One example of a hybrid approach from Cook Pharmica (WWW.COOKPHARMICA.COM)

At a recent conference, there was much talk about a major biopharmaceutical project in Asia for which the owner of a company chose a design with primarily traditional multiuse stainless steel tanks and processing equipment, rather than single-use polymer equipment. There were even some stainless steel equipment vendors toasting at the bar that this may be the beginning of a “renaissance” of stainless steel.

Is the single-use systems (SUS) honeymoon over? Are many industry professionals hoping this is the end of the single-use “fad”? Is bioprocessing experiencing a dotcom-like balloon trend that is ready to burst?

More likely, single-use technologies have simply reached a plateau, maybe even just a pause. The single-use era has met most of its quick wins. There has been much innovation on the parts of both suppliers and end users, and the industry has realized great gains. It is now time to ensure that this “trend” is not just a peak. SUS need to continue to improve and to help the industry make better therapies. But to do so, some significant changes need to happen.

The benefits of SUS have been well documented: primarily among them being a reduction in contamination risk, both environmental (microbial) and product-to-product. Use of SUS has reduced such risks significantly by supplying closed sterile processes.
Manufacturers using SUS benefited from the well-established irradiation sterilization methods, which were developed by the medical device industry. Increases in productivity have allowed them to scale down their processes, which enables smaller batches for the same yield of product. More protein product can be manufactured in a 2,000-L single-use process than was produced in a 20,000-L stainless steel system just a few years ago (1).

SUS modularity and ease of use have helped accelerate clinical and contract manufacturing timelines. At the 2015 BioProcess International Conference and Exposition, keynote speaker Kimball Hall (vice president of manufacturing Amgen Singapore) explained how Amgen’s Singapore facility successfully implemented SUS
and benefited from many related advantages, especially significantly less classified space. BioPlan Associates noted in the 12th Annual Report on BioPharmaceutical Manufacturing and Capacity (2) that 50% of respondents expect to implement single-use technologies in most of their commercial/clinical operations by the year 2020 (see Langer’s introduction to this issue). That report also found that the top products desired were far and away single-use components, with stainless steel getting only 6.4% of the respondents interested, a slight increase from last year’s 4.7%.

It has not been an easy road for SUS. Many issues have come up as such technologies increase their presence. Most audience members attending the SUS standards town hall at the BioProcess International Conference admitted to still feeling that SUS has major associated risks (3). Paramount issues that continue to be on industry minds are

At the town hall, one attendee said, “We have known these things are issues for some time. Where can I go to help resolve them? It is not clear on where this is going and where I can go for help.” This statement captures the current situation well and the bioprocess community’s general sentiment.

Chris Smalley (Merck and Company) discussed some current myths within single-use dialog at the town hall. He referenced his experience with borosilicate glass extractables. Lead and arsenic are present in the glass and can be extracted with the proper conditions. He asks: “Imagine if we found lead or arsenic in SUS?” We have addressed these concerns for years, and glass is the primary material used for finalproduct container vials and syringes. He challenges the industry: “Why should we not use similar reasoning in applied science to the SUS extractables?”

Similarly, at the 2015 Bio-Process Systems Alliance (BPSA) International Single-Use Summit, R. Thomas Warf (Retired, Merck Operations) discussed the issues between SUS and stainless steel (4). He pointed out the evolution of the bioprocess industry and advantages of stainless steel systems, which are cleaned and steam-sterilized by validated processes immediately before use. Their risk of particles and especially endotoxin are greatly reduced by these practices. This is unlike practices with SUS in which the systems are routinely not cleaned. Particles are generated during their fabrication, transportation, and assembly. Many suppliers address these risks with “ clean build” practices that are similar to those for semiconductors, but as noted above, the industry is still concerned about particulates. As Warf queried, “Is there sterile dirt (foreign particles) in the SUS?” Such issues have naturally risen to the top of the list because of increased use of SUS, which are similar to many mature applications. The real underlying issue is a paradigm shift from end users being responsible for preparation of equipment to suppliers being responsible for it. In the case of SUS, end users are still accountable to the regulatory authority. This is something the SUS community needs to address. Otherwise, it will not progress further.

Cleaning Contaminants (particulates, biologicals, endotoxin, and chemicals) from equipment and/or the environment(s) must be minimized regardless of which system it is, stainless steel or SUS. The industry’s goal is zero contaminants, and the requirements for final drug products in their final containers are well established, (e.g., USP <85>, <788>, and <790>).

The industry has adapted the same goals for SUS as for final containers. We have applied those requirements to the in-process SUS. But is this practical?

Contaminants are more critical issues if a drug product is a vaccine or a cell therapy, which cannot be processed through filters to remove particulates. Particulate levels in SUS have been discussed, and the risks are well characterized in a 2014 BPSA paper (5).

The fact is that current SUS now can include multiple environments, including those from assemblers, suppliers, and supplier’s subsuppliers. They all need to ensure that SUS products are clean and free of contaminants, just like validated stainless steel cleaning processes do.

The counter argument is that we do not know the exact particulate levels of stainless steel equipment. Particulate levels are not typically taken in routine operations nor validation studies. But processes have been visually “verified” as clean, and they have demonstrated low TOC and bioburden levels routinely over time. Stainless steel equipment also has a lengthy history of delivering safe drug products with acceptable particulate and endotoxin levels downstream.

