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2017年全球生物制药行业五大发展趋势

生物药之家2020-08-19 11:27:04

转自“国际药政通”(SYPHU-IFDPL)

孙莉

沈阳药科大学国际食品药品政策与法律研究中心

 

前言

生物制药行业总是复杂多变的,但整体基本保持14%—15%的行业增长率。根据美国BioPlan咨询公司2017年生物制药行业年度报告相关数据表明,有几个主要趋势正对这一增长率产生着影响。这些主要趋势包括:

  • 生产效率的需求增大;

  • 包括中国在内的国际生物制造中心的发展;

  • 生物类似物的扩张;

  • 细胞和基因疗法的批准。


这些总趋势也正影响着行业更具体的方面。例如,目前和未来生产能力和效率的提高已受到雇佣困难的冲击(请点击《中国生物医药产业正面临人才短缺的困境》一文,查看详情)。事实上,今年超过50%的生物制造设施正遭遇因雇佣困难所面临的产能问题。随着产业的扩大,雇佣问题将继续增大。人力资源问题或许最后会导致质量问题,同时也会增加对诸如自动化设备等需要人员较少技术的需求。如果问题继续延伸,外包组织如CMOs也会面临同样的挑战。


生物制药行业正迫切需求生物技术的改进以及新的生物技术,旨在降低成本,提高效率,改善弱势研发管线,特别是对于发展中国家而言。一些持续的生物制药趋势支撑着未来发展愿景,包括:


  • 更多针对细分市场的生物制品;

  • 更多生物类似物及生物通用名药品(biogenerics);

  • 更多产品且弹性更强的制造设施;

  • 更多地一次性生产系统的使用;

  • 更高效的生物工艺技术——滴度和产量(titers and yields);

  • 更多地使用连续生产技术,包括下游生产加工;

  • 更多地应用自动化、监控和过程控制。


2017年BioPlan咨询公司对“影响生物制药行业的趋势”进行了调查研究。该项研究涉及227个生物技术专业人员(其中包括50名中国和100名印度生物技术专业人士)、131个生物制药设备、服务供应商的反馈以及来自中国和印度150多名生物技术专业人员提供的资料。


趋势一:对更高生产效率和更大生产力的需求

生物制药行业的许多趋势都是由提高效率、改善质量和制造成本降低的需求所驱动。若公司对技术和创新持续进行投资,从而可实现四两拨千斤之效。为了保持持久的竞争力,最好的做法是:


  • 提高生产效率、降低生产成本

  • 缩短新产品上市时间

  • 引进新技术并简化技术测试


在该项调查研究中,生产力/生产效率被认为是生物制药领域最重要的发展趋势,其占比为16.4%。在2014—2017年的不同年度调查研究中,排在前三的发展趋势以及其他领域都是通过提高生产效率和生产力从而实现节约成本。图1表示在2014—2017年度中,认为“生产力/生产效率”是最重要的发展趋势的占比。


图1 2014—2017年生物制药领域最重要的发展趋势


相关研究结果包括:

  • 2017年,形成商业规模的生物制剂的平均滴度水平为2.80 g/L,与2008年相比,显示出稳定的增长趋势;

  • 与20世纪80年代几十克/升的滴度水平相比,目前滴度水平已有显著提高,并呈逐年增长态势;

  • 目前,临床规模生物制剂的平均滴定度为3.29 g/L,这些数据都显示出滴度水平在稳步持续提升。


趋势二:下游工程技术仍是制约生物技术发展的主要瓶颈

下游纯化,包括色谱分离仍被认为是最需要改进的技术领域。根据最近BioPlan公司的其他研究表明,提高下游产量可以增强公司抵御外界威胁及变化的能力。此次调查中,74.3%的受访者称,由于下游技术问题,他们正在经历一些产能瓶颈(some capacity bottleneck )。总之,这些受访者认为,他们正在经历比2011—2015年更大的瓶颈。10%的受访者认为,他们正在经历“严重的(serious)”下游瓶颈问题。CMOs认为下游瓶颈问题更严重,60%的CMOs受访者认为下游技术对产能限制的程度为“serious”或“some”。欧洲和美国的受访者认为下游技术对产能限制的影响也有所上升,为11.5% VS 5.7%。下图2为受访者认为下游瓶颈问题的严重程度分布。


