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Drug Reconstitution: Market Needs and Technical Challenges

Mon, 03/12/2007 - 1:18pm

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Drug reconstitution can be a challenging task for non-healthcare trained patients trying to prepare a drug for self-administration. The following article examines some of the concerns 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.

By Graham Reynolds
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.

Top: Mix2Vial needleless reconstitution systems enable simple vial-to-vial transfer and mixing between diluent vial and lyophilized drug vial.
Bottom: Vial Adapters enable rapid transfer and reconstitution of drugs between vials with optimal aspiration of mixed and reconstituted drugs. They are compatible with Luer slip and lock syringes.

In an effort to reduce healthcare 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 introduces certain issues to consider.

Need for 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 liquid, 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 powder 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 the 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 surprising, 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 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 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.

Advanced Reconstitution Benefits
at a Glance

  • Ease of Use  –  Advanced reconstitution systems with well-engineered components and processes introduce structure that simplifies their usage. For instance, a simple locking adapter can snap onto the neck of a standard vial, a plastic spike pierces the stopper, and the reconstituted drug gets transferred to the syringe by a luer connection. Such a simple system is usable by non-healthcare professionals without difficulty. That encourages patients to conform to their prescribed regimen.
  • Better Patient Compliance  –  Advanced reconstitution systems can package the precise amount of diluent and drug with a properly sized needle in a single kit. This helps improve dosing accuracy.
  • Improved Safety  –  Needle-free reconstitution can help prevent accidental needlesticks. Calibrated doses also prevent incorrect dilution or administration and accidental contamination or exposure.
  • Less Waste  –  Reduce the amount of overfill – a significant factor for expensive drugs.
  • 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 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.

The MixJect transfer system is a single unit for reconstituting a powder drug with a diluent prefilled syringe. Upon reconstitution, the drug is available for immediate injection with a dry integral needle.
 

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 either a prefilled 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 the various alternatives for advanced reconstitution, pharmaceutical makers should carefully consider various factors. Among the key criteria:

  • The type of drug  –  If it’s expensive or more toxic, that carries implications for the type of reconstitution method chosen.
  • The diluent volume type  –  Different volumes will offer a varying number of options.
  • The administration method  –  Is the drug to be injected subcutaneously, intravenously, or intramuscularly?
  • Linkage to secondary administration  –  If there is a 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. These systems connect a syringe of a diluent (either prefilled 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.

Making Challenging Medical Conditions
a Little Easier

It’s the reality that every hemophiliac knows and lives with: administering expensive medications to control these serious conditions can be a complicated, time-consuming process. And when you’re a young child, simplicity and safety are of even greater importance.

For 6-year-old Brock, hemophilia is more than a chronic disease. With its need for regular dosages of intravenous medications, hemophilia is also a chronic annoyance as well. Earlier, Brock was on high-dose Immune Tolerance Therapy that required a two or three vial dose. Each vial reconstitution needed a set of more than 10 different steps just to prepare a dose. According to his mother Katherine, it was getting to be too great of a burden.

As Brock gets older, “I want to help foster a greater sense of independence and control in him,” she said. “He’s battling a difficult disease and if I could find a way to put him more in control, it would be good for his self-esteem and easier for all of us. With his previous medication, we’d have to pop off tops, get a syringe packet, puncture the vials with a double ended needle, transfer the water, carefully dispose of the needle in a sharps container, then open a filter needle to draw up the solution only to have to remove it to administer the product. It’s just a lot to deal with for anyone on a daily basis, especially a 6-year-old.”

“So we consulted our physician and were able to obtain free trials of three appropriate medications. We chose Helixate FS and the determining factor was the much easier system for preparing and administering the doses.”

Helixate FS is an advanced recombinant FVIII (rFVIII) factor product for the treatment of hemophilia A and offers a small diluent size of 2.5 mL compared to 10 mL for the leading rFVIII product. This means less volume, which translates to fast, easy infusions and convenience. Further, Helixate FS uses a significantly easier drug-delivery system: the Mix2Vial system from West Pharmaceutical Services.

