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Formulations for pulmonary inhalation comprise spherical, porous particles that are 1–3 microns in diameter.
The market for biotherapeutics has grown significantly since the first biologic drug was launched over 50 years ago. More than 250 biologic molecules have been developed and launched since 1996, and today biologics account for nearly 30% of compounds in the drug-development pipeline.
Recently, research and development (R&D) resources have focused not only on new molecular entities but also on improvements to commercially available products. Reformulations now comprise nearly 50% of new drug application (NDA) approvals at the US Food and Drug Administration (FDA).2 At drug-delivery companies focusing on injectable therapeutics, over 50% of the molecules in the pipelines are biologics, with many projects focused on developing sustained-release formulations.3
The challenge for drug makers, however, is to bring about these improvements while addressing the added packaging, manufacturing, and formulation challenges inherent in biologics, due to their unique sizes, structures, and stability profiles. More than 95% of large molecules are administered either through intravenous (IV) infusion or through subcutaneous injection,4 routes of administration that are highly efficacious yet undesirable to many patients. As a result, new technologies continue to emerge to improve administration and storage of these molecules.
Life cycle management through enhanced packaging and newer drug-delivery technologies may ensure that a biologic compound's commercial potential is fully realized and that drug makers can stay ahead or at parity with the competition. Depending on a company's situation and time frame, a number of improvements can manage a product's life cycle (Table 1).
Table 1. Selected packaging and formulation strategies for differentiating biologics
In the short term, drug makers are moving toward enhanced packaging that allows for safer, more intuitive reconstitution of lyophilized powder formulations and less complicated administration of biologics.
Mid-range improvements typically involve improved drug-delivery devices, a substantial growth area for drug manufacturers. Industry analysts predict that over the next three to four years the sale of biologics packaged with a device will show higher growth than the same product packaged alone, driven by the market appeal of devices that make administration of biologics easier.4
Long-term improvements involve reformulations to reduce the frequency of administration or to enable less invasive treatment, such as pulmonary inhalation.
The best approach for a particular biologic compound depends on the molecule's market environment, point of use, and the company's short- and long-term strategy for its product and business.
Today approximately 75% of biologics are administered via subcutaneous or intramuscular injection.4 Most recent advancements in drug-delivery technologies related to injectable biologics have focused on devices and technologies that improve safety, patient compliance, and convenience in both administration and storage.
Short-term strategies primarily deliver improvements in convenience, compliance, or improved safety for healthcare workers as well as patients.
With up to 50% of biologics requiring lyophilization,5 healthcare providers and patients are seeking easier and safer solutions for reconstitution. If a biotherapeutic is currently lyophilized and produced in a vial, a sensible first step in product differentiation is to market the product in a kit with a diluent syringe. To reduce the risk of needle-stick injuries during reconstitution, needle-less admixture systems can be packaged in the kit with the biotherapeutic and prefilled diluent syringe. The goal of this packaging solution is to eliminate cumbersome preparation steps and make reconstitution easier and safer, particularly for patients self-administering their medications, thus reducing risks of medication error or contamination.
To improve speed to market for these systems, a number of contract manufacturing organizations have established their own diluent syringe drug master files (DMFs). These can be referenced by the pharmaceutical company buyer, and thereby allow this life cycle management solution to be implemented in less than 12 months.
Another route toward easier self-administration of biologics—particularly for drugs available in liquid formulations—is distributing medication in prefilled syringes. Because patient compliance may be increased with seamless self-administration of injectables, other improvements to drug-delivery devices include the use of auto-injectors and cartridge pens, pre-filled with medication. For biologics, the time-to-market with a prefilled syringe is shorter and faster if the compound is already formulated in a liquid vial form. Another simple solution that drug makers use to differentiate products already in prefilled syringes involves adding safety devices to prevent the risk of needle-stick injuries.
With slightly more time for development, a next step would involve moving a lyophilized product from a vial to a prefilled syringe or other delivery device. Reformulation of a lyophilized molecule into one that is stable in liquid may in some cases consume more than 36 months for development and approval.
The longest-term improvement—but perhaps the one with the biggest payoff—is to develop a new formulation of a product. The development time frame required depends on whether validation or new clinical trials are necessary for launch. Typically, reformulations such as these can require eight years to develop the product, conduct clinical trials, and secure marketing approval.
Current reformulation strategies for biologic drugs focus on meeting market demands for therapeutics that are more convenient and comfortable to administer—either by reducing the frequency of administration or by altering the mode of delivery.
