[China Packaging Network News] The biopharmaceutical industry is the main body of new drug development. This market has been growing in double digits and is expected to grow further in the next decade. This irreversible development trend is related to the cracking of human DNA that leads to enhanced drug efficacy and reduced side effects.
Many newly-developed biopharmaceutical candidate breeds have the potential to succeed in the healthcare market. However, the investment needed to develop a candidate species as an effective treatment method is growing, and it contains multiple risks, which has also led to a decline in the number of new drug applications in the past decade. At the same time, the substantial increase in hopes of enhancing efficacy and reducing side effects has also placed greater pressure on the biopharmaceutical industry.
The production of proteins and peptides in biopharmaceuticals is mainly faced with challenges such as reproducibility, ease of scale-up, and process robustness. In addition to being safe and effective, patients must also be given medication in the right way to achieve their efficacy. The administration of proteins by means of injection (injection means not passing through the gut of a human or animal body) is a complex challenge, including studies on stability, bioavailability and pharmacological mechanisms that may lead to failure The root cause.
As similar to foods, peptide- and protein-based biopharmaceuticals will be dissolved in the digestive system without efficacy if administered orally. Therefore, it is usually necessary to use injection or infusion. The difficulty is that the required solubility must be achieved, as well as a limited drug shelf life. Therefore, the packaging elements used for injectable biopharmaceuticals will play an important role in the development phase of the drug delivery concept, and they can significantly affect the stability of various drug formulations.
In short, the unique properties of biopharmaceuticals mean that they require more complex sealed vessel systems, and glass, as a conventional bottle-making material, sometimes reaches its limit. Plastic polymers such as polyethylene and polypropylene are good substitutes for glass and can be used as primary packaging materials in many applications such as solid and ophthalmic preparations and infusion preparations. However, these polymers are not ideal packaging materials for injection preparations due to lack of transparency after sterilization and insufficient gas barrier properties.
The use of polyolefins
There are two examples of polyolefin-based plastic polymers that can be used in primary packaging materials for long-term storage of liquid drug products. One is a cyclo-olefin copolymer (COC) and the other is a cyclo-olefin polymer (COP). Its performance is better than that of polyethylene or polypropylene, and its transparency is high (Fig. 1). It can precipitate low organic content (typical characteristics of plastics) without precipitation of metal ions. The question is, why are these plastic compounds not used by the primary packaging department for injectables and biopharmaceuticals?
The reasons that have not been widely adopted are due to the limited environmental experience in the strictly regulated pharmaceutical industry and the lengthy drug development cycle. Another reason is cost pressure because high-quality polymers such as COC and COP are much more expensive than glass. Finally, the operation of plastic bottles is different from the standard glass bottle filling lines. They are not suitable for the operation of the heat source box. In contrast, the Japanese pharmaceutical market has been using COP materials for injection plastic bottles and syringes for many years.
The complexities and sensitivities of biopharmaceuticals have caused changes and made high-end plastic polymers an attractive primary packaging solution for injectable containers.
Stability and adsorption
There are many decomposition mechanisms that affect the stability of biopharmaceuticals during storage in the final container. A number of investigations have been conducted to determine the degree of adsorption of proteinaceous molecules on the surface of different materials used for primary packaging. The observations show that the degree of adsorption is directly proportional to the size of the surface area and is related to the type and formulation of the protein. Other publications claim that absorption is an extremely dynamic process of protein resorption that occurs within 24 hours until equilibrium is reached. Therefore, a low-concentrate protein drug formulation will withstand degradation up to 50% of the initial concentration. As a protein model, bovine serum albumin (BSA) shows a mild degree of absorption, ie 9%. Even for such “moderate†losses, significant overfill must be performed to compensate for product losses, which will have an adverse effect on production efficiency and manufacturing costs. Figure 2 shows that a portion of the BSA is adsorbed to the inner wall of the glass bottle, thereby damaging the product.
