Securing Supply In Single-Use Systems — The Second-Source Decision

By Wayne Koberstein

The use of disposable systems for bioprocessing manufacturing has become a viable and cost-effective way for many pharmaceutical manufacturers to handle bioproduction requirements during clinical trials of drug candidates. The impact of single-use systems on cost reduction in manufacturing has been well-documented elsewhere. However, a company’s reliance on such systems also comes with a stronger tie to the suppliers of single-use systems and components, because only products qualified for use and validated in the process can be used in production. What happens if the supplier cannot deliver?

Recently, geographic and environmental events, such as the Japan earthquake and tsunami, have disrupted many resin suppliers, which is the basis of all of the films used in single-use systems. Qualifying a second source for supply of products is a logical solution and can reduce the risk of manufacturing supply gaps, but qualifying each supplier is costly. And so, how does a manufacturing executive balance the risk against the reward of the second supplier?

Here we describe the context, challenges, and consequences of single-use supply disruption — looking at available solutions; focusing on the benefits, costs, and criteria for choosing a second-source solution; and examining the current and long-term implications for single-use technology and supply. In practice, the term “second source” may actually refer to multiple sources for different sets of single-use components.

VULNERABLE STATES
Supply-chain management in traditional biopharmaceutical production technology mainly concerns raw materials such as medium and column resins. Single-use technology requires a wider management strategy.

“By working with single-use technology, producers massively extend the supply chain to include all single-use components on top of the raw materials,” says Alain Pralong, former VP of process development at Crucell and now head of Pharma-Consulting ENABLE. “Hence, procurement, storage, and QC need to be set up to match the new requirements.”

Generally, procurement should ensure the manufacturer has enough stock of single-use components to maintain operations for four to six months, depending on how long it would take to replenish them. Because most single-use components can be sterilized by gamma radiation and used up to five years thereafter, the risk of maintaining larger stocks is low.

Beyond stockpiling, the only other way to reduce vulnerability to supply interruptions is to secure and validate second sources, compatible with the first. All suppliers must be fully qualified, including QC release (conformance with use specifications) and validation of the process as well as leachables and extractables.

“It comes down to excellence in supply chain management that includes qualification of suppliers, keeping the leachables and extractables validation up to date, and using well-planned QC-release procedures,” Pralong says. In short, the manufacturer must have a system that allows release of disposables based on the qualifying certificates supplied with the single-use components. Lack of efficient, advance supplier qualification puts the production line at risk, he says. “In general, the risk of supply disruption is biggest when the organization is immature with regard to activity planning, demand forecast, and procurement.”

TRUTH & CONSEQUENCES
Even with the best planning, stocks may not outlast a disruption in supplies. The worst case scenario is that the company must stop production until a new supplier has passed qualification and validation — a complete regulatory review of all batch manufacturing and packaging records for correctness, completeness, and compliance to GMP standards. (See http://www.cgmp.com/qcRelease.htm.)

The obvious but still challenging solution is to already have a second qualified supplier in place. Additional suppliers may be necessary to cover all components, except for integrated systems that offer bags equipped with tubing, connectors, and filter cartridges. For example, the ready-to-use bag assemblies in Xcellerex systems can be supplied by Advanced Scientifics or Charter Medical, among others.

Among all single-use system components, bioreactors and mixer systems are the most critical because they are used together with specific hardware. For customized parts, second supply can only be assured if the integrated-system supplier grants licenses to other suppliers of bag assemblies. Nonlicensing suppliers usually have manufacturing sites at multiple locations to mitigate disruption risk, but global corporate procurement and warehousing guidelines could threaten that strategy.

For example, special components are used in bioreactors and mixers to enable engine drives with magnetic couplings which are supplier-specific. With such components, a second-source approach might be difficult due to technical complexity and IP considerations. Thus, warehousing and stringent quality control mitigate the manufacturer’s risk.

Pralong cites a real-life experience with supply disruption at Crucell in the form of delivery delays with key components, which “required quite some management to keep the programs on track.” A complicating factor was that suppliers do not offer standard bag manifolds “without further customization, as a baseline product for purchase on short notice.”

Films — the basic material of bags used for storage of media, buffers, and process intermediates, as well as in mixer and bioreactor vessels — represent the most problematic supply issue, as the Japanese situation attests. For all other items, alternate suppliers are readily available. Film suppliers are not only few in number, but each one is also unique; there are no common film standards.
“When complete and extruded films are the base of the supply issue, then manufacturers are stuck,” says Pralong. “Hence, having enough film-based material in stock, or better, owning the technology to do film extrusion from raw materials is critical.”

