Medical Device & Diagnostic Industry
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Polyvinyl chloride (PVC) and polyolefins are among the most popular polymers used in medical applications. In 1996, PVC is projected to make up around 27% (750 million pounds) of the total medical plastic volume consumed in the United States (Figure 1). Another 36% of that total will be made up of polyolefins, including high-density polyethylene (HDPE) at about 12%, low-density polyethylene (LDPE) at about 7%, and polypropylene (PP) at about 17% ( Figure 2). However, most of the dollars spent for medical plastics go for minor components made from specialty polymers and engineering plastics. PETG, for example, is the predominant material used for rigid trays, while polyester and nylon are commonly used in medical films and packaging.
PVC is a versatile plastic that can satisfy a wide range of product function, safety, performance, and cost criteria. Plasticized PVC has been widely accepted for use in flexible medical products, and many products made from it have passed critical toxicological, biological, and physiological testing. Nevertheless, because of its connection with toxic by-products of processing and postuse incineration, PVC continues to receive increasing criticism.
As a prospective replacement for PVC, the family of polymers known as metallocene polyolefins has shown great potential. Metallocene polyolefins can deliver many of the same material properties and functions as plasticized PVC. When considering the use of components made from metallocene polyolefins, however, medical producers will also need to assess their suitability from the viewpoints of design, processing, and product performance.
This article discusses the advantages and disadvantages of PVC and metallocene poly-olefins for use in flexible medical products. The challenges that metallocene polyole-fins must meet in order to succeed in today's medical industry are also explored.
As previously mentioned, the factors that govern the development of medical products can be categorized into four distinct areas: material selection, design, processing, and product performance. The detailed requirements of these four areas are listed in Table I on page 134.
These considerations can greatly restrict a manufacturer's choices for developing a product. In the area of material selection, for instance, firms must consider design flexibility, cost-effectiveness, and finished-product safety, quality, and performance.
On the processing side, manufacturers need to consider yield potential as well as a material's ability to be extruded, molded, bonded, sealed, assembled, and sterilized. Additional concerns focus on water-vapor transmission or barrier, oxygen and carbon dioxide permeability, leachable elements, processing window, operating-temperature range, biocompatibility, heavy-metal content, regrind percentage, shelf life, and interference with drugs and solutions.
Selecting Materials. In order of priority, the material selection process for medical products emphasizes safety, performance, and cost. Safety issues are dominated by concerns about possible interactions between plastics and drugs, proteins, blood, biological cells, and medical solutions. Cost has gradually taken on greater importance in recent years because of the cost-reduction pressures related to health-care reform.
The process of selecting suitable materials for medical products begins with the creation of a precise and accurate definition of the product's material and functional requirements (see Table II on page 136). For example, finding the right polymer for an enteral-fluid package or blood container requires simultaneous consideration of design, processing, and performance needs.1 Other critical factors considered at the material selection stage include biocompatibility, leachability, drug-plastic interaction, oxygen and moisture barrier protection, optical clarity, ultraviolet (UV) stability, shelf life, the end-use environment, and total system costs. In addition, designers must consider the demands of downstream operations such as component bonding, assembly, sterilization, shipping, storage, and postuse disposal.
Recent progress in metallocene technology, including the ability to produce inexpensive metallocene catalysts, has led to the development of cheaper metallocene-based polyolefin materials. Metallocene polyolefins have the potential to achieve much better performance than existing polyethylene (PE) and PP formulations. Because they have properties similar to many specialty polymers and engineering plastics, metallocene polyolefins have the potential to replace PVC and some expensive engineering plastics, particularly for medical products requiring high impact strength and ductility at low temperatures. As a result, this polyolefin family is showing great potential for use in the medical and health-care product industries.
To be useful in today's medical products, however, metallocene-based polyolefins must also fulfill product design, processing, and performance criteria simultaneously. To meet these criteria with high product quality at the lowest possible cost will require a broad spectrum of material characteristics and processing capabilities.
Material Performance Versus Product Performance. A polymeric material can be processed in many ways to achieve a desired set of functional characteristics. For this reason, the characteristics of the base material may not be reflected in the performance of the finished product. In reality, that performance reflects the combined influence of material, design, and processing.
For example, plastic film with a low glass-transition temperature (Tg) has a better impact energy than a film with a high Tg. The finished product made with a low-Tg film is expected to have a better cryogenic impact resistance than the product made with a high-Tg film if it is designed and processed properly.
