An MD&DI April 1999 Column
New materials developed for use in flexible bags can offer significant advantages.
Polyvinyl chloride (PVC) is widely used in the medical device industry for applications ranging from flexible containers for intravenous solutions or blood to many of the accessories employed in the collection and administration of these substances.
Flexible PVC originally found its way into this medical market segment as a replacement for the glass bottles then used for blood storage (Figure 1). The superior performance and value of PVC containers led to their wide acceptance as both blood bags and IV solution containers. The growth in PVC use has continued, despite constant scrutiny brought on by well-publicized claims that vinyl-containing products represent a health risk or environmental hazard.
Figure 1. Glass IV containers have largely been replaced with flexible PVC bags.
Even though unequivocal data justifying efforts to remove PVC as a material of choice in medical products has not been found, many healthcare companies have nevertheless undertaken programs designed to find replacements for PVC. Prudence dictates that if a company can supply its products in PVC alternatives without loss of function or property characteristics and without cost penalty, it would be sufficiently motivated to consider switching from PVC-based offerings. Although many material options have been shown to be acceptable, the change to new materials is generally influenced by a desire for product improvement or expansion. Feature improvements such as reduced handling or compounding, lower levels of waste generation, or improved product shelf life can drive the change to a new material.
The early efforts to find new materials for blood bags were led by polymer engineers at Fenwal Laboratories Inc. (Morton Grove, IL) in the late 1960s or early 1970s.1 The goal was to identify a replacement material that could be processed like PVC, on the same equipment, with similar assembly methods, making the transition as uncomplicated as possible. Among the materials investigated were polymers such as thermoplastic polyurethanes,2,3 silicone polycarbonate block copolymers, ethylene-vinyl acetate (EVA) copolymers,4 flexible polyesters and copolyesters, and various thermoplastic elastomer and polyolefin blends.5 These plastics presented a familiar product profile to end-users. In film form, they could be radio-frequency (RF) heat-sealed or welded into flexible containers, and the resulting IV bags were steam-sterilizable.
Eventually, alternate processing techniques compatible with the new materialsfor example, multilayer film coextrusion and laminationwere also included in the investigations. Some of the new materials resulted in solution containers with property improvements such as wider use temperatures, higher moisture barriers, or greater strength. In sum, the evolution of a long line of candidate polymers and alternate processing modalities has brought a number of new materials to the forefront as replacement options for PVC. Several of these materials and processing methods will be described in this article.
One drawback to the conversion from PVC containers to other materials is the initial lack of economy of scale that has given PVC such an advantage in the IV-container product line. This hurdle has resulted in a very slow adoption of new products, given that users are generally not willing to pay a premium for alternative materials in the cost-conscious environment of today's market.
EVA polymer is a soft, clear, RF-heat-weldable material that can be manufactured into medical solution containers and tubing sets (Figure 2). Unlike PVC containers, those made from EVA have no plasticizers. However, the surfaces of EVA bags have a higher tendency for abrasion or surface-to-surface tack and adhesion, and the bags cannot survive steam sterilization without additional processing. In addition, the water-barrier properties of EVA are not significantly different from those of PVC. Thus, at first glance, there appears to be little improvement gained by switching to EVA.
Figure 2. A closed system for blood component separation via centrifugation combines EVA and PVC components.
However, by taking additional processing steps with the EVA material, each property weakness can be overcome. Specifically, empty heat-sealed bags can be cross-linked by high-energy radiation to render the material steam-sterilizable. Cross-linking by either gamma or beta irradiation at levels of approximately 50 to 100 kGy (5 to 10 Mrd) has been found to be effective.6 The use of a high-energy electron-beam irradiator is preferable, since the faster rate at which the process occurs yields a lower level of extractables compared with delivering the equivalent dosages using the much slower gamma irradiation process.
The EVA surface-abrasion problem can be managed or resolved by using a matte finish on the film or by taking additional care when handling end products in the autoclave. But the matte finish detracts from bag clarity, and no procedure has been found that would eliminate autoclave footprint on the bottom of processed bags.
