in strategically avoiding creating capacity crunches, or leaving expensive capacity under-utilized. In the future these manufacturers are improving their ability to meet demand for more production by rapidly deployed single-use technologies and planning using modular facilities. Further, production processes are being constantly developed to increase productivity and yield. Still not fixed, yet, are the more human factors like availability of trained, proficient scientific and operations staff. And if the drive towards more targeted therapies with smaller populations continues, biomanufacturers will need to produce a larger number of products in the same facilities, with many more changeovers. Efficiency is contingent on enabling technologies, like single-use systems, but also on improving human operations (such as staggered changeover times) in which bioprocessors have limited experience. Further, technological improvements, such as for complex continuous bioprocessing will also require an entirely new set of experienced operators. All of which could add to the capacity constraint equation in the future.

References

1. 13th Annual Report and Survey of Biopharmaceutical Manufacturing Capacity and Production, BioPlan Associates, Inc. Rockville, MD., April 2016,

Survey Methodology: The 2016 Thirteenth Annual Report and Survey of Biopharmaceutical Manufacturing Capacity and Production yields a composite view and trend analysis from 222 responsible individuals at biopharmaceutical manufacturers and contract manufacturing organizations (CMOs) in 27 countries. The methodology also included over 150 direct suppliers of materials, services and equipment to this industry. This year's study covers such issues as: new product needs, facility budget changes, current capacity, future capacity constraints, expansions, use of disposables, trends and budgets in disposables, trends in downstream purification, quality management and control, hiring issues, and employment. The quantitative trend analysis provides details and comparisons of production by biotherapeutic developers and CMOs. It also evaluates trends over time, and assesses differences in the world's major markets in the U.S. and Europe.