Conquering Glass Delamination
Since 2008, glass delamination has been the subject of recalls for a variety of drug products. Manufacturers of pharmaceuticals and glass containers have joined together to identify risks for delamination and have developed strategies that could reduce occurrences. The compatibility of a glass container for a given drug formulation is associated with methods of glass manufacture, formulation and surface composition. Action can be taken to mitigate the risk of delamination and include tighter controls over glass manufacturing and handling of glass containers, predicting delamination potential, coating glass surfaces or using alternative plastic materials.
As the pharmaceutical industry continues to advance biotherapeutics, complex drug formulations are inevitable, which could be a challenge to any container material. In certain cases it is possible the pharmaceutical formulation may need to be modified to be suitable with today’s common container materials. Selection of appropriate container materials early in drug development stages will provide added assurance of successful development and commercialization of quality medicine
There are various aspects to be considered when selecting the appropriate container closure system. Glass delamination is a serious issue, but overall compatibility through-out shelf life encompasses several factors of risk. The container must be compatible with the drug or biologic formulation as well as the pharmaceutical manufacturing process, and protect the final product during storage and shipping. Hazards can include interactions between the container materials and the pharmaceutical product resulting in leachables; shift in pH; reduced activity or potency of active, pharmaceutical ingredients; and/or formation of particles in addition to glass lamella. Another critical consideration for sterile drug products is for all components in a system to be compatible, ensuring proper fit. Dimensional inconsistencies, fine cracks or chips can compromise the container closure integrity, putting the final product and patient at risk. Choosing the proper container material early in the development process can help to prevent compatibility issues while maintaining the safety and efficacy of the drug product. There are a variety of benefits and potential risks to the use of both glass and polymeric materials. Knowledge of the compatibility of container closure materials with the drug product, as well as the intended use, can help pharmaceutical manufacturers make the right choice when selecting materials for their pharmaceutical products.
Understanding Compatibility of Container Closure Materials
The process for selecting container closure materials compatible with pharmaceutical products and the intended use is an important aspect of delivering safe medicines to patients. In today’s regulatory environment assessing and managing risk is key to successful drug development and commercialization. The physical and chemical nature of materials used in a container closure system can exhibit behavior that has the potential to compromise the drug or biologic product, resulting in harm to a patient.
Even though glass has a long history of use with a variety of pharmaceutical products, it has been the subject of several recalls often associated with delamination. Review of Medwatch FDA safety alerts, associated with glass, included as many as 15 recalls in 2010. This number decreased to 12 in 2011 and 10 in 2012; through second quarter of 2013 only five were noted. It is s not clear if the recent reduction in recalls is due to increased control measures, improved quality of glass, or if the events are fairly random and unpredictable. Considering the multiple variables associated with numerous drug or biologic products , it is difficult to ascertain the ultimate cause of delamination. While there is a concerted effort to improve glass quality and tighten manufacturing controls, the fact remains that the material selection is significant when ensuring container closure suitability throughout the pharmaceutical lifecycle.
The manufacturing and use of pharmaceutical products including its container components entail some degree of risk and therefore, an informed decision relies on understanding potential hazards. Whether the container material is a polymer or glass there are multiple formulations and manufacturing and processes that can influence the chemical and physical nature. Challenges include understanding current weakness in a given application in addition to unexpected hazards that could be experienced such as those associated with formulations enhanced for solubility with novel excipients. Recent estimates show that approximately 90% of pipeline drugs fall into low solubility categories of the Biopharmaceutical Classification System BCS.1 The approaches to overcome poor drug solubility employ use of co-solvents, emulsified systems, molecular complexes, amorphous drug forms and modification of the aqueous microenvironment. It is not always readily understood if these novel medicines will present unforeseen challenges to container materials.
It is important to realize that no one material can perform optimally under all conditions. Material compatibility and performance data will guide benefit to risk analysis. Major considerations for selecting materials suitable for the drug product’s intended use include permeation, leaching, sorption, chemical interaction, dimensional consistency , alteration in the physical properties and ensuring functional characteristics during rigors of processing, storage and distribution.
Considerations of Glass and Polymer Container Materials
Glass is an non-permeable transparent material that is typed or rated for use based on chemical resistance but this test alone will only indicate the solubility of glass in waterafter autoclave. All glass is not equal, different elemental compositions, manufacturing and forming processes will influence suitability for use. The risk of using glass stems beyond this challenge since this test will not indicate the potential for delamination, surface adsorption or extractable elements that could leach and interact with the pharmaceutical product. The variability in dimensions is another critical concern since a poor fit can result in leakage and loss of sterility. Glass does have high compression strength, yet can be broken easily, and applied strain can cause a crack to propagate, leading to fractures during filing or distribution. Data should be acquired at the appropriate time to scrutinize overall suitability of glass for intended use.
Polyethylenes (PE), polypropylenes(PP) and cyclic olefin polymers (COP), such as Daikyo Crystal Zenith® (CZ), or copolymers (COC) are commonly used materials for injectable containers. The type of polymer selected, as well as the drug product formulations and manufacturing processes will influence suitability for use. Just as with glass, not all polymer types or formulations behave in the same manner. The same container attributes and risks should be scrutinized for all materials being considered. Table 1 shows a broad based comparison of vital properties of glass and two different polymer types derived from materials data sheets. In general terms, all materials will have weaknesses and need to be examined relative to function with other components in the system, final drug or biologic form, filling/manufacturing, processing, storage and distribution.
The comparison of two types of plastic with glass indicate glass and cyclic olefin polymers have the highest performance ratings; however, there will be allowable tolerance for each pharmaceutical product/container closure combination depending on final formulation and intended use. Data on the candidate materials should be gathered at the appropriate stages to show shelf-life compatibility by understanding the impact of potential leaching, degradation,
formation of particles, transmission or permeation of gases or vapors, dimensional consistency or material instability in various environments. The propensity of a drug or biologic formulation to interact with a specific material’s surface and other sensitivities related to the active ingredient or excipients is case by case and may not be readily observed. A high level Material Suitability Risk Chart (Figure 1) derived from literature and material data sheets illustrates the likelihood of quality impact with concern of relative occurrence. The drive to improve quality is for industry to move toward proactive approaches providing innovative solutions rather than to react to failures or even worse, recalls. Identifying suitability pitfalls of current and innovative container closure materials will result in a greater upfront investment by the pharmaceutical company, but scrutiny of components and systems early in the development cycle can reduce risk of failure due to material incompatibility.
Rationalization for Early Qualification of Container Closure Materials
Only one out of approximately 8,000 new chemical entities makes it to the market, and the related overall research and development process takes on average approximately 13.5 years.3 Failures or interaction of container closure materials with pharmaceutical products can occur over short (days) or long (years) periods of time and may only occur after being subjected to certain processing, storage conditions and possibly near the end of the drug product’s shelf life. The container closure qualification process is dynamic and progresses throughout the pharmaceutical development cycle with an initial step of assessing risk for intended use. It is difficult to determine failures when a final dosage form or the processing conditions have not been confirmed, but early understanding of the probability of a hazard occurring for a specific use can help narrow down material options and alert to mitigating these risks. Recent cost estimates for full development of novel medicine vary and range to $1.8bn for the full development (capitalized).4 Will the cost for a science based- data driven material selection process for container closure suitability tip the economic scale at this level of investment? The benefit of a comprehensive container closure risk assessments will certainly outweigh a product recall and/or adverse event. While it is uncertain if the mysteries of glass delamination have been unlocked, it is clear that due diligence in the material selection process will play a central role in supplying quality medicines to patients.
1. Ralph Lipp, Ph.D. , “The Innovator Pipeline: Bioavailability Challenges and Advanced Oral Drug Delivery Opportunities,” American Pharmaceutical Review, April 30, 2013.
2. Stephen Perrett and Gopi Venkatesh at Eurand, “Enhancing the Bioavailability,” Innovations in Pharmaceutical Technology, Issue 19, Samedan Ltd. 2006.
3. S.M. Paul, D.S. Mytelka, C.T. Dunwiddie, C.C. Persinger, B.H. Munos, S.R. Lindborg, A.L. Schacht, “How to improve R&D productivity: the pharmaceutical industry’s grand challenge,” Nature Reviews Drug Discovery, vol. 9, 203-214, 2010.
4. S.Morgan, P.Grootendorst, J.Lexchin, C.Cunningham, D.Greyson, “The cost of drug development: a systematic review,” Health Policy, vol. 100, issue 1, pg. 4-17, April 2011.
About the Author
Diane Paskiet has more than 20 years of experience in polymer analysis relating to product failures, deformulation and migration studies. She has served as a project advisor in support of qualification studies associated with container closure systems for IND and NDA filings. Her current responsibilities as Director of Scientific Affairs include coordination of studies for technical support and innovations as well as providing a forum for education of those technologies. Previous to this role, she was in charge of site operations for West-Monarch Analytical Laboratories.
Diane is currently serving a five-year term on the United States Pharmacopeia (USP) Packaging, Storage and Distribution Expert Committee and Chair of the PQRI Parenteral and Ophthalmic Drug Product (PODP) Leachables and Extractables Working Group. She holds a degree in chemistry from the University of Toledo and a QA/RA Graduate Certificate from Temple University School of Pharmacy. Diane has authored national and international papers on the subject of leachables and extractables and is a faculty member of the PDA Training Institute as well as a frequent speaker and organizer of conferences.