The preferred method of solving the surface-abrasion problem is to use a coextruded film with an abrasion-resistant outer material as a skin layer. High-density polyethylene (HDPE) has been shown to be a very effective skin layer and in the appropriate thicknesses is both transparent and sufficiently flexible. Employing a coextruded film with HDPE has the added advantage of improved water-vapor-transmission-rate properties, which can reduce costs by allowing the elimination of the separate overpouch required for PVC bags.7
Other material challenges with EVA were to make tubing, connections, and fitments that were similar to PVC products but without the plasticizers. Each specific design requirement has been satisfactorily met by EVA material, and fabricated products have been taken through stability studies for peritoneal dialysis solutions. The EVA containers were not commercialized as PVC replacements, however, primarily because there was never enough marketing incentive to make the switch. They remain an "on-the-shelf" option.
A material that is clear, RF-sealable, steam-sterilizable, and able to pass all the extractables testing was developed in the 1980s during a lengthy joint development program between Eastman Chemical Co. (Kingsport, TN) and Baxter Healthcare Corp. (Deerfield, IL). This material was a copolyester, and when used as a blood bag it eliminated the extraction of plasticizer into stored blood. Although this polymer was found to be an acceptable alternative to PVC, film-processing complications coupled with superior red-blood-cell survival in the plasticized PVC containers drove the decision to suspend efforts to convert to the polyester material. As a result, Eastman offered the material to Abbott Laboratories (Abbott Park, IL) as a solution-container material. A blow molding process was developed, and the product was eventually marketed as a PVC alternative for packaging the drug product dopamine.
If a clear, flexible, inert polyolefin blend could be developed, it was believed that PVC in blood or IV bags could be replaced through the use, for example, of blow-molded containers (Figure 3). Following years of investigation, a series of materials combining Kraton (Shell Chemical, Houston)a styrene, ethylene-butylene, styrene block copolymerwith EVA and polypropylene was found to have the required properties.5,8 However, one property not previously considered, that of high carbon dioxide permeability, made this an ideal material for long-term storage of blood platelets.
Figure 3. Non-RF-sealable materials can be made into containers using custom blow molding techniques.
Simply put, stored platelets produce CO2, which if not dissipated causes the solution pH to drop, adversely affecting the platelets. If the CO2 dissipates through the bag material, the pH will remain constant, resulting in high platelet survival and enabling longer storage potential. Platelets stored for up to seven days in the polyolefin-blend containers have a higher rate of survival than those stored for three days in PVC.5
Figure 4. Olefin containers continue to offer product benefits with PVC in combination products.
The blow-molded polyolefin blend was never able to replace PVC as an IV bag material since the blow molding process could not compete with the efficiencies of RF-sealed PVC. In this case, however, development of the polyolefin blend allowed a new product to be brought to market that dramatically expanded the viability of blood platelets used in healthcare. In addition, McGaw Inc. (Irvine, CA) has had moderate success with a blow-molded IV solution container, although the product lacks the soft, flexible characteristics of a PVC bag (Figure 4).
Another way to create a PVC alternative is to design a film having the required properties in a composite structure rather than as a single layer (Figure 5). A laminate film structure using linear low-density polyethylene (LLDPE) on both sides of an oriented nylon film results in a clear, flexible IV bag material.9 Of course, this material cannot survive steam sterilization. In conjunction with a process using sterile fill that eliminated the need for terminal sterilization, however, this material has been found acceptable. A program at Baxter Healthcare to make an IV container using form-fill-seal technology and sterile-fill methods resulted in FDA market clearance, representing the first commercialized sterile-fill IV product with a polyolefin laminate film as the bag material.
Figure 5. Olefin laminates can approximate the look and feel of flexible PVC.
In this case, the target product was a heat-sensitive, premixed antibiotic that could not be exposed to steam sterilization without causing decomposition of the drug. In fact, the drug is so sensitive to heat that it needs to be stored frozen until a few hours before its intended time of use.
Prior to the development of the laminate film, the drug was packaged in a mass-produced PVC bag. During shipping and storage, there was a very high rate of product failure caused by the fracture of the PVC material, which became extremely brittle at the storage temperatures used (i.e., below 20°C). At these low temperatures, the glassy PVC often cracked or shattered when the product was handled, and returns from field failures were often reported to be as high as 40 to 50% of product shipped. The obvious solution was to use a material that had good low-temperature properties, such as the LLDPE-nylon laminate developed for this product. The compatibility of the laminate with the sterile-fill technology and form-fill-seal process permitted its successful use.
