As Biotech Grows, So Does The Need For Effective Packaging

By Frances L. DeGrazio
Vice President, Marketing & Strategic Business Development
West Pharmaceutical Services, Inc.

As biotechnology grows in importance, the science and engineering of primary packaging for injectible biopharmaceuticals has taken on new prominence. This article discusses the science, engineering, and regulation of primary packaging for injectible biotech drugs by exploring the issues that can make or break a product's regulatory submission.

Requirements for product purity, activity, and shelf life dictate a very high standard for injectible drug packaging, particularly for highly active biopharmaceuticals.

The U.S. Food and Drug Administration's requirements, as spelled out in the Guidance Container Closure Systems for Packaging Human Drugs and Biologics, discuss understanding levels of extractables/leachables and test methods related to these contaminants along with other considerations relating to packaging components.

The Guidance requires that each New Drug Application (NDA) or Abbreviated New Drug Application (ANDA) contain enough information to demonstrate that a proposed package and its components are suitable for their intended use.
Packaging and Product: Not Always Perfect Together
Minute concentrations of metals, plasticizers, and other materials from biopharm packaging may deactivate or denature biopharmaceuticals such as monoclonal antibodies.

Whether in liquid or lyophilized form, biologically-derived products possess properties that make them more sensitive to their packaging or delivery system.

Proteins and peptides have a tendency to adsorb onto the surface of packaging containers and closures.

Lyophilized proteins are no less immune from the effect of packaging. Since most lyophilized 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. Recently introduced fluoroelastomer coatings on stoppers provide needed lubricity in addition to an added level of chemical inertness, barrier protection, and safety. Fluroelastomers thus serve as both lubricant and a barrier to improve compatibility between product and the rubber closure.
Sources of 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 a solvent and package or delivery device under certain exaggerated conditions. Extractables testing is recommended even if containers or components meet compendial suitability tests, and should be carried out as part of the qualification for the container and its components.

A leachable is a chemical that has migrated from packaging or other components into the biopharmaceutical dosage form under normal conditions of use or during stability studies.

The potential impact of extractables on drug products is significant, especially with highly active biopharmaceutical drug products which may contain just femptograms of active ingredient. Perhaps more important than these materials' toxicology is their potential to elicit serious immunologic responses, even at infinitesimal dosages.
Mitigating the Risk from Rubber Stoppers or Syringe Plungers

During Phase I, a sponsor company should begin screening for vial 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, sponsors should begin developing precise, validated methods for determining extractables and leachables.
In our experience fluorocarbon film coatings provide the best combination of protection from extractables from the elastomeric material while providing a high level of barrier protection for the drug product, therefore, minimizing leachables.

When applied to stoppers or plungers, fluorocarbon films significantly 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.

Because 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. Normally this separate activity is contracted out to firms that specialize in packaging components.

During Phase I a package component expert company will begin screening for closure designs and materials.

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. When method development and validation is completed, testing is carried out using samples stored under typical ICH conditions.
Strategies for Minimizing Risk

Fluorocarbon film coatings provide the best combination of protection from extractables from the component material while providing a high level of barrier protection for the drug product, therefore minimizing leachables. When applied to stoppers and syringe plungers, fluorocarbon films reduce absorption of the drug onto the component, which is critical for maintaining the product's potency and shelf life. Fluorocarbon films provide extra lubricity without the need for silicone oil and reduce the possibility of extractables migrating from the component into the biopharmaceutical product.
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 to use a particular closure because it has been validated with the contractor's fill line. Stoppers need to be qualified with the product first, and only then with the filling machinery.
Lyophilization - a Special Case
Many biotech products are lyophilized which presents its own peculiar process and packaging requirements.

For instance, stopper rubbers adsorb and desorb water at different rates. Under storage conditions stoppers which 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 very 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 as well, which may be caused by contaminants, can seriously affect protein structure and activity. Fluoroelastomer-coated stoppers minimize 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.
Examples from West's Experience

Fluorocarbon film coatings reduce stopper clumping during autoclave sterilization and help prevent stoppers from sticking to the shelves in lyophilization chambers. The film is applied during the molding process and is conformable to complex-shaped closures, which are typically required for dry powder and lyophilized applications. Lyophilization closures with fluorocarbon film are available in a single-vent igloo design that is proven effective in eliminating mechanical twinning, the interlocking of double-vented stoppers during processing.
The globalization of the pharmaceutical supply chain presents new challenges for biomanufacturers.

Seemingly trivial changes in formulation can affect drug-package compatibility. A West customer had received European approval to market a protein drug, but was asked by European regulators to eliminate an additive stabilizer, human serum albumin. The sponsor found a surfactant stabilizing agent that worked as well as HAS with this drug. Unfortunately they did not pay close attention to potential interactions between the new stabilizer and the rubber plunger in the prefilled syringe used to deliver this medication. Initial data showed acceptable levels of leachables so the product gained European approval, only to be recalled several months later due to serious adverse events related to leachables. This manufacturer's error was assuming that the uncoated rubber stopper would provide the same level of compatibility with the new formulation as in the old one. This problem could have been avoided by leachables testing and by employing a fluoroelastomer coating for the syringe plunger, which is eventually what the manufacturer did. But not before a debacle that cost the company many millions in lost sales and opportunity.
The high value of biopharmaceuticals, coupled with injectible delivery in most cases, demand a high level of awareness of primary packaging. 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.