“I gave Brock two of the reconstitution systems from the trial products and he greatly preferred the Helixate/Mix2Vial system because it was just so much easier for him to figure out. He even taught his 3-year-old sister how to do it!” Katherine said. “It requires just four steps to reconstitute the drug and has a built-in filter. He has a completely filtered product that is ready to be infused.”

Katherine and Brock also appreciate the fact that there are no needles involved in the reconstitution process. “With hemophilia, the smallest needle-stick can obviously become a major problem, so this system is much nicer. Brock can’t accidentally prick himself and there are no needles needing careful disposal.

This would be a great option for any patient, but it has been particularly well suited for Brock,” she said. “The simplicity of the process takes out some of the frustrations” and that’s a really good thing.

It’s a similar story for Jessica Kocsis and her son Jeremy. Nearly 10 years ago, shortly after his birth, Jeremy was diagnosed with Type 3 von Willebrand disease (vWD), another type of bleeding disorder. For years, Jeremy endured multiple hospitalizations, surgeries, CAT scans, and other major disruptions while Jessica child-proofed and padded her home.

As a Type 1 vWD sufferer herself, Jessica takes Stimate, a nasal spray, if she has a major injury. For Jeremy, the situation called for a different therapy to help alleviate the condition. His tiny veins made it difficult to receive treatments at home and he had to take much of his medication at a hospital. Currently, Jeremy takes Humate-P, which is derived from human plasma and helps the body form clots and shorten instances of bleeding.

By the Spring of 2003, persistent nosebleeds and treatment needs prompted doctors to give Jeremy a mediport – a central-access device under the skin that delivers medicine directly to the bloodstream. Combined with the Mix2Vial drug reconstitution system, the mediport enables Jessica to give Jeremy his intravenous Humate-P treatments at home, creating significantly greater freedom and dramatic lifestyle improvements. Together, Jessica and Jeremy have found ways to prophylactically treat his condition, enabling him to become more independent, attend Cub Scout camp, and take up swimming.



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. Different variations of the vial adapter can be used 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 diluent). This is an ideal solution for connecting vials of different sizes. The adapters can be color-coded (e.g., blue side is for diluent) and particulate filters and venting can be added if necessary or 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.

Needleless Transfer Devices

This option is a more sophisticated form of vial-to-vial reconstitution. 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. The connected syringe then 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 doesn’t need to attach the vial.) This replaces the use of the traditional aluminum seal.

This approach requires fewer steps for the patient – he 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 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. These systems provide a high level of end-user benefits. The pharmaceutical company, however, has additional challenges in terms of manufacturing and regulatory requirements because of the change in primary container.

Reconstitution Solutions Provide Many Advantages

By successfully addressing these challenges, advanced reconstitution systems can create a host of 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 needle sticks.Many provide needleless reconstitution and transfer.Since 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 because the system promotes the use of all of the drug in the calibrated dose.They can reduce problems during the mixing process, such as foaming or incomplete reconstitution of the drug.

Conclusion

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 the U.S. FDA and carry CE certification for European markets.

For the person administering the drug, whether a healthcare professional or not, advanced reconstitution systems can help promote safe and effective drug delivery and compliance with a dosing regimen. For pharmaceutical companies, advanced systems can differentiate products in the market. Since the dosing is accurate, manufacturers may be able to reduce the need for drug overfills.

One important consideration for pharmaceutical makers centers on the need to educate their users. Advanced reconstitution systems represent an important leap forward in usability and safety. However, it is also undeniable that they introduce a level of change that is non-trivial to people who are not healthcare professionals. 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.

ONLINE

For additional information on the technologies and products discussed in this article, visit West Pharmaceutical Services Inc. at www.westpharma.com.

Graham Reynolds is the Vice President of Reconstitution and Transfer Systems at West Pharmaceutical Services Inc. Offering 25 years of experience with the company, Reynolds is responsible for West's business in the reconstitution and transfer systems market segment. He can be reached at 610-594-2935 or graham.reynolds@westpharma.com.

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