Contamination with glass flakes caused by delamination of the internal finish of container closure systems or prefilled syringes has caused numerous drug recalls. Surface imperfections and aggressive drug components can lead to interaction between product and container, resulting in leaching, dissolution, ion exchange and formation of precipitants or particles; use of cyclic olefin polymers as an alternative to glass can avoid these issues
In the light of recent drug recalls attributed to glass delamination, Diane Paskiet, West Pharmaceutical Services, reviews possible causes and aspects of glass container compatibility that can affect product quality.
Glass has long been considered the traditional material for use in drug product container closure and delivery systems and dominates the pharmaceutical market. Desired properties for container closure suitability include strength, transparency, stability, impermeability and resistance to chemical attack.
These characteristics are critical to preserving the quality of pharmaceutical products, and glass is an affordable choice. However, the potential for hidden costs related to breakage, glass delamination and contamination may not be readily apparent. An alternative choice of material may provide a lower total cost option as well as overall long-term benefits.
A recent rash of recalls concerning glass breakage, delamination and particulate has alerted the pharmaceutical industry to risk associated with glass containers. In 2010, certain lots of anemia drugs were recalled due to potential contamination of the products with glass flakes. More than 324,000 vials of drug product indicated for the treatment of anemia related to HIV therapy, chronic renal failure and chemotherapy were recalled in this instance.
In the past three years, there have been more than a dozen recalls including, but not limited to:*
Selection of suitable container closure systems can be judged best through the performance of risk assessment based on an understanding of the physical, functional and chemical characteristics of the container closure system along with drug product. During drug product development, materials that will be in contact with the drug product should be evaluated for protection, function, compatibility and safety. An initial assessment of materials should help to understand potential risks to quality. The drug-container interaction, adsorption, chemical resistance and the stability of packaging over time and in extreme environments are critical to the manufacturing, storage, distribution and integrity of the marketed product.
Glass variation can lead to delamination. Basic glass formulations are simple yet capable of enormous variations based on the source of raw materials and the forming process. Glass is not inert and the presence and proportion of minor ingredients and trace contaminants can profoundly impact the quality of drug products. Because glass is a solution and its ingredients and proportions can be varied over a wide range, both the processing and final properties are affected.
The basis of glass is silica from naturally occurring sand or rock; the higher the silica content the higher the temperature needed to melt the material (~1200°C), resulting in a harder glass. A second constituent in glass is a flux, such as sodium (Na) or potassium (K), used to lower melt temperature to facilitate forming. A stabiliser, such as limestone derivatives, can be added to prevent devitrification or breakdown of the glass into its constituent parts. Variations in the glass batch constituents and forming conditions can affect quality, durability, workability characteristics and aesthetic appearance with an overall impact on short- or long-term quality.1
Pharmaceutical manufacturers are responsible for ensuring the suitability of the chosen container according to categories established in USP, EP and JP. By law, drug containers are not to be reactive or additive so as to alter the safety or quality of the drug product.2
Mounting concerns related to glass include:
Several product recalls have been initiated due to glass flakes. The flakes, also known as siliceous flakes or lamella, are the result of glass delamination that can occur slowly over time, in the presence of neutral, slightly acidic or basic solutions. The interior surface finish of the glass vial or syringe can be a major factor in delamination because pitted surfaces can exhibit an early onset. The Na2O and K2O fluxes that are added to glass formulations reduce melting for forming glass but are weakly bonded and can leach into solutions contacting the glass surface. When sodium and potassium ions can be solvated from the glass surface, the SiO2 enriched layer can delaminate, forming small glass flakes. This is more pronounced as the temperature and alkalinity of the contacting solutions increases.
Figure 1: Pitted glass vial surface
While it may not be possible to tell which drug product and delivery system interactions may result in delamination, several tests can help predict the possibility. Container closure systems can be examined microscopically for visible indications of defects, particles, pitting or delamination before filling. The neck and base of the vial represent areas of high stress in the glass. Microscopic evaluation of these areas after exposure to a stressed environment can detect the potential for delamination.
For example, photo-micrographs of the product contact surfaces of glass were compared with Daikyo Crystal Zenith cyclic olefin polymer after 57 days’ exposure in pH 10 solution. The image in Figure 1 displays a compromised glass surface, which indicates the possibility of glass lamella in the drug product; a Daikyo Crystal Zenith cyclic olefin polymer surface is shown in Figure 2.
Figure 2: Daikyo Crystal Zenith surface
In addition to the chemical factors, manufacturing conditions may predispose glass containers to delamination. The glass formulation and manufacturing processes can influence the potential for leachables and glass flakes. Delamination can occur at any point in the drug manufacturing process, including vial manufacture and heat treatment or sterilisation processes.
While there have been no incidents associated with adverse effects, the presence of the flakes poses considerable risk to patients. According to the FDA, when injected into humans, these flakes can cause embolic, thrombotic and other vascular events. The flakes may also cause the development of foreign body granuloma subcutaneously, as well as local injection site reaction and increased immunogenicity.
Based on the rise in recalls due to glass delamination, the FDA has advised drug manufacturers to ‘re-examine their supplier quality management programme with glass vials manufacturers to assure that this phenomenon is not occurring.’3
Selecting an appropriate container closure system during the early stages of development will mitigate the risk of drug product recalls and contribute to drug product stability, functional performance and integrity. The drug product formulation characteristics such as pH, buffer type and ionic strength in relation to the area of contact with the container can be considered early, and when the potential for glass attack is identified, an alternative material, such as a cyclic olefin, can be a beneficial solution.
High performance polymer materials such as cyclic olefins can fulfil the same desired properties as glass for container closure systems. Novel materials, such as the Daikyo Crystal Zenith polymer, have comparable properties to glass with added characteristics that mitigate risk of breakage during shipping or filling. These stable materials can be subjected to sub zero temperatures, and have relatively few constituents that have less potential for drug product interaction.
Cyclic olefin polymers possess a variety of advantageous properties that are particularly suited for application in the biopharmaceutical industry. The material has optical clarity, permitting automatic and visual inspection of drug products to ensure delivery of high quality medicines. In addition, cyclic olefin polymers are excellent moisture barriers and a quality choice for sensitive aqueous-based drug products.
Potential for drug product-material interaction is not inherent to the forming or moulding process for Daikyo Crystal Zenith as in glass; and there is opportunity to consider forming multiple configurations based on a single consistent material. Once qualified to be a suitable material to be in contact with a drug product, shapes and sizes can be readily customised to meet needs of the drug product lifecycle.
For instance, a prefilled syringe can be fabricated with the needle inserted, which can reduce the risk for protein aggregation resulting from residual tungsten oxides. These residuals often are present in glass due to use of a tungsten pin, which is necessary for insertion of the needle into the formed syringe barrel.
Vial-based container closure systems can be used to store bulk drug substances of various sizes for preclinical trials. Prefillable syringes formed of the same material can take the product to market, thus reducing the need for testing and qualifying materials for multiple container closure configurations. This will lead to efficiencies and greater understanding of the product throughout the lifecycle. Vials and syringes made from cyclic olefin polymers are currently used for both brand and generic drug products in a variety of therapeutic areas, including oncology, antifungal and radiology.
Whether faced with a recall or initiating a new drug development process, the selection of a container can be vital to the success of the drug as it moves toward market. By partnering a packaging manufacturer early in the drug development process, drug makers not only help to establish suitability of materials used in container closure systems but also have the ability to rely on expert advice and counsel throughout a drug’s lifecycle. Innovative solutions for container closure and delivery systems such as cyclic olefin polymers will help to meet regulatory compliance and can help to eliminate the risk associated with issues such as breakage and glass delamination.
As drug manufacturers re-examine their quality management systems, partnering a packaging manufacturer capable of offering multiple solutions for these issues will be vital in assuring that drug products reach the market in an effective container closure or delivery system that will mitigate patient risk and help to ensure market success.
1. K. Cummings, 2002. A History of Glass forming. University of Pennsylvania Press ISBN 0812236475
2. Code of Federal Regulations Title 21 Food and Drugs Part 211.94(a) Subpart E Control of Components and Drug Product Containers and Closures
3. FDA “Advisory to Drug Manufacturers: Formation of Glass Lamellae in Certain Injectable Drugs” www.fda.gov/Drugs/DrugSafety/ucm248490.htm, 3/25/2011. Accessed on 7/11/11
* For additional recall information, please visit the FDA website: www.fda.gov/Safety/Recalls/default.htm
The author would like to thank Julian Popchock, Chemist, West Pharmaceutical Services Inc, for his contribution to this article.