As the bioprocess industry progressively adopts single-use technologies for large-scale manufacturing (1, 2), biomanufacturers’ increased reliance on integrators for critical production equipment continues to raise concerns about supply chain security. The need to mitigate risks associated with the supply of single-use components (e.g., bioreactors, aseptic connectors, tubing, filters) has led to growing interest in the dual sourcing of those materials. To that end, integrators and end users alike are exploring the definition of functionally equivalent products, how functional equivalency can be demonstrated, and strategies for managing functionally equivalent parts.
Using platinum-cured silicone tubing as an example, ASI-Life Sciences proposed a way to define functional equivalency and demonstrate functional equivalency of materials from two suppliers, with a third party (Chemic Laboratories) conducting the necessary tests. Our methods includes two options for managing the dual supply of tubing.
Risk Mitigation Through Redundancy in the Supply Chain
Single-use systems have largely been used in clinical settings, and only recently has the biologics industry begun to make a concerted move toward using disposable processing technology for large-scale manufacturing. Switching from permanent, stainless-steel processing equipment to single-use systems offers many advantages, including reduced contamination risks, shorter set-up times, and lower capital and consumable expenditures. On the other hand, end users do not have as much control over single-use (3) process trains as they do of multiuse equipment because of the large variety and number of components. They depend on integrators to provide the needed disposable systems and components. As a result, implementation of single-use processes introduces supply chain risk and consequently raises concerns about supply chain security.
To mitigate supply chain risks, end users expect integrators to have dual supply sources of single-use components so that (in theory) they can seamlessly — and with applicable change control — interchange one supplier’s functionally equivalent component with an alternative supplier’s component. The use of an approved second supplier can minimize impact of a supply interruption on a single-use manufacturing process. This approach assumes that a single-use supplier would be able to source “functionally equivalent” material from two suppliers and be able to rapidly and controllably switch from the first to the second source without affecting production or cost. That would need to be done while maintaining full traceability as well as change and document control.
Dual sourcing requires identification of two completely independent suppliers or manufacturing facilities with no overlap in their supply chains. Those suppliers would offer equivalent materials with respect to both physicochemical properties and functional performance.
Defining Functional Equivalency
Unfortunately, dual sourcing is a challenge because no standard or definition has yet been established for the term functionally equivalent (4). For dual sourcing of single-use systems to be achievable, end users, integrators, and regulators together must define what constitutes functionally equivalent materials. Without such a definition, change control will remain a significant hurdle.
Some chemical products from different suppliers can be tested to determine whether they are equivalent. The same is not readily achieved for plastics and/or elastomers used to produce single-use systems. All material, component, and film suppliers have their own proprietary formulations that are designed to impart certain sets of characteristics. Therefore, composition alone cannot be used to determine equivalency. So functional equivalency must be based on physical and chemical properties of a single-use product or component, as well as its performance under process conditions. At minimum, the following five criteria should be used to determine functional equivalency:
- output (what a material does and its intended purpose)
- composition (a material’s specifications and mechanical attributes)
- integration (how a material is applied in an end-user process and in the supplier’s manufacturing process)
- geometry (a material’s form)
- quality (a supplier’s internal quality management system).
Plastic- or elastomer-derived components that are intended for use in integrated single-use systems must meet certain criteria. Such requirements include a component’s physical properties, (including temperature and chemical/solvent resistance and sterilization stability), mechanical properties (such as tensile strength and glass transition temperature), and extractable profile. In addition, characteristics of a supplier must be considered, including its manufacturing process, lead time, capacity, and its own supplier approval process.
Some physical and mechanical properties can be assessed by comparing product specifications. But other properties need additional physical and/or chemical testing. Some industry experts recommend that an independent third-party laboratory perform such testing.
It is important to note that functional equivalency cannot be defined with a “one size fits all” rationale. For example, the intended use and residency time of a component also will dictate the level of equivalency. Tubing and other pass-through components (through which a fluid flows) should be considered on a different tier than films that contact fluid for days or months.
Platinum-Cured Silicone Tubing: A Comparative Study
As an integrator of single-use systems, ASI is seeking a practical approach for implementing dual sourcing of its unassembled components, including determining functional equivalency. To test this proposed option, ASI elected to focus on platinum-cured silicone tubing (5) because of its wide use in biopharmaceutical manufacturing. Demonstrating equivalence of the physical properties and functional performance of platinum-cured silicone tubing materials is relatively straightforward. However, one question is whether extractable profiles can be sufficiently similar such that two tubing materials are considered to be functionally equivalent.
To address that question, ASI commissioned Chemic Laboratories to complete an independent, blinded, comparative study of extractables from two platinum-cured silicone tubing materials with similar specifications, mechanical properties, and performance profiles under typical use conditions. Test materials were incubated in different solvents (USP purified water, 50% ethanol/USP purified water, hexane, and 5% HNO3) with orbital shaking at 80 rpm and 40 °C for 24 and 48 hours. Analysts then assayed the solvent extracts using qualitative and quantitative analytical methods developed by Chemic Laboratories, including high-performance liquid chromatography equipped with diode array and mass spectrometry detectors (HPLC-DAD/MS), direct injection and headspace gas chromatography/ mass spectrometry (HS-GC/MS and DI-GC/MS), and inductively coupled plasma/mass spectrometry (ICP/MS). Those methods were chosen because they can detect a diverse range of chemicals, including volatile, semivolatile, and nonvolatile organic compounds as well as inorganic metals as extractables.
