Drug Reconstitution: Market Needs and Technical Challenges

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Drug Reconstitution: Market Needs and Technical Challenges
March 2007
By: Graham Reynolds
Controlled Environments Magazine
Many reconstituted drugs are administered at home by the patient. Different technologies for reconstitution have gained approval and acceptance among pharmaceutical companies and their patients.
For patients who must manage chronic diseases ? such as hemophilia, multiple sclerosis, rheumatoid arthritis, diabetes, and others ? medication issues can present significant challenges regarding safety, ease of administration, cost, compliance, and other factors. Fortunately, continual advances and breakthroughs from pharmaceutical companies are delivering tremendous improvements in the form of more effective medications. However, these medications typically require frequent injections; depending on the nature of the disease and the patient?s individual condition, those injections could be weekly, daily, or even multiple times a day.
In an effort to reduce health care costs and improve patient satisfaction, there has been a marked increase in patient self-administration of medications for chronic conditions. Many pharmaceutical companies are turning to home-delivery and administration of these injectable medications, most of which are manufactured and sold in lyophilized (or ?freeze-dried?) form and require reconstitution, mixing, or transfer before administration. This reconstitution process can be complex and introduce certain issues to consider.
WHY DO WE NEED RECONSTITUTION SYSTEMS?
Many new drugs, especially those developed by bio-pharmaceutical companies, are initially marketed in lyophilized form for two primary reasons: shelf-life and time-to-market. A lyophilized drug maintains its stability and potency over time, extending its shelf-life for prolonged storage. Some drugs marketed in lyophilized form may eventually be available as liquids, but lyophilization provides the fastest route to market for many drugs, and the only option for those not stable in a liquid form.
These drugs ? often packaged in a powdered form in vials ?require an additional preparation step prior to administration. That additional step is the traditional reconstitution process. With traditional reconstitution, there are two vials and one disposable syringe. One vial contains the lyophilized drug and the other contains the diluent (often water, but occasionally another liquid). The patient or caregiver must use the syringe to insert air into the vial containing diluent, withdraw the diluent into the syringe, insert the diluent into the vial containing the lyophilized drug, mix the solution to create an injectable medication, and draw a measured dose back into the syringe for injection. Not surprisingly, this rudimentary reconstitution process presents several formidable challenges.
A Lack of Expertise ? In most instances, reconstituted drugs are administered in non-clinical settings (typically at home) by patients or caregivers who are not trained health care professionals. While it?s far more convenient for patients who can avoid repeated trips to clinics and other facilities for routine injections, it can be a daunting experience to prepare and administer an injectable drug. Pharma companies need to ensure that the process is simple and safe.
Added Risks ? Any drug that requires mixing presents complications and risks. For instance, a hemophiliac must be especially vigilant to prevent accidental needle sticks. There can be inadvertent contaminations or exposures to sometimes-toxic drugs (often resulting from so-called ?spray-back?). And there?s a greater risk of inaccurate process ? such as using improper concentrations, resulting in incorrect dosing.
Compliance Concerns ? If the process is complicated, dosing accuracy may suffer. And if the process is difficult, unpleasant, or painful, it can become an impediment to patient compliance.
Waste ? Pharmaceutical manufacturers often overfill the vial by as much as 35 percent to ensure that there is a sufficient quantity of the reconstituted drug to administer the correct dose. The overfill compensates for the inherent variability of the manual process, as well as the difficulty of removing the liquid completely from the vial. From the patient?s perspective, there?s a risk of mishandling or contamination that can necessitate throwing out very expensive drugs.
A number of newer, advanced products on the market can provide both professionals and non-professionals alike with safe, convenient, and easy-to-use systems for reconstituting and administering injectable drugs. These systems can be provided either as a total packaged solution or as components for specialized use.
