BioPlan Associates Inc. recently released its Top 15 Trends in Biopharmaceutical Manufacturing, which provides analysis of data from the firm’s 12th Annual Report and Survey of Biopharmaceutical Manufacturing Capacity and Production. BioPlan has drawn these insights, and the ranking of trends based on an internal analysis of the most commonly discussed industry problems, and from input from their Biotechnology Industry Council, a panel of over 500 biopharma industry subject matter experts.

TREND 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, over 27% of respondents to the 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% at clinical production scales. Titers will continue to increase;
• Downstream continues to be the area requiring technological improvements, with 19.1% of respondents citing “chromatography columns” as currently causing significant or severe capacity constraints; and
• However, downstream productivity is getting better, and key indicators like capacity constraints have declined dramatically; this year only 45% expected moderate or worse capacity problems, compared with 88% of the industry back in 2005.

TREND 2
Budgets for biomanufacturing operations are up as much as 6.1% while all operational budgets have increased this year. Budgets for operational aspects of bioprocessing have increased across-the-board, from 1.9% average budget increase for R&D, to 6.1% for new capital equipment, and 5.3% for process development. Budget areas can be considered an indication of where facilities are focusing their attention and resources in the coming year(s).

TREND 3
Single-use systems and disposable devices are in hot demand: 7 of 10 top new bio-innovations are single-use; expect more adoption of single-use systems, including for commercial manufacture. A large majority of biomanufacturers are demanding better single-use devices—disposable chromatography, downstream purification and throw-away sensors lead the pack in what buyers want. Over 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, noted by 75%. With breakage a relatively rare occurrence, this suggests that adoption hurdles are becoming increasingly less of a problem. Essentially all, 90%, of respondents report currently using single-use bioprocessing equipment, with disposable filter cartridges cited the most, used by 94.2%, followed by tubing and depth filters.
Single-use bioreactors of any size were reported as used by 73.6% of respondents. The single-use products with the highest reported growth in annual adoption rates (first use in facility) were membrane adsorbers with annual growth of 16.8%, mixing systems 16.2% and bioreactors 14.9%. The lowest reported adoption rate, 1.5%, was for disposable chromatography devices. Both single-use mixing systems and bioreactors have seen over a 50% increase in adoption since 2006. Over two-thirds (68.8%) cited single-use equipment as improving their bioprocessing in the past year, including 73.9% of U.S. respondents. Over one-third of respondents cited desires for improved single-use downstream purification equipment, including 35.7% citing desires for improved chromatography equipment.

TREND 4
Healthy 14% biopharma industry segment growth. Growing consistently at ~14% based on sales of biologics over the past 18 years, currently sales of biotherapeutics are at $200 billion. In manufacturing, current capacity utilization is a healthy 70% for mammalian production; facilities expect to expand their mammalian production by 49% on average over the next 5 years by 2020; and by 25% for microbial facilities.

Bioprocessing related budgets are expanding in essentially all areas. Companies are investing more in biomanufacturing-related 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% vs. 4.4% last year. Budgets for process design are up 5.3%. At the same time, 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.

TREND 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% capacity utilization for mammalian cell culture and 57.9% for microbial fermentation. These rates are in a health range—not too high, with bottlenecks, and not too low, but high enough to be cost effective. But despite this, 56.7% of respondents reported 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% for mammalian cell culture and 68.3% for microbial fermentation—and also much higher significant constraints, 32.7% vs. 10.3% for product developers. U.S. mammalian capacity utilization rates are higher than for Europe—72.3% vs. 51.4%—while Europe has higher microbial capacity utilization—65.8% vs. 55.3. Overall, 60.1% 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% in their facility’s mammalian bioreactor capacity and 25% increase in microbial capacity.

TREND 6
Purification/downstream processing continues to be the most problematic area. However, DSP problems appear to be slowly abating. Today 41% of industry feels better DSP technologies will reduce capacity problems. Nearly half the biopharma industry (41%) 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 are highly desired. “Chromatography Products” and “Disposable Products: Purification” were the top-cited areas of interest in new bioprocessing equipment, both cited by 35.7% and rising to 43.5% 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% of respondents reporting expected to use other products for existing bioprocesses, but there is high interest in alternatives, with a majority (54.4%) considering alternatives for new bioprocesses.

TREND 7
Biosimilars to add more products and competition; cost-effective bioprocessing is 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. The 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 biopharmaceutical R&D and manufacturing. But these countries pose no threat to U.S. and other major market dominance of the biopharmaceutical industry, particularly, in terms of adopting innovations and manufacture of products for major markets. With biosimilars increasing competition, including with their reference products and other biosimilars, biobetters and biogenerics, it will become increasingly important to cost-efficiently manufacture products.