Analysts found no significant differences in the extraction profiles of the two tubing materials. No extractable antioxidants, additives, or volatile compounds were present in either product. Comparable concentrations of total extractable linear siloxanes were detected, with the exception of trace concentrations of cyclic siloxanes observed in one tubing material in the 50% EtOH extracts. The only notable difference was the presence of trace concentrations (<0.01 μg/cm2) of extractable platinum observed in one of the tubing products. The detected levels were sufficiently low as to be considered insignificant. The two assayed tubing materials generated similar extraction profiles when subjected to the same extraction and assay conditions, and analysts concluded that they are comparable within the variability of the analytical techniques used in this study.
The study intentionally used more aggressive conditions than those found in typical biopharmaceutical processes. Doing so ensures that the extraction of all possible substances at detectable levels allows a comparison of the data. Thus, extraction profiles predict the tubing to be equivalent when exposed to more benign, at-use process conditions and therefore interchangeable from an extractable perspective when used in single-use bioprocess systems.
Options for Managing Dual Suppliers
Determining the functional equivalency of two materials from different suppliers is the first step. Once dual suppliers of a material have been identified, both supply chains must be properly managed. To ensure true interchangeability of one component for another, an end user can specify a single part number that directly cross references the suppliers’ product numbers on the bill of materials (BOM). This enables complete traceability and direct change control.
The question then remains whether traceability of a single part number with a preapproved, interchangeable BOM for equivalent materials is sufficient for a customer. If such an approach is adopted, then an integrator could choose when to purchase the raw material and thus treat the two materials as interchangeable. In other words, an integrator would be able to change the BOM using prespecified substitutes with full traceability maintained. Then the company would specify the material’s preapproved on a BOM. The benefit of this approach is that both supply chains are always functioning, with no delay in supply in the event that an interruption occurs in the supply chain for one source.
In a second scenario, an end user would approve the design and product number with either component A or component B specified. In such a case, that end user determines what product to use and when to use it. Consequently, it is possible that one supply chain will not be used for extended periods. In the event of an interruption in the supply chain of the main source, time will be needed to confirm availability from the second source (which could delay supply). More important, if a second source is not regularly exercised, it may turn out that the supplier is not able to meet the lead time or price originally agreed upon, or the source could cease operations. Consequently, ASI strongly believes that to realize the benefits of dual sourcing, a company should use both sources routinely to ensure both functional and operational equivalency.
Although the bioindustry has shown real interest in dual sourcing of single- use systems to help mitigate risks associated with using disposable processing equipment, uncertainty
remains with respect to strategies for implementation. A number of concerns and issues must be addressed.
For the approach outlined above, with an integrator managing the original equipment manufacturer (OEM) part number, perhaps the greatest challenge will be alleviating concerns regarding transparency and change control. End users must be comfortable with the preapproval of single-use components from different suppliers and the full traceability of materials. Flexibility is required to achieve true dual sourcing, so current regulatory requirements for change control may need to be reconsidered to enable adoption of effective dual sourcing strategies. Whenever possible, end users should make reasonable attempts to add flexibility and latitude into regulatory filings to allow for dual sourcing.
We chose tubing as our example because it is a universal type of single- use component and thus suitable for establishing an initial dual-sourcing approach. Determining functional equivalency and developing approaches for implementating appropriate dual-sourcing strategies can be more challenging for many other types of single-use equipment and parts. For example, aseptic connectors may be considered equivalent, but they are not interchangeable. Single-use bioreactors are constructed of proprietary plastics and designed to have unique performance attributes, so truly functionally equivalent products may not be available. On the other hand, filters from different suppliers often are already qualified for the same process, even though they are not truly interchangeable.
Different industry groups are focusing on the issue of dual sourcing. Both the BioPhorum Operations Group (BPOG) and Bio-Process Systems Alliance (BPSA) are working to define equivalency for dual sourcing. With adoption of any new business approach, however, it is necessary for all stakeholders to share their perspectives on the key issues, which means that moving forward can be a slow process.
As an integrator, ASI recognizes the concerns that end users have regarding supply chain security for single-use processing equipment. The company is actively working to bring together those who can contribute to the development of appropriate dual-sourcing solutions. Its independent laboratory study of silicone tubing materials and the strategy proposed herein for management by the integrator of approved dual-sourced single-use components are important first steps. The goal is to develop an effective approach to dual sourcing. It is also ASI’s hope that these concepts will help to move forward current discussions on functional equivalency and dual-sourcing management strategies.
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5 Pothier N, et al. Extractables Isolated from Two Competitor Pt-Cured Silicone Tubing Materials; A Comparative Study. Single-Use Applications for Biopharmaceutical Manufacturing Conference, IBC Life Sciences, Boston, MA, 2014.
John Briggs is director of quality, regulatory, and compliance (email@example.com); Niraj Chandarana is the director of product development at ASI, 163 Research Lane, Millersburg, PA 17061; nchandarana@asisus. com.