What is the current state of acceptance of single-use technologies in the pharmaceutical industry? In your opinion have they become “mainstream”?
Andrew Bulpin, Head of Process Solutions Strategic Marketing & Innovation, MilliporeSigma: Over the past 10 years, we have seen a steady increase in the adoption of single-use technologies (SUT) by the biopharmaceutical industry. The widespread utilization of single-use filter cartridges and capsules paved the way for acceptance of single-use bags and assemblies. The speed and flexibility of deployment coupled with a reduction in capital costs are the key drivers pushing industry adoption of SUT. Furthermore, the advantages of pre-sterilization and reduced risk of cross-contamination have made these technologies the preferred choice for many applications.
Dr. Stefan Robert Schmidt, Senior Vice President Process Science and Production, Rentschler Biotechnologie GmbH: They are mainstream typically in manufacturing for clinical supply. They are less frequently used for market production.
Don Potter, Director of Sales & Marketing, Savillex Corporation: I believe they have already become mainstream, as evidenced by the activities of working groups like BPSA and BPOG, who are doing great work in developing guidance documents for suppliers and users to follow.
Patricia Seymour, Senior Consultant, Bioprocess Technology Consultants: Disposables and single use assemblies have become nearly universal in biomanufacturing processes and “acceptance” is no longer the issue. Disposable technologies are used in almost every manufacturing step, from media and buffer prep bags, to filtration, to chromatography resins and columns, etc. The industry has now moved onto more technical issues such as leachable and extractable (E/L), microbial control, integrity (in the case of bags)
Surendra Balekai, Senior Global Product Manager, Single-Use Technologies, 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 singleuse 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 singleuse technologies for the first time – what advice would you give them?
Bulpin: Develop a team with experience and expertise in SUTs, and partner with a vendor with extensive knowledge and experience to provide design input, advice on regulatory requirements and the validation services to meet them as well as implementation support. Moreover, look to industry organizations and trade groups such as BPSA, BPOG, and ISPE, for recommended best practices such as risk assessments, quality test matrices, and implementation road maps.
Schmidt: Check if you are able and willing to rely on the quality systems of your supplier. Look at your product range, does the available scale of disposable equipment match your scale demands?
Potter: Take the time to identify and select the right supplier to partner with. Every pharma company wants to have the best SUT solution, but success depends on more than just choosing on face value what appears to be the best product on the market. What if you need some customization – will the supplier deliver on their promises? Are they committed to your success? What about when problems occur? Is the supplier responsive? How good is the communication between the two companies? It’s difficult to know the answer to these questions up front, but by close communication in the investigation phase, the pharma company can learn a lot about how the supplier will perform as a partner. Our company supplies single use storage containers for bulk drug substance, prior to final fill and finish, so the avoidance of particulate contamination is of critical importance. We worked closely with our customer to develop manufacturing processes and enhanced inspection to optimize particulate removal/elimination. To do that, the SUT supplier must fully understand the needs of the pharma company. The pharma company must find the right partner and work with that partner as if it were a part of the company.
Seymour: The company must assess where and how the SU technology will be used in the process and perform a quality risk assessment accordingly. For example SU technologies for media and buffer prep may have a lower risk score than the final sterilizing filter. Using the risk score evaluate vendors for not just for their components performance, but also for the level of information they provide regarding their components, e.g., E/L, supply chain security and visibility, change control notification, cell growth in SU bioreactor bags, etc.
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 singleuse technologies and why?
Bulpin: Unit operations (e.g., mixing, filtration, and fluid transfer) associated with the preparation and storage of cell culture media and buffers are the easiest operations to transition to SUTs, assuming the end user is </+ 2000L scale. These operations are low risk and the cost of failure is low too (compared to the loss of drug product in a purification or filling operation).
Schmidt: Obviously processes that are developed utilizing disposables already at small scale. On the other hand, processes with high cell densities might not be compatible for larger scale cultivation in disposable reactors.
Potter: Smaller scale production, and the downstream handing of high value drug products lend themselves well to SUT. An example is the use of disposable storage systems for a high value bulk drug substance (BDS) such as a vaccine or therapeutic protein that needs to be stored frozen for long term stability. The BDS can be stored in fluoropolymer bags or bottles and easily shipped to another site or to a contractor for final fill. Because the volume of each storage unit is small (from a few liters down to even 50 mL) only the precise amount of BDS needed to fill an order is processed, which minimizes wastage of what is typically a very high value product.
Seymour: Most companies have moved to disposables for at least some of their media and buffer preparation because the relative low risk of having an adverse effect on the actual process. Other disposables include filters.
Balekai: In the last three 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/crossflow 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 singleuse technologies with stainless steel equipment?
