Parenteral Packaging Concerns
Biotherapeutics have unique demands
by Frances L. DeGrazio
Today's biopharmaceutical pipeline promises treatments that were unimaginable just a few years ago. As biotechnology grows in importance, the science and engineering of primary packaging for injectable biopharmaceuticals has taken on new prominence. For reasons of safety, packaging design, integrity, and materials are therefore reviewed by the FDA as stringently as the products themselves. We shall discuss the science, engineering, and regulation of primary packaging for injectable biotech drugs by exploring the issues that can make or break a product's regulatory submission. This information is presented in light of FDA's June, 1999 Container Closure Guidance.
Photo courtesy of West Pharmaceutical Services
Biotechnology promises treatments, even cures, for many diseases previously thought to be intractable. Although the biotech industry began just a quarter-century ago, since the late 1990s the number of new biopharmaceutical approvals has approximately equaled those for small molecule drugs.
Despite a significant effort at delivering biotherapeutic peptides and proteins through non-traditional means such as inhalation, transdermal patch, and direct contact with mucous membranes, injection remains the principal delivery system for biotherapeutics today.
The unit dose for 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 that the caregiver reconstitutes and injects via syringe.
Requirements for product purity, activity, and shelf life dictate a very high standard for injectable drug packaging, particularly for highly active peptides and proteins. However, with biopharmaceutical development times averaging seven to 10 years, and costs measured in the hundreds of millions of dollars, it is too easy for innovator companies to dismiss primary packaging as an afterthought.
Packaging represents the first line of defense for all formulated pharmaceuticals. A good package protects the drug product from the outside world and vice versa. At the same time the package -- including the vial itself, stopper, and seal materials -- 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, discuss understanding levels of extractables/leachables and test methods related to these contaminants.
The Guidance, which addresses evaluation of packaging systems for pharmaceutical and biopharmaceutical drug products, 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. It clearly indicates that all injectable products need to be evaluated for leachables that may have migrated over the product shelf life during formal stability testing and beyond. In addition to addressing leachables/extractables, the Guidance also discusses evaluation of packaging components and related materials.
By placing much more scrutiny on stopper processing and handling, barrier films, and leachables/extractables, FDA's Container Closure Guidance significantly raised 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. Protein function and activity is much more complex than simple linear chemical structure. Proteins are sensitive to heat, light, and chemical contaminants. Minute concentrations of metals, plasticizers, and other materials from biopharma packaging may deactivate or denature therapeutic proteins. The seriousness of chemical contamination is compounded by the extremely low concentrations of most protein drugs.
Whether in liquid or lyophilized form, biopharmaceuticals 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 which, due to the small amount of drug present, can essentially remove all active material from the drug formulation. In situations where the drug desorbs back into 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. Fluroelastomers thus serve as both lubricant and a barrier to improve compatibility between product and the rubber closure.
Primary packaging should be a top priority with all drug products, even pills and tablets. These concerns are amplified several-fold with injectable biotech products due to proteins' chemical and physical unpredictability, as well as the fact that such products are injected.
Sources of Contamination
Extractables are the most common source of leachables contamination arising from product coming into contact with package materials.
An extractable is a chemical species, released from a container or component material, which has the potential to contaminate the pharmaceutical product. Extractables are frequently generated by interaction between product and package (including the glass vial and stopper) over time depending on solvent and temperature 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 dosage form under normal conditions of use or during stability studies.
Package component fabricators test for 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 goal of testing is to determine that package materials are generally safe, compatible with the dosage form, and present acceptable risk of contamination for particular products.
The potential impact of extractables and leachables on drug products is significant, especially with highly active biopharmaceutical drug products that may contain mere 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 Closures
In our experience, 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 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.
Fluoroelastomer films, which are made from highly inert materials, also significantly reduce the possibility of extractables migrating from the rubber stopper into the biopharmaceutical product.
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, just as they do to molecule and clinical development. Normally this separate activity is contracted out to firms that specialize in packaging components.
Some typical deliverables one could expect from such a relationship include:
- An understanding of the product
- Capability to work off-site on the product and proposed packaging
- Recommendations for components, especially for seals and stoppers
- Knowledge of the engineering and regulatory aspects of the packaging appropriate for that application
- Forewarning of potential problems
- Support for package option evaluation through engineering and laboratory service
One way or another, these functions must be acquired by Phase I, since this is the point at which sponsors and regulators get “serious” about product and package working together, not at odds. 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. When method development and validation is completed, testing is carried out using samples stored under typical ICH conditions. Accelerated testing is typically done over six months at high temperature and humidity, whereas realtime testing uses standard 25° C and 60% relative humidity conditions over a two- to three-year period.
It is difficult to overestimate the importance of carrying out these studies for the full testing period. In our experience 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 a product's 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 is in fact 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.
Submissions that lack properly generated data on product stability within the proposed package are very likely to be held up until such data are provided. Often the information is generated, and that's the end of the problem. Occasionally, when rigorous testing uncovers leachables/extractables, product inactivation, or other packaging-related problems, approvals can be held up for months. Very few biotechnology companies are willing, or prepared, to gamble significant delays in clinical programs for the sake of a minor shortcut.
Lyophilization: a Special Case
Many biotech products are lyophilized in the package, usually a vial, 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 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 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. In addition, pH differences, which may be caused by contaminants, can seriously affect protein structure and activity. In our experience 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
- Compatibility during lyophilization between vial and elastomeric closure.
Examples from Our Experience
The globalization of the pharmaceutical supply chain presents new challenges for biomanufacturers. One customer of ours, a large pharma manufacturing an injectable U.S. orphan drug product in Europe, had difficulty obtaining validated pre-sterilization washing services for rubber stoppers produced by one of our European subsidiaries. To save time this customer went ahead and utilized local washing services, which resulted in FDA rejecting the U.S. regulatory application.
Curiously, this customer had had a similar experience with a different product. The approval delay cost the company tens of millions of dollars in lost revenues and considerable prestige. Even more seriously, patients were denied the only effective treatment for their chronic condition for several months. The problem eventually was resolved by shipping the stoppers to our Pennsylvania facility for washing, then re-shipping to the finishing plant in Europe. Today this product treats 15,000 patients per year.
Seemingly trivial changes in formulation can affect drug-package compatibility. One customer had received European approval to market a protein drug, but was asked by European regulators to eliminate an additive stabilizer, human serum albumin (HSA). The sponsor found a surfactant stabilizing agent that worked as well as HSA 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 plain rubber stopper would provide the same level of compatibility in the new formulation as in the old one. This problem could have been avoided by careful stability and 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, 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 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.