What is the current state of acceptance of single-use technologies in the pharmaceutical industry? In your opinion have they become “mainstream”?
Eric Langer Managing Partner, BioPlan Associates, Inc.: Single-use devices have been part of the bioprocessing industry for 20 years, including starting from storage and freezer bags, based on designs from the medical industry. So they are not new. What’s continuing to emerge and develop are the strategic applications for which these time- and resource-saving devices are being used. It’s not just to eliminate cleaning requirements, where there may be some minor cleaning operations savings, but more strategic purposes, such as when a facility needs to be commissioned in a fraction of the time it could be done using stainless steel. Or where a late-stage clinical facility needs to be constructed prior to an FDA approval, or where a facility expansion needs to be made, but that extra capacity may or may not be a permanent requirement.
Even as technologies, new materials, and production processes continue to improve their strength, robustness, inertness, and innovativeness, costs are becoming an increasing concern. According to our Annual Report on biomanufacturing this year, 23% of the industry note the high costs of Single-use devices as the #1 reason they may not increase their use. On the other hand, major operational concerns, such as breakage and leachables, have dropped by nearly half during the past 5 years. This clearly suggests that the operational worries associated with single-use devices are abating, and what’s becoming the ‘problem’ is that facilities would like to have them for ‘cheaper’. That’s actually a good trend for the segment; when the problem comes down to pricing, then many of the major hurdles to adoption are clearly being resolved.
Mark Trotter, President, Trotter Biotech Solutions: Single-Use Technologies (SUT) have been well accepted and have matured into the mainstream of biopharmaceutical manufacturing processes. Primary markets and applications focus on liquid formulations. While accepted into powder, oral and topical therapeutics, the major benefits in cost savings and efficiencies are found mostly in the biopharma processes for producing proteins, polysaccharides, vaccines, therapeutic enzymes, as well as for virus concentration and purification. Both upstream (bioreactors and feeds) to downstream (separation, clarification and purification) applications are amenable to SUT.
Surendra Balekai, Sr. Global Product Manager, Thermo Fisher Scientific: Current trends indicate significant adoption of single-use technologies for clinical and some commercial manufacturing operations. It is evident from multiple market survey reports as well as financial results reported by suppliers of single-use technology that the growth opportunity is significant and single-use technology continues to see increased adoption. With further advancement in cell culture media and feeding strategies, expression rates in the range of 6 – 8 g/L have helped to reduce processing volumes. Hence it is apparent that single-use technologies in the pharmaceutical industry have become “mainstream”. However, this is applicable to research, development and manufacturing of expensive therapeutic molecules, such as cancer treatments and vaccines for pandemic situations. Some of the large contract manufacturers who currently rely on 10,000L and larger stainless steel systems have announced their intent for future facility expansion using single-use platforms.
If a pharma company was looking to adopt single-use technologies for the first time – what advice would you give them?
Trotter: Initial investigation would entail gathering and understanding their SOPs and best practices prior to analyzing which upstream / downstream stages and platforms could be amenable to conversion to SUT. Adopting SUT into an existing legacy system can be very time and resource consuming. Usually these technologies are more effectively and efficiently implemented during the Process Development of new drug products. However, that does not preclude the implementation into legacy processes where the cost / benefit ratios could lower the COGS.
Good resources are plentiful in the literature and publication abound on SUT. A simple on-line search for SUT and Disposable use in biopharma will produce a plethora of material. The list is too expansive to list here, however a short search on APR website will reveal many sources to follow.
An initial cost/benefit analysis of each stage/process using one of the many software programs would be advisable. The SUT suppliers and manufacturers have extensive expertise and knowable scientists and engineers to assist in making the implementation process understandable. The caveat of course is their desire to promote their selection of products.
Balekai: “The faster, the better. ”At this point, there are no questions about the overall advantages of single-use technologies. The real questions are about how to maximize the benefit of single-use platforms. This is dependent on the molecule one is working on (innovative or biosimilar or biobetter), how fast molecules need to reach the patients and at what cost. As a pharma company, it is critical to maximize resources and scientist’s valuable time to develop and manufacture efficient molecules and bring more molecules to market. In today’s world, multi-product facilities are needed and single-use technology is the backbone of such facilities.
What processes are easiest to transition to disposable technologies and why?
Langer: The original applications for single use were the simpler processes such as media shipping in bags, FBS freezing, buffer storage, etc. These are the leaders. But the real value of single-use is where they’re being applied for strategic purposes, as noted above. So it’s not just about saving on operations, it’s increasingly about facilitating and enabling a process that otherwise would not have been possible.
