Single-use Technology Integral to Advancing Biomanufacturing

Disposable bioprocessing equipment has been widely adopted in development and clinical manufacturing. Most biopharmaceutical companies have at least begun to explore its use for commercial manufacturing. The potential benefits are significant, particularly when it comes to small-volume manufacturing in modular facilities. Concerns about security of supply and standardization have yet to be addressed, however.

New investments require new technologies
Strong growth in the global biopharmaceutical market—from $162 billion in 2014 to $278 billion by 2020 at a compound annual growth rate (CAGR) of 9.4%—is driving investment in new facilities and expanded capacity/capabilities by both traditional biotechnology companies and conventional pharmaceutical manufacturers.¹ Regeneron, Roche, Boehringer Ingelheim, Amgen, Eli Lilly, Bristol-Myers Squibb, Pfizer, Novartis and Genzyme have recently spent significant dollars on biomanufacturing capabilities.

Contract manufacturers are, not surprisingly, following suit. The global biopharmaceutical contract manufacturing market is estimated to be growing at an overall, healthy, annualized rate of 8.3%² with capacity for mammalian cell culture and microbial fermentation production expected to respectively increase by 14 and 16% by the end of 2016.³ Some of the contract development and manufacturing organizations (CDMOs) actively investing in biopharmaceutical production capabilities include, AbbVie, Catalent Pharma Solutions, Fujifilm Diosynth Biotechnologies, KBI Biopharma, and Patheon Biologics.

Many of the new facilities being constructed today are quite different from those built during the early days of the biopharmaceutical industry. Advances in manufacturing technologies have led to as much as a 10-fold increase in productivity due to significantly higher titers. It is therefore now possible to produce in a 2000-L reactor what previously required a 20,000-L vessel, allowing for significant reduction in the scale for biopharmaceutical manufacturing facilities and associated capital expenditures.

Meeting local demand
A significant portion of the growth in demand for biologics is coming from emerging markets, and in many countries local manufacturing is required by the government. Technologies that can ensure consistent production in multiple locations are increasingly important. At the same time, demand for each individual biotherapeutic remains limited within a country, and thus technologies suitable for smaller production volumes are also needed.

Highly efficient and cost-effective processes and facilities will be crucial for companies looking to be first to market with profitable new biosimilars. Due to the intense competition in this segment, each manufacturer is likely to end up with limited market share for each product, once again leading to the need for small-volume manufacturing capabilities.

The most forward-thinking companies are also implementing continuous processing capabilities for both upstream and downstream operations in their new facilities. Continuous processes can help reduce overall manufacturing footprints and production times, provide more consistent product quality, and even result in lower overall costs.

Many of these new facilities are also designed with multi-product manufacturing and/or fill finish capabilities. Technologies that enable the safe handling of many different products with different physical, chemical, and therapeutic properties without risk of cross contamination between batches are crucial in such production sites.

Going beyond small-scale manufacturing
Implementation of innovative process technologies is clearly a necessity for biopharmaceutical contract manufacturers. In particular, single-use technologies help to reduce the risk of contamination, reduce scheduling times, increase operational efficiencies, and reduce capital expenditures, including both fixed and consumables costs. Disposable systems come pre-sterilized, thus eliminating the need for cleaning and sterilization and significantly reducing setup and switchover times. As a result, they also provide flexibility and enable manufacturers to quickly change their portfolios in response to market needs. To put it in measurable terms, an example from 2015 showed that customers of Sartorius reported capital cost reductions of 40 to 50%, operating cost reductions of 20 to 30%, and acceleration of time-to-build by 30%, when compared with traditional stainless-steel technology, after employing single-use technologies for 10 years.⁴

Disposable technologies are particularly ideal for scaling down biologic manufacturing processes, which as noted above is a key trend in the biopharmaceutical industry. Indeed, single-use technologies are well suited for use in modular facilities designed to enable high-quality production of biologic APIs and formulated products around the world, including in places where traditional facilities cannot be constructed.

In fact, according to a 2015 report by BioPlan Associates, more than 90% of facilities use single-use/disposable technologies, and manufacturers and suppliers consider both disposable and stainless-steel options when planning their manufacturing strategies.5 In addition, more than two-thirds of biomanufacturers and suppliers (69%) reported improvements in biomanufacturing performance at their facilities in the previous 12 months due to the use of disposable devices.

Of the announced plans for new and expanded biologics facilities listed above, the vast majority include the incorporation of some level of single-use technologies for one or more phases of production, from fed-batch and perfusion bioreactors for upstream API production to various separation, purification, and filtration devices for downstream processing to disposable fill/finish systems.

Single-use technologies are seen as supporting flexible cGMP manufacturing and enabling efficient and rapid adjustment of production schedules and volumes and even system reconfigurations combined with ease of process replication and relocation to other global sites or transfer to contract manufacturers. These attributes also facilitate the implementation of key regulatory initiatives such as quality-by-design (QbD), the use of process analytical technology, and continuous processing. The ability to use a similar equipment configuration and the same materials for production equipment at the process development and commercial-scale manufacturing phases also simplifies process scale-up and can accelerate time to market.

