Continuous / Large Molecule

Bio Pharma Manufacturing's Top 15 Trends for 2015

The quest for efficiency continues as demand fuels capacity growth and process throughput.

By Eric S. Langer and Jean-Claude Lupis, BioPlan Associates Inc.

What's driving Bio Pharma manufacturing production in 2015? To get to that answer and rank the industry's Top 15 trends for 2015, we drew insight from our "12th Annual Report and Survey of Biopharmaceutical Manufacturing Capacity and Production" as well as input from BioPlan's Biotechnology Industry Council, a panel of more than 500 biopharma industry subject matter experts.

1) Manufacturing efficiency and productivity — where biomanufacturers are putting most of their attention.

In an effort to reduce costs associated with bioprocessing, launch biosimilars and address other strategic issues, the top trend this year involves "productivity and efficiency." Of the 13 key areas studied, more than 27 percent of respondents to our annual study noted these, along with cost reductions as their primary focus in 2015. This is demonstrated in areas including:

• Improvements in productivity from bioreactors, where average titer for clinical-scale biologics rose to 3.4 g/L this year, compared with 1.9 g/l in 2008
• Average mammalian titer at commercial scales is 2.50 g/L and 3.41 percent at clinical production scales.

Titers will continue to increase. Downstream continues to be the area requiring technological improvements, with 19.1 percent of respondents citing "Chromatography columns" as currently causing significant or severe capacity constraints. However, downstream productivity is getting better, and key indicators like capacity constraints have declined dramatically; this year only 45 percent expected moderate or worse capacity problems, compared with 88 percent of the industry back in 2005.

2) Budgets for Biomanufacturing operations up as much as 6.1 percent; all operational budgets have increased this year.

Budgets for operational aspects of bioprocessing have increased across-the-board, from 1.9 percentage average budget increase for R&D, to 6.1 percent for new capital equipment, and 5.3 percent for process development. Budget areas can be considered an indication of where facilities are focusing their attention and resources in the coming year(s).

 3) Single-use systems and disposable devices in hot demand: 7 out of 10 top new bio-innovations are single-use.

A large majority of biomanufacturers are demanding better single-use devices, disposable chromatography, downstream purification and throw-away sensors, which lead the pack in what buyers want. More than a third are demanding more and better devices today. The most urgent problem with adopting more single-use devices is simply breakage, and loss of production material. With breakage a fairly rare occurrence, this suggests that adoption hurdles are becoming increasingly less of a problem.

Essentially all, 90 percent, of respondents report using single-use bioprocessing equipment, with "Disposable filter cartridges" cited the most, used by 94.2 percent, followed by "Tubing" and "Depth filters." Single-use bioreactors were reported as used by 73.6 percent of respondents. The single-use products with the highest reported growth in annual adoption rates (1st use in facility) were "Membrane adsorbers" with annual growth of 16.8 percent, "Mixing systems" 16.2 percent and "Bioreactors" 14.9 percent; with the lowest reported adoption rate, 1.5 percent, for "Disposable chromatography devices." Both single-use "Mixing systems" and "Bioreactors" have seen more than a 50 percent increase in adoption since 2006. More than two-thirds (68.8 percent) cited single-use equipment as improving their bioprocessing in the past year, including 73.9 percent of U.S. respondents. More than one-third of respondents cited their desire for improved single-use downstream purification equipment, including 35.7 percent citing the desire for improved chromatography equipment.

4) Healthy, 14-percent Bio Pharma industry segment growth.

Growing consistently at ~14 percent and based on sales of biologics over the past 18 years, sales of biotherapeutics are currently at $200 billion. In manufacturing, current capacity utilization is a healthy 70 percent for mammalian production; facilities expect to expand their mammalian production by 49 percent on average over the next 5 years (2020); and by 25 percent for microbial facilities.

Bioprocessing-related budgets are expanding. Companies are investing more in biomanufacturing R&D, including hiring staff and expanding manufacturing capacity. Budgets for new capital equipment continue to grow; respondents report their budget up this year by an average of 6.1 percent versus 4.4 percent last year. Budgets for process design up 5.3 percent; new facility construction budgets are at an all-time high. Overall, companies appear to be investing in increasing productivity with what they already have, e.g., process development and new technologies for downstream manufacturing receiving high budget increases.