图2 下游技术对总产能的影响程度


色谱分离技术仍被认为是下游生物技术最亟待改进的领域。48.3%的受访者认为使用“色谱柱”给他们造成“重度限制”或更糟糕。


趋势三:生物类似物使生物制品市场竞争更激烈

当今,生物类似物正在加速发展,并且美国生物类似物市场占据主导地位。根据Biosimilars/Biobetters Pipeline Database 显示,有850种生物类似物处于在研发或销售状态,其中125种处于临床试验中;超过515 种biobetters处于开发阶段或销售状态,其中超过200种处于临床试验中。按这样的发展趋势,大约在5年之内,生物类似物市场将超过原研产品或其他创新产品,包括美国市场在内。这种增长将改变生物制药行业的潜在属性(underlying nature),生物类似物将逐渐占领绝大部分市场份额。由于生物类似物的发展,CMOs的业务也将随之增加,收入约有15%的增幅。


生物类似物的发展,促使很多公司进军生物制药行业,包括大型制药企业、创业公司、虚拟公司、仿制药公司以及一些正致力于开发生物类似物组合的公司。美国仍然是生物类似物研发的主要国家,也是生物类似物最大的市场。其他几大生物类似物研发和上市的国家及地区主要是欧洲、印度和中国。新生物工艺技术设施和生产线中的很大一部分最近已经上线或正在建设中,将完全或大部分用于生物类似物的生产加工。


趋势四:一次性使用系统的需求仍在增长

大约90%的受访者表示,他们目前正在使用一次性生物工艺设备,其中使用最多的是“管道系统或单次使用系统(disposable operations)”。相比之下,下游一次性使用系统中使用率最高的是“一次性色谱装置”,为55.6%,膜吸附剂为49.6%。近年来,生物制药行业中一次性装置的使用率趋于稳定,针对于小型临床试验机构市场而言,其已接近饱和。据BioPlan公司估计,约85%的商业规模前生物制药设备使用一次性系统,尤其是在生物工程技术上游。相信在未来,随着越来越多生物制造商通过一次性系统将产品推向商业化生产,一次性使用系统的销量将随之进一步增加。


业界自身也希望继续采用一次性使用系统。绝大多数生物制造商(66%)希望自己的设备能够使用一次性系统来完成其至少50%的操作单元。


趋势五:国际生物制药市场在增长;中国和印度的市场逐渐成熟

印度、中国等国家和地区的国内制造能力正在迅速提高,然而,目前大多数产品都是针对国内市场开发的,包括生物通用名药品(biogenerics)(即用于较小规模市场的非符合GMP生产的生物药品)。虽然,这些国家和地区的生物制药研发和制造能力快速增长,但至少现在很少涉及创新产品。中国、印度、韩国和新加坡的生产制造能力增长最快,新型和扩大的在线设施增长最为迅速。相比而言,其他一些国家和地区也在以较缓慢的增速在发展。


BioPlan公司对中国TOP60的生物制药设施设备分析发现,中国约占全球生物重组蛋白/单抗产能的2.4%,大约为1700万升。但是,对生物制药设施设备的投资绝大部分都来源于国内,外商对其投资还处于相对较低的水平。


大多数生物制药开发商都希望自己的产品如biogenerics走向国际主流、高端市场。但是,现今发展中国家的大多数基础设施设备都不具备市场友好(market-friendly)的符合国际GMP生产的能力。除硬件设施外,有待改善的方面还包括企业文化、对数据造假的监管等。


下面是对“在国际竞争中,中国生物制药行业最迫切改进因素”的调查:

  • 生物制药研发管线的创新(58%);

  • 整体“质量”形象(50%);

  • 产能:商业规模(50%);

  • “科学/技术”专长以及“跟踪记录的合规性”(52%)。


印度生物技术专业人士认为,印度生物制药缺乏核心竞争力的主要因素包括:

  • 创新/研发产品线(35%);

  • 产品质量改善(35%);

  • 教育、专业知识、专业技能(16%)。


结语

生物制药行业的大趋势以及创新将加速发现,并将降低成本、提高生产力。伴随着新技术、生物类似物的扩张、细胞和基因疗法的出现以及新兴市场的崛起,生物制药行业的前景非常可观。

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原文阅读

Top Trends in Biopharmaceutical Manufacturing, 2017

Innovation speeds discovery, drives down costs, and improves productivity.

Sep 02, 2017

By Eric Langer, Ronald A. Rader

Pharmaceutical Technology

Volume 41, Issue 9, pg 58–60

Lightspring/shutterstock.comThe biopharmaceutical industry is dynamic and complex, and in addition to the overall consistent 14-15% industry growth, data from BioPlan Associates’ 2017 14th Annual Report and Survey of Biopharmaceutical Manufacturing (1) shows that key trends are affecting this growth. These include the following: 

  • Demand for production efficiency

  • Growth of international biomanufacturing centers, including China

  • Biosimilars expansions

  • Cell- and gene-therapy approvals.


