In fact, improved analytical methods continues to be cited as a current need for nearly every aspect of biopharmaceutical manufacturing, according to BioPlan’s “14th Annual Report and Survey of Biopharmaceutical Manufacturing and Production.”1 Figure 1 shows examples of this year’s “General New Product Areas of Interest,” excluding specific up- and downstream technologies, the need for better assays continues to be a critical are of interest, with nearly 18% of respondents seeking better tools.
The top concerns included proving comparability between manufacturing batches/lots, host cell protein assays, and biophysical characterizations during process development. The need for improved analytical capabilities exists nearly everywhere in biomanufacturing. Another major arena is in analytical testing for biosimilars. Manufacturers need to show similarity and determine the unique difference between products, often with the same analytical technology used to show comparability between manufacturer’s batches/lots.
The reason for this interest is that better analytical methods are needed to increase productivity in active agent design, discovery, screening, and optimization. There are still too many products failing, at a great expense, later in development. If a drug candidate is to fail, it is preferable that it occur fast and early.
Analytical testing commonly outsourced
Nearly all biopharmaceutical developers use outsourcing for at least some of their services, including analytical testing. Outsourcing allows companies to focus on their core competencies, and allows them to send out more complex activities, or the more repetitive tasks. This provides cost savings by allowing companies to avoid building specialized facilities, hiring staff, etc.
Looking at 24 different areas of outsourcing today, “analytical testing (other bioassays)” was the top area of outsourcing for biomanufacturers. Approximately 9 in 10 (90.4%) companies outsource at least some of this specialized activity. This trend has held relatively steady over the last six years. As more companies continue to outsource such testing, and as in-house capabilities dwindle, it will become increasingly difficult for biomanufacturers to bring such testing activities back in-house.
Analytical methods are outsourced partially due to the need for highly specialized staff to run the assays and prepare regulatory filings as well as having the related expensive, high-maintenance equipment up and running. The amount of outsourcing will likely increase in the future, if for no other reason than regulatory agencies will be wanting more characterization and data about products. While it’s clear the industry is already outsourcing at least some of its analytical testing, it’s also clear that this trend will continue into the foreseeable future.
Given the trends in outsourcing over the past decade, it is not surprising that biomanufacturers indicated the top outsourcing activity projected to be done at significantly higher levels in the next 24 months was “analytical testing: other bioassays” at 29.6%. While this is trending down from a high point of 40.9% in 2015, it still remains the number one response. In addition, analytical testing, the top response for future outsourcing areas, was also near the top (29.1%) in estimated average percentage of activity outsourced by facilities today.
Trends in process analytical technologies
Quality management is a critical area for avoiding problems, capacity bottlenecks, and failures in today’s biopharmaceutical manufacturing industry. Regulators are increasingly expecting product applications to include extensive studies showing optimization of product quality, which is largely determined by bioprocessing. One of the crucial quality-related issues of biomanufacturing is process analytical technology (PAT).
PAT is defined by the FDA as “a system for designing, analyzing, and controlling manufacturing through timely measurements (i.e., during processing) of critical quality and performance attributes of raw and in-process materials and processes with the goal of ensuring final product quality.” Adoption of PAT is costly and likely requires dedicated equipment and staff in bioprocessing. Since PAT is voluntary, the added cost and hassle of implementing modifications to already-approved biomanufacturing processes and going through regulatory approval explains why it has not been adopted by the majority of the industry. However, implementing PAT for new processes makes sense as it is an effective method to increase productivity, reduce waste, improve yields, and facilitate other cost-saving measures.
BioPlan surveyed biomanufacturers on the top hurdles hindering the implementation of Process Analytical Technology. The top concern was “time required to implement”, cited by 80.7% of respondents. That concern was followed closely by “insufficient people in-house to manage implementation” (79.7%) and “cost” (51.7%). An interesting jump seen in this year’s report in analysis of what quality initiatives companies are planning to pursue in the next 12 months. PAT held the top spot again, but the response jumped from 20.3% in 2016 to 29.6% in 2017.
It is clear from the responses from industry members that PAT adoption will continue to increase. Regulatory agencies will expect more quality programs, particularly as more companies adopt the quality initiatives. In addition, PAT will be accepted as providing more robust bioprocessing, as well as being more cost-effective. The data derived from PAT will become routine and expected, it’s simply a matter of companies realizing they need to allocate the time, resources, and staff toward it or similar programs, particularly for new manufacturing efforts.
Better analytics needed
Analytical techniques create improvements in optimization and process control. However, progress in the development and implementation of bioprocessing-related assays and analytical instrumentation has not kept up with industry demands. It’s clear from the survey data that there is a need for improvements in analytical technologies for disposables and single-use systems and increased implementation of process analytical technologies. And while there is a strong trend to outsource analytical technology to their CROs and CMOs (contract research and manufacturing organizations), analytical testing remains a major concern in causing future capacity constraints.