5) Bioprocessing capacity, including among CMOs, is at a healthy level, with no capacity crunches expected. Many new facilities and expansions are recently completed, underway and planned.

Survey respondents reported an average 69.9 percent capacity utilization for mammalian cell culture and 57.9 percent for microbial fermentation. These rates are in a healthy range — not too high (with bottlenecks) and not too low. But despite this, 56.7 percent of respondents reporting having experienced at least minor capacity constraints in the past year, mostly with commercial manufacturing (a factor driving capacity expansions and new facilities). CMOs reported higher capacity utilization — 81.8 percent for mammalian cell culture and 68.3 percent for microbial fermentation — and also much higher "significant" constraints, 32.7 percent versus 10.3 percent for product developers. U.S. mammalian capacity utilization rates are higher than for Europe — 72.3 percent versus 51.4 percent, while Europe has higher microbial capacity utilization, 65.8 percent versus 55.3. Overall, 60.1 percent expect "facility constraints" as likely to create capacity constraints at their facility within the next 5 years. Respondents projected an average 5-year planned increase of 49 percent in their facility's mammalian bioreactor capacity and 25 percent increase in microbial capacity.

6) Purification/downstream processing continues to be the most problem area.

However, DSP problems appear to be slowly abating. Today, 41 percent of industry feels better DSP technologies will reduce capacity problems. Nearly half the biopharma industry (41 percent) point to downstream purification as the cause of their most significant capacity problems. Easing these will involve developing more efficient, cheaper, single use disposable filtration and chromatography devices. Survey respondents reported an average 5.2% increase in their "Process development" budgets this year.

Respondents noted that improvement in DSP technologies is highly desired. "Chromatography Products" and "Disposable Products: Purification" were the top-cited areas of interest in new bioprocessing equipment, both cited by 35.7 percent and rising to 43.5 percent among CMO respondents. But industry is adapting and finding ways to increase downstream productivity. Purification is no longer a continually worsening bottleneck for much or most of the industry. Use of Protein A resins will remain the dominant initial monoclonal antibody capture step, with only 7-16 pecent of respondents reporting expected to use other products for existing bioprocesses, but there is high interest in alternatives, with a majority (54.4 percent) considering alternatives for new bioprocesses.

7) Biosimilars to add more products and competition; cost-effective bioprocessing becoming even more essential.

FDA finally approved its first biosimilar, and biosimilars will, in coming years, outnumber their reference products, changing the underlying nature of the biopharmaceutical industry, with everything becoming more like mainstream drugs, with generics dominating. BioPlan's Annual Survey indicates that the industry recognizes the top two critical trends to biosimilars success include efficient bioprocessing and the ability to cost effectively produce these follow-on products; this will likely include the applications of novel technologies for production.

China, India and other ROW countries are rapidly developing domestic, mostly biogenerics-oriented, biopharmaceutical industries. These are the fastest growing geographic areas for biopharma R&D and manufacturing. But these countries pose no threat to U.S. and other major market dominance in biopharma, particularly in terms of adopting innovations/manufacture of products for major markets. With biosimilars increasing competition, including with their reference products and other biosimilars, biobetters and biogenerics, it will become more important to cost-efficiently manufacture products.

8) Hiring new staff creating serious problems in bioprocessing; 46 percent of U.S. facilities can't fill their process development jobs.

The most difficult-to-fill positions this year continue to be associated with process development, where 39 percent of the industry cannot fill their upstream PD positions, and 37 percent cannot fill their downstream PD jobs. The U.S. has the greatest problems, where nearly half of biomanufacturers (46 percent) report inability to fill downstream PD jobs.

9) Innovative bioprocessing technologies and products still needed; suppliers are increasing their R&D and focus on improved productivity.

End-users' budgets are up 5.2 percent this year for acquiring better downstream technologies, and up 4.1 percent for improved upstream technologies. Factors contributing to better bioprocessing have been attributed to a broad set of attributes, but single-use devices were noted by 69 percent — the greatest of all 15 areas measured. Many deficiencies in bioprocessing, particularly, involving downstream technologies/equipment, are increasingly being addressed. Among supplier/vendor respondents, the leading areas where they report developing new products are "Bioprocess development/optimization services/bioprocess modeling" (39.8 percent), and "Disposable/single-use bioreactor bags/consumables" and "Disposable/single-use bags/films" both tied at 26.6 percent. However, problems with vendors continue, with 52.7 percent of vendor respondents citing demands for "Better customer service."