This example indicates that, in addition to a product's material, its design and processing can affect the performance of a finished medical product. Accordingly, it is critical to consider material, design, process, and performance simultaneously at every phase of product development and production.
PVC VERSUS METALLOCENES
Device manufacturers that wish to consider the use of metallocene polyolefins for use in their products or packaging will need to look at a wide range of characteristics. While the major traits of PVC have been established through a long history of use, those related to metallocenes are still emerging as the technologies develop and improve. Following are some of the key advantages and disadvantages of each, as their respective technologies now stand.
Advantages of PVC. PVC can be used to produce a variety of medical products ranging from rigid components to flexible sheeting. The type and amount of plasticizer used determine the compound's Tg, which in turn defines its flexibility and low-temperature characteristics and thereby establishes its range of suitable applications.
Because rigid and flexible PVC components have the same material structure, they can be easily assembled by solvent bonding. The two solvents most commonly used in PVC bonding are cyclohexane and methyl ethyl ketone (MEK). Rigid parts that have been molded of PVC are suitable for ultrasonic bonding, while flexible extruded or calendered PVC films can be sealed using heat or radio-frequency (RF) sealing.
Medical products made from PVC can be sterilized by steam, ethylene oxide, or gamma radiation. Plasticized PVC can have a Tg as low as 40°C and still be suitable for steam sterilization at 121°C. Additional characteristics that make PVC attractive include its low cost, broad Tg spectrum, wide processing-temperature range, high seal strength, thermoplastic elastomerlike material properties, high transparency, wide range of gas permeability, and biocompatibility. Medical products made from PVC have passed critical toxicological, biological, and physiological testing. In sum, PVC is one of the best medical materials in terms of cost and function. No other single material has such broad material latitude.
Disadvantages of PVC. Even though many medical products have been made from PVC, the material continues to receive criticism.2 The most commonly cited shortcomings involve toxic effluents produced during manufacture, and the generation of hydrogen chloride (HCl) during incineration. Because HCl is a component of acid rain, postuse disposal costs for incinerating PVC can be quite high. Other concerns related to PVC depend largely on the type and amount of plasticizers used. For some PVC compounds, there is evidence of plasticizer leaching to medical solutions, chemical interaction with drugs, water-vapor loss during long-term storage of medical solutions, and gas permeability.
Although these disadvantages sound serious, most can be eliminated or managed using existing technologies. For instance, current PVC manufacturing techniques can reduce residual vinyl chloride monomer levels to less than 1 ppm, thus minimizing the toxic effects of the compound. Similarly, modern emission-scrubbing equipment can adequately prevent releases of HCl and other effluents during incineration disposal.
With regard to the leaching of the plasticizer DEHP, however, expert opinion remains divided. California's Safe Drinking Water and Toxic Enforcement Act of 1986 raised concerns about the toxicity of DEHP. But a long-term hemodialysis study that covered more than 7 billion patient-days of exposure resulted in no widely accepted data linking DEHP exposure to carcinogenicity in human beings.3
Advantages of Metallocenes. The rev-olution in polyolefin materials spurred by new metallocene-catalyst technologies has created a great opportunity for medical and health-care industries. High yield, high clarity, high impact resistance, and low extractables are just a few useful characteristics of this plasticizer-free polyolefin family.
Metallocene PP is one group of compounds for which research has shown great potential. Unprecedented control over the microstructure of PP has led to commercial production of syndiotactic PP (s-PP); material scientists are also exploring new elastomeric PP using oscillating catalysts.46 The material properties of these two new PPs are similar to those of thermoplastic elastomers (TPEs), particularly the oscillating catalyst compound, which requires only a propylene monomer. This is different from current commercial PP elastomers that are based on the monomer C3 but have C2 and C4 as comonomers.
Metallocene PE (m-PE), on the other hand, has been targeted for use as a film in the medical packaging industry.7, 8 Enhanced clarity and reductions in both initial seal temperature and crystallinity certainly create many advantages for the packaging industry. Metallocene PE is also expanding into packaging applications traditionally dominated by ethylene-propylene-diene monomer and ethylene-propylene rubber.