These general trends are also impacting more specific aspects of the industry. For example, current and future capacity and production are already being hit by the inability to hire and train staff—in fact, more than 50% of bioprocessing facilities are experiencing capacity problems this year due to difficulties hiring certain operations staff. Hiring problems will continue to increase as the industry expands. These human resources issues may ultimately also create quality problems, and are already increasing demand for technologies that reduce staffing, such as automation and single-use device applications. Even outsourcing to contract manufacturing organizations (CMOs) may well be challenged if CMOs continue to experience growth and hiring problems. 

The biopharmaceutical industry is continuously demanding new and improved bioprocessing technologies to reduce costs, increase efficiencies, and improve weak development pipelines, especially in developing economies. Some of the ongoing biopharmaceutical trends support a future vision that includes:

  • More biological products, but often each targets smaller markets

  • More biosimilars and biogenerics

  • More multi-product and flexible manufacturing facilities

  • More adoption of single-use systems 

  • More efficient bioprocessing—titers and yields

  • More use of continuous processing, including for downstream processing

  • More automation, monitoring, and process control.


The following is a summary of a few of the top 15 trends affecting biopharmaceutical manufacturing from the BioPlan 2017 study. This year’s survey included responses from 227 bioprocessing professionals, 131 industry equipment and services suppliers; and data from more than 150 bioprocessing professionals in China and India. 

Trend number one: Greater demand for manufacturing efficiency and productivity

Many of the trends in the bioprocessing industry are being driven by perceived needs for improved efficiencies, quality, and cost reductions in manufacturing processes. Companies invest in technology and innovation so they can more with less. To remain competitive, better ways are needed to: 

  • Make bioprocessing more efficient and less expensive

  • Decrease new products’ time-to-market (increase speed)

  • Streamline new technology testing and adoption, make adopting new technologies less painful. 


The largest portion of survey respondents, 16.4%, noted that “Manufacturing Productivity/Efficiency” was the “single most important biomanufacturing trend or operational area on which the industry must focus its efforts, 2014–2017.” Essentially, all of the top three—and most other cited trends or operational areas—are related to cost savings though increased efficiency and productivity (see Figure 1). 

Figure 1: Single most important biomanufacturing trend area, 2014-2017. (Figures are courtesy of the authors).

Related survey findings include: 

  • Average reported titer for commercial-scale biologics (for new monoclonal antibodies [mAbs]) this year was 2.80 g/L, with yearly data back to 2008 showing overall consistent year-to-year incremental increases to the present.

  • Average reported upstream titers have been growing rather steadily over the past three decades from a baseline of at best a few tenths of a gram/L back in the 1980s.

  • Average reported titer for clinical-scale biologics was 3.29 g/L, with these data also showing an overall consistent incremental growth. 


Trend two: Downstream processing remains the major bioprocessing bottleneck


Downstream purification including chromatography continues to be the area cited as requiring the most technological improvements. Yet, other recent BioPlan studies confirm that downstream yield improvements remain much more resistant to change. This year, 74.3% of respondents reported their facility was experiencing at least some capacity bottleneck due to downstream processes. Overall, respondents are experiencing a higher level of bottlenecks than seen in 2011–2015. Approximately 10% reported that their facility is currently experiencing “serious” downstream bottleneck problems. CMOs perceive downstream bottlenecks as more serious, with 60% of CMO respondents reporting either “Serious” or “Some” capacity constraints due to downstream processing. “Serious” capacity constraints were also reported much more frequently by European vs. US respondents, 11.5% vs. 5.7% (see Figure 2). 

Figure 2: Impact of downstream processing on overall capacity.

Chromatography remains the top-cited downstream (or any) bioprocessing problem area. This included 48.3% of respondents citing “Chromatography columns” as causing them “Moderate constraints” or worse; with 80.8% reporting “Minor constraints” or worse. 


Trend three: Biosimilars are bringing more competing biopharmaceutical products (competition) and players


Biosimilar product development continues worldwide, and appears to be accelerating now that the US biosimilars’ market is coming online. The Biosimilars/Biobetters Pipeline Database (2) reports nearly 850 biosimilars (including biogenerics) in development or marketed worldwide, including approximately 125 in clinical trials; and more than 515 biobetters in development or marketed worldwide, including more than 200 in clinical trials. With such a healthy development pipeline, within approximately five years, biosimilars will outnumber reference and other innovative products, including in the US market. This increase will change the underlying nature of the biopharmaceutical industry, as biosimilar products eventually affect overall sales. CMOs are also reporting increased business, about 15% increase in revenue, attributed to biosimilars development projects.


