Lyophilising biopharmaceuticals enables prolonged storage but reconstituting the drug prior to use can pose challenges. Graham Reynolds from Reconstitution and Transfer Systems, part of West Pharmaceutical Services, highlights the benefits of reconstruction devices
As the number of lyophilised or freeze-dried drug products being developed and put on the market increases, so too does the need for systems and devices to administer these drugs.
Many new drugs, especially those developed by biopharmaceutical companies, are initially marketed in lyophilised form. A lyophilised drug maintains its potency over time, extending its shelf-life for prolonged storage. Some drugs marketed in lyophilised form may eventually be available as liquid, but lyophilisation provides the fastest route to market for many drugs, and the only option for those not stable in a liquid form.
Lyophilised products require an additional preparation step prior to administration. This process, known as reconstitution, entails mixing the dry drug with a liquid to create an injectable solution.
Many of these drugs are used to treat chronic conditions. As a result, the number of patients who have to administer the drug themselves or rely on a non-healthcare professional is increasing. The reconstitution process can be complex and may put patient (and caregiver) at risk from accidental needle sticks or inadvertent exposure to the drug via spray-back, or cause inaccurate dosing and non-compliance with a dosing regimen.
Traditional reconstitution requires two vials - one of the lyophilised drug and one of a diluent - a disposable syringe and two needles. It also requires training and experience and has the potential to put the person administering the drug at risk of an accidental needle stick. Further, the patient may be at risk of an under- or overdose because the diluent may not be measured precisely. Furthermore, pharmaceutical manufacturers usually 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 variability of the manual process, as well as the difficulty of removing all liquid from the vial.
A number of products available on the market can provide both professionals and non-professionals 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 specialised 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 prefilled syringe, vial or infusion bag. Reconstitution devices can be sterile and fully supported by appropriate regulatory filings. For further convenience, all required items to perform the reconstitution can be packaged in kit form.
Dual-chamber syringes provide a lyophilised 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 a solution. The drug can then be injected using an attached needle or 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.
One example of a simple system is the vial adapter. 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 lyophilised or dry powder drug; they offer quick and safe transfer from vials, allowing convenient, optimal quantity aspiration. The adapter is snapped to the neck of the 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 and with venting and inline filter options, as well as the option of an incorporated valve system to allow for the maintenance of stability for multi-dose applications.
Adaptations of the vial adapter include systems to connect to other containers such as IV bags and cartridges (for subsequent insertion into a pen system) as well as other administration routes such as nasal or oral.
Advantages of advanced reconstitution systems include:
- ease of use for a non-health care person
- added protection against drug spray-back and accidental needle sticks
- needleless reconstitution and transfer in many cases
- convenience that encourages compliance with a dosing regimen, helping to ensure a positive outcome
- less overfill in the drug vial because it promotes use of all of the drug" and
- reduced problems such as foaming or incomplete reconstitution of the drug during the mixing.
Many marketed products incorporate reconstitution systems, including drugs for treatment of haemophilia, multiple sclerosis, rheumatoid arthritis, cancer and hormone treatments. Several devices are sold in conjunction with the drug product; devices are also sold directly to hospitals and clinics.
Reconstitution systems are especially beneficial for products used to treat chronic conditions and that are administered in a home setting. Many systems are approved as medical devices by the US FDA and carry CE certification for European markets.
For pharmaceutical companies, advanced systems can differentiate products in the market. As the dosing is accurate, manufacturers may be able to reduce the need for drug overfills.
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 lyophilised drugs, systems are available that can be used without the need to change processing and filling lines or packaging components.
Among the criteria used to select an advanced reconstitution system are the type of drug; the diluent volume type; the administration method (sub-cutaneous, IV, IM); requirements for linking to secondary administration (bag, auto-injector); the competitive environment; speed-to-market requirements; and overfill requirements.
The use of advanced reconstitution systems can add value to currently marketed and pipeline drugs. They provide benefits for pharmaceutical companies, people who administer drugs and patients, can differentiate products and promote compliance and safety.