OR WAIT null SECS
Single-use systems (SUS) have become established in biopharmaceutical drug development. As confidence in the technology has increased, the adoption of disposable equipment for commercial manufacturing has begun to take place. With this shift has come a dependence on suppliers that is related to production capabilities, a situation that did not previously exist. This reliance on suppliers translates to increased risk, and consequently biopharmaceutical manufacturers are focused on managing this risk and ensuring security of supply. Dual sourcing of single-use systems and components was initially proposed as the key solution. After further consideration of the issues surrounding the supply of single-use systems, however, many in the industry believe that dual sourcing presents many challenges that can often be avoided by taking alternative approaches.
Today, single-use systems are used throughout the entire process chain from upstream to downstream and from bench scale to production scale. In the past, when drugs were manufactured in stainless steel, the manufacturer was in control of the infrastructure once its facility was in place, sourcing only critical disposable components such as filters and chromatography sorbents. Although disposable systems do provide numerous advantages, such as reduced contamination risks, shorter set-up times, and lower capital costs, biopharmaceutical manufacturers do not have that same level of control over the disposable systems as they did with traditional stainless-steel equipment because the systems and components must be purchased from a supplier, according to John Briggs, director of quality, regulatory, and compliance at ASI-Life Sciences. As a result, adds Mario Philips, vice-president of single-use technologies at Pall Life Sciences, there is a greater dependence on the single-use supplier, which increases the risk for the manufacturer and thus requires greater vendor transparency and supply-chain security.
“Unlike with traditional equipment, where almost everything is physically located at the facility, single-use systems are delivered to the site from a supplier. If the user operates on a just-in-time basis with no inventory, any delay in delivery could put the manufacturing schedule at risk. Consequently, an SUS is a critical part of drug substance manufacturing, and there is a greater need to understand and secure the sourcing of these systems,” says Roman Rodriguez, global market development manager for single-use technologies with EMD Millipore. As such, it is logical to consider qualifying a back-up supplier as part of the SUS risk-management system, and dual sourcing is a response to a need for anticipating unforeseen issues and scenarios.
The implementation of single-use systems in commercial manufacturing has had the additional consequence of shifting the purchasing of these systems from those in development to sourcing professionals. As a result, according to Tony White, a founding director of the BioPhorum Operations Group (BPOG), some biopharmaceutical manufacturers are now starting to consider single-use technologies as a strategic commodity and managing their purchases across their manufacturing network, which often leads to the identification of risks that were not previously perceived. “In addition,” says White, “they are realizing that they have been single-sourcing key components by default--a position they do not find very comfortable.”
Past experience with SUS sourcing problems is also a driver for the increasing focus on multisourcing, according to Terry Hudson, director of process development engineering with Genentech. “At any conference with single-use as a topic, you can find a case study or conversation about a single-use component being changed with either no prior notification or inadequate notification to the end user, and in several cases that has been tied to a negative impact on production,” he explains. In addition, Hudson notes that companies are also learning that occasionally a given process may be more sensitive to a leachable or film type than other processes, and it is beneficial to have an alternative film that can be used with that process.
There are regulatory drivers as well. Regulatory authorities have had a clear and simple message with respect to single-use products, according to Ross Acucena, product strategy manager-ReadyToProcess with GE Healthcare Life Sciences, which is that their use is analogous to outsourcing crucial elements of GMP operations, such as presterilization. “The role of the supplier is therefore now more critical, and regulators expect drug manufacturers to mitigate any risk with close partnerships and thorough knowledge of their suppliers’ quality systems and supply chains,” he says. Furthermore, the increased focus on suppliers has highlighted the fact that SUS supply chains are both broad and deep because of the integration of many components into the end products. “Single-use customers recognize that it is difficult to fully control the supply chain, which presents a potential risk to their operations and subsequent supply of needed drugs to patients,” Acucena asserts. The industry response has been to increase its focus on mitigating such risk through multisourcing.
Different views of dual sourcing
The ultimate goal of multisourcing is to have the ability to seamlessly transfer from one single-use product source to another without risk to patient safety, according to Acucena. “There is a strong need to characterize and understand this issue for all parties in the complex supply chains that exist within the industry. Upon investigation, it may materialize that some parties have a robust supply chain where risk is small. The converse is that unacceptably high levels of risk are detected, requiring either dual-source or multisource strategies, or even exiting a specific relationship,” he observes.
In an ideal state, according to Hudson, the multisourced component would be supplied by two different companies with different supply chains to minimize the potential for a single change impacting both components. At a minimum, multisourcing needs to provide assurance that a change or disruption to one source will not also occur at the second source. Thus, risk mitigation can be achieved by using one vendor that has two plants or by using two separate vendors. “The latter option also provides some commercial leverage and tends to be the preferred approach for end users,” Philips says, “but a lack of industry standards for single-use systems makes it more difficult, if not impossible.” Not surprisingly, suppliers prefer the dual site or manufacturing redundancy concept, according to Spencer Parkinson, senior product manager for bioproduction with Thermo Fisher Scientific. “If it is truly assurance of supply that is of interest, then more than one production site addresses this need, while allowing a supplier to provide ‘best-in-class’ products,” he notes.