Interestingly, CMOs were more likely than branded drug manufacturers to adopt single-use technologies—86% vs. 66%, respectively. This phenomenon was attributed to the ease of use and the efficiency of these systems and devices when dealing with multiple products and bioprocesses that require fast turn-around times.⁵ Single-use systems provide CDMOs with more flexible production capacity in terms of rapid switching between product campaigns and the ability to manufacture over a wider range of production scales. Implementing single-use systems and integrating them into manufacturing operations is, in fact, the single most important biomanufacturing trend or operational area that the industry must focus on, according to CMO representatives surveyed by BioPlan Associates.⁶

Hybrid approach and risk mitigation
It is important to note, though, that there are limitations to single-use technology, and it is not always the most effective or economical solution. Many companies, in fact, take a hybrid approach, using a combination of disposable and reusable stainless steel/glass equipment. In general, in addition to economics, several factors are considered in determining whether single-use systems are appropriate for a given project; including whether existing equipment is available, the timing and budget for a project, the potential need for future replication of the process, and whether the process will be performed in a multiproduct facility.

Technical Report Number 66—Application of Single Use Systems in Pharmaceutical Manufacturing—from the Parenteral Drug Association (PDA) describes a risk-based decision-making process for determining if implementation of single-use technologies is appropriate for a given process. It is based on QbD principles and involves a step-wise approach that considers factors such as the suitability and availability of particular single-use equipment systems/components, plus many different potential risks. If the answer to each question in the series is yes, then single-use technology is appropriate for the project and as a bonus the reasoning supporting implementation of disposable systems is well documented.

Upstream vs. Downstream
While single-use bioreactors are widely used in upstream cell-culture-based biopharmaceutical manufacturing processes, disposable technologies for microbial fermentation are less well developed. Fermentations are generally higher volume, which can be an issue for disposable bioreactors. Single-use solutions for common downstream operations are also more limited. For many downstream unit operations, large-scale single-use technologies that can handle the higher titers achieved upstream have not yet been introduced. Notably, disposable technology is also finding increasing use in final formulation and filling processes for both non-sterile products and those that require aseptic processing conditions.

Suppliers of single-use technology systems are making rapid advances in developing effective downstream solutions. For example, various tangential flow filtration (TFF) devices are now commercially available that can be effectively combined with other downstream unit operations. Disposable, pre-packed chromatography columns have also been introduced to the market, and continuous chromatography systems (e.g. simulated moving bed (SMB), counter-current extraction) are being developed that have economics similar to single-use systems.

Single-use equipment manufacturers are also focusing efforts on the development of bioreactors for adherent cell manufacturing for cell-based therapies, small-scale bioreactors for scale-down modeling in the laboratory, and a wider array of disposable sensors for real-time monitoring.

Considering the risks
While single-use technologies provide many benefits, they also carry risks that tend to be magnified on the commercial-scale and of greater importance when implemented at the final drug manufacturing stages. Of concern are leachables and extractables from the plastics used in disposable systems. Many issues with leachables and extractables have been addressed; however, as single-use technologies are increasingly employed at the commercial scale and in manufacturing processes close to the final drug product, the risks they present increase. Regulatory scrutiny is significantly heightened when using disposable technology for final formulation and filling processes compared to media preparation or cell culture, for example, and there is a need to demonstrate extractables/leachables performance.

Change management is also an issue for single-use systems. Changes to reusable equipment are much easier to implement, largely because it can take much longer to assess extractables data and qualify modified disposable equipment. Both biopharmaceutical manufacturers and single-use suppliers must have rigorous change management procedures in place to ensure that disposable equipment consistently meets specifications for every application.

At present there remains a lack of industry consensus on what data should be provided by suppliers, particularly given that needs can vary depending on whether the disposal systems are being used upstream, downstream, or for final filling operations. The regulatory requirements are also rather vague and tend to be considered on an individual basis. Discussions are underway to address such concerns (see more below).

The risk of being committed to a single supplier of disposable equipment has also created concerns in the industry. In most cases, components from one supplier cannot be used with those of another. This lack of interoperability often forces drug manufacturers to use only one supplier or to purchase duplicate versions of the same components. In addition to increasing inventory management costs, this situation creates supply chain security concerns. In essence, suppliers of disposable equipment are as critical to ensuring that drug products reach patients as suppliers of key raw materials in terms of both reliable and on-time delivery and quality consistency.

Many biopharmaceutical manufacturers that initially purchased single-use components from many different suppliers looking to maximize their options have come to realize the increased costs associated with maintaining such a large number of different part numbers. The trend today is consolidation and internal standardization on a set number of basic components that can be used to build the various configurations they require for different unit operations. In general, components/systems from suppliers that can guarantee dual sourcing through production at various sites are preferred.