A product closely related to the laminate film described above uses a barrier material within its structure. This high barrier property enables the film to be employed as an IV container for premixed drugs stored at room temperature. The barrier material selected is Saran from Dow Chemical Co. (Midland, MI), a polyvinylidene chloride (PVdC) film that can be incorporated into the LLDPE-nylon structure using the same sterile-fill and form-fill-seal manufacturing process.
These last two examples show how a product extension can result from taking advantage of the properties of a material option. Because PVC is inherently brittle at the required storage temperatures and incompatible with the form-fill-seal process ultimately used, the change to the laminate film was based on product need rather than on the desire to "get out of PVC."
The latest in the line of materials developed as alternatives to PVC are polyolefins that have the requisite properties of being clear, flexible, RF-heat-sealable and steam-sterilizable. Many of these materials are metallocene-based polymers (e.g., Affinity by Dow, Exact by Exxon, and Engage by DuPont/Dow) that have a functionalized component that makes them RF-sealable and compatible with high-speed, PVC bagmanufacturing equipment.
Even if all other properties of the new materials are the same as those of PVC, the functionalized olefins offer several characteristics that are distinctly advantageous for this product line. The specific gravity or density of olefins results in greater yields on a per-unit basis compared with PVC. The ability to downgauge the films while achieving the same or better properties also adds to the benefits of olefin-film containers,10 while the lack of any plasticizers eliminates questions of product safety related to plasticizer extraction from PVC. Finally, olefin IV containers elicit none of the controversy regarding disposability that has plagued PVC-based products.
It is important to emphasize that research continues to demonstrate the safety of PVC products, whether the issue is plasticizer extraction, effects of PVC as an endocrine disrupter, dioxin levels during incineration, or any other allegation. Nevertheless, if the market is demanding alternative materials, there is a potent incentive to respond to that demand rather than struggling to change the underlying misapprehensions concerning PVC.
Although a number of options exist as alternatives to PVC for medical solution containers, the preferred materials are those that offer an extension to the product line or bestow additional property benefitsas has been shown in the cases of EVA, polyester, blow-molded polyolefin, and laminates. Whereas meeting market demand will sometimes be the motivating factor driving a change in materials, more often than not, product improvements and the desire for enhanced material capabilities will be the reason for PVC's replacement. In conjunction with improved processing techniques, these new materials and others certain to follow will continue to provide practical alternatives to PVC as the material of choice in the medical device industry.
1. Thomas G Cody, Innovating for Health(Deerfield, IL: Baxter International, 1994).
2. Michael Szycher, "Biostability of Polyurethane Elastomers: A Critical Review," in Blood Compatible Materials and Devices (Lancaster, PA: Technomic, 1991).
3. Thomas Darby et al., "An Evaluation of a Polyurethane for Use as a Medical-Grade Plastic," Toxicology and Applied Pharmacology 46 (1978): 449.
4. Daniel Boggs, Flexible collapsible blood freezing containers, U.S. Pat. 4,112,989, 1978.
5. Henry Gajewski, Clear, autoclavable plastic formulation free of liquid plasticizers, U.S. Pat. 4,140,160, 1979.
6. Len Czuba, Method of making a sterilizable multi-layer container, U.S. Pat. 4,892,604, 1990.
7. Dean Laurin, Sterilizable multi-layer plastic materials for medical containers and the like, U.S. Pat. 5,066,290, 1991.
8. M Sweeney, Polymer Blends and Alloys: Guidebook to Commercial Products (Lancaster, PA: Technomic, 1988).
9. William Johnston, Film laminate for sterile flexible containers, U.S. Pat. 4,686,125, 1987.
10. Bruce Lipsitt, "Metallocene Polyethylene Films as Alternatives to Flexible PVC Film for Medical Device Fabrication," in Proceedings of the Society of Plastics Engineers Inc. Annual Technical Conference (ANTEC 97) (Brookfield, CT: SPE, 1997), 2854 2858.
Len Czuba is the director, medical sector, at Herbst LaZar Bell Inc., a product design and development firm located in Chicago.