TREND 8
Hiring new staff is creating serious problems in bioprocessing; 46% 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% of the industry cannot fill their upstream PD positions, and 37% cannot fill their downstream PD jobs. The U.S. has the greatest problems, where nearly half of biomanufacturers (46%) report inability to fill downstream PD jobs.

TREND 9
Innovative bioprocessing technologies and products are still needed; suppliers are increasing their R&D and focus on improved productivity. End-users’ budgets are up 5.2% this year for acquiring better downstream technologies, and up 4.1% 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%—the greatest of all 15 areas measured. Many deficiencies in bioprocessing, particularly, involving downstream technologies and 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%), and “Disposable/single-use bioreactor bags/consumables” and “Disposable/single-use bags/films” both tied at 26.6%. However, problems with vendors continue, with 52.7% of vendor respondents citing demands for “Better customer service (ordering, delivery, support, etc.).

TREND 10
Fill-finish operations going high-tech, and single-use. The most critical fill-finish trend in 2015 was the introduction of innovative, single-use devices, where 75% of this segment believes industry change will have the greatest impact (and 36% of the segment has developed plans to adopt SUS technologies in 2015). In addition, innovative RABs and isolators were indicated by 33% of this segment as hot trends and opportunity.

TREND 11
International growth in biomanufacturing continues; China and India are maturing biomanufacturing locations, with 15% 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% 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% 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%, while 22% cited China and 12% cited India. Among U.S. respondents, Germany was the leading expected outsourcing destination over the next 5 years, cited by 50.0%, followed by Singapore at 38.6%. China was indicated by 25% of U,S. respondents as a likely ‘outsourcing’ destination, up from just 2.8% in 2009. India, as a destination for outsourcing, has held steady at around 11% among U.S. respondents. Among European respondents, the U.S. and China were similarly tied with 36.4% citing this as their expected outsourcing destination.

TREND 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 vs small molecules is increasing, while the size of targeted marketsis generally decreasing. More products and smaller markets means more bioprocessing facilities and process lines, but these increasingly at smaller scale.

TREND 13
Continuous bioprocessing is 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), vs Batch operations. In our annual study, process operational complexity was a primary concern to 77% of biomanufacturers. And of the 19 comparative areas evaluated, the Top 3, where respondents reported perfusion/CBP as presenting more concerns (vs. 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% of respondents cite more “Process operational complexity” with perfusion vs. 3.6% with fed-batch processing; 76% cite more “Process development control challenges” vs. 3.6% for fed-batch; both values for perfusion are at record highs. Despite this, 51% of respondents noted they would likely specify perfusion for a new clinical process, with 37% using single-use equipment.

TREND 14
New and better assays are needed to improve industry performance. Thirty-two percent of the industry is demanding better analytical assays while 66% believe that such analytical testing improvements will improve their biomanufacturing performance.

TREND 15
Bioprocessing is getting better with failure rates reduced by nearly 50% 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.

Other Trends to Follow in Coming Years
Industry continues to concentrate on use of just a few current leading expression systems, such as CHO and E. coli; microbial manufacturing on the rise. This year, 85.9% of survey respondents noted their facility currently has mammalian production operations, nearly all using CHO. Microbial manufacturing, compared to mammalian, is increasing. Related technologies are advancing and more microbial-expressed products are being developed. Vendors are introducing single-use microbial bioreactors, which may grow to become a dominant manufacturing platform.

Outsourcing of biomanufacturing and operations becoming more strategic. Use of CMOs is increasing, becoming more strategic, but growth in outsourcing has been slowing. Outsourcing is becoming more targeted, better planned and executed by clients, but is approaching saturation. This year a record low of only 35.3% reported no outsourcing of bioprocessing in the past year; and record highs of 76.5% of respondents projected that at least mammalian and 86.5% of some microbial bioprocessing will be outsourced in the next 5 years.

Biopharma supplier mergers: As many innovators merge to create larger organizations, fewer nimble innovators remain. As many as 50 recent mergers of equipment and services suppliers may be taking its toll on innovation; integration of technical companies can result in less, not more innovative opportunities. Mergers, acquisitions and partnering are becoming more strategic, rational and directed to improving R&D pipelines and profitability, but financing remains tight.

Stainless steel, fixed bioprocessing, a staple for 50 years, is at the bottom of the list of demands for better, more innovative products. Only 6.4% of the bioprocessing industry is demanding better innovation in their stainless steel, fixed equipment. When an industry stops demanding innovation in an area, the likelihood that it may be relegated to ‘commodity’ status grows. 

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For more information contact BioPlan Associates at 301-921-5979, or visit: www.bioplanassociates.com.