Appropriate packaging can protect your biotech drug products

Quality Control: PACKAGING

Fluorocarbon film coatings, which are applied during the molding process, reduce stopper clumping during autoclave sterilization and help prevent stoppers from sticking to the shelves in lyophilization chambers.

ALL IMAGES COURTESY OF WEST PHARMACEUTICAL SERVICES, INC.

The Perfect Package is the Best Defense

Appropriate packaging can protect your biotech drug products

B iotechnology promises treatments, even cures, for many diseases previously thought to be intractable. Although the biotech industry began just a quarter century ago, the number of new biopharmaceutical approvals since the late 1990s has more or less kept pace with those for small-molecule drugs. Despite a significant effort aimed at delivering biotherapeutics, peptides, and proteins through non-traditional means such as inhalation, transdermal delivery, and direct contact with mucous membranes, injection remains the principal delivery system for today's biotherapeutics. The unit dose for injectable biotech products is the single-dose vial, with pre-filled syringes a distant, though promising, second. Product is provided either as a solution or, more commonly, as a lyophilized cake 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. With biopharmaceutical development times averaging seven to 10 years, however, 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 stopper, the seal materials, and the vial itself, must be fully compatible with the product, whether in solution or lyophilized.

The U.S. Food and Drug Administration's requirements, as spelled out in its guidance document "Container Closure Systems for Packaging Human Drugs and Biologics," cover acceptable levels of extractables/leachables and test methods related to these contaminants.

Addressing evaluation of packaging systems for pharmaceutical and biopharmaceutical drug products, the guidance requires that each New Drug Application or Abbreviated New Drug Application 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 must be evaluated for leachables that may have migrated over the product's 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 increasing scrutiny on stopper processing and handling, barrier films, and leachables/extractables, the FDA's container closure guidance significantly raises the bar on what is expected from biopharmaceutical drug sponsors.

Pairing Package and Product

By and large, modern biopharmaceuticals are proteins and peptides-molecules with unique chemical, physical, and mechanical properties. Protein function and activity involve much more than simple linear chemical structure. Proteins are sensitive to heat, light, and chemical contaminants. Minute concentrations of metals, plasticizers, and other materials from biopharm 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 and delivery systems. Proteins and peptides have a tendency to adsorb onto the surface of packaging containers and closures; given the small amount of drug present, this propensity can essentially remove all active material from a drug formulation. In situations in which the drug desorbs back into solution, this interaction could cause a critical loss of potency.

Lyophilized proteins aren't immune from the effects of packaging, either. Because most lyophilization cakes are sensitive to moisture, an inadequate seal that allows water and other contaminants to enter the package can 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 provide lubricity and an added level of chemical inertness, barrier protection, and safety. Fluroelastomers serve as both lubricant and barrier, improving compatibility between the 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 because of the chemical and physical unpredictability of proteins, as well as the fact that such products are usually injected.

Sources of Contamination

During Phase I, a sponsor company should begin screening for vial closure designs and materials. By Phase II, sponsors should begin developing precise, validated methods for determining extractables and leachables.

Extractables and leachables are the two most common sources of contamination arising from the contact between product and package materials. An extractable is a chemical species, released from a container or component material, with 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.

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 because of the chemical and physical unpredictability of proteins, as well as the fact that such products are usually injected.

Package component fabricators test for extractables and leachables in their materials as part of their manufacturing and qualification operations. More importantly, these 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, are compatible with the dosage form, and present an acceptable risk of contamination for particular products.

The potential impact of extractables and leachables on drug products is significant, especially when it comes to highly active biopharmaceutical drug products, which may contain just femtograms of active ingredient. Perhaps more important than these materials' toxicology is their potential to elicit serious immunologic responses, even at infinitesimal dosages.

Risk from Rubber Closures

I believe fluorocarbon film coatings provide the best combination of protection against extractables/leachables that come from the stopper material, while providing a high level of barrier protection for the drug product. When applied to stoppers, fluorocarbon films significantly reduce adsorption of the drug onto the stopper, helping to maintain the product's potency and shelf life. In addition, fluorocarbon films provide extra lubricity for proper vial seating, eliminating the need for silicone oil.

When applied to stoppers and syringe plungers, fluorocarbon films reduce adsorption of the drug onto the component, which is critical for maintaining the product's potency and shelf life

Fluoroelastomer films also significantly reduce the possibility that extractables will migrate from the rubber stopper into the biopharmaceutical product. Pharmaceutical-grade fluoroelastomers, made from highly inert materials, are formulated specifically not to leach.

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 in molecule and clinical development. Normally this activity is contracted out to firms that specialize in packaging components. Some deliverables that typically arise 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; and

• Support for package option evaluation through off-site laboratory services.

These functions must be acquired, in one way or another, by Phase I, the point at which sponsors and regulators get serious about product and package working together instead of at cross purposes. During Phase I, a package component expert company will begin screening for closure designs and materials.

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 in molecule and clinical development.

Screening involves assessing packaging alternatives, generating preliminary data on leachables, and choosing one or several alternatives that provide the highest degree of product consistency and the lowest level of leachables.

By Phase II-earlier if possible-sponsors need to develop precise, validated methods for determining extractables and leachables. For products that get this far, methods development is almost a separate phase of stability testing. Methods development may be carried out under either accelerated or real-time protocols. Accelerated testing is typically done over six months at high temperature and humidity, whereas normal testing uses a standard 25^oC temperature and normal 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 my experience, many product-package combinations that showed little or no degradation over the first few months became totally inactive, due to adsorption onto the glass vial, long before expiration of the 18-month 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. Packaging problems often arise 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's all well and good-and even necessary. Stoppers need to be validated with the product first, however, and with the filling machinery only after that important first step. 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 likely to be held up until such data are provided. Often, once the information is generated, the problem is solved. 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 on significant delays in clinical programs for the sake of a minor shortcut.

Lyophilization: A Special Case

Many biotech products are lyophilized in the package, which is usually a vial, before the stopper and cap 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 not designed specifically for lyophilization, including those with convex rather than flat bottoms, make the lyophilization process less efficient and result, in some cases, in a lyophilization cake with a higher moisture content than normal. Rubber closures that do not permit adequate venting during sublimation can hinder freeze drying.

Rubber stoppers adsorb and desorb water at different rates. Under storage conditions, stoppers that have not been properly dehydrated can release water into the lyophilized product, affecting product stability over time. This can be especially problematic with biopharmaceuticals, which tend to have much smaller cake weights than traditional pharmaceuticals following lyophilization. Because 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 change in moisture in the lyophilization cake can mean the difference between an active and denatured protein. Differences in pH, which can be caused by contaminants, can also seriously affect protein structure and activity. The wrong rubber closure can generate differences of two pH units in a small volume of product or in a diluted lyophilization cake. Fluoroelastomer-coated stoppers eliminate many of these concerns due to hydrophobicity during sterilization and extremely low levels of leachables.

The precautions that are usually 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 between vial and elastomeric closure during lyophilization.

The high value, clinical efficacy, and price tags of biopharmaceuticals, coupled in most cases with injectable delivery, 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 knowhow and experience to assure a smooth transition from lab to clinic to market.

Specifying advanced coatings such as 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 the costly consequences of being wrong, these measures are actually prudent and will lower costs in the long run. �