Biosimilars are resulting in a number of new players entering the biopharmaceutical industry. Established drug companies, including Big Pharma, startup and virtual companies, foreign companies, generic-drug companies, and others are working to develop portfolios of biosimilars. The United States remains a primary location for biosimilar R&D and the largest market for biosimilars. Europe, India, and China are the other major centers for biosimilars development and marketing. A good portion of the new bioprocessing facilities and process lines have recently come online or under construction and will be solely or largely devoted to biosimilars manufacture. 


Trend four: Single-use systems in demand, use still growing


Approximately 90% of respondents currently use single-use bioprocessing equipment, with “Tubing or disposable operations” cited the most. More than 80% reported use of single-use bioreactors. In contrast, the highest rate of reported downstream single-use systems use was “Disposable chromatography devices,” reported by 55.6% and membrane adsorbers at 49.6%. The rates of usage of diverse disposables in biopharmaceutical manufacturing have remained relatively steady in recent years, with the market nearing saturation, for smaller, clinical-scale operations. BioPlan estimates that approximately 85% of pre-commercial biopharmaceutical manufacture is done using single-use systems, particularly upstream. Sales of single-use systems will further increase as more manufacturers advance to commercially manufacture their products using single-use systems. 

And the industry itself expects to see continued adoption. A significant majority (66%) expect their own facility to involve at least 50% of its substantial unit operations to be done using single-use system devices (see Figure 3). 

Figure 3: Single-use/disposable device adoption factors.

Trend five: International growth in biomanufacturing; China and India are maturing


India, China, and other regions are rapidly increasing their domestic manufacturing capabilities; however, most of the current products are developed for home markets, including biogenerics (i.e., non-GMP biopharmaceuticals for lesser-regulated markets). While these are fast-growing geographic areas for biopharmaceutical R&D and manufacturing, little (as yet) involves innovative products. Growth in capacity and  new and expanded facilities coming online are most rapid in China, India, Korea, and Singapore, but some of these countries’ capacities are growing from low baselines. 

BioPlan’s analysis of China’s bioprocessing facilities, Top 60 Biopharmaceutical Facilities in China, (3) found that China holds approximately 2.4% of the total worldwide estimated 17 million L capacity for recombinant protein/mAb bioprocessing capacity. And nearly all growth in China is domestically financed, with foreign investment in Chinese biopharmaceutical manufacturing remaining relatively low.  

Most biogeneric developers aspire to bring their products as biosimilars into major highly-regulated markets. But it will take years for developing country-based facilities (aside from a few outliers) to develop major market-friendly GMP manufacturing capabilities. Besides physical plant and needed staff expertise, improvements are needed in business culture, including aspects that have fostered persistent fraudulent data manipulation. 

This year, the BioPlan survey includes data from interviews with 50 Chinese and more than 100 Indian bioprocessing professionals. Among the attributes noted as most required in Chinese facilities to enable international sales/competition are: 

  • More innovative biopharmaceutical pipeline (58%)

  • Overall ‘quality’ image (50%)

  • Capacity: Commercial scale (50%).

  • In terms of citing the weaknesses, 52% cited “Scientific/technical expertise” and the same percentage noted “Compliance track record/expertise.” 

  • From Indian bioprocessing professionals, the core competencies noted as being lacking in Indian biopharmaceutical manufacturers included: 

  • Innovation/R&D product pipeline (35%)

  • Production quality improvements (35%)

  • Education, expertise, skills (16%).


Summary

Bioprocessing industry trends and innovation speeds discovery and can drive down costs and improve productivity. The current situation in biopharma is exciting, with new technologies, biosimilars, cell and gene therapies, and opportunities in emerging markets.

References

1. BioPlan Associates, 14th Annual Report and Survey of Biopharmaceutical Manufacturing Capacity and Production (BioPlan Associates, April 2017).
2. BioPlan Associates, Biosimilars/Biobetters Pipeline Database 
3. BioPlan Associates, Top 60 Biopharmaceutical Facilities in China, 2nd edition (BioPlan Associates, February 2017). 

Article Details

Pharmaceutical Technology
Volume 41, Number 9
September 2017
Pages: 58–60

Citation

When referring to this article, please cite it as E. Langer and R. Rader, “Top Trends in Biopharmaceutical Manufacturing, 2017," Pharmaceutical Technology 41 (9) 2017.

 



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