There’s no escape: specifying extractables for pharmaceutical films
Robin Van Landeghem, Tekni-Plex, outlines how to specify pharmaceutical films with low extractables for medical device liquid drug reservoirs.
There are four major pharmaceutical packaging trends that are driving the need for films with low extractables: growth in specialty medicines; growth in biological versus chemical drugs; increased healthcare costs; and a shift from hospital to home care for self-administered maintenance therapies.
These trends explain why the importance of pharmaceutical films with low extractables has increased significantly and will become even more important in the years to come.
When selecting plastics for parenteral applications, a number of important design considerations need to be made. Foremost, the structure needs to ensure stability of the active product and offer temperature, moisture and oxygen protection.
For liquid formulations, the structure also needs to provide sufficient barrier to minimise moisture loss so that the concentration of the active product remains stable. Additionally, there is often a requirement for transparency to allow for visual inspection. Conversely, product components could also be sensitive to light. Careful consideration of these attributes are necessary with the additional stipulation that the container should not leach anything out into the product.
Oftentimes the answer to these environmental and shelf-life challenges is a multilayer film. However, consideration need to be given on how to bond individual layers together, and what manufacturing process is selected.
A critical step in the qualification of plastic films for parenteral containers is performing extractables/leachables studies. The EMEA Guideline on Plastic Packaging Materials provides companies with a decision tree for interaction studies based on the particular administration form. The selection of materials as well as the film manufacturing process directly impacts the amount of leachables into the product.
Another obvious benefit of plastic structures is that they are shatter resistant, and are capable of infinite medical device design possibilities. When combining all of these requirements for stability, barrier, flexibility, sealing, and so forth, companies are left with a limited number of options with regards to materials and processes.
Polyolefins (polyethylene, polypropylene, COC or COP) are typically selected as the product contact material. Barrier layers for moisture and/or oxygen protection, found in the middle of the structure or used as an exterior layer, are typically EVOH or PCTFE.
Polyolefins have been widely studied for interaction with drug products, and resin companies have developed specific product portfolios for medical applications. Polyethylene is a versatile material that is very stable, contains a minimum of additives and shows very good resistance to radiation sterilisation, such as gamma or e-beam. Polypropylene is often selected when there is a requirement for higher heat resistance necessary for steam sterilization. For some specific drug products, polyethylene and polypropylene have shown some absorption or scalping, leading to alternative material considerations.
Attention has also been given to cyclic olefins, such as COC and COP. These materials are of high purity and very inert and have shown excellent results in drug interaction studies. While the increased interest for cyclic olefins is recent, they have been around for quite some time, mostly as a glass replacement for vials and prefilled syringes. Cyclic olefins show high transparency, low protein adsorption and high chemical resistance.
The disadvantage of polyolefins is that they provide insufficient barrier to prevent moisture loss, which affects the concentration of the active product. In order to guarantee a long shelf life, strong moisture barrier protection is needed.
An excellent moisture barrier material is PCTFE, or polychlorotrifluoroethylene, commonly known as Aclar. This flexible thermoplastic film offers high inertness, low extractables and high resistance to heat and sterilisation.
The higher the thickness of this PCTFE film, the higher the barrier and the lower the moisture vapor transmission rate. If we consider the same material thickness, PCTFE provides 30 times better moisture barrier compared to PP and 100 times better barrier compared to PVC.
Let’s also consider manufacturing processes for multilayer films. In adhesive lamination, each film layer is produced individually, and those layers are then combined by applying an adhesive in between.
The preferred manufacturing process is extrusion, which begins with granulates. Through multiple extruders and a multilayer die head, only one pass is needed to produce a multilayer film. In this process, there are no adhesives involved. Instead “tie resins” (large molecules, created by grafting functional bonding groups onto a polyolefin backbone) form a chemical bond between the layers. An extension of the coextrusion process—coextrusion coating—is when multiple layers are extruded onto a film substrate.
In many projects for liquid drug reservoirs for parenterals, it has been demonstrated that using tie resins in a coextrusion process leads to a lower amount of leachables into the product.