OR WAIT 15 SECS
Volume 30, Issue 9
Choosing a suitable material for fill/finish containers begins during the product development stage.
Maintaining the safety and efficacy of drug products throughout their lifetimes is crucial. Selection of appropriate packaging container materials is a fundamental aspect of the product development process. The physical and chemical properties of the glass, plastic (typically cyclic olefin co-polymer [COC] or cyclic olefin polymer [COP]), and/or elastomeric materials (surface chemistry, wettability, and roughness, for instance) used in a container/delivery system determine whether it will interact with the formulated drug, suffer from permeability, and exhibit sufficient durability under processing, storage, and use conditions. Interactions with trace metal ions, silicone oil, and tungsten; acids, bases, and salts in buffer systems; gases; and leachables such as rubber additives and fillers can impact the stability of containers and container-closure systems as well as biologic drug substances.
The type of packaging chosen for a biologic drug product will depend on the properties of the drug product, the intended route of administration, and patient use considerations. Glass and plastic vials, pre-filled syringes, and cartridges not only have different closure systems, but also different compatibility issues that must be considered. For glass vials with rubber stoppers, potential delamination and breakage issues, along with leachables from the rubber, must be considered. With prefilled syringes, the presence of residual tungsten and silicone can be a concern. Overall, the goal when selecting a container material is to minimize the potential for damage of the biologic drug substance via absorption, oxidation, chemical reaction due to pH changes, and interactions with leachables and extractables.
One of the most common challenges for container selection is compatibility, according to Mark Petyak, director of technical operations with Alcami. “Extensive and proactive planning is required in determining compatibility of the solution with the -container and stopper,” he observes. As an example, Petyak points to stoppers, which can leach materials, inactivating biologics or causing unwanted reactions even with small molecules. As a result, it is important to understand the materials used by stopper manufacturers.
“Discussions with vendors should be an ongoing process and in parallel to formulation development,” Petyak states. “An analytical profile and fingerprint of every stopper should be created and specific to the solution enclosed in the container. Compatibility testing with the formulation requires extreme care and consideration to provide analytical insights that may be crucial for proper stopper selection,” he continues.
Another issue is related to the manufacturing processes implemented by container suppliers, according to Christian Lavarreda, product manager with Robert Bosch Packaging Technology. “Material quality issues stemming from insufficient in-process controls at container manufacturers continue to arise and show up during stability testing, partly prompting the recent revisions of [United States Pharmacopeia] (USP) and [International Council for Harmonization] (ICH) guidelines,” he notes.
Specifically, the ICH M7 guideline (1) states that “application of this guideline to leachables associated with drug product packaging is not intended, but the safety risk assessment principles outlined in this guideline for limiting potential carcinogenic risk can be used if warranted.” “Indeed,” remarks Laverreda, “with the rapid growth of DNA-based medicines (particularly vaccines) and the potential of leachables to react with and modify genetic material, the applicability of risk assessment methodology has become highly relevant for many of these dosage forms.”
Working with material vendors is the first step in understanding any compatibility issues associated with a given product solution or suspension with a particular component, according to Petyak. “Vendors understand their particular componentry best and are able to guide the user as to the best fit,” he explains. Alcami works with glass manufacturers and stays up to date with any changes to glass manufacturing processes.
“Although they may look very similar, glass vials can be extremely varied. There are several types (Type 1 borosilicate, a treated Type 1 vial, and a Type 1+ vial), all of which have advantages and disadvantages depending upon solution properties and intended uses,” he says. In addition, glass has to be checked for physical and chemical attacks from the formulation. “It is well known that tartrates and citrates are notorious drivers of delamination in tubular glass vials,” Petyak notes. Changing vial types is one approach to solving the delamination issue. In this case, a tubing vial could be changed to a molded vial.
With regards to stoppers, Petyak observes that manufactures have an array of different formulations and coatings, so initial discussions with the vendor are crucial for finding the best fit for the solution and the intended uses.
Rigorous new vendor qualification and the implementation of an effective vendor audit program are also essential (particularly when multi-sourcing), according to Lavarreda, as is the implementation of available in-process container integrity testing (primarily leak testing) as part of the fill/finish operation.
The choice of plastic or glass depends upon the intended application, according to Petyak. Each has its own sets of advantages and disadvantages. “The main considerations are the degree of protection required and the compatibility with both the dosage form and the filling and sterilization methods employed, although customer convenience considerations (e.g., weight and feel) are also important,” says Lavarreda.
Glass advantages include that it is transparent, has good protection power, can be easily labeled, is economical, and comes in a variety of standard sizes, according to Lavarreda. Disadvantages are that it is fragile and can release alkalis to aqueous preparations.
Plastic advantages for Lavarreda include that it is light-weight yet strong (also good protection power), can be handled easily, is a poor conductor of heat, is resistant to inorganic chemicals, and also comes in a variety of standard sizes. It can also be formed into shapes not possible with glass.
For Petyak, plastic also has the advantage of not having an issue with delamination or the classic breakage problem that is possible with glass containers. He also finds plastic a better choice for some solutions because it may not exhibit a significant pH change over time whereas glass containers will, as exemplified by bicarbonate injections.
On the other hand, Petyak points out that visual inspection of some types of plastics is more challenging than glass due their opacity. Additional disadvantages of using plastic vials are that plastic is comparably permeable, can be chemically and thermally deformed, and has a much worse absorption profile compared to glass.
“Overall,” Petyak concludes, “understanding how a particular solution will interact with the container closures chosen is critical to a successful injectable project.”
Suppliers of container materials for fill/finish applications have recognized the issues that drug manufacturers have faced in recent years with glass delamination and the presence of particulates, interactions with residual tungsten in prefilled syringes, and silicone oil in various glass delivery systems. Stopper manufacturers have also begun to address concerns about leachables and extractables.
For example, there are specific coatings that glass and stopper manufacturers utilize to ensure minimal interaction with the solutions of interest, according to Petyak. He does note that for multi-dose products where multiple punctures are expected, the physical properties of stoppers are also of concern and must be evaluated. “Overall, we have seen container-component manufacturers take approaches to ensure proactive developments that are designed to keep up with the advancements in drug-product formulations,” Petyak says.
Lavarreda agrees: “Slow but steady implementation of process analytical technology and quality by design is taking place at many major container manufacturers, as is an increase in the offering of pre-sterilized, ready-to-use container options, which can reduce the container integrity risk during fill/finish operations.”
Ready-to-use containers offer several benefits to drug -manufacturers, including the elimination of the need for washing and depyrogenation. The reduced handling leads to less breakage, lower rejection rates, increased flexibility and improved safety as well. Overall costs can be reduced and processing times reduced
Other new container designs are proving advantageous for parenteral drug manufacturers. Double-chamber cartridges from Schott allow the combination of different liquids or liquids with lyophilized products in one device for greater storage stability and reduced risk of error during administration. Gerresheimer’s MultiShell polymeric vials made of COP/polyamide/COP offer improved barrier properties combined with high transparency. Wheaton’s DualFusion vial has a COP outer shell bonded to a fusion material comprising an inner organosilicate layer and an outer silica layer, which is bonded to the COP shell. These two layers protect against acids and bases and act as a barrier, respectively. The result is a container that offers the advantages of both glass and plastic, according to the company.
1. ICH, M7(R1) Assessment and Control of DNA Reactive (Mutagenic) Impurities in Pharmaceuticals to Limit Potential Carcinogenic Risk, Step 4 version, March 31, 2017.
Volume 30, Number 9
When referring to this article, please cite it as C. Challener, “Glass or Plastic? Container Material Choices," BioPharm International 30 (9) 2017.