 10) Fill-finish operations going high-tech/single-use.

The most critical fill-finish trend in 2015 was the introduction of innovative, single-use devices, where 75 percent of this segment believes industry change will have the greatest impact (and 36 percent of the segment has developed plans to adopt SUS technologies in 2015). In addition, innovative RABs and isolators were indicated by 33 percent of this segment as hot trends and opportunity.

11) International growth in biomanufacturing continuing; China and India maturing biomanufacturing locations, with 15 percent concentration, employment increases over 5 years. China, India and other ROW countries rapidly developing domestic, mostly biogenerics-oriented, biopharmaceutical industries.

China and India have shown growth of up to 15 percent, according to BioPlan's top1000bio.com website, which has tracked biomanufacturing concentration (capacity, employment and # products) on a regional basis over 5 years. Offshoring of various bioprocessing operations to these areas is an indication of opportunity. Outsourcing costs are rising, and quality problems in many developing countries are becoming more apparent. Offshoring using ROW CMOs has increased, with 14.3 percent of respondents reporting offshoring bioprocessing in the past year.

Among all respondents, the U.S. and Germany were the leading expected future outsourcing destinations, both cited by 27 percent, while 22 percent cited China and 12 percent cited India. Among U.S. respondents, Germany was the leading expected outsourcing destination over the next 5 years, cited by 50 percent, followed by Singapore at 38.6 percent. China was indicated by 25 percent of U.S. respondents as a likely "outsourcing" destination, up from just 2.8 percent in 2009. India, as a destination for outsourcing, has held steady at around 11 percent among U.S. respondents. Among European respondents, the U.S. and China were similarly tied with 36.4 percent citing this as their expected outsourcing destination.

12) Flexible facilities: More flexible, multi-product, hybrid and even whole modular facilities are coming.

Bioprocessing is becoming more flexible; multiple-product and stainless-steel facilities are being upgraded to hybrid, and fully modular facilities are starting to have an impact. More bioprocessing technology vendors are developing modular approaches. Companies will be able to assemble systems using off-the-shelf or customized modules ready for plug-and-play with other modules. This modular trend will likely accelerate worldwide proliferation of commercial manufacturing, including to lesser-developed countries. Flexibility may be warranted as more biopharmaceutical R&D is done on more, but smaller market drugs. The percentage of biopharmaceuticals in R&D versus small molecules is increasing, while the size of targeted markets is generally decreasing. More products and smaller markets means more bioprocessing facilities and process lines, but these increasingly at smaller scale.

13) Continuous Bioprocessing emerging as a critical new technology: GMP issues, around consistency and reproducibility, and process complexity are critical factors.

GMP issues associated with continuous bioprocessing ranked highest in a recent comparative analysis of Continuous BioProcessing (CBP), versus Batch operations. Process operational complexity was a primary concern to 77 percent of biomanufacturers. And of the 19 comparative areas evaluated, the Top 3, where respondents reported perfusion/CBP as presenting more concerns (versus fed-batch) included: 1) Process operational complexity, 2) Process development control challenges, and 3) Contamination risks.

Perfusion is the leading continuous bioprocessing technology, but perceptions concerning implementation persist, e.g., 77 percent of respondents cite more "Process operational complexity" with perfusion versus 3.6 percent with fed-batch processing; 76 percent cite more "Process development control challenges" versus 3.6 percent for fed-batch; both values for perfusion are at record highs. Despite this, 51 percent of respondents noted they would likely specify perfusion for a new clinical process, with 37 percent using single-use equipment.

14) New and better assays are needed to improve industry performance.

Thirty-two percent of the industry is demanding better analytical assays, and 66 percent believe that such analytical testing improvements will improve their biomanufacturing performance.

15) Bioprocessing getting better; failure rates reduced by nearly 50 percent over past 8 years.

Fewer failed batches in biomanufacturing are occurring, based on time between failures; the average weeks between failures declined steadily since 2008 when the frequency was one every 40.6 weeks. By 2015, that rate had declined to one failure every 60.2 weeks.

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