GE Healthcare s End-to-End Approach to Building Biomanufacturing Capacity through KUBio

Transcription

1 GE Healthcare s End-to-End Approach to Building Biomanufacturing Capacity through KUBio Allison Mages 1, Olivier Loeillot 2 1 General Electric Company 2 GE Healthcare Presenting author s address: allison.mages@ge.com Session Number: TH3-SE03-04 Keywords: knowledge transfer, biopharmaceutical, capacity Abstract Biopharmaceuticals are in high demand and few countries have the capability to produce them. In light of potential export challenges, many countries may find it desirable to establish local production capabilities. Biomanufacturing requires specialized knowledge that may not exist today in many developing countries. To address this challenge GE Healthcare introduced KUBio, a modular biomanufacturing facility leveraging a single-use bioprocess production train. The facility can be assembled, qualified, and ready-to-run within 14 to 18 months and provides a cost-effective alternative to traditional plants. In addition to the facility construction, GE Healthcare assists in all stages of biomanufacturing, from facility design to production and through continuing education. This allows countries without existing capacity to access expertise in bioprocess development and hands-on training for facility personnel. As a result, developing countries have the opportunity to efficiently develop local capacity in biomanufacturing. 1

2 Benefits of establishing local production of biopharmaceuticals Adequate supply of bio-pharmaceutical products, such as vaccines, insulin, plasma derivatives, and monoclonal antibodies could lead to better healthcare outcomes and significantly reduce related spending throughout the developing world. (Rios 2010) Not surprisingly, global demand for such products is high, while being difficult to import to the developing world. (Radar and Langer 2014) Unfortunately, currently only a few countries in the developing world have the capability to manufacture these potentially life-saving and life-sustaining products. In the past, both the start-up costs and the expertise required to establish and operate the requisite facilities have presented substantial roadblocks to local production. How bio-pharmaceuticals can help improve healthcare in developing countries Ninety percent of child deaths occur in developing countries, with a large percentage of those caused by vaccine-preventable diseases. (WHO et al. 2009) The children who survive these diseases often suffer from debilitating conditions and extended illness. (WHO et al. 2009) However, only one in five children born each year receives even the most basic immunizations. (WHO et al. 2009) The cost of insulin required to treat many of the over 300 million people in low to middle income countries that have diabetes can be as high as 50% of a family s income, in part due to lack of availability. (World Diabetes Foundation 2013) Complications due to diabetes are a major cause of disability, reduced quality of life, and death, burdening the global healthcare and economic system. For many developing countries, there is little to no supply of safe blood plasma products. (WHO 2010) Demand for plasma continues to increase dramatically and many patients who require its life-saving support are without access. (WHO 2009) Cancer is a major cause of death globally with almost half of cancer deaths occur in developing countries. (IEA 2012) Many common cancer types have higher cure rates when treated early using monoclonal antibodies that specifically bind to cancer cells. (Jemal et al. 2011) However, these drugs are in limited supply. GE Healthcare s and its Approach to Establishing Local Capability in Biomanufacturing About GE Healthcare GE Healthcare provides transformational medical technologies and services that are shaping a new age of patient care. GE Healthcare s broad expertise in medical imaging and information technologies, medical diagnostics, patient monitoring systems, drug discovery, biopharmaceutical manufacturing technologies, performance improvement and performance solutions services help our customers to deliver better care to more people around the world at a lower cost. In addition, GE Healthcare partners with healthcare leaders, striving to leverage the global policy change necessary to implement a successful shift to sustainable healthcare systems. GE Healthcare s healthymagination vision for the future invites the world to join us on GE Healthcare s journey as it continuously develops innovations focused on reducing costs, increasing access and improving quality around the world. Headquartered in the United Kingdom, GE Healthcare is a unit of General Electric Company (NYSE: GE). Worldwide, GE Healthcare employees are committed to serving healthcare professionals and their patients in more than 100 countries. About KUBio To respond to local healthcare market needs and in particular the worldwide demand for biopharmaceuticals, GE Healthcare introduced KUBio an off-the-shelf, modular factory for biomanufacturing. The solution, which leverages single-use bioprocessing, can significantly reduce start-up time and capital investment compared to traditional stick-built facilities for biomanufacturing. KUBio s pre-fabricated modules serve as a fully functional 2

3 ready-to-run bioprocessing facility that can be installed anywhere in the world and readily meet existing local and international regulatory requirements. In addition to providing the factory and its equipment, GE Healthcare supports knowledge transfer from early stage development through scale-up and final manufacturing. As a result, GE Healthcare is able to help countries establish local biomanufacturing capability quickly and at a reasonable and predictable cost. Streamlining facility set up by partnering with experts in global engineering construction While biomanufacturing facilities may look like other commercial buildings from the outside, they involve a high degree of specialization. For example, these facilities must accommodate specific ventilation and air purification systems and in some areas employ clean rooms that protect the biomanufacturing process from becoming contaminated. (MassBio 2010) The facilities must also conform to a host of regulatory standards and building codes. Therefore, designing and constructing a biomanufacturing site requires expertise in bioprocessing, the construction practices to accommodate them and knowledge of local regulatory frameworks. In countries that lack existing biomanufacturing capacity, construction firms with such expertise are unlikely to exist locally. (Levine et al. 2012) To help countries bridge this knowledge gap, GE Healthcare partners with the M+W Group, a leading global engineering, construction and project management company. Headquartered in Stuttgart, Germany, the M+W Group has offices throughout the developed and developing world, enabling them to provide global and local knowledge and support. The alliance combines GE Healthcare s expertise in technologies for biopharmaceutical manufacture with M+W Group s global capabilities in bio-engineering and construction. M+W Group constructs the KUBio modules and also provides knowledgeable support for on-site construction needs. This partnership allows GE Healthcare to offer KUBio as an integrated offering, from construction of the plant through training of the operational staff, making it easier for countries to establish their own facilities even when there is an initially limited knowledge base. Reducing time to establish capacity using a pre-engineered solution Unlike traditional biomanufacturing facilities, KUBio is essentially a turnkey solution. KUBio can be set up faster than other solutions since the conceptual engineering design and part of the basic engineering design activities have already been completed prior to initiating the project. While KUBio building consists of modules, the equipment is installed and tested by a team familiar with the unique requirements and demands of biopharmaceutical construction and validation. Each module is subsequently transported as a complete single piece to the final location and assembled on-site. The resulting facility design follows current Good Manufacturing Practices (cgmp) and complies with other relevant local, international and earthquake safety standards. KUBio s production areas are further designed to meet Biosafety Level 1 (BSL1) requirements. Figure 1: Biomanufacturing project phases Since the KUBio is a pre- engineered solution the Conceptual Design and part of the Basic Design phases have already been considered, reducing time to start up. While the modules are being constructed and transported, other site activities such as permitting, environmental activities and construction of the facilities foundation can be done in parallel. As a result, KUBio can be built, assembled, and qualified in months (see Figure 2). By contrast, stick built facilities take between two to four 3

4 years to set up, validate, and test. (Levine et al. 2013) In addition to time savings, KUBio s pre-engineered design leads to fixed and more modest investment costs with reduced operational and financial risks. (Levine et al. 2012) Figure 2: KUBio's rapid setup KUBio s high degree of flexibility in a small footprint makes it ideal for developing countries Traditionally, biopharmaceutical manufacturing facilities were designed to produce just a few products, with fixed equipment including heavy duty stainless steel machinery, large clean rooms and hard-piping. (Levine et al. 2012) However, today s biomanufacturing facilities need to be more flexible. The ability to manufacture a wider variety of products is particularly important for developing countries where few production facilities exist to fulfill local needs. Considering the high demand for many biopharmaceuticals, local production of several products in a single facility may be advantageous to ensure adequate availability of potentially life-saving and life-sustaining medicines. KUBio makes extensive application of single-use process equipment making it highly configurable and thus well suited for use in developing countries that may need to produce multiple biopharmaceuticals in one location. Unlike more traditional equipment, single-use process technologies are replaced after use rather than sanitized. With fixed equipment, cleaning is a significant source of facility downtime and requires substantial power and water supplies (GE Healthcare 2013) In many countries, a constant access to supplies of power or pure water can be challenging. By implementing single-use technology, demands on these precious resources are decreased while reducing operating costs. (Rawlings and Pora 2009) A recent study found that operating costs for single use facilities are at least 10% lower than their stainless counterparts. (Levine et al. 2012) Time between production runs is also shortened, making it possible to increase the output of the facility over traditional approaches. Another advantage of KUBio is its compact footprint of approximately 1200m 2 with a total area of 2200m 2 split on two levels. Since the KUBio takes up limited physical space, it can be easier to find suitable locations for its deployment. Space requirements for facilities Figure 3: KUBio s modular construction 4

5 employing single-use technology are less than their stainless steel counterparts. For example, stainless steel equipment must be washed, requiring utilities such as water for injection (WFI) and clean in place systems to ensure proper sanitation. (Hodge 2009) By contrast, KUBio s reliance on single-use equipment makes such systems unnecessary. Using its expertise in bioprocessing, GE Healthcare also optimized KUBio s layout, minimizing distances between unit operation steps and between utilities source and end user points. Deploying KUBio at JHL Biotech In September 2013, JHL Biotech, a multinational biopharmaceutical company with operations in China, selected GE to provide KUBio as their manufacturing capacity. In addition to managing the construction, GE Healthcare is validating the equipment through its Shanghai Education and Consulting team and providing training to JHL Biotech s staff. After completion, the JHL Biotech KUBio facility will contain 4 x 2,000L single-use bioreactors. According to Racho Jordanov, Co-founder, President and CEO of JHL Biotech, In realizing our vision of making it the largest single-use facility in the world, KUBio was the natural choice. Utilizing manufacturing innovations was always a key part of our strategy and GE Healthcare s KUBio delivers the technologies we want, with the technical support and training we need. (GE 2013) The staff for JHL s plant is being trained at the company s pilot plant in Taiwan so they are ready as soon as the China plant opens. Training is being supported by GE Healthcare s Education and Consulting team based in Shanghai. The KUBio will be located at the Biolake Science Park in Wuhan, China and will be fully operational in Knowledge transfer at all stages of implementation Biomanufacturing is a complex field, requiring specialized expertise in a variety of disciplines. (WHO 2011) In all but a few countries in the developing world, such knowledge is extremely limited or non-existent. What makes KUBio different from other biomanufacturing offerings is the emphasis on building capacity in biomanufacturing through partnership. GE Healthcare uses a well-defined knowledge transfer framework to assist customers at all stages of biomanufacturing, from facility design to production and through continuing education. A coordinated approach to drive lasting knowledge transfer With each KUBio facility, GE Healthcare forms a project team with experts in their fields of operation and technology specialty. At the start of each project, a Transfer Program is established including identification of specific activities and deliverables. GE Healthcare also appoints an experienced project leader who serves as the main point of contact for the new facility owner, working closely to execute both the facility set up itself as well as the knowledge transfer process. This coordinated approach yields benefits beyond the knowledge transfer itself. It provides an opportunity for GE Healthcare to leverage its relationships with suppliers reducing costs. In addition to project coordination functions, the project leader provides mentoring to the owner and can help identify specific training needs. The knowledge transfer process takes place in a staggered manner. At the beginning phases, GE Healthcare coordinates the necessary arrangements for the initial project design and construction. In the second phase, the new facility owner is actively involved as the program plan includes knowledge transfer training, requirements and resource planning, hands-on training and support during pilot and engineering runs. Access to biomanufacturing consulting services Developing biomanufacturing capacity can be extremely difficult without the right technology knowledge base. However, gaining that expertise can be facilitated by partnering with experts who specialize in bioprocess 5

6 development. Through GE Healthcare s Development and Manufacturing Services, early collaboration with such experts to build in-depth practical skills and the broader experience and insight essential for developing a strong and sustainable biomanufacturing strategy for the facility can be arranged. Based in Marlborough, MA, USA the group has over 10 years experience in scaling up single-use biopharmaceutical processes to manufacturing scale. Projects are executed in a specialized facility that houses pilot scale plants and other facilities featuring similar equipment to what will be deployed within the new facility. This allows processes to be designed and tested, along with the requisite transfer of knowledge prior establishing the factory itself. GE Healthcare provides additional services to troubleshoot and optimize existing bioprocesses and provide guidance for securing regulatory approvals. Serving as a matchmaker for IP licensing Access to intellectual property (IP) related to specific technologies and bioprocesses may be required to produce a desired medicine or vaccine. Using our experience in bioprocess, GE Healthcare can help identify the technology partners who own the desired solution. Leveraging our relationship with these technology partners, GE Healthcare is able to facilitate discussions to help secure any requisite IP. Developing specialized capabilities of the local workforce In addition to designing the desired bioprocesses, establishing a new facility requires skilled personnel. Many countries will find themselves building a work force from the ground up as they develop biomanufacturing capacity. GE Healthcare helps its customers identify staffing requirements as part of the process. Once engaged, hands-on training is critical to efficiently building up the local knowledge base. To facilitate the necessary knowledge transfer, GE Healthcare provides access to a global team of scientists with knowledge in upstream and downstream bioprocessing, analytical technique and biopharmaceutical industry working experience through its Education and Consulting organization. Aimed at process developers, manufacturing scientists, staff scientists, engineers, plant operators and support staff, our courses brings expertise in a wide variety of technologies and techniques used in biopharmaceutical manufacturing for example process development, column packing, system control and membrane filtration to help attendees maximize their capabilities and bring product to market faster. The scheme is unique in the life sciences sector in that it offers training that covers the whole of the downstream bioprocessing workflow. GE Healthcare currently has Education and Consulting Centres in China, Germany, India, Japan, Singapore, Sweden and the United States, each equipped with some of the latest technologies for bioprocessing, in an environment that closely replicates the industrial setting. The goal of these centers, especially those located in regions currently working to build or enhance biopharmaceutical expertise, is to fill in some of the gaps in resources and expertise. Worldwide, over 1,000 people attend GE courses each year with sixty courses available annually. 6

7 Introduction to Downstream Techniques and Bioprocessing Description: This four day basic practical course covers downstream processing techniques suitable for productionscale protein purification and illustrates how these techniques should be considered for process development. The focus of this course is on the understanding of the techniques and the parameters governing separation. Detailed presentations of the downstream processing techniques used (cross flow filtration & chromatography) are included as well as lectures covering optimization (e.g. DoE) and purification strategies. Scale-up issues, column maintenance and process hygiene are briefly presented to describe the industrial environment and its principal objectives. Additionally, an overview of analytical techniques used for product identification is presented. Who should attend? This course is designed for those who are new to the purification industry, as well as R&D scientists and process engineers who need to update their basic knowledge of downstream processing techniques used in industrial protein purification. After the course you will be able to: Screen and optimize bioprocesses in your process development work Apply effective chromatographic techniques in your downstream purification process Understand the issues associated with optimizing chromatographic unit operations in biopharmaceutical production processes Figure 4: Example training course in downstream bioprocessing Charting New Territory The introduction of flexible biomanufacturing capabilities in the developing world has the potential to improve local quality of life and economic prospects. (Bloom et al. 2004) For most countries, building capacity will be unchartered territory leading to unique challenges in technology deployment. Several of these challenges are discussed below. Navigating Regulatory Frameworks Throughout the developed world, biopharmaceutical products are highly regulated. For example, the European Union provides an established framework for the approval of biosimilars. However, unlike generic drugs, biosimilars are relatively new entrants to the market and are similar but not identical to the biologic drugs they seek to replace. (Mellstedt et al. 2008) This makes establishing regulations challenging, as this is a new and rapidly changing field. As a point of illustration, countries have not even agreed on what to call these drugs, having coined a variety of terms to describe these medicines, such as biosimilar products and follow-on protein products. (WHO 2009) While the World Health Organization (WHO) has established guidelines that serve as a template for the regulation of these products, many countries are either in the process of setting up their own regulatory framework, or have yet to initiate the process. (Bogaert et al. 2011) Regulations for biomanufacturing and the resulting medicines can be expected to evolve for some time. The stakes are high, as the end products go into the human body and have a direct effect on a person s health. This dynamic lends itself to a conservative approach to regulation, especially in circumstances where local knowledge may be limited. KUBio was designed to comply with regulatory frameworks for biomanufacturing in both the European Union and the United States. In addition, our Education and Consulting team continually monitors the regulatory landscape. This approach makes it more likely that KUBio complies with applicable regulations and can be qualified quickly. Where possible, policymakers should try to align their own regulatory schemes with existing ones, such as those currently available in the European Union and the United States, or through the WHO. Dramatic deviations from these systems will slow down capacity building, as manufacturing facilities and the processes they support will need to be re-qualified under the new approach. Governments should consider whether it is possible to recognize the qualifications made in other jurisdictions in order to speed up the availability of biomanufacturing. Policymakers 7