Trotter: Those processes that are closest to the final finishing and fill stages are under the highest regulatory scrutiny, especially aseptic processes. Moving up the downstream processes typically the lower the regulatory compliance and industry standards requirements. Therefore, the ‘easiest’ or more appropriately, the least complex and costly (in terms of time and capital) processes to qualify and validate may be in the upstream fermentation/cell culture stages and mid-stream separation and clarification applications. As indicated in the above question #2, legacy system conversion come at a higher cost/benefit ratio. New drug development process in this sense would be considered ‘easier’ to transition to SUT.
Balekai: In the last 3 years, transition has happened and will continue to increase for almost all unit operations relying on single-use products. These include - Media preparation and storage, bioreactors, harvesting, intermediate storage, chromatography pooling, virus inactivation, buffer preparation and storage, final bulk storage, process vessels for TFF/Cross flow filtration systems, Freeze/Thaw applications, Frozen shipping and some of the fill and finish operations and finally all the fluid transfer applications. Manufacturers indicate > 70% of unit operations use single-use products.
What are some best practices for integrating disposable technologies with stainless steel equipment?
Trotter: This issue of integrating SUT disposable technologies with or replacing SS has a long history and again the literature is rife with articles on such conversions, costs/benefits and applications. The ‘best practices’ begin with a detailed understanding of a processes SOP along with the qualification and validation requirements for change control.
Some application or processes are ‘easier’ based on these requirements. Regulatory categorizes these changes as minor, moderate(major) or significant(critical) depending on the impact on the therapeutics’ …’safety, identity, strength, quality, or purity of the drug products…’ (21CFR§211.65.) For example, changing out a stainless steel storage tank with a polymeric disposable bag or container may be consider either a minor (annual report of change) or moderate CBE30 (change being effected in 30 days.) Either would require demonstrating compatibility and meet compliance for materials of construction as well as the plethora of regs and standard for SUT.
Balekai: While industry shifts to increase use of disposable products, it is critical to use existing stainless steel infrastructure and establish processes optimized for hybrid environments. To my knowledge, so far there is only one company that provides connection between single-use and stainless steel equipment (Steam-thru connectors). These applications necessitate steam sterilization at least once or twice depending on the product. Therefore, the product has to be able to handle single or multiple sterilization capabilities of these connectors.
What are some of the biggest concerns/problems with using single-use technologies? Are there easy and effective ways to overcome these challenges?
Langer: The biggest concerns and problems with single-use technologies, according to our 14th Annual Report are the following, in priority order:
- Breakage of bags and loss of production material is a concern
- Leachables and extractables are a concern
- High cost of disposables (consumables)
- We do not want to become vendor-dependent (single-source issues)
- Material incompatibility with process fluids
- Limited scalability over a broad range (such as 2 L to 2,000 L)
- Lack of uniform standards for testing and measuring
- We have already invested in equipment for current system
- No clear Regulatory guidance on Leachables and Extractables
- High cost of non-disposable equipment (housing, controllers, etc)
- Availability of disposable scale-down models that represent larger scale disposable bioreactors
- Incompatible controllers & data management systems that don’t work with existing systems
- Lack of disposable equipment that meets process requirements
- No clear Regulatory guidance on OTHER (non-L&E) aspects
- We have already invested in validation for current system
- Lack of technical information on mixing performance
- For regulatory reasons, we can’t change our current systems
- Inability to take on high pressures (leading to foaming)
- Current general budget constraints
- No lifetime operating cost data exist on the differences between stainless steel and disposable options.
- Validation package for controllers, software, non-disposable containers
- Complicated operation (e.g., loading bags, probe insertion)
- Since disposable processes still need to be validated, there’s no benefit
Trotter: In general, the biggest concerns come from regulatory agency and to a lesser degree from QC/QA. There are several major concerns expressed by FDA are burst strength and microbial and vapor integrity of the bag layers. These issues are usually addressed in the SU supplier’s validation and qualification documents.
One significant article is by Dr. John Finkbohner, Deputy Director, Div. of Manufacturing and Quality, CBER. His observations, although from 2005, are even more compelling today. The FDA’s stated mission is primarily patient and drug safety, secondarily supply and lastly costs. However, Dr. Finkbohner elevates the production processes for not only the ‘safety’ issues but highlights the need for SUS technologies to provides even greater safety while providing for ‘…Cost Savings’ and ‘Speed to Market.’