Bulpin: Hybrid systems require compatible devices and connectors suited to this task. When attaching a single use assembly to a stainless steel component, use steam-tolerant connectors to allow steaming up to the point of attachment. This will assure that the system remains sanitary.
Aseptic connectors provide an easy way to connect traditional stainless steel systems or tanks with single-use systems. This allows customers to easily transfer media, buffers or process intermediates out of stainless steel tanks and into plastic bags for storage. The Aseptic connectors can also be used to perform tank additions, such as media feeds, carbonate or anti-foam.
Schmidt: Many processes already apply some kind of hybrid solution as not all scales and dimensions are available in single use. For best practices look at process steps where disposables offer the most benefits.
Seymour: Similar to what was stated above use of disposable bags for media and buffer preparation are widely used with stainless steel bioreactor equipment.
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 singleuse and stainless steel equipment. 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?
Bulpin: One of the biggest challenges is remembering that single-use technologies are made from plastics and thus have different material characteristics than stainless steel. The end user must be conscious of the fact that the single use polymers are less tolerant of pressure than stainless steel, so it is critical to understand and limit the stresses SUTs are exposed to in hybrid applications. Even something as straight forward as opening the shipping box needs to be considered – you can easily damage the single use assembly when slicing the packing tape on a carton with a packing knife. Vendors are a good source of help to train your team how to handle single use technology when it arrives at your site and when it is installed in your process.
A second concern is that plastics contain processing agents (slip agents, antiblock agents, and antioxidants) not used in stainless steel production. These compounds can become extractables that may (i) be a health risk to the patient (e.g. BPA from polycarbonate), (ii) interact with the drug product to form unwanted byproducts (e.g. protein interaction with silicone oil to produce aggregates), or (iii) interfere with the production of the drug product (e.g. the antioxidant Irgafos 168, whose gamma breakdown byproduct (bis-di-tert-butyl phenol phosphate (bis-DtBPP) has been shown to retard cell growth in the bioreactor). This concern can be avoided by selecting single use assemblies that are compatible with your application and having the data to prove that they are robust and will not affect your product or process.
Schmidt: Supplier dependency, long lead times, high running costs, leaks and other quality issues, incomplete leachable and extractable information.
Potter: Especially with downstream processes, a big concern for pharma companies is that the BDS, which often has a very high value at that point, comes into direct contact with products supplied by a third party – the SUT supplier. The pharma company does not have direct control over the quality of the SUT product. It is critical that the pharma company develops a very strong partnership with the SUT supplier and treats them as an extension of the company. The closer and more frequent the communication, the less likelihood of problems occurring.
Seymour: While widely accepted, there are still concerns with some SU technologies. For example, SU bioreactors and bags still have some relatively high failure rates regarding integrity. Post use integrity testing being applied on up stream side and methods establishing integrity of system have gotten much more attention; if a user does a “use test” they risk damaging bag; there is a risk in too much testing on these SU technologies; pressure testing can damage assembly (not reliable); leak testing not reliable
Unfortunately, there is no “gold standard” test for integrity other than using it, and once used, the user has committed all consumables so this is big cost
Some CMOs have reported that 50% of SU component failures don’t show up until they run the process; 50% are id’d when received, etc.
Also, some customers have more failure rates due to more extensive testing that are excessive.
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, single-use 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?
Bulpin: Small volume parenterals, regenerative medicine, gene therapy and ophthalmic drugs may all be produced with single-use technology that is available today. Historically, the components only needed to be compatible with aqueous solutions or very dilute organic solutions. However, more applications such as antibody-drug conjugates, which use stronger solvents, are looking to capitalize on the benefits of SUTs. The components will need additional testing to demonstrate compatibility with these new solvent streams.
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 single-use technologies?
Bulpin: More growth in their use. Innovations in aseptic connectors, films, downstream process technologies, automation and improved quality will enable the implementation of single-use technologies across broader scales and more critical applications. I believe that turnkey solutions will become prevalent, providing complete processing suites along with the documentation and regulatory packages necessary to streamline the end-user’s path to marketing approval. Some of the key components are also expected to evolve over time, such as pumps and sensors, becoming better tailored to current applications and opening up new applications, aided by feedback from the accumulating end-user experiences.
Schmidt: More integrated solutions, more application in market supply, more use in continuous processing.
Potter: SUT, or disposable technologies are here to stay. Continued work by BPSA, BPOG and others will result in easier and more successful implementation of SUT by pharma companies. But the SUT suppliers must also work hard on standardization, which in turn will help pharma companies adopt SUT more easily. I think the SUT business will look very different in five years’ time: there will be more standardization in solutions and even more widespread adoption by pharma companies.
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.