Key points for material selection in non-PVC infusion bags
The global market for intravenous fluid bags is steadily shifting towards non-PVC materials. This article outlines the trend towards PVC-free IV bags, introduces the characteristics of various materials, primarily polyolefin-based materials, that are attracting attention as alternatives, and presents solutions offered by Mitsubishi Chemical's Zelas™ series.
Table of Contents [hide]
- 1.Main concerns regarding the use of PVC in medical applications
- 1.1.Health concerns due to plasticizer (DEHP) leaching
- 1.2.Concerns about a decrease in content due to adsorption of active ingredients.
- 2.PVC substitute resins in infusion bag films
- 2.1.List of materials for medical bags
- 2.2.PE (Polyethylene)
- 2.3.PP (Polypropylene)
- 2.4.COP/COC (Amorphous Olefins)
- 2.5.EVOH・PA (Polyamide)
- 2.6.EVA (Ethylene-vinyl acetate copolymer)
- 3.If you are looking for polyolefin-based materials for IV bags
- 4.References
Main concerns regarding the use of PVC in medical applications
Health concerns due to the leaching of plasticizers (DEHP)
While plasticizers are added to flexible PVC to impart flexibility, DEHP (di-2-ethylhexyl phthalate) has been reported to leach out upon contact with blood or lipid-soluble chemicals.
In Japan, in 2002, the Ministry of Health, Labour and Welfare issued a notice to medical institutions regarding DEHP leaching from PVC medical devices. For feeding tubes used for newborns and infants, early discontinuation of use and switching to alternatives are recommended, and priority should be given to switching to alternatives for highly susceptible patients. 1)
Furthermore, while DEHP is classified as a "reproductive toxicity 1B substance" in the EU, the expiration date for DEHP use in medical devices has been revised following the REACH amendment in November 2023 (application deadline: January 1, 2029, expiration date: July 1, 2030). 2)
Furthermore, regulatory and legislative efforts are progressing, such as the "Toxic-Free Medical Devices Act" in California, USA, which aims to ban the use of DEHP in certain medical devices after 2030. 3)
Region and system | Timing of regulations and notifications | Target substances/materials | Main target medical applications and products | Required actions and regulations | Practical implications | Supporting evidence and references |
|---|---|---|---|---|---|---|
Japan (Ministry of Health, Labour and Welfare) | October 17, 2002 (Heisei 14) | Medical devices made of flexible PVC containing DEHP as a plasticizer | Medical devices that come into contact with blood, medical devices that come into contact with lipid-soluble medications, milk, etc., especially feeding tubes for newborns and infants. | Regarding PVC medical devices, DEHP leaching into the liquids they come into contact with has been confirmed, prompting healthcare professionals to be urged to exercise caution regarding proper use. For feeding tubes used for newborns and infants, it is recommended to discontinue use as soon as possible and switch to alternative products, considering the risk of exposure to highly susceptible patients, the possibility of DEHP leaching from fat-soluble milk, etc., and the availability of alternative products. | In patient groups where susceptibility to DEHP or cumulative exposure is a concern, such as neonates, infants, pregnant women, breastfeeding women, and patients receiving long-term treatment, priority should be given to the adoption of non-DEHP plasticized PVC or PVC alternative materials. In product selection, elution evaluation considering the application solution, contact time, temperature, and lipid content is crucial. | Ministry of Health, Labour and Welfare, "Safety Information on Pharmaceuticals and Medical Devices," No. 182 |
EU (REACH regulation) | European Commission Regulation (EU) 2023/2482, published on November 13, 2023. | DEHP (bis(2-ethylhexyl) phthalate) | Medical devices and in vitro diagnostic medical devices that fall under the scope of the EU MDR (Regulation (EU) 2017/745) and IVDR (Regulation (EU) 2017/746) | For DEHP used in medical devices, the latest application deadline under REACH Annex XIV has been extended to January 1, 2029, and the sunset date to July 1, 2030. After the sunset date, REACH authorization will be required to market or use DEHP. | For products destined for the EU, it's not enough to simply make materials DEHP-free; change management, biological safety assessments including ISO 10993, E&L, performance and durability, MDR technical documentation, and supplier certificates must all be integrated into a single system. If alternative materials are uncertified or not yet implemented, the need for certification and the application strategy must be confirmed early on. | European Commission Regulation (EU) 2023/2482 and ECHA guidance. |
EU (Material Hazard Classification) | Current CLP classification / REACH candidate substance / Management as a substance subject to authorization | DEHP | Supply and use of DEHP-containing molded articles and mixtures, including medical devices. | DEHP is classified as reproductive toxicity category 1B (Repr. 1B). In medical devices, under the MDR, if a substance is present in concentrations exceeding 0.1% and is suspected of being CMR or endocrine-disrupting, justifying the benefits and risks, including the possibility of alternatives, is crucial. | Regulatory compliance for DEHP is not limited to REACH alone. It also requires justification of CMR/endocrine-disrupting substance content in the MDR, and verification of consistency with labeling, technical documentation, and risk management files. | Updated guidance from the European Commission on the assessment of benefits and risks in the MDR (Mean Dispute Resolution). |
California, USA (Toxic-Free Medical Devices Act, AB 2300) | From January 1, 2030 | DEHP added intentionally | intravenous solution containers | Effective January 1, 2030, the manufacture, sale, or commercial distribution of intravenous solution containers intentionally containing DEHP will be prohibited within California. | For California, the material composition of IV bags, IV containers, and container systems will be individually reviewed. Whether the entire system, including tubing, clamps, ports, etc., is subject to regulation will be determined after reviewing legal definitions, exemptions, and future administrative interpretations. | California AB 2300 (State Law Text) |
Concerns about a decrease in content due to adsorption of active ingredients.
In addition to health risks, there have also been reports of cases where the expected drug effect is not fully achieved. Because the surface and plasticizer of soft PVC are hydrophobic, highly lipid-soluble drugs (insulin, nitroglycerin, diazepam) tend to adsorb to the inner surface of the tube, leading to a significant decrease in content. This can result in reduced and inconsistent dosages for actual patients, so switching to tube materials with less adsorption is being considered. 4)5)
PVC substitute resins in IV bag films
The materials used in infusion bags are selected based on the bag's intended use (single/multi-chamber, barrier/low-adsorption requirements) and sterilization method. The characteristics of the main materials are summarized below.
List of materials for medical bags
Material | Key Features |
|---|---|
PE | ✓ Gamma, EOG sterilization. |
PP | ➔ Zelas™ TPO as inner layer (7025, MC634) |
COP, COC | ➔ Zelas™ CP as inner layer (CP209) |
EVOH, PA | ➔ Zelas™ TPO as tie layer (MC787AP) |
EVA | ✓ Gamma, EOG sterilization. |
*This table provides general information about each material group and representative grade. Actual sterilization suitability, interactions with drugs and lipid emulsions, bonding properties, transparency, and mechanical properties may vary depending on the grade, additives, molding conditions, component design, sterilization conditions, and usage environment.
*Evaluation of drug adsorption and interactions with lipid emulsions depends on the type of drug/formulation, concentration, contact area, contact time, temperature, and flow rate. Please conduct actual equipment evaluation with the final product, as well as E&L evaluation and biocompatibility evaluation as needed.
PE (Polyethylene)
Polyethylene (PE) is a representative polyolefin that has been used in the medical field for a long time. Low-density polyethylene (LDPE) and linear low-density polyethylene (LLDPE) have excellent flexibility, stress crack resistance, and heat sealability, but they have low heat resistance and are not suitable for autoclave sterilization at the global standard of 121°C or higher.
PP (Polypropylene)
Polypropylene (PP) offers excellent heat and chemical resistance and is used in bags requiring autoclave sterilization at 121°C. Mitsubishi Chemical's Zelas™ TPO is a thermoplastic olefin elastomer compound for medical use that maintains the heat and chemical resistance derived from PP while providing rubber elasticity and flexibility. Zelas™ 7025, in particular, is suitable for the inner layer of multi-compartment bags because its seal strength can be adjusted in stages from weak to strong depending on the heat sealing temperature.
Furthermore, adding MC634 to 7025 allows you to shift the heat seal temperature to a lower level. While 7025 alone requires a sealing temperature of 130°C or higher, adding 30 wt% MC634 allows sealing from around 120°C, making MC634 suitable for use as a heat seal modifier. Zelas™ 7025 is autoclavable and EOG sterilized, and has been confirmed to comply with the Japanese Pharmacopoeia (JP7.02), ISO 10993-5, and ISO 10993-10. EP and USP certifications are also available upon request.
COP/COC (amorphous olefin)
COP and COC bags offer excellent transparency, low hygroscopicity, and low elution, making them suitable for bags containing contents that are unstable to light, moisture, and adsorption. There is a need for low-adsorption bags that can minimize adsorption for a wide range of drug categories, from high molecular weight drugs such as biologics and protein preparations to low molecular weight lipid-soluble drugs such as insulin and nitroglycerin.
Mitsubishi Chemical's Zelas™ CP is an amorphous polyolefin compound, different from COP and COC, but it is a material that achieves both low adsorption and heat sealability.
In adsorption tests using tocopherol acetate (vitamin E), Zelas™CP209 exhibits lower adsorption compared to PE. Furthermore, it is heat-sealable over a wide sealing temperature range of 120–160°C, making it an attractive material that combines heat-sealability with features difficult to achieve with conventional COP and COC. Zelas™CP209 is compatible with EOG and gamma ray sterilization, has been confirmed to conform to the Japanese Pharmacopoeia (JP7.02), and EP and USP certifications are available upon request.
For infusion bags where low adsorption is required, the selection of the inner layer material that comes into contact with the contents is crucial. In particular, for lipid-soluble low-molecular-weight drugs and protein drugs, the concentration of the active ingredient may decrease due to adsorption to the inner surface of the bag, so material design tailored to the characteristics of the formulation is required.
Zelas™ CP is a low-adsorption material that can be used in combination with polyolefin-based outer layers. By placing Zelas™ CP in the inner layer, direct adhesion to polyolefin and heat sealing become possible, allowing for a bag configuration that does not require an adhesive layer (tie layer). This reduces the number of constituent layers, simplifies material design, and allows the inner layer that comes into contact with the liquid contents to be designed as a low-adsorption material.
For lipid-soluble small molecule drugs
In evaluations targeting lipid-soluble low-molecular-weight drugs, tocopherol acetate was used, and the amount of drug adsorbed by the extruded film was quantified by HPLC under conditions of 50°C for 2 weeks. In-house evaluations showed that the drug adsorption rate was approximately 9% with LLDPE, while it was reduced to approximately 2% with CP208.
These results suggest that applying CP208 to the inner layer of a bag may suppress the adsorption of lipid-soluble low-molecular-weight drugs to the inner surface of the container. For formulations such as vitamins, where adsorption to the container material due to hydrophobic interactions can be a problem, CP208 is a candidate inner layer material for low-adsorption bags.
For protein-based pharmaceuticals
In evaluations simulating protein-based pharmaceuticals, a 1.0 mg/mL solution of BSA (bovine serum albumin) was applied to the extruded film surface at 37°C for 30 minutes, and the amount of protein adsorbed to the surface was evaluated using the µ-BCA method. While the protein adsorption amount for LLDPE was approximately 0.40 µg/cm², that for CP209 was approximately 0.04 µg/cm², showing a value approximately 90% lower.
Therefore, CP209 is a promising inner layer material that suppresses nonspecific protein adsorption. It can be considered as a candidate material for the wetted surface of containers in applications where it is important to minimize the loss of trace components and fluctuations in administered concentration, such as in protein pharmaceuticals, biopharmaceuticals, and cell culture-related solutions.
EVOH・PA (Polyamide)
EVOH offers excellent gas barrier properties and is used in oxygen barrier bags to protect contents from oxidation and deterioration. PA (polyamide) provides excellent impact resistance and pinhole resistance, maintaining the strength of the bag.
However, EVOH and PA have a drawback: when used in a multilayer configuration with heat-sealing layers such as polyolefins, they exhibit poor adhesion to polyolefin-based materials, making delamination more likely. This is where Zelas™'s adhesive layer grade MC787AP comes in handy.
When MC787AP is used as an adhesive layer between PP and EVOH (PA), the polyolefin backbone that adheres to the polyolefin and the polar groups imparted by the graft reaction bond to polar materials such as EVOH, PA, PET, and metals, resulting in strong interlayer adhesion. MC787AP is sterilizable by autoclave and EOG sterilization, has been confirmed to conform to the Japanese Pharmacopoeia (JP7.02), and EP and USP certifications can be obtained upon request.
EVA (ethylene vinyl acetate copolymer)
EVA is an ethylene-vinyl acetate copolymer and has a proven track record, particularly as a material for IV bags used in TPN (total parenteral nutrition). Due to its relatively high gas permeability, multilayering with PP or COC/COP is considered for applications requiring oxygen or water vapor barriers.
If you are looking for polyolefin-based materials for IV bags
Mitsubishi Chemical's Zelas™ series is a medical compound material with over 30 years of market experience in the medical and pharmaceutical fields. We provide technical support tailored to each development phase, from material selection and evaluation data provision to documentation support for various national pharmacopoeias (EP/USP), biocompatibility testing (ISO10993), and DMF compliance.
The lineup of IV bags introduced in this article can be categorized into the following three categories according to their application.If you are having trouble designing materials for non-PVC IV bags, please feel free to contact us.
Purpose | grade | Key points |
Double-compartment bag (Easy Peel inner layer) | Zelas™ 7025, MC634 | The seal strength is controlled by the sealing temperature. For low-temperature shifts, add MC634. |
Oxygen barrier bag (Adhesive layer) | Zelas™ MC787AP | Achieves strong interlayer bonding between polyolefin and EVOH/PA. |
Low-adsorption bag (inner layer) | Zelas™ CP208, 209 | Low adsorption properties equivalent to or better than COP Achieves both heat-sealability and processability. |
References
1) Pharmaceuticals and Medical Devices Agency (PMDA), Notification No. 1017002, "Regarding Plasticizers (DEHP) Leaching from Polyvinyl Chloride Medical Devices" https://www.pmda.go.jp/safety/info-services/devices/0116.html
2)European Commission. Commission Regulation (EU) 2023/2482 of 13 November 2023 amending Regulation (EC) No 1907/2006 of the European Parliament and of the Council as regards the substance bis(2-ethylhexyl) phthalate (DEHP) in medical devices. Official Journal of the European Union, L 2023/2482, 14 November 2023. https://eur-lex.europa.eu/eli/reg/2023/2482/oj
3)California State Legislature. Assembly Bill No. 2300, Chapter 562: Medical devices: Di-(2-ethylhexyl) phthalate (DEHP). Approved by Governor September 25, 2024. California Health and Safety Code, Division 104, Part 3, Chapter 18, Sections 109050-109052. https://leginfo.legislature.ca.gov/faces/billNavClient.xhtml?bill_id=202320240AB2300
4) Treleano, A.; Wolz, G.; Brandsch, R.; Welle, F. Int. J. Pharm., 2009, 369, 30-37.
5) Baker, RC; Josephson, RL Drug Intell. Clin. Pharm., 1983, 17, 726–731.