Tackling standardization issues
Both interoperability and extractables/leachables are key topics under discussion by numerous industry groups and standards organizations seeking to find workable solutions for standardization. The Bioprocess Systems Alliance (BPSA), Biophorum Operations Group (BPOG), Parenteral Drug Association (PDA), US Pharmacopeial Convention (USP), International Organization for Standardization, ASTM International, and the American Society of Mechanical Engineers (with its Bioprocessing Equipment (BPE) group) are actively involved in developing workable standards related to the use of disposable technologies ranging from standardization of extractables and integrity testing, particulate control, change control/notification procedures, and product characteristics/specifications to increase interoperability.

BPSA and BPOG, for instance, have joint User Requirement Specification and Change Notification Teams. The former is looking at quality requirements and product specifications, among other issues. A PDA team, meanwhile, has provided comments to ASTM as it works on its design verification standard. ASTM is also working on a standard for the determination and characterization of extractables from single-use materials with considerable input from BPOG and BPSA. ASME, ASTM and BPOG are looking at leachables, USP and ASTM are addressing sub-visible particles, and ASTM, ASME, and BPSA are working on system integrity testing issues.

Many of these groups have published various technical documents and guidelines on these topics. For instance, BPSA developed a quality assurance template for establishing an agreement between a single-use supplier and biopharmaceutical manufacturer regarding quality consistency.  BPSA’s Quality Test Reference Matrices lists existing standards that are applicable to disposable technologies and should be referenced by suppliers in their quality procedures. BPSA also published the Guide to Gamma Irradiation and Sterilization of Single Use Systems and the Guide to the Observation, Measurement and Control of Particulates in Single Use

Systems
With respect to interoperability, there is discussion of developing standards that would enable a plug-and-play approach. Some suppliers are resistant to such standardization because they fear it will eliminate any opportunity to establish competitive advantage. Many, however, believe that such standardization would lead to greater efficiencies and lower costs, which in turn would encourage biologics manufacturers that have previously avoided disposable technology to adopt single-use systems and thus expand the market.

Further growth expected
According to the Nice Insight 2015 Pharmaceutical Equipment Study6, 76% of respondents (n=560) indicated that their companies spend over $50 million on equipment per year. A growing percentage of those dollars is being invested in single-use equipment. Indeed, respondents to a separate Nice Insight survey of biologics outsourcers indicated that they prefer single-use disposable reactors as often (67%) as they do stainless steel systems (68%)⁷ (see Figures 1, 2 and 3).

If the various standards under development by industry groups representing both biopharmaceutical manufacturers and single-use suppliers evolve, growth of the disposable market may be quite significant. Technavio forecasts a high compound annual growth rate (CAGR) of 34.38% from 2014-2019 for the single-use bioprocessing system market.⁸ Transparency Market Research estimates that commercial cGMP manufacturing applications account for just 25% of the market.⁹ This segment is poised for significant growth, however, and will be a major driver of future market expansion. 

References

1. Persistence Market Research, “Global Biopharmaceuticals Market Will Reach US $278 Bn by 2020”, Press Release, July 27, 2015; http://www.persistencemarketresearch.com/mediarelease/biopharmaceutical-market.asp.
2. Roots Analysis, “Biopharmaceutical Contract Manufacturing Market, 2015 – 2025”, Press Release, May 5, 2015; http://www.rootsanalysis.com/reports/view_document/biopharmaceutical-contract-manufacturing-market-2015-2025/92.html.
3. Lupis JC and Langer ES. Critical Trends Driving BioManufacturing Production Strategies. Pharma Manufacturing. June 3, 2015. Accessed at: http://www.pharmamanufacturing. com/articles/2015/trends-driving-biomanufacturing-production-strategies/
4. Hernandez R. Top Trends in Biopharmaceutical Manufacturing: 2015. Pharmaceutical Technology;39(6). June 2, 2015. Accessed at: http://www.pharmtech.com/top-trends-biopharmaceutical-manufacturing-2015
5. Hammeke K. As Biologics Development Rise at Pharma Companies – What Does it Mean for Outsourcing? BioProcess Online. February 3, 2014. http://www.bioprocessonline.com/doc/as-biologics-development-rise-at-pharma-companies-what-does-it-mean-for-outsourcing-0001.
6. Nice Insight 2015 Pharmaceutical Equipment Annual Study, April 2015.
7. Ladage TJ. Bioreactor Preferences from an Outsourcing Perspective – Part I.  Pharma Manufacturing. February 5, 2015. Accessed at: http://www.pharmamanufacturing.com/articles/2015/bioreactor-outsourcing-perspective-part1/.
8. Technavio. Global Single-use Bioprocessing System Market 2015-2019. Press Release, July 29, 2015.
9. Transparency Market Research. Single-Use Bio-processing Systems Market – Global Industry Analysis, Size, Share, Growth, Trends and Forecast 2014 – 2020. Press Release, October 21, 2015.