Medical Device Link.

PARENTERALS

The MixJect transfer system is a single unit for reconstituting a powder drug with a diluent prefilled syringe. Upon reconstitution, the drug can be injected.

For patients managing chronic diseases such as hemophilia, multiple sclerosis, rheumatoid arthritis, diabetes, and others, medication can present significant challenges in terms of safety, ease of administration, cost, compliance, and other factors. Advances in medicine are definitely delivering 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. Many of these medications are being administered at home by the patient; a number of these drugs are manufactured and sold in lyophilized form and require reconstitution, mixing, or transfer before administration.

Reconstitution can be complex. The following article examines some of the challenges and market trends associated with drug reconstitution, along with brief explanations of different technologies that have gained approval and acceptance among pharmaceutical companies and their patients.

WHY DO WE NEED RECONSTITUTION SYSTEMS?

Many new drugs, especially those developed by biopharmaceutical 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. It is also the only option for those not stable in a liquid form.

These drugs—often packaged in powder form in vials—require reconstitution prior to administration. 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, draw the diluent from the vial and into the syringe, inject 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. Reconstitution presents several formidable challenges:

• A lack of expertise. In most instances, reconstituted drugs are administered in nonclinical settings (typically at home) by patients or caregivers who are not trained healthcare 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 needlesticks. There can be inadvertent contamination or exposure to sometimes-toxic drugs (often resulting from so-called “spray-back”). And there’s a greater risk of inaccuracy, 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% to ensure a sufficient quantity of the reconstituted drug for correct dose administration. This overfill compensates for the inherently variable 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.

A number of new systems offer alternatives for reconstituting and administering injectable drugs. Often marketed as safe, convenient, and easy to use, these systems can be provided either as total packaged solutions or as components for specialized use. Many can be adapted to currently marketed drugs without the need to change manufacturing processes or such packaging components as vials, stoppers, and seals. They are offered as a total system that can be packaged in a kit form 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. Reconstitution devices can be sterile and fully supported by appropriate regulatory filings.

SELECTING THE RIGHT ALTERNATIVE

An advanced reconstitution system can add value to currently marketed and pipeline drug products. When evaluating the various alternatives for advanced reconstitution, pharmaceutical makers should carefully consider the following factors:

• Drug type. If it’s expensive or more toxic, it carries implications for the reconstitution method.
• Diluent volume. Different volumes will present varying options.
• Administration method. Is it to be injected subcutaneously, intravenously, or intramuscularly?
• Linkage to secondary administration. If you need to connect to a bag or autoinjector after reconstitution, certain options are more advantageous.
• Competition. 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 may 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 ADAPTERS

Mix2Vial needleless reconstitution systems enable simple transfer and mixing between a diluent vial and a lyophilized drug vial.

Vial adapters can provide quick, safe, and cost-effective diluent transfer (See Figure 1). The low-cost systems connect a syringe of a diluent (either prefilled or filled from another container such as a vial or ampule) to a vial with a lyophilized drug. They 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 with venting and in-line filter options; an optional incorporated-valve system maintains stability for multidose applications. Different variations of the vial adapter 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 diluent). This is an ideal solution for connecting vials of different sizes. You can color-code the adapters (e.g., blue side for diluent) and add particulate filters if needed. 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 require no changes to the vials already in use.

NEEDLELESS-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 prefilled with the proper amount of diluent and is directly attached to the vial during manufacturing. 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 drug makers must change their manufacturing process. Some newer direct-connection systems offer more manufacturing flexibility by using vial adapters to support standard vials and drug packaging or a range of syringes or even autoinjectors.

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 diluent 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 needle, or can be transferred through a luer connection.

RECONSTITUTION ADVANTAGES

By successfully addressing these challenges, advanced reconstitution systems offer benefits for both pharmaceutical companies and their patients:

• They are easy to use by patients and caregivers who aren’t healthcare professionals.
• They help protect against drug spray-back and accidental needlesticks.
• Many provide needleless reconstitution and transfer.
• Because they are more convenient, they encourage patients to comply with a dosing regimen, helping to improve patient outcomes.
• They may help the pharmaceutical company reduce the amount of overfill in the drug vial.
• They can reduce problems during mixing, such as foaming or incomplete drug reconstitution.

Reconstitution systems are especially beneficial for products that are used to treat chronic conditions that are administered in a home setting. Many systems are approved as medical devices by FDA and carry CE certification for European markets.

Advanced reconstitution systems represent an important leap forward in usability and safety. Manufacturers must assume the burden of ensuring that patients receive complete and clear training on using the new reconstitution systems.

The ideal time to evaluate systems for developmental drugs is during Phase II and Phase III clinical trials when the effectiveness of the delivery system can be evaluated. For currently marketed lyophilized drugs, systems are available that can be used without the need to change processing and filling lines or packaging components.