Evaluating Technology and Innovation in Biopharmaceutical Manufacturing

Roger van den Heuvel, Timo Simmen, Stefan Merkle, Ranjit Thakur, Camal Handor, Ramanathan Venkataraman
Pharmaceutical Technology, Pharmaceutical Technology-08-02-2016, Volume 40, Issue 8
Pages: 22–27

A technology management process identifies and evaluates new technologies in biopharmaceutical manufacturing to aid business decisions.

 

  Biological science is reaching new heights with every passing year. The scientific community keeps unlocking more facets of human life, and pharma/medicinal researchers keep finding new pathways to cure diseases or improve human health. However, these innovations are sooner or later confronted with the realities of commercial manufacturing. Manufacturing equipment, material technologies, and processes in the supply chain need to constantly evolve in order to keep up with the demands of patients and healthcare providers. Besides this ethical aspect, accelerating new product introduction by anticipating the required technology portfolio has a significant financial upside.

Janssen Supply Chain (JSC), the pharmaceutical manufacturing organization of Janssen, has defined a technology management process to improve supply chain capabilities. This technology management process is divided into four phases: observe, align, decide, and act.

The observe section is about gathering information and data--internally and externally. External data can come from peers, other industries, universities, suppliers, contract manufacturing organizations, media, or industry forums. These data are aligned with internal technology objectives and the company’s product pipeline. This “market intelligence” provides the input for strategy decisions on testing, piloting, and introduction of emerging technologies.

Companies have a fair idea of internally available technologies, replacement time, and product requirements. Key challenges faced by firms, however, are to identify technologies that are new but possess the potential to provide a competitive advantage and to match them up with the new product pipeline. It is key, therefore, to have a strong process in place to identify and evaluate these new technologies.

This article highlights some of the outcomes of a market study conducted by JSC to assess the technology landscape in biopharma manufacturing. The outcome of the study guides development of the technology strategy which, along with the product strategy, influences the supply network.

Observation process

The exercise was conducted by JSC, with the support of KPMG and their proprietary tools, to provide an outside-in perspective of technology trends in biopharmaceutical manufacturing, while capturing the state of readiness of underlying technologies and stage of adoption across the industry.

A structured approach was followed to gather market trends as well as identifying key technologies that leading biopharma companies are adopting, developing, or evaluating. The approach shown in Figure 1 consisted of five steps: identify technology trends, identify supporting technologies, shortlist technologies, evaluate shortlisted technologies, and synthesize the outcomes into an “outside-in” strategy document.The assignment included the end-to-end biopharma manufacturing spectrum from API to finished and packaged product. Two angles of change were considered--firstly, disruptive changes impacting the industry through emerging technologies that may become available and secondly, step changes provided by incremental improvements in existing processes and technologies.

A panel of 12 external industry experts based out of the Americas, Europe, and Asia provided input during this process, covering all major manufacturing phases. Literature research examined data from multiple patent authorities and close to 350,000 research sites, publications, news sources, and blogs. Input was further augmented by a primary survey of approximately 50 participants, internal and external to JSC, with experience in various facets of the biopharmaceutical manufacturing.

More than 100 technologies were identified and mapped to trends from which 30 technologies were shortlisted based on their relevance to JSC. Each of the shortlisted technologies was further scored based on specific criteria mapped to business value and then ranked.

 

Trends observed in biopharma manufacturing

Recognizing and understanding trends are key steps that help to identify important emerging technologies. By following the approach defined in the previous section, relevant drivers of change and their potential impact on the manufacturing process were evaluated. These drivers and their impact are presented in

Figure 2

This potential impact was then monitored to observe whether technological changes are addressing these developments. Additionally, the panel of experts provided insights into developments being followed at other companies and affecting other industries. All areas driving large change at a unit operation or process level were mapped as trends.

Approximately 30 technological trends impacting various manufacturing steps were captured from a combination of expert interviews, surveys, and KPMG proprietary analytics. These trends were clustered systematically into seven key themes (see Figure 3) which are considered as providing the biggest impact for JSC.

The seven themes are:

  • Process innovation: relates to area-specific innovations improving the current process

  • Single use/modularity: addresses single-use equipment, including modular systems and skids

  • Continuous: integrating process steps, continuous manufacturing, and reducing process time

  • Automation/robotics: using robots or automation to improve quality, reliability, and safety

  • Data analytics: relates to (big) data management, analytical tools, and process analytical technology

  • Disruptive: connected with technologies that might provide breakthrough solutions to disrupt the current manufacturing process

  • Customer-facing: supporting technology to meet customer needs.

Clustering the identified trends into themes facilitates an end-to-end view of technologies. This method also helps the organization across sites and process areas to be aligned and take decisions from a theme perspective, ensuring consistency throughout the manufacturing process to realize business objectives set at a strategic level (e.g., speed, reliability). 

Shortlisted technologies were evaluated on eight criteria linked to specific business objectives, as shown in Figure 4. Scoring each of the technologies on these criteria helps identify technologies that strengthen different business objectives.

Technologies by area

The following section describes, per process step, highlights of technologies.

API upstream. API upstream covers pre-culture of cells and multiplication of cells in production bioreactors. It appears that the industry is increasingly embarking on continuous processes. Most of the technologies observed during the analysis are either improvements in the perfusion process or disruptive technologies that can impact future manufacturing if applied successfully.

Disposable products for bioreactors, mixers, tubing, etc. are becoming increasingly common in the biopharma industry. Use of process analytical technology (PAT) and real-time monitoring is increasing significantly. However, these technologies are still ages away from application compared to small-molecule manufacture, where PAT is used more extensively.

As an alternative to mammalian cells in making biopharmaceuticals, various other process methods are being researched with varying degrees of success. Cell-free protein synthesis could become one of the disruptive technologies; this entails the production of protein without use of living cells.

The study indicated that the majority of work in the field of upstream manufacturing is focused on process intensification to consistently achieve high titers.

API downstream. API downstream processing follows growing of cells and focuses on separating and purifying the desired protein from the rest of the growth system. During this process, cells are harvested and then undergo filtration, separation (e.g., through chromatography), purification, and viral inactivation.

High-capacity ion-exchange resins are known to have very high binding capacity for purification of bio-therapeutic molecules, thereby minimizing the need for very large columns and massive buffer consumption, while simultaneously increasing throughput.

Continuous in-line dilution entails much smaller buffer storage capabilities (up to 10-20 times reduction in size) and more precise on-demand dilution, bringing two liquid streams together in a controlled environment to meet a specified diluted solution concentration. The technique is a key advancement in end-to-end downstream processing techniques.

Single-use systems are now gaining popularity as a means to reduce cost as well as increase flexibility. Improvements in downstream systems include the use of disposable prepacked columns that save time and overcome handling issues associated with small-scale column packing.

Other methods like continuous chromatography and flocculation are also being considered and are currently in the process of commercialization.

Formulation and filling. The formulation and filling phase entails product formulation; sterile filtration; filling the product into vials, syringes, or premixed bags; sealing within final containers; and optical inspection. Flexibility offered by modular units in the formulation phase can influence investment strategy in manufacturing going forward.

There is a growing trend toward the use of disposables across biologics manufacturing, which is also seen in filling systems, where alternatives to stainless steel are coming up. Single-use systems providing higher throughput and reliability are available for biologics manufacturing, which has been aided by the availability of improved disposable elements. Aseptic fillers and single-use dosing systems are some of the new technologies available.

Vision-guided, flexible robotic filling systems are another crucial innovation related to filling. The robots can effectively “see” the drug product containers being filled using their sensors. The end-of-arm tooling can fill as well as attach stoppers to the containers without requiring them to be precisely positioned. These systems can be used for a wide range of container types, irrespective of their shapes and sizes.

PAT for lyophilization is a technology that enables faster decision making, driven by integrating data collection and analysis from multiple points. Supplier firms along with university research teams have recently initiated collaborative efforts aiming to help pharmaceutical companies gain greater efficiency and control in their lyophilization processes through the use of PAT tools.

Packaging, devices, and layout. In the packaging area, customer demands and governmental regulations are driving development and adoption of new technologies. White label packaging solutions are being considered by companies due to the increase in cross-border manufacturing and supply chain complexity.

Regulators are driving increased serialization as one of the measures for anticounterfeiting. Experts could not pinpoint a specific technology that can be universally used for serialization. Each technology comes with its own pros and cons and is selected depending on a company’s strategy. Examples of other anticounterfeiting measures indicated by experts include holograms, self-destructing labels, void labels, watermarks, and security graphics.

Glass is the most commonly used primary packaging material for biologics, and there have been technology developments to increase shelf life and reduce delamination risk. No real transition from glass to plastic is being observed due to material characteristics, which impact stability. When these material issues are solved, blow-fill-seal and other plastic packaging technologies can play a more prominent role in packaging.

