Bernhard Hladik is director of Business Development at SCHOTT.

Bernhard Hladik

	The days of one-size-fits-all solutions for the primary packaging of injectable pharmaceuticals are over. Pharmaceutical advances are placing new demands on primary packaging for parenteral drugs. In an increasing number of instances, these demands are being met with highly tailored solutions that meet these exacting packaging requirements across a range of parameters.

	Primary packaging manufacturers are working with pharmaceutical companies to offer modular approaches to packaging design, with features that enhance the process robustness of the primary packaging container and its compatibility with the drug/formulation. These new approaches to packaging are not based on disruptive changes. Rather, they are based on adapting, optimizing, or more tightly controlling established principles that have guided the pharmaceutical industry for decades.

	Borosilicate glass of highest chemical durability has been the gold standard for more than a century for parenteral packaging. Pharmaceutical companies have generated thousands of data sets and long-term trends for a large variety of formulations. This long track record reduces the risk in the selection process for new containers and the regulatory effort for filing.

	The parameters that drug formulation and drug manufacturing impose on packaging are extensive. The development of new drug formulations is going through a paradigm shift. More than 70% of today’s pharmaceutical drug pipeline for injectables are highly sensitive biologics, which require specialized primary packaging solutions.

	A broad range of challenges for the development of these new biologics need to be addressed to ensure the efficacy of the drug (e.g., the sensitivity toward extractables and leachables, protein adsorption, glass delamination, or fogging during freeze-drying).

	Lyophilization and consumer acceptability

	Approximately 40% of biologics for injectable drugs in development are not suitable for long-term storage in liquid form but need to be stored as a freeze-dried product. Lyophilization places high requirements on the primary packaging container.

	An increase in fogging due to drug product creeping upwards along the inner vial surface during lyophilization has been observed by pharma manufacturers. A haze of dried powder is visible, making it difficult for visual inspection and acceptability for commercial distribution from a cosmetic point of view. The most reliable approach to avoid fogging is a hydrophobic inner surface coating, which is produced by plasma impulse chemical vapor deposition (PICVD). It is also possible to apply the PICVD process without generating any residual silicone, avoiding the formation of protein aggregates known to trigger immune response.

	The PICVD process is also able to generate a hydrophilic quartz-like inner surface coating that combines a protective ion-barrier with minimized adsorption characteristics for specific proteins. This technique, in various forms, can be used to store highly sensitive biologics in liquid and free-dried forms.

	The ion-barrier prevents leaching of any ion from the glass matrix, which can be especially important for aluminum sensitive drugs. The ion-barrier also avoids pH-shift, resulting in increased shelf life.

	A large variety of highly sensitive drugs are filled with volumes below 2.0 mL, such as monoclonal antibodies, therapeutic proteins, drugs for ophthalmic applications, and particularly, new vaccines produced with DNA recombinant technology.

	For those low-filling volumes, high concentrations of leachables have been found when the standard manufacturing technology is applied. The result is a pronounced pH-shift and a loss of efficacy of the drug. 

	Further, the established standard of the hydrolytic resistance test is not the right criteria to limit leaching for low-filling volume applications as the container is filled with 90% of its brimful volume. An additional testing protocol is required, and pharmaceutical container manufacturers have developed tests that can determine leaching tendency of low-fill biologics that rely on a validated quantitative threshold value.

	Due to the remarkably high strength of glass, breakage is a rare occurrence. In fact, freshly produced glass containers without pre-damages will withstand tremendous mechanical loads.

	Therefore, numerous approaches have been established to avoid pre-damages to the glass surface such as scratches to secure the naturally high break resistance of glass.

	Especially, the avoidance of any glass-to-glass and glass-to-metal contact is highly beneficial to conserve the break resistance of the glass container. This is crucial throughout the entire value chain-from the production of the pharmaceutical tubing and the primary packaging container (100% control of cosmetic defects, no glass to glass contact on the production line) to the supply chain.

	To optimize beyond that point, or in cases where quality or process steps cannot be influenced or changed, other approaches can be applied to reduce breakage.

	Mathematical simulations, supported by extensive side compression and axial load testing in vial design, are able to reduce the risk of glass breakage by optimizing the dimensions of the vial within the established International Organization for Standardization (ISO) specification.

	Further, there are still numerous older fill/finish operations running with rough handling and pronounced glass-to-glass and glass-to-metal contact. For those cases, a transparent protective outer surface treatment can be applied.

	The heavy costs of developing and producing highly potent biologic drugs put pressure on the pharmaceutical filling process to increase yields and reduce waste. Choosing the right container can aid this goal.

	Because the demands of biologics are complex and difficult to predict, modular approaches to containers can match the exact needs of pharma manufacturers. Modular vial platforms that let drug companies select specific properties for their drug can be combined with a number of functional coatings so that companies can get the containers they need in bulk or in a ready-to-use format, using time-tested materials with proven performance. This approach also quickens the pace of validation and certification, and time-to-market.

	Working closely, pharmaceutical companies, pharmaceutical packaging manufacturers, and contract manufacturers can find the solutions they need that fit both their drug formulations and the demands of their fill/finish lines without compromising yield, performance, quality, and safety.

Articles

Advanced packaging requirements for parenteral drugs are being met with highly tailored solutions.