8 should also study whether it would be possible to develop international standards for biomanufacturing, designed to accelerate the availability of biomanufacturing capacity. In developing such a standard, care should be taken not to mandate any specific technology, as not to stifle the ability to innovate in this critical area. Identifying the right local partner to establish capacity Governments are increasingly exploring opportunities to establish biomanufacturing capabilities. They are well positioned to evaluate a country s healthcare needs, identify appropriate life-saving and life-sustaining products to produce, and prioritize national budgets to satisfy local needs. However, governments may require additional expertise to successfully build and operate the necessary manufacturing facilities to realize local production. As countries work on developing biomanufacturing capabilities, they need to consider how they will bridge these gaps. Partnering with the private sector, either with global firms having biopharmaceutical expertise or local companies with related expertise may be useful in this regard. With respect to identifying appropriate partners, companies with expertise in food or chemical production may be natural fits as they deal with similar manufacturing processes. Designating a contact with manufacturing expertise during facility commissioning can be helpful in accelerating its set up, even if the factory will ultimately be operated within the public sector. Today biomanufacturing facilities are owned and operated by both public and private sectors. Some factories are jointly owned by parties in both sectors or involve contracted operations. Governments should consider what types of arrangements work best for their particular circumstances and needs. In addition to commissioning the facilities within the public sector, establishing incentives such as tax credits, procurement compacts and similar mechanisms may itself encourage the development of local capacity. Conclusion The potential of biopharmaceutical products to save and sustain lives is enormous. With these products in high demand in all countries, establishing local biomanufacturing facilities may be desirable to fulfil local demands. However, few developing countries currently possess the knowledge to set up the necessary facilities. Given the complexity of biomanufacturing and the sophisticated requirements to build the factories themselves, developing countries could benefit from expert guidance to build appropriate facilities and set up production. Through its KUBio offering, GE Healthcare provides the necessary facilities, equipment, and know-how to begin producing life-saving and life-sustaining medicines in developing countries. Since many countries where KUBio is deployed will be new to biomanufacturing, GE Healthcare s approach is to deliver and build the necessary foundation of knowledge for KUBio to be operated independently. To accomplish this, GE Healthcare injects its own expertise in bioprocessing and combines its efforts with strategic partners to provide an end-to-end solution to build capacity. KUBio employs a modular design and single-use bioprocessing, making it possible to set up quickly and in a small footprint. Using a pre-engineered design reduces financial investment and risk, as the processes and costs to build the facility are well established. The modular layout allows much of the facility to be constructed off-site, other activities can be done on location in parallel, reducing construction time. Compared to traditional facilities with fixed equipment, KUBio s use of disposable technology reduces power demands and access to pure water, which are scarce resources in many developing countries. The single-use equipment also provides a high degree of flexibility, making it easier to reconfigure production operations to make new products as necessary. GE Healthcare appoints a project leader to coordinate all aspects of KUBio s set up and knowledge transfer. To ensure a complete transfer of knowledge, a well-defined knowledge transfer framework is used to assist in all stages of biomanufacturing, including process design and staff training. Much of the effort can be done during the 8

9 facility s construction, by leveraging GE Healthcare s resources. For example, the new owner can get help designing the bioprocessing using GE Healthcare s Development and Manufacturing Services. Staff can also be trained at GE Healthcare s facilities where attendees get hands-on experience using the same equipment which they will operate. The GE services team can help countries new to biopharmaceutical development get up to speed quickly. Yet, countries wanting to establish local biomanufacturing capacity will meet challenges along the way. For example, they will need to set up regulatory frameworks and identify the right local experts to operate the new facilities. GE Healthcare s approach to partner with countries looking to build capacity provides a solid path to overcoming many of these difficulties. 9

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