In facilities and their design, modularity and flexibility are key drivers. There is a trend toward prefabricated manufacturing plants with flexible modules, which brings together a number of technologies. Lonza announced in 2015 that it is building a multi-purpose space with eight independent modular cleanrooms with 2000-L scale single-use bioreactors in Houston. A prefabricated plant was set up by GE Healthcare for JHL Biotech in China and became operational in 2016. A prefabricated process can trim significant project costs related to setting up a plant. However, making such a facility operational requires a skilled workforce and a high degree of planning and coordination.

Key takeaways

Future manufacturing needs will most likely be impacted by scale rebalancing and flexibility

. The need to respond to more customized patient requirements and narrower drug indications require manufacturing facilities to be more flexible and agile. Future sites are also expected to handle a larger variety of drugs than currently managed, which creates demand for faster (automated) changeover along with efficient and flexible use of facilities. On the other hand, reducing the overall cost of production is a key criteria driven by a combination of developments in modular manufacturing, for more effective use of assets, and continuous manufacturing, enabled by advances in data analytics. This approach can reduce the manufacturing footprint while increasing the overall site throughput.

Specific pockets of technology require in-house development and customization. Certain product-specific technologies, such as growth mediums, require a high degree of custom development and need investment for commercial-scale production to maximize the process effectiveness. These technologies represent only a small percentage of overall innovation, but they can provide a high degree of exclusivity and competitive advantage, which could bring down specific cost elements by as much as 90%.

Real-time decision making enabled by advanced data processing capabilities. Decision-making cycles typically have been waiting for information derived from sampling, analytical testing, and data processing. Using advanced data analysis capabilities, less time is required to analyze data generated from in-process sensors that provide better resolution and reliability. Artificial intelligence is also enabling drastic reduction of the time required to optimize a system once operations have begun.

Capability development to keep pace with the changing landscape. New technologies need to be fine-tuned and fitted to the production process, requiring companies to invest in developing specific capabilities by either re-skilling talent or acquiring the capabilities in the marketplace. The process of capability development takes time and is a key factor in the successful application of new technologies being considered by the management team (e.g., data management and analysis).

Manufacturing has traditionally played a rather reactive role in innovation in pharma. Now it finds itself best positioned to understand complex technologies and potential disruptions at a commercial scale and, therefore, can pay a pivotal role within innovation and strategy development. This creates the need to revisit the innovation approach, updating existing processes including innovation governance and identifying specific capabilities.

Suppliers are key partners driving technological innovation. Analysis of the available technologies, new emerging technologies in the offering, patent holders, and the trend of technology adoption by market players indicate that suppliers are one of the key influencers driving change in technology use. Large biopharma provides large (scale) challenges, access, integration, and funding. On the other hand, a substantial part of technological innovation and change comes from suppliers of all sizes, which makes suppliers a key partner in the innovation journey requiring a strategic supplier selection lens. Industry consortium collaborations-with the goal of defining common technology strategies and jointly working towards them-have proven successful in other industries but are still in the infancy state in the biopharma environment.

Sustainable review of technologies helps reconsider parked/rejected technologies that may have evolved. The pace of exchange of information has drastically reduced the cycle time for change, accelerating innovation. Technologies that may have failed to pass the company’s strategic decision-making process three to five years ago may have drastically evolved. Hence, there is a need for comprehensive and sustainable innovation management processes within a company, complemented by a frequent refresh to the available and emerging technologies, their readiness, and the evolution of various participants linked to a technology.

About the Authors

Ranjit Thakur is senior principal engineer, Timo Simmen is director, and Stefan Merkle is senior director, all in the Technical Operations-Parenteral Network at Janssen Supply Chain, the pharmaceutical manufacturing organization of Janssen, Hochstrasse 201, Schaffhausen, Switzerland. Ramanathan Venkataraman is manager, Camal Handor is partner, and Roger van den Heuvel is partner, head of Life Sciences, all at the Global Strategy Group, KPMG Advisory N.V., Laan van Langerhuize 1, 1186 DS Amstelveen, Netherlands.

Article Details

Pharmaceutical Technology


Vol. 40, No. 8
Pages: 22–27

Citation

When referring to this article, please cite it as R. Thakur, et al., "Evaluating Technology and Innovation in Biopharmaceutical Manufacturing,"

Pharmaceutical Technology

40 (8) 2016.