Biopharmaceutical manufacturers and CMOs indicate that increasing productivity pressures are forcing them to do more with less, in addition to the increased demand by regulatory agencies for better data and documentation on product quality. Regulators want to see that assays and analytical data are used to design bioprocess scale-up through development from the beginning stages. All of these factors move the industry toward better and more analytical technologies.
The good news is the industry is adopting analytical techniques like PAT, and survey data indicate that companies are looking to adopt new analytical technologies going forward, whether that’s within the biomanufacturers’ companies or through outsourcing. Analytical techniques can create improvements in process control and optimization, and better testing using single-use/disposable bioprocessing equipment can prevent delays in product development. As analytical technologies continue to improve and help move the industry toward better process control, and reduce costs, companies will rely on comparative analytical data to inform development and scale-up of new products. In the end, as companies realize that improved analytical assays will improve bioprocessing productivity and quality, implementation of new analytical technologies will continue moving forward.
Need for better assays, analytical testing and single-use sensors
One aspect of biomanufacturing in need of better analytical methods, is in the demand for improved and robust disposable sensors. Single-use equipment or disposables are currently being used in a wide range of applications in biomanufacturing. This demand for sensors is logical, as single-use and disposable equipment can provide faster change-overs and reduce shut-down times. However, one factor that is inhibiting more widespread adoption of single-use equipment involves analytical testing, specifically single-use sensor technology. Most of the sensors and probes used today in stainless steel facilities do not translate well into single-use systems. Unfortunately, there are relatively few robust single-use sensors available, and the ones that are in use remain limited to relatively few analytes. In our report, respondents were asked which single-use sensors they most wanted to be introduced or that needed improvements. Of the 14 analytes identified, not surprisingly, it is the more common ones like pH (70.1%), cell density (61.7%), and dissolved oxygen (57.0%) that topped the list for 2017. The demand for these sensors has continued consistently over the past five years, and although new technologies are emerging, robust, easy-to-use devices are not coming as quickly as many biomanufacturers would like.
As biomanufacturers and CMOs integrate disposables into their bioprocesses, the need for reliable and robust disposable sensors will increase. Currently, the majority of single-use disposable systems are in the scale up/clinical production as opposed to commercial applications. Yet, as the industry and regulatory agencies gain more confidence and performance, the greater adoption of single-use systems will necessitate better quality sensors and more analytical testing technologies to drive their use in commercial applications.
Capacity constraints and analytical testing
Future capacity constraint in biopharma manufacturing is being impacted by the lack of analytical testing. In fact, after general facility constraints, the lack of effective analytical testing was identified as the second biggest concern in terms of how the industry will handle capacity issues.
Looking ahead to future capacity issues in biopharmaceuticals, we identified 21 factors that the industry believes may restrict future growth. Defining the factors that manufacturers foresee as capacity constraining issues in the future can guide development today, with the goal of circumventing capacity issues. Overall concerns over capacity constraints have increased in recent years, from about 17% of the industry indicating ‘severe’ or ‘significant’ capacity concerns at commercial scale in 2009, to nearly 30% in 2017. This is partly due to stronger pipelines and fewer developmental failures for many of the larger biopharmaceutical companies. We saw similar results for capacity constraints at clinical scale.
Causes of future problems, according to our respondents included “analytical testing and drug product release” (36.4%) as the second largest factor. This ranked behind “facility constraints” (60.0%) as likely to cause capacity constraints within the next five years. Although analytical testing was seen as slightly less of a concern compared with the last three years, it is still a significant issue. Separately, when comparing concerns of biopharmaceutical developers versus CMOs, biopharmaceutical developers have significantly higher levels of concern in a few areas, the second being analytical testing and drug product release (37.7% for developers vs. 27.8% for CMOs).
It is clear that manufacturers and CMOs alike are concerned, specifically about analytical testing, and its impact on future production. Development of better analytical tests, testing methods, and technologies, such as better sensors, will help prevent these capacity constraints that the industry is clearly concerned about.
- 14th Annual Report and Survey of Biopharmaceutical Manufacturing Capacity and Production, April 2017, BioPlan Associates, Inc. www.bioplanassociates.com.
Eric S. Langer
Eric S. Langer is president and managing partner at BioPlan Associates, Inc., a biotechnology and life sciences marketing research and publishing firm established in Rockville, MD in 1989. He is editor of numerous studies, including “Biopharmaceutical Technology in China,” “Advances in Large-scale Biopharmaceutical Manufacturing”, and many other industry reports. email@example.com; 301-921-5979; www.bioplanassociates.com