Many of the new reconstitution systems can be adapted to currently marketed drugs without the need to change manufacturing processes or packaging components such as vials, stoppers, and seals. They are offered as a total system that can be packaged with the filled drug vial and the reconstitution components. Such systems usually consist of a plastic device that joins the drug vial to the diluent container that can be a pre-filled syringe, vial, or infusion bag. Reconstitution devices can be sterile and fully supported by appropriate regulatory filings. To further enhance convenience, all required items to perform the reconstitution can be packaged together in a kit form. The following section examines some of the leading reconstitution options.
SELECTING THE RIGHT RECONSTITUTION ALTERNATIVE
An advanced reconstitution system can add value to currently marketed and pipeline drug products. When evaluating various alternatives for advanced reconstitution, pharmaceutical makers should carefully consider various factors. Among the key criteria are the following:
The type of drug ? If it?s expensive or more toxic, there are implications for the type of reconstitution method you choose.
The diluent volume type ? Different volumes will present you with a varying number of options.
The administration method ? Is the drug to be injected subcutaneously, intravenously, or intramuscularly?
Linkage to secondary administration ? If you need to connect (post-reconstitution) to a bag or auto-injector, certain options are more advantageous.
The competitive environment ? Many drug makers use reconstitution and delivery as differentiators for products that may be approaching commodity status.
Time-to-market requirements ? Reconstitution systems that use existing, approved packaging avoid the need for regulatory review.
Overfill issues ? Systems that reduce the need to overfill vials with lyophilized medications are ideal for expensive pharmaceuticals.
Vial Adaptors
Vial adaptors ? which provide quick, safe, and cost-effective transfer of the diluent ? are a low-cost solution to improving the reconstitution process (see Figure 1). These systems connect a syringe of a diluent (either pre-filled or filled from another container such as a vial or ampoule) to a vial with a lyophilized drug and provide for quick and safe transfer from vials, allowing convenient, optimal quantity aspiration. The adapter snaps to the neck of the standard vial after the plastic button has been flipped off. A plastic spike pierces the stopper; needles are not used. The reconstituted drug is transferred to a syringe by a luer connection. Vial adapters come in a variety of sizes as well as venting and inline filter options; an optional incorporated valve system maintains stability for multi-dose applications. One can even use different variations of the vial adapter to connect to other containers such as IV bags and cartridges (for subsequent insertion into a pen system) as well as nasal or oral administration routes.
Vial-to-Vial Systems
Vial-to-vial systems offer a similar level of simplicity and cost-effectiveness through a double-adapter that connects to the top of each vial (lyophilized drug and dilu-ent). This is an ideal solution for connecting vials of different sizes. You can color-code the adapters (e.g., blue side is for diluent) and add particulate filters and venting if necessary/desired. This is a very easy process for patients and no needles are required to reconstitute the drug. For manufacturers, vial-to-vial systems are attractive because they necessitate no changes to the vials they currently use.
Needle-less Transfer Devices
This is a more sophisticated form of vial-to-vial reconstitution (see Figure 2). This single-device model allows for pressurization and transfer of the diluent into the vial containing the lyophilized drug. The patient snaps on both vials. The diluent mixes with the powdered drug and the connected syringe draws in the reconstituted drug for administration.
Direct Connection to Vial
In some instances, pharmaceutical companies may opt to deploy a package in which the syringe is directly connected to a vial. The syringe is pre-filled with the proper amount of diluent and is directly attached to the vial during the manufacturing process. (The patient needn?t attach the vial.)
This replaces the use of the traditional aluminum seal. This approach requires fewer steps for the patient. He or she simply injects the diluent directly into the vial holding the powdered drug, gently mixes the solution, and draws a measured dose back into the syringe for injection. The disadvantage is that this does require a new manufacturing process for the drug maker. Some newer direct-connection systems offer more manufacturing flexibility by using vial adapters (to support standard vials and drug packaging) and a range of syringes or even auto-injectors.
Dual-Chamber Syringes
Dual-chamber syringes provide a lyophilized drug and diluent in a single unit. Reconstitution is achieved by pushing down on the syringe plunger, forcing the dilu-ent through a channel and into the second chamber where it mixes with the drug to create the injectable solution. The drug can then be injected using an attached n