For Rodriguez, multisourcing is the basic view, and the real issue relates to supply chain understanding, assurance, and control, as well as taking action to reduce inherent risks. “Doing so is not as easy as it seems due to supply chain complexity down to the resin suppliers and the varying approaches that can be taken. It really starts with a close interaction with SUS integrators on a whole supply chain view. An alternative supplier’s products must be assessed with the same science-based qualification process, and if different suppliers adopt slightly different approaches, the end-user must determine what is acceptable,” he says. As an example, Rodriguez points to bioburden levels, which can be tested on every single lot or using a statistical approach. Both methods may be acceptable depending on the end-user’s specifications.
The challenges of complexity and cost
There are numerous challenges when considering true dual sourcing, and many relate to the complexity of the single-use supply chain. The SUS business is highly customized, and there are thousands of single-use components, many of which only work with other components made by the same supplier. Of course, not all those components need the same scrutiny depending on their criticality and demand, according to Rodriguez, but due to the huge number of components and suppliers, it is a complex task to track and understand the supply chain to secure and control it. As an integrator, EMD Millipore has prioritized and ranked SUSs based on criteria (i.e., criticality, volume used, lead time, reliability of the suppliers) and customer interaction.
Qualification and validation are, in fact, the critical criteria that must be met to achieve dual sourcing, according to Acucena. “To achieve dual sourcing, one must have documented evidence that a change in input (product contact materials) will not affect the output (product quality, efficacy, safety), and it is ultimately through qualification and validation that such assurance is achieved,” he notes.
ASI-Life Sciences is taking a close look at how to demonstrate functional equivalency of materials obtained from different suppliers. “At this point there is no standard or definition for functional equivalency, but it is necessary to define what constitutes functionally equivalent materials in order to ensure change control,” Briggs observes.
“The challenge lies in the fact that proprietary plastics/elastomers are used by different suppliers, and thus composition alone cannot be used to determine equivalency, and other characteristics, such as the physical and chemical properties of the single-use product and its performance under process conditions must be evaluated. In addition, the ability to integrate the product into an end-user process and the quality system of the supplier must also be considered,” he comments.
Standardization is frequently raised as another issue for dual sourcing of single-use systems. Philips notes that with limited standards in place, variation in SUS design continues to be significant, and it is much harder to have contingency in supply. Hudson agrees that the main challenge to dual sourcing is the current business model used by most single-use companies, which involves the development of hardware for a SUS that will only work with their single-use components. “This approach for end users is a significant impediment to deploying such systems into a GMP environment. Until companies are willing to standardize enough on their design that they fit more than one single-use assembly, including an assembly from another company, it will be difficult to achieve true dual sourcing,” says Hudson.
Parkinson, on the other hand, argues that standardization would lead to a halt in innovation. “Single-use products are not commodities and will not be in the foreseeable future; innovation is critical to improving the technology. While it also leads to the development of different designs and materials by each vendor, improvements would not occur otherwise” he states.
The continued advancement of single-use technology adds to the complexity, however, with new products constantly introduced that require change management. “We are aiming at full process integration by adding supply chain considerations from the lead times associated with single-use items, which requires discussions with the end-user because it is an integral part of technology transfers into manufacturing operations,” Rodriguez says. “Obviously the primary action is to communicate and build a basis of understanding about the supply chain itself and the potential associated risks, which naturally leads to actions to minimize those risks at every level of the supply chain, starting with the single-use integrator. Focusing on the product attributes, quality, and specifications may not be enough, however, as there are other steps involved such as sterilization and transportation (sometimes international) that may impact the product and lead time. Ultimately, therefore, the first challenge is to get a clear understanding of the supply chain, to communicate about it, and then establish an action plan on a case-by-case basis,” he continues.
Thoroughly understanding the supply chain is, however, an intense endeavor that requires significant resources, according to Acucena. He in particular points to the case where two SUS suppliers purchase equipment from the same precursor company, and thus qualifying the two SUS suppliers does not achieve dual sourcing. He also notes that there are significant costs associated with qualifying dual-source suppliers, and the value of such an investment is an important consideration. “In essence,” says Acucena, “dual-sourcing or multisourcing can be likened to an ‘insurance policy’ that is relatively expensive to buy.”
Not the only option
While the initial reaction of many biopharmaceutical manufacturers to concerns over single-use supply chain security was to look at dual-sourcing solutions, the focus has since shifted to the broader issue of security of supply and how best to manage it, according to Acucena. “The need is security of supply,” agrees Kevin Ott, executive director of the Bio-Process Systems Alliance (BPSA). He adds that dual sourcing is one possible solution, but there are others with fewer validation challenges, including redundant supply sources from a single vendor and inventory plans, for example. “The question,” he continues, “also becomes complicated by how far back in the supply chain one needs to go. That depends on volume versus demand, structure of the supply chain, etc.”
For example, Ott notes that suppliers of biocontainers that can assemble containers in two locations and carry sufficient inventory of finished units and film to cover film supply disruptions do not necessarily need to be dual sourced to ensure continuity of supply, just perhaps be “dual located.”
