Single-use systems (SUS) have become an accepted component of animal-cell–based bioproduction. No longer a merely exciting possibility, they have emerged as a significant and growing resource for companies to use from process development to manufacturing of approved products. Having been examined for years in less regulated environments, off-the-shelf SUS are now in regular use to some extent in nearly every segment of the production train by contract manufacturing organizations (CMOs) and biopharmaceutical companies in mid-scale production applications. For many operations, in fact, the question has evolved from, Is there an SUS available that can support my process? to, Which system best supports my needs?
Drivers of this rapid acceptance and widespread use in such a conservative industry have been well reviewed in recent years as early adopters experimented with emerging technologies and products (1). In general, advantages are found in capital investment, cost of goods, safety, production scheduling, surge capacity, and process replication.
PRODUCT FOCUS: ALL BIOLOGICS
PROCESS FOCUS: UPSTREAM PRODUCTION AND DOWNSTREAM PROCESSING
WHO SHOULD READ: PROCESS DEVELOPMENT, MANUFACTURING, FACILITY DESIGN/ENGINEERING, OPERATIONS
KEYWORDS: BIOREACTORS, DISPOSABLES, PROCESS MODELING, SUSTAINABILITY, QBD, FLEXIBILITY, SEPARATION, PURIFICATION
But this acceptance may not be more generally recognized. Hybrid or integrated implementation is common, with disposable elements operating in line or in concert with reusable materials. Also, bioproduction incorporates many divergent products and production processes, each with its own requirements. Although SUS are now fully accepted for some operations, their potential in others remains to be demonstrated.
Single-use technologies are in a state of remarkable growth, which determines a range of implementation maturity — from systems clearly established by industry leaders to emerging systems being introduced by equipment vendors and academic institutions. Even though such exciting innovations as entirely disposable operations and even closed and modular process trains are possible if yet to be fully realized, the ubiquitous existence and acceptance of an array of disposable components has been firmly established (2,3,4). Reviewed here are some previous concerns regarding SUS implementation that have been clarified recently (Table 1).Table 1: Most initial challenges for SUS have been resolved by many available systems.
Table 3: Many demands on single-use systems (SUS) have been met, but many remain for certain unit operations and available systems.
Cost and Finance Advantages
Although accurate comprehensive models of SUS implementation have turned out to be more complex than originally envisioned, solutions or clear paths forward are now available. To begin with, biopharmaceutical manufacturing costs and their modeling per se are not very perspicuous (5). Nevertheless, the consequences of SUS implementation to facility and operational costs — as well as financial strategies — have been determined for many applications and implementations (6). In fact, a growing number of models and case studies are publicly available and supplied for the most part by independent consultants.
Although the list of general features and advantages provided by disposables is long and growing (see “Demonstrated Advantages” box), the cost and financial implications of a particular system often remains case specific. Project- or facility-specific factors include such considerations as what conventional manufacturing equipment is currently in place; the desired type and timing of expenditures; and the value of capacity expansion, facility replication, or rapid product changeover ease (7).Component Offerings
Introduced over 30 years ago, the first disposable products used in bioproduction included T-flasks, pipettes, and tubings. Since that time, the number and sophistication of SUS has steadily grown. They can now replace stainless steel in entire manufacturing operations. Disposable processing solutions range from such simple equipment as transport containers to completely closed unit operations.
Some advanced systems have been accepted into even the stringent field of biopharmaceutical manufacturing (8). These include process fluid mixing and storage systems, bioreactors, bulk material and product storage and cryopreseveration systems, distribution assemblies and manifolds, sensors, connectors, and a number of disposable filtration and chromatography systems (9). Their “acceptance” by the industry is evidenced by the number of companies successfully using them, their involvement in the manufacture of FDA-approved products, the number of suppliers providing alternative sourcing, and published engineering data (10).
A number of SUS for formulation and holding of media and buffers have been available for some time, supporting 25-L to 2,000-L working volumes (Photo 1). The first mid-scale disposable bioreactors used wave-action agitation, but shortly thereafter, stirred-tank reactors based on marine impellors appeared, paralleling traditional production reactors (Photo 2). Remarkably, more than a dozen styles of disposable bioreactors with capacities of ≥100 L are now available (11), offering process developers a choice of supply and performance features. The number of options is even greater if lesser known, more specialized systems are included (12).