For drugs already available as injectables, development of sustained-release formulations is a leading area of research; by the end of the decade, industry analysts expect almost 40% of biologics for subcutaneous injection will be sustained-release formulations.4 The benefits of this switch are clear: enabling less frequent injections (for example, from once daily to once monthly) may improve patient compliance, and it offers distinct marketing advantages. Meanwhile, researchers seeking to move injectable biologics to a less invasive route of administration must overcome natural barriers to delivery such as stability of bioengineered proteins and large molecular size, which typically precludes oral administration.
Pulmonary administration of biologics is a promising area of research for drug makers. Of the drugs in the pipeline to treat disease systemically through inhalation therapy, almost one-half are biologics, and most of these are reformulations of commercially available molecules.3,4,6–8 Even so, reformulating traditional biologics for inhalation is a challenging prospect. To reach the deep lung with therapeutic quantities of drug, airborne drug particles need to meet tight specifications in size, shape, and structure.9 Successful formulations for pulmonary inhalation comprise spherical, porous particles that are between 1–3 microns in diameter.9-11 Moreover, the aerodynamics of the powder can be influenced by a number of other factors, including temperature, humidity, and electromagnetic relationship among drug particles.11
Approximately 23% of large molecules are administered via IV infusion.4 Although highly efficacious, IV infusion has some drawbacks: It typically ties treatment to a clinical setting, can be time-consuming to prepare and administer, and may be uncomfortable for patients. Most IV preparations are distributed in vials for reconstitution in the IV bag. Preparation of IV drugs in the clinic typically requires multiple steps and supplies, all of which can increase the dangers of error and contamination.
As a consequence, drug makers are moving toward enhanced packaging or alternatives to IV formulations. A company's individual strategic outlook will determine which improvement and time frame will work best for extending the life of a particular IV product.
As with injectable formulations, short-term improvements for IV formulations involve increasing convenience and safety. Integrated admixture systems, in which a liquid or lyophilized molecule in a vial is preattached to the reconstitution system, offer clear benefits for healthcare workers and patients by improving convenience and reducing risk of medication errors.
A mid-term solution for molecules that are stable in liquid formulations is development of premix IV packaging. Although premix packaging is common for small molecule therapeutics, few drug-delivery companies are working on similar packaging for biologics, given stability issues with biologics. The first biologic IV premix, albumin, was introduced in 2005.12
For obvious reasons, long-term packaging and reformulation efforts are focused on moving IV formulations toward subcutaneous injection. As with any reformulation to change mode of administration, the process can consume as many as eight years for development, clinical testing, and regulatory review.
In tandem with research to improve formulation technologies and delivery devices for biologics, companies also are looking to address issues in the stability and security of biologic drug products. The time between when biologics are readied for market and when they are administered to patients is a critical one for pharmaceutical companies, their manufacturing partners, distributors, and providers.
The fragility of protein- and peptide-based molecules, as well as their economic and clinical value, requires stable and secure packaging. Not only are biologics sensitive to heat, moisture, light, and oxygen,13 but minute amounts of metals or packaging materials can also denature the proteins.14 Therefore, the choice of delivery device is as critical as product formulation in ensuring the stability of the biologic throughout its shelf life. New coatings and device materials are being developed to protect compounds from air, moisture, and product leaching, as well as from other potential contaminants.
Security is also a critical issue for healthcare providers and manufacturers, given the appeal and cost of biotech drug products. Healthcare providers need help tracking and securing inventories of valuable biologics, the costs of which can range from $10 to $2,000 per dose,1 and the pharmaceutical industry is trying to avert a global trend of drug counterfeiting.15
One tactic available to manufacturers is smart packaging, which can use holograms or unique printing to produce distinctive and difficult-to-reproduce labeling. A more thorough option involves the use of electronic pedigrees, such as those enabled by RFID technology, to track and trace pharmaceuticals as they move from manufacturer to distributor, and then to retailer or provider.15 The use of electronic pedigrees may accelerate in the next few years because the FDA has asked that all drugs sold in the US carry some type of tracking mechanism.16
Drug manufacturers have a number of short-, mid-, and long-term options for improving the value of their biologic molecules. Reformulating biologics for less invasive and more convenient modes of delivery enables drug companies to address market demands for more user-friendly biologics, to extend product life cycles, and to differentiate their products in crowded therapeutic categories. While reformulations can consume years of research, development, and regulatory review, companies can distinguish their products in the short- to mid-term through the use of enhanced packaging and delivery devices.
Tom Polen is senior director, marketing, for BioPharma Solutions, Baxter Healthcare Corporation, Route 120 and Wilson Road, Round Lake, IL 60073, 847.270.2937, 1.800.4BAXTER, firstname.lastname@example.org
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