How To Mitigate Single-Use Supply Chain Risks

Nick Hutchinson, Ph.D., Bioprocess Lead, Parker domnick hunter

Against impossible odds you have managed to develop a high-titre, high-yielding, single-use manufacturing process for a biopharmaceutical blockbuster on-time and within budget.  You have wrestled with the laws of physics during scale-up and won. The Quality by Design approach you insisted upon, which has delighted regulators across the globe, will increase operational flexibility. Process validation was a breeze, and with a post-approval lifecycle plan in place, there is time to have numerous free lunches on the conference circuit before accepting an offer of promotion. Is there anything standing in the way now of this molecule’s success?  Hopefully not — especially if detailed consideration has been given to the quality and risk management of the supply chain that forms the foundation upon which your bioprocess palace has been built and must stand for the upcoming years (or even decades).

However, the industry has not yet reached this halcyon state of oversight. For example, never was the need for traceability through the supply chain more tragically demonstrated than in the case of Baxter and the tainted heparin from overseas supply chains which was linked to 80 deaths in the U.S. and caused hundreds of allergic reactions. This example goes to show that manufacturers of pharmaceuticals need to not only understand their immediate suppliers (or tier-one suppliers), but also their tier-two suppliers and beyond, as quality problems with components may originate as far down the chain as tier-three and even tier-four suppliers.

Traceability Challenges In Single-Use Biomanufacturing

The widespread adoption of single-use technologies has exacerbated the problem of traceability within bioprocessing. In contrast to when biomanufacturing facilities contained stainless steel equipment operated with a relatively small proportion of purchased consumables, nowadays, batches of a product can be manufactured with systems in which every product contact surface is a disposable component that must be sourced from the supply chain.

At the beginning of the supply chain, the plastics companies that underpin single-use technology see the biopharmaceuticals market as a relatively small volume yet highly demanding market. Biosimilars, however, are increasing competition among final end-users and putting downwards pressure on prices for single-use technologies. Some biomanufacturers have factored the value of risk-mitigated supply chains into their economic calculations and have been prepared to increase costs to achieve security of supply. Where this doesn’t happen, however, single-use component and assembly manufacturers are in danger of being squeezed by negative pricing forces from both their plastics suppliers and end-user customers. While a higher level of standardization of components such as films and connectors would be a potential solution to traceability issues, suppliers have not yet democratised the technology in this way. Given the current state of non-standardization, oversight of complex protracted supply chains requires greater resources that will lead to increased cost somewhere along the chain.

These costs are relatively small compared to the opportunity cost incurred by biopharmaceutical manufacturers not being able to supply the market demand should a supply chain problem shut down production. Much more significant still is the human cost of patients being unable to obtain the life-saving treatments they require. To avoid this nightmarish scenario, biopharmaceutical companies tend to second-source ‘critical’ components or favour suppliers with redundant supply from multiple locations.

These solutions may mitigate risks to some extent. If an accident at a nuclear power-plant on one continent causes disruptions from a supplier’s nearby facility, then the incident might have no impact on the biomanufacturer if it can switch to supply from an alternative location away from the radiation-leak.

However, when it comes to having two suppliers, we should ask ourselves: Are supply chain vulnerabilities really resolved once we start sourcing from two suppliers? It can be easily argued, not at all, if both suppliers are purchasing some key components, such as a filter cassette or connector, from the same source. In this case, the supply chain is only as strong as its weakest link — in this case the tier-three, component supplier.

A biomanufacturer may choose to specify two of these critical components from two different tier-three suppliers, but this creates further challenges. Studies would need to be performed to demonstrate that the manifolds they are dual-sourcing are equivalent in performance and provide consistent product quality. In addition, two suppliers will need to be audited and two relationships managed. A decision needs to be made about how the business would be allocated to the alternative suppliers that provides incentives to both suppliers to support the manufacturer’s risk management objectives. Mitigating risks in this way leads to a substantial increase in cost due to additional operational complexity. The amount of single-use manifold part numbers will increase substantially and maintaining traceability will become more difficult.

Can Risk Mitigation Stifle Single-Use Innovation?

Dual sourcing of key components may not even be an option for biopharmaceutical manufacturers. Innovative technologies are incorporated into manufacturing processes, not because engineers are looking for the latest and greatest, but because they are a necessity to deliver the product to the market. Patented innovations will not be available from multiple sources. While innovation can originate from companies of any size, many observers recognise that small companies prepared to take risks and able to make rapid decisions play a significant role within our industry in the development and commercialization of new-to-world technology. Vital as small suppliers are, they also provide biomanufacturers with a dilemma, for, as much as they would like to use the technology, they would probably be categorised as higher-risk suppliers given, say, that a high proportion of investments made to develop or expand their business may have been borrowed. Hence, small suppliers can easily become financially distressed if unpredictable operating cash inflows fail to cover interest repayments on loans. Redundancy of supply for companies such as these may be nothing more than a mere pipe dream.

Tier-one and maybe even tier-two suppliers can and should assess their own supply chains for vulnerabilities. There are several continuous-improvement activities that reduce supply chain risk, including: 

• Regularly reviewing the suppliers with which the biopharmaceutical company works
• Working closely with existing suppliers so they understand the needs of the market in which components will eventually be used
• Encouraging suppliers to sign long term supply agreements which detail specific quality requirements that must be delivered

Taking on and overcoming technical challenges is what bioprocess engineers get out of bed in the morning to do, but this is only half of the battle. Great success has been achieved because of the development of modern bioprocesses and bioprocessing technology. However, there also needs to be significant thought placed on how to ensure these processes are carried out effectively.  Biopharmaceutical companies must work closely with their supply chains to ensure patients receive the medicines they desperately need.