RESPONSE STEPS
Manufacturers’ immediate response to a supply disruption should include the following: Notify customers, and thereafter keep them informed; keep the supply repartition between two suppliers equal, thereby lowering the risk of a supply gap before the second supplier ramps up; and turn to noncustomized components that can be adapted by adding filter cartridges and other components in-house, which requires much more work than using ready-to-use assemblies but can prevent a production halt. It is possible to validate entirely new single-use components (other than bioreactors and mixers) but that might take more time than is feasible, according to Pralong. Similarly, he believes having a backup, stainless-steel system is impractical because “the maintenance, qualification, and validation effort is too big.”

Ideally, manufacturers should prepare before disruptions occur by working with customers on risk-mitigation strategies in the design of customized components and leachables/extractables validation. Specifically, they must qualify several connector, tubing, and filter producers to build and supply customized single-use components. That stage must be managed in concert with customers to ensure they take the possibilities for second-supply into consideration for process validation.

Several major steps are involved in engaging a second source:
1) audit of the supplier and assessment of the quality system in place, continuous oversight, and quality control
2) leachables/extractables studies to complete validation requirements
3) validation of connections, gamma irradiation, etc.
Pralong estimates completing the steps will typically take from five to nine months, depending on the component. Securing the second source will also require an assurance of “significant business” for the backup supplier, he says: “Ninety percent for supplier A vs. 10% for supplier B does not work.”

How does a biomanufacturing executive balance the risk and reward of having a second supplier to decide whether one is appropriate? A second supplier takes more effort, but mitigates the risk of losing supply — only, that is, if the first and second suppliers are fully integrated into the risk-mitigation approach, including full process validation, on the customer side.

The current lack of standard product specifications among single-use suppliers becomes even more problematic when a major supply source is interrupted. All suppliers provide validation guides showing data on leachables and extractables gathered according to U.S. Pharmacopeia and European Pharmacopeia guidelines (USP 661 and EP 3.1.5). But, to perform a process-specific, leachables/extractables validation would require full testing and analysis of reactions, including toxic byproducts, among all materials and components from all suppliers. “Clear common guidelines should be established to take away most of this burden from manufacturers using single-use systems,” Pralong says. “This would require a major collaboration initiative of the different suppliers of single-use components to match chemistries so that potential cross-reactions are prevented.”

Standardization will also have to occur in other forms: consistency of single-use technology adoption, supply, and regulation among world regions. Although most of the new single-use technology originates in the United States, Asia may lead in actual adoption by the pharma industry and its regulators. Thus, a crisis in Asia can affect supply in the United States and Europe.

SINGULAR AFFIRMATION
Could supply disruption be the Achilles’ heel for single-use technology? Among traditionalists, even the potential for such cutoffs strengthens the case for stainless-steel versus single-use technology. But Pralong draws the opposite lesson.

“At first glance, traditional technology seems safer from the supply point of view. But, its dependence on huge amounts of water and utilities — as well as the whole control, monitoring, and validation process — makes it more vulnerable to poor output than single-use components,” he concludes. “The risks of single-use sourcing can be mitigated through a mature and holistic approach to demand planning, procurement, warehousing, QA oversight, and QC release. It is also important that the single-use suppliers be aware of their impact on their customers’ process validation and drug-product supply.”

Supply & Demand

Alain Pralong, former head of process development at Crucell, believes the only remedy for the dependence of U.S. and European companies on Asian suppliers is greater overall acceptance and adoption of single-use technology: “Dependence on non-U.S. suppliers for single-use components can be mitigated by creating a basis for business in this field within the United States and Europe. To do that, decision makers have to change their ways of thinking. U.S. and European suppliers have to wake up before they lose biomanufacturing to Asian and emergent countries, which are much more open to new technologies offering them major cost benefits.”

Pralong sees a bright future for single-use as the technology further develops: “The increase in productivity and the development of high-capacity membrane chromatography (e.g. Natrix Separations) in downstream bioprocessing allows manufacturing of biopharmaceuticals, such as antibodies, at much smaller scales that are today already within the range of what can be done with single-use components (up to 2000L). There are, however, processes (especially microbial) that will continue to rely on traditional, stainless-steel technology due to size and physical/chemical constraints for which single-use components are not designed. Hence, both technologies will coexist. But using traditional technology for antibodies will prove too expensive in the future.”