The following measures are recommended to reduce protein adsorption:
â— Add a high concentration of inert protein to the pharmaceutical formula to saturate the glass surface
â— Add carbohydrates, amino acid surfactants to reduce the interaction between the inner wall of the container and the protein
â— Treatment of glass surfaces with silicone oil to reduce adsorption
The last measure has a certain degree of danger. It has been reported that droplets of silicone oil may cause the polymerization of proteins, rendering them ineffective. Last but not least, the choice of container material also affects the stability of the protein solution. In an empirical study, Burkeetal evaluated the adsorption properties of proteins and different materials such as glass, polyester, polypropylene, and polyamide. The results of this study indicate that choosing the right container material for each protein is crucial to minimize the loss of product due to adsorption.
The use of COP plastic bottles can reduce the adsorption of the container surface and increase the effective utilization rate, thereby saving the usually very expensive cost of biologic drug overfill and should be sufficient to offset the higher cost of the COP plastic bottle.
Precipitation of metal ions at high pH
Glass consists of a group of inorganic oxides that form a three-dimensional structure during the manufacturing process. An injection drug solution with a pH above 7 will attack the surface. In this case, the glass releases metal ions that can adversely affect the stability and availability of sensitive biopharmaceuticals. In severe cases, the erosion of the glass surface may even result in surface flaking, resulting in an increase in product recall. It is not difficult to imagine that the change in pH or the precipitation of metal ions is sufficient to denature the proteins in the biopharmaceutical formulation, thereby impairing the efficacy of the drug. COP bottles are an ideal solution for problems associated with high pH injection drug solutions.
Increased barrier properties
Despite its superior compatibility, the gas barrier properties of COP bottles are as weak as glass, which may affect the shelf life of oxygen-sensitive biopharmaceuticals. Poor barriers force the industry to add additional barrier bags to prevent oxidation and moisture effects; or to improve drug stability through freeze-drying. This bag may consist of polyethylene/polyamide/polyethylene, or polyethylene/vinyl alcohol/polyethylene, or even an opaque aluminum bag. Translucent plastic bags may also be suitable as the silica evaporates. However, additional bags not only increase production costs but also have to carry additional investment in equipment. Freeze-drying will also greatly increase the production cost of the bottle, and it is also necessary to purchase freeze-drying equipment. From this point of view, by adding a layer of polyamide polymer to create a multilayer plastic bottle with a higher barrier properties, it is an attractive solution. It has a higher gas barrier properties, making the COP's excellent characteristics more perfect.
Multi-layer COP plastic bottles with enhanced barrier properties offer a new option for sensitive biopharmaceuticals, and do not have the limitations typically found with existing single-layer PE, PP, COC, or COP plastic bottles.
The multi-layer design brings higher impact resistance, which can solve many problems, such as ensuring the sterility of the injection solution during transportation or storage, and can protect the medical staff and patients from accidental damage and suffer toxic drug solution. damage. The comparison of the impact resistance of glass bottles and plastic bottles depends on the selected test method and plastic grade. The multilayer COP plastic bottle has five to ten times higher impact resistance than the glass bottle. Figure 5 shows the impressive impact resistance of a multi-layer plastic bottle, which remains intact in the case of a broken shell. The puncture-resistant polyamide layer in the multilayer structure prevents liquid leakage and the multilayer bottle is destined for use in cytotoxic drug solutions, for example in anti-cancer treatments. Extremely high resistance to breakage prevents breakage during filling and transport, thereby reducing biopharmaceutical production costs. This will also make a significant contribution to the overall cost reduction.
to sum up
Therefore, the higher gas barrier properties further enhance the main characteristics of high-end cycloolefin polymers without losing any of their original advantages such as low adsorption, no metal ion precipitation, high transparency, and high water filtration performance. With regard to gas barrier properties, oxygen barrier tests on new multilayer plastic bottles have demonstrated that their barrier levels are superior to any existing plastic packaging material used for injectable drug packaging. A particular advantage of the multilayer design is the higher resistance to breakage due to the reinforced structure of the polyamide with extremely high puncture resistance and makes this package suitable for use in cytotoxic drug solutions.
It is expected that more comprehensive considerations will make multi-layer plastic bottles no longer confined to the special purpose of injection containers. With its stability throughout the entire shelf life, safety in filling, transport, and operation, combined with its economy, it will surely be promoted more widely. This will create packages that are suitable for the specific functional needs of sensitive biopharmaceuticals and will make the drug ultimately more effective and safer.