“The justification for dual sourcing should depend on the risk and the level of simplicity, and single sourcing is in many cases appropriate as long as the relationship between the supplier and the end user is a partnership,” asserts White. He notes that many automotive manufacturers only single source strategically important materials because the investment in establishing a reliable supplier is significant and not worth doubling.
One alternative to dual sourcing is, according to Philips, to limit the number of contact materials in single-use systems and aim to create interchangeability for any layer (e.g., films, filters, valves, and tubes) that comes in contact with a drug product. Pall Life Sciences has taken a step forward in this direction by vertically integrating its own production processes one step back in the supply chain. The company uses its own in-house extruded film to make the supply chain more robust and is working to mitigate any potential changes from resin suppliers. “While we can’t prevent change, we are prepared to manage that change, and if we fully understand our supply chain, we have the power to support customers through any change that may occur through our supply strategy, which adds up to an increased ability to offer a greater level of supply-chain security and continuity to users,” remarks Philips.
Business continuity planning and inventory management are additional mechanisms for reducing risk, according to Acucena. He notes that suppliers are now engaged in an increased focus on these aspects, and thus the crucial first step of increasing industry awareness is already taking place. He also notes that the experience with reducing the risk associated with the single-sourcing of critical chromatography media, such as protein A, can be translated to single-use systems. “GE Healthcare sought to satisfy the industry’s need to mitigate this risk through a strong focus on business continuity planning (in accordance with ISO 22301 and achieving conformance to this standard), including qualifying dual sources for critical raw materials and a significant investment in safety stock. These efforts have delivered supply-chain security improvements that should help to eliminate end-user dual sourcing. Similar approaches should be applicable to single-use technology,” he explains.
Both White and Ott also note that focusing on dual sourcing at this stage in the industry’s development may not be appropriate. “Many biopharmaceutical manufacturers are not yet in a good position to dual source, as they are just starting to understand the extent of their complete single-use portfolios across their networks,” White says. Ott adds that it may be premature or counterproductive to imagine risks. “It is better to actually study, evaluate, and understand your own supply chain and the real risks. Once that is done, the need to establish truly independent dual sources and the difficulty that such an approach represents with respect to validation and regulatory filing begins to look like much less of an issue than might be imagined,” he comments.
Supply-chain security is a top challenge for both BPSA and BPOG moving forward into 2015. The Parenteral Drug Association (PDA) is also working on concepts to facilitate multisourcing. While these initiatives are important, Philips would prefer to see vendors, users, and regulators working together to bring one set of standards forward, rather than multiple associations working on multiple standards. “The biopharmaceutical industry is still a relatively immature industry, and substantial changes can be expected over the coming decade. Standardization is going to be a key element of true multisourcing, and having one body regulating the industry will make supply chains more transparent and keep user expectations realistic,” he says.
Many of the industry-wide initiatives already underway to provide standardization and guidance on change notification, leachable/extractable testing, and other end-user needs for increased adoption of single-use systems, and particularly for components and systems that already allow some interchangeability such as buffer bags and tubing connectors, will help speed up multisourcing, according to Hudson. On the other hand, where the supplier’s business model is to design a system that only works with its components, education is the key. “Genentech recently presented a proof-of-concept design for a single-use bioreactor that could work with top- and bottom-mounted bags from two different suppliers. The next step is convincing management at suppliers that designs such as this one will lead to higher future sales because they help open the doors to more GMP applications and greater adoption of single-use technology in general,” he states. Genentech is also partnering with several single-use supplier companies to gain greater visibility into their supply chains, to provide recommendations on what it considers “multisourced”, and to communicate what applications of single-use simply will not occur until they can be multisourced.
EMD Millipore, meanwhile, in addition to implementing a business continuity plan and supply risk management and emergency management programs focusing on products, suppliers, and its sites, respectively, has teamed with a third party (Resilinc Corporation) to map its supply chain for key products and suppliers to identify and mitigate risks with suppliers, according to Rodriguez.
In its quest to identify a practical approach for determining the functional equivalency of unassembled components, ASI-Life Sciences submitted platinum-cured silicone tubing with similar specifications, mechanical properties, and performance profiles under typical use conditions obtained from two suppliers to Chemic Laboratories for comparative analysis of their extractable/leachable profiles. “Tubing was selected for this exercise because it is a common component of single-use systems and can be evaluated in a fairly straightforward manner,” Briggs observes. Importantly, no significant differences in the extraction profiles were observed for the two tubing samples. “These results indicated that the materials were comparable within the variability of the analytical techniques used,” Briggs says. He also recognizes that tubing is a universal single-use component, and establishing the functional equivalency of other, more proprietary single-use systems and components will be more challenging. “Our goal is to initiate a dialogue around the practical considerations for achieving dual sourcing of single-use systems.”
Article Details Pharmaceutical Technology
Vol. 38, Issue 12
Pages: 24–26, 57
Citation: When referring to this article, please cite it as C. Challener, "Securing the Single-Use Supply Chain," Pharmaceutical Technology 38 (12) 2014.