Biotechnology promises treatments for many diseases previously thought to be intractable. Despite a significant effort at delivering biotherapeutics, peptides, and proteins through nontraditional means, injection remains the principal delivery system.
The unit dose for many injectable biotech products is the single-dose vial, with prefilled syringes a distant second. Product is provided either as a solution, or, more commonly, as a lyophilized cake, which the caregiver reconstitutes and injects via syringe.
Requirements for product purity, activity, and shelf life dictate a high standard for injectable drug packaging, particularly for highly active peptides and proteins. Packaging represents the first line of defense for all formulated pharmaceuticals, protecting the product from the outside world and vice versa. At the same time, the package must be fully compatible with the product, whether it is in solution or lyophilized.
The FDA's requirements, as spelled out in the "Guidance Container Closure Systems for Packaging Human Drugs and Biologics," include levels of extractables/leachables and test methods related to these contaminants, raising the bar on what is expected from biopharmaceutical drug sponsors.
Packaging and Product: Not Always Perfect Together
Modern biopharmaceuticals are overwhelmingly proteins and peptides, molecules with unique chemical, physical, and mechanical properties. Proteins are sensitive to heat, light, and chemical contaminants. Minute concentrations of metals, plasticizers, and other materials from packaging may deactivate or denature therapeutic proteins. Proteins and peptides have a tendency to adsorb onto the surface of packaging containers and closures, which can essentially remove all active material from the drug formulation. In situations where the drug desorbs back into the solution, the interaction could cause the drug to lose potency.
Lyophilized proteins are no less immune from the effect of packaging. Since most lyophilization cakes are sensitive to moisture, an inadequate seal could cause water and other contaminants to enter the package and deactivate the drug.
Many biopharmaceuticals are sensitive to silicone oil, a material commonly used to lubricate elastomeric stoppers during fill/finish to facilitate insertion of the stopper into the vial. Silicone oil has been associated with protein inactivation through nucleation of proteins around oil droplets. Recently introduced fluoroelastomer coatings on stoppers provide needed lubricity in addition to an added level of chemical inertness, barrier protection, and safety. Fluoroelastomers thus serve as both a lubricant and a barrier to improve compatibility between product and the rubber closure.
Sources of Contamination
Extractables are the most common source of leachables contamination. An extractable is a chemical species, released from a container or component material, which has the potential to contaminate the pharmaceutical product. Extractables are generated by interaction between strong solvents and the package (including the glass vial and stopper) over time depending on temperature and extraction conditions.
A leachable is a chemical that has migrated from packaging or other components into the dosage form under normal conditions of use or during stability studies.
Package component fabricators evaluate extractables from their materials as part of their development and qualification operations. More importantly, leachables tests are carried out at the point of use, in real-life situations in the presence of the actual drug product.
The potential impact of extractables and leachables on drug products is significant, especially with highly active biopharmaceutical drug products, which may contain just femptograms of active ingredient.
Mitigating the Risk from Rubber Closures
Fluorocarbon film coatings provide the best combination of protection from extractables from the stopper material while providing a high level of barrier protection for the drug product, therefore minimizing leachables.
When applied to stoppers, fluorocarbon films reduce adsorption of the drug onto the stopper, which is critical for maintaining the product's potency and shelf life. In addition, fluorocarbon films provide extra lubricity for proper vial seating, without the need for silicone oil. Fluoroelastomer films, which are made from inert materials, also reduce the possibility of extractables migrating from the rubber stopper into the biopharmaceutical product.
Since the cost of specifying the wrong closure components and materials is so high, biopharmaceutical manufacturers need to devise a separate development plan for primary packaging, just as they do for molecule and clinical development.
Normally this separate activity is contracted out to firms that specialize in packaging components by Phase I when sponsors and regulators get serious about product and package. During Phase I a package component expert company will begin screening for closure designs and materials.
Screening involves assessing packaging alternatives, generating preliminary data on leachables, and choosing one or several alternatives that provide the highest degree of product compatibility and the lowest level of leachables. By Phase II, earlier if possible, sponsors need to begin to develop precise, validated methods for determining extractables and leachables. For products that get this far, methods development becomes almost a separate phase of stability testing.
It is difficult to overestimate the importance of carrying out these studies for the full testing period. Some product-package combinations that showed little or no degradation over the first few months may lead to significant inactivity, due to adsorption onto the glass vial prior to expiration of a two-year shelf life. Similarly, leachables that do not appear for the first several weeks may emerge later on, well within the products specified shelf life.
Strategies for Minimizing Risk
Drug developers who do not understand the impact of packaging on their biopharmaceutical products are courting an unnecessary level of regulatory and product-related risk. Problems often arise in this regard when a contract manufacturer tries to convince a sponsor that a particular stopper, vial, or other closure product is appropriate because it has been validated with the contractor's fill line. That is all well and good, and even necessary. However, stoppers need to be validated with the product first, and only then with the filling machinery. It is far more prudent, and in the long term much more cost-effective, to test and validate packaging within the context of the drug product.
Lyophilization a Special Case
Many biotech products are lyophilized in the package before the stopper and seal are introduced. Lyophilization presents its own peculiar process and packaging requirements.
As with solution-phase biopharmaceuticals, packaging can make or break final formulation for lyophilized products, particularly with respect to the product's long-term stability and compatibility with the package. Vials that are not designed specifically for lyophilization, for example with convex rather than flat bottoms, make the lyophilization process less efficient, leading to an extended lyophilization cycle. Rubber closures can also hinder freeze-drying if they do not permit adequate venting during sublimation.
Stopper rubbers adsorb and desorb water at different rates. Under storage conditions stoppers that were not properly dehydrated can release water into the lyophilized product, affecting product stability over time. This can be especially problematic with lyophilized biopharmaceuticals, which tend to have small cake weights when compared to traditional pharmaceuticals following lyophilization. Since their weight is often in the range of milligrams or less, these cakes are significantly more sensitive to moisture, pH changes, and extractables that migrate from the rubber closure.
A small difference in moisture in the lyophilization cake can make the difference between an active and denatured protein. pH differences, which may be caused by contaminants, can seriously affect protein structure and activity. The wrong rubber closure can easily shift pH units in a small volume of product or a diluted lyophilization cake.
Fluoroelastomer-coated stoppers eliminate the rubber closure as a source of the leachable that could impact pH because of its barrier properties. Glass vials, however, can also leach ions, which can impact pH.
Whatever precautions are taken with solution-phase preparations are doubly applicable to lyophilized biopharmaceuticals. During lyophilization all the primary package components must work together without interfering with either the product or the process. Some packaging issues to be aware of for lyophilized products include closures that allow adequate sublimation rates and cleanly insert into the vial without "back out" or sticking to the lyophilization chamber shelves; glass vials that provide adequate contact between the base of the vial and the lyophilization shelf; and compatibility during lyophilization between vial and elastomeric closure.
The high value, clinical efficacy, and price tags for biopharmaceuticals, coupled with injectable delivery in most cases, demand a high level of awareness of primary packaging. Biotech companies entering the clinical stage need to take the same science- and risk-based approach to packaging materials as they exercise with molecule development. Where that expertise is lacking in-house, developers of biotherapeutics must look outside their organizations for the know-how and experience to assure smooth transition from lab to clinic to market.
Specifying advanced coatings, for example fluoroelastomers, for most stoppers or plungers used with lyophilized or solution-based therapeutic proteins and peptides may seem like an extravagance. In reality, given the long development times and consequences of being wrong, these measures are actually prudent and will lower costs in the long run.