As explained in his paper; ‘The most common elastomeric (polymeric) issues noted during …PAIs are related to;
- Equipment-related failures in processing, bag ruptures, leaks, microbio penetration,
- Documentation of extractable profile characterization; leachable contaminates
- Vendor qualification and/or fitness-for-use criteria definitions
He concludes his presentation with:
‘Careful consideration during the process design state can be very beneficial and contribute to successful implementation of a well-controlled and reliable production system.’ (APR Article Archives, ‘Adoption of Single-use Disposable Technology in Biopharma Industries – Manufacturing, Economic and Regulatory Issues to Consider, March 30, 2012, A. Mark Trotter.
Balekai: Some single-use analytical technologies have not yet reached the desired process needs and reliability. Though efforts are being made, it looks like solutions are still a few years away from reality. Some of the basic measurements (pH and Do) were introduced to the market about four years ago. Other areas are still under development.
Many end users have expressed concerns of leakages. Their concerns are primarily on seals, tubing connections, and connectors. Suppliers are fast tracking solutions in that area and it looks like these problems will be resolved soon.
Currently, disposable technologies are primarily used for biopharmaceutical production. Do you see their use expanding into other dosage forms? If so, what might that be and why?
Trotter: As I detailed in Question #1, the primary markets for SUT is in biopharma manufacturing. The higher hurdle for implementation is base on the cost/benefit ratio of substituting polymeric materials for the hardware, stainless steel and glass. The issue of cleaning, disposing chemicals, sanitization/ sterilizing equipment, cross contamination (batch to batch and microbial) labor, materials costs, amortization, etc. all play important parameters to these calculations. The higher costs associated with biopharma production make it more amenable to conversions to SUT. However, as SUT costs decline and general regulatory and industry acceptance increases in using these maturing SUT products, we may expect adoption in closely related pharmaceutical product production, such as storage and compounding of powder and oral medicines in bags and carboys, topicals and ointments may lend themselves to similar applications, e.g., poly-tubing replacing stainless steel.
Balekai: Biopharmaceutical applications are less aggressive on the contact surfaces, which makes it easier to adopt single-use platforms compared to other dosage forms. Cost of treatment, cost of product development, regulatory oversight, and ease of manufacturing are some of factors influencing development of robust single-use technologies suitable for other dosage forms.
What do you see as the future for disposable technologies specifically regarding their adoption, materials of construction, and processing capabilities?
Langer: The future of single-use technologies and their increased adoption will be based on the problems they address, and the critical reasons that decision-makers strategically select this as a manufacturing option. From our Annual Report, to summarize the ‘Top 20 Critical Reasons’ to increase Singleuse in 2017, in order:
- Reduce capital investment in facility & equipment
- Eliminate cleaning requirements
- Faster campaign turnaround time
- Decrease risk of product cross-contamination
- Flexibility of a ‘modular’ approach
- Reduce time to get facility up and running
- Shorter initial installation time
- Greater assurance of sterility
- Avoid costs associated with system re-design and modifications
- Reduce operations staff
- Reduce space requirements
- Higher total annual capacity at my facility
- Easier QA/QC
- Improved scheduling ability
- Lower annual maintenance costs
- Decrease documentation requirements
- Simplify operations, and reduce learning curve for new operators
- Decrease risk of ENDOGENOUS contamination (e.g. bacterial)
- Disposable filters more convenient
- Ease of control of bioreactor (use of probes, etc.)
Trotter: As the SUT products grow in scope and volume with new suppliers and manufacturers, especially from Asian countries, the market will move into a more mature stage. The beginning of disposables date to the late 1980s with the SUT product demand mushrooming in the early to mid-2000. Today these products and applications are well established and accepted by both regulators and the BioPharm industry. The general expectation is continued penetration of the downstream stages, with the most challenging being chromatography and purification stages. This bottle-neck is undergoing a transformation with the adoption of Continuous Chromatography Processes (CCP) technology that is receiving acceptance by drug manufacturers.
The suppliers must continue to innovate with new bag films, lower leachables, stronger tiedowns, standardization of connectors and devices. Eventually there will be multiple drug and therapeutics manufactured solely by SingleUse Technologies from upstream through all downstream stages. That day is not that far away, if not already done.
Balekai: We are getting closer to the day when biological molecules will be manufactured using single-use technology exclusively. The need for pharmaceutical companies to research & develop a pipeline of molecules, multi-product facilities, stringent compliance requirements and the necessity for affordable treatments will drive the growth and development of single-use technologies. It is not just current pipeline of molecules, future developments in cell therapy and personalized medication will continue to motivate suitable single-use technologies.