How does each SUS vendor demonstrate levels of control? How can end users assess that ability? This is the core issue, especially when a nonconformance or deviation arises. End users require a timely investigation to properly assess risks of incidents to ensure that their drugs are safe. SUS are suitable for that intended purpose. But this strategy becomes amplified and more complicated when suppliers and/or their subsuppliers are involved.

The industry requires different cleanliness grades for SUS. The community has discussed establishing different grades of cleanliness for SUS, such as for chemical reagents. Perhaps the bioprocessing industry can establish a “clean” grade for most processing and a “super clean” grade for critical processes. Such “super clean” SUS then will be supplied with more supporting information, more testing, and so on.

Sterilization
Sterilization of SUS has been addressed for the most part by adapting the medical device sterilization standard, ISO 11137 requirements (6). That document provides guidance on sterility assurance levels and a “family” approach to validations. Stainless steel multiuse systems have had longstanding steam-in-place (SIP) and autoclave processes, validated and operated by end users. Those processes have been effective for the most part, with the exception of nonconformances from malfunctions and operator errors.

I suggest using the family approach and dose levels to ensure that irradiation dose levels are not too high. Not implementing these strategies can result in decreased material properties and increased risk of other types of failures.

Changes
Change notifications from SUS suppliers have been diverse. Some provide all information from their own operation and their subsuppliers; others have much less. The BPSA/ BioPhorum Operations Group (BPOG) change notification team has highlighted many of these issues and are hoping to address many of them (7).

SUS suppliers are trying to provide high-quality products. They want to be helpful, but most do not have current good manufacturing practice (CGMP) operations, and many are not fully aware of CGMPs and what end users require to provide proper assurance to regulatory authorities. In addition, the basic psychology of providing change notifications and/or deviations — essentially saying “I need to change, I can no longer supply that part, or I messed up” — is a difficult notion to present to a customer, especially in this highly regulated industry. That task becomes more complicated with layers of subsuppliers.

The solution is to build trust and strong relationships among all parties in the supply chain. Perhaps a better phrase is “trust but verify.”

The challenge is to align expectations, which can be difficult for different risk tolerances. It is like hiring a cleaning person for your home and holding him or her to the exact same cleaning regime that you performed yourself. I do not know of anyone, especially my wife, for whom that worked the first time, or even over some time, without a strong relationship and dialog.

Strong supplier–user relationships are sometimes influenced by business transactions and the drive to obtain the lowest price. Other mature industries have learned to navigate through such difficulties. We have seen great strides with the change notification group and the ongoing “alphabet soup” standards organizations (8). Specifics can be referenced in the Single-Use News L-e-t-t-e-r-s.

The bottom line is that we have delicate processes and products that require meticulous handling and assurances of their design, preparation, and use. Cells and molecules must be treated with care and respect. They do not have a preference for stainless steel or plastic, they just need a conducive environment to grow and remain pure and safe. We remind attendees at our URI Introduction to BioPharmaceutical Manufacturing workshop to think like a cell or a protein when processing them: They want to be treated with care. Whatever we use to process them should treat them like the precious commodities that they are.

The Path Forward
Hybrid systems are the natural progression. Existing plants using stainless steel are more likely to apply SUS as intermediate steps to improve efficiencies. Even so, CMOs are more likely to implement SUS because such systems have lower capital and validation costs. And manufacturers of clinical products are more likely to use SUS beause of scale and lower upfront costs. Long-term producers are a mix. High volumes may look at long-term cost of goods and validation for multiproduct and decide on stainless steel processes. And microbial batch times are currently short and more likely to be stainless steel processes. These decisions all can change with a few bad supplier experiences in which trust is broken.

Where is the future taking us? Balancing technology with business drivers will be the key. Costs and change management trust are critical and they must get better with efforts such as the BPSA/BPOG change notification group. Other influences are out there. Open architecture may make it easier for SUS, and continuous operations may show the need for more robust systems.

Does “robust” mean SUS or stainless steel? The industry does not know. Ask: What do cells or proteins need to thrive, and provide safe and efficacious therapies for the patients?

References
1 Vogel JD. The Maturation of SingleUse Applications. BioProcess Int. 9(5) 2012: 10–17.

2 12th Annual Report on BioPharmaceutical Manufacturing and Capacity. BioPlan Associates: Rockville, MD, 2015.

3 Single-Use Standardization: Progress in Improved Alignment of Guidelines. BioProcess International Conference, Boston, MA, 26–30 October 2015.

4 Warf T. Keeping Plastic Fantastic: Perspectives on Steel and Polymer BioProcess Systems. 2015 BPSA International Summit, Washington, DC, 13–15 July 2015.

5 Recommendations for Testing, Evaluation, and Control of Particulates from Single-Use Process Equipment. BPSA: Washington, DC, 2014.

6 ISO 11137-1:2006 — Sterilization of Healthcare Products. ISO: Geneva, Switzerland, last reviewed 2009.

7 White T, Ott K. Management, Notification, and Documentation of SUS Change Orders. BioProcess Int. 13(9) 2015: 24–30.

8 Vogel JD. The Single-Use Watering Hole: Where Innovation Needs Harmonization, Collaboration, and Standardization. BioProcess Int. 13(1) 2015: insert.

James D. Vogel is founder and director of The Bioprocess Institute in North Kingstown, RI; 1-401-294-9000; [email protected]. Single-Use News L-e-t-t-e-r-s is a central resource for information and updates on the expanding role of single-use technologies in the world of bioprocessing. It can be found at www. bioprocessinstitute.com/sus-newsletter.html.