There are a number of other characteristics that make metallocene-based polyolefins attractive for use in medical packaging. Most important, the TPE-like materials are chemically inert and do not interact with drugs. Their narrow molecular-weight distribution (MWD) results in low leaching and extractable levels, and their high thermal stability minimizes the need for stabilizers. The materials accommodate gamma radiation, and impact-resistant s-PP film tolerates steam sterilization. Lastly, the compounds are environmentally sound and can be cleanly incinerated or recycled, thereby reducing disposal costs.
Potential Metallocene Disadvantages. The current formulations of metallocenes have a number of disadvantages that researchers may in time overcome. For instance, concern over metal residues makes researchers' efforts to reduce the use of the cocatalyst methylaluminoxane a matter of some urgency. The usefulness of some formulations may also be limited by processing concerns: because of its narrow MWD and long crystallization half-time, for instance, s-PP is difficult to process.
Sealing presents another difficulty. Metallocene polyolefins are suitable for heat sealing, but not for solvent bonding or RF sealing, which are required steps in assembling medical device kits. Similarly, metallocene PE cannot be autoclaved because of its low melting point (Tm). Finally, metallocene technology must still confront the key challenge of cost reduction to meet market constraints.
CHALLENGES FOR METALLOCENE MATERIALS
Although their potential is great, metallocene polyolefins will have to overcome a number of challenges before they gain wide acceptance in the medical and health-care industries. These include concerns in the areas of product safety and resin quality, product design and processing, and product performance.
Safety and Quality. Although metallocene polyolefins can supply many desirable properties and carry out many functions, at present their safety standing is not fully understood because there are not enough historical data. Establishing biocompatibility is perhaps the most important challenge ahead.
Similarly, medical product manufacturers cannot deliver high-quality products without lot-to-lot consistency provided by resin suppliers. Metallocene resin quality, however, will not be established overnight; it will take time and teamwork to learn, fine-tune, and troubleshoot the production lines. Additives and stabilizers different from those used with traditional polyolefins may be required to formulate metallocene medical products that achieve the desired characteristics. Not every commercial additive and stabilizer is suitable for medical applications. Metallocene engineers will therefore have to develop suitable additive and stabilizer packages while preventing toxicity.
Product Design and Processing. In order to meet the design and processing requirements of medical product manufacturers, researchers will need to develop metallocene-based polymers that have suitable material properties and fit into existing production systems. To develop a new metallocene part or to replace a PVC component with one made of metallocene, for example, designers will need to address their compatibility with existing bonding, assembly, and sterilization techniques. Challenges for the future will include how to overcome the limitations of metallocene material properties, how to provide the latitude needed to meet various product design and processing constraints, and how to integrate metallocene materials into an existing pack or kit.
For example, medical products such as blood-collection units and solution bags require clarity, high cryogenic impact strength, and autoclavability.9, 10 Metallocene s-PP is known to have a low modulus and high impact strength at room temperature; however, it has a Tg of 5°C (compared to 40°C for plasticized PVC) and is therefore not a suitable replacement for low-temperature applications (see Table III). Fortunately, an impact modifier used with metallocene PE can enhance its cryogenic impact resistance. As shown in Table III, the low beta peak of m-PE indicates that this formulation can achieve low ductile-brittle transition temperatures. However, the Tm of m-PE is too low to permit steam sterilization.
Metallocene PP and PE by themselves may not meet the bonding and sealing requirements of medical products. Unlike PVC, the molecular structures of metallocene polyolefins have no dipole, and for this reason cannot be sealed using RF. This difficulty can be overcome by enhancing copolymerization and reactor technology or by blending metallocenes with other polyolefins or specialty polymers. To make metallocenes competitive with PVC for RF sealing, metallocene researchers must find a way to copolymerize polar functional groups and introduce dipoles into the molecular structures of PE and PP.
Product Performance. Safety, quality, integrity, functionality, and cost are the key factors that determine a medical product's success in a competitive market. A high-quality product associated with a low cost is the goal of medical device manufacturers throughout the world. To achieve and maintain this goal, manufacturers working with metallocene-based polyolefins must be careful to prevent polyolefin materialdrug interactions, maintain strict quality control, maintain product integrity, prohibit dose concentration change, and keep extraneous costs to a minimum.
Product cost is a function of total system costs, which include costs related to materials, processing, assembly, sealing, scrap, sterilization, QA/QC, packaging, shipping, storage, shelf life, and the end-use environment. The key to making metallocene polyolefins competitive in the medical market may be not the cost of the materials themselves, but the total system costs of products made with them.
Progress in metallocene polyolefin technology has encouraged the medical device industry to take advantage of these newly developed TPE-like materials. But before deciding to use metallocene polyolefins in their medical products, manufacturers will need to simultaneously consider the material, design, processing, and product performance characteristics of the compounds as they relate to every phase of product development and production.
Metallocene polyolefins have a great potential to replace existing PVC formulations and traditional engineering plastics in medical applications. The ability to achieve this goal will depend on cooperation among medical product manufacturers and metallocene resin suppliers.
1. Carmen R, "The Selection of Plastic Materials for Blood Bags," Transfusion Med Rev, 7(1):1, 1993.
2. Goodman D, "Global Markets for Chlorine and PVC: Potential Impacts of Greenpeace Attacks," J Vinyl Technol, 16(3):156, 1994.
3. Finney DC, and David RM, "The Carcinogenic Potential of DEHP in Humans: A Review of the Literature," Med Plast Biomat, 2(1):48, 1994.
4. Shamshoum ES, Sun L, Reddy BR, et al., "Properties and Applications of Low Density Syndiotactic Polypropylene," in Proceedings of the Worldwide Metallocene Conference, Metcon '94, Spring House, PA, Catalyst Consultants, p 30, 1994.
5. Shamshoum ES, "Syndiotactic Polypropylene Catalyst: Properties and Possible Applications," in Proceedings of the Second International Business Forum of Specialty Polyolefins, SPO '92, Brookfield, CT, Society of Plastics Engineers, p 199, 1992.
6. Borman S, "Elastomeric Polypropylene: Oscillating Catalyst Control Microstructure," C&EN, January 16, p 6, 1995.
7. McAlpin JJ, and Stahl GA, "Applications Potential of Exxpol Metallocene-Based Polypropylene," in Proceedings of the Worldwide Metallocene Conference, Metcon '94, Spring House, PA, Catalyst Consultants, p 7, 1994.
8. Knight GW, and Lai S, "Constrained Geometry Catalyst Technology: New Rules for Ethylene Alpha-Olefin InterpolymersUnique Structure and Property Relationships," Polyolefins, vol VIII, Brookfield, CT, Society of Plastics Engineers, p 226, 1993.
9. Shang SW, "What Makes Clear Polypropylene Discolor?" Med Plast Biomat, 2(4):16, 1995.
10. Woo L, and Ling MTK, "Cryogenic Impact Properties of Medical Packaging Films," SPE ANTEC '90, p 1116, 1990.
Sherwin Shang is program manager in the Biotech Group, Fenwal Div., and Lecon Woo is the Baxter distinguished scientist at the Medical Materials Technical Center, of Baxter Healthcare Corp. (Round Lake, IL).
Figure 1. Projected U.S. consumption of all medical plastics in 1996. Source: The Freedonia Group
Figure 2. Projected U.S. consumption of medical polyolefins in 1996. Source: The Freedonia Group
|Material Selection||Meet requirements of safety, design, processing, and performance.|
Material compatibility with other components used in the same pack.
Drug and solution contact.
Biocompatibility and chemical inertness.
Leachables and oligomer residues.
Material aging, particularly after sterilization.
Additive chemicals and catalyst residue.
Lot-to-lot consistency from resin supplier.
Technical service from supplier.
|Design||Flexibility for medical product design. |
No built-in residual stress in plastic components.
Bonding/assembly capability among product components.
Easy quality control by visual inspection or instrumental sensor.
|Processing||Extrusion/molding/thermoforming capability. |
High production output rate.
Wide processing operation window.
Compatibility with the plant's existing manufacturing systems.
|Product Performance||Safety and quality. |
|Medical Product||Product Requirements|
|Intravenous solution pack||Flexible moisture barrier film. |
No interaction with medical solution.
|Blood-collection units, containers, and packs||Breath film for platelets. |
Low-temperature ductile impact film for plasma.
|Peritoneal dialysis solution pack||Flexible moisture barrier film. |
No interaction with medical solution.
|Disposable stem cell container||Biocompatible to be able to incubate the cells. |
Breath film for cells to grow and multiply.
|Biohazard bag||Puncture resistance. |
High drop impact strength and autoclavable.
|Pharmaceutical blister pack, bottle, and container||Barrier for moisture, oxygen, and carbon dioxide.|
|Material||Tg (°C)||Tm (°C)||Beta Peak (°C)||Crystallinity|