Many parenterals, especially biotherapeutics, are unstable in aqueousbased formulations for long periods of time and are, therefore, lyophilized. Lyophilized drug products must be reconstituted with sterile diluent prior to use. The reconstitution operation is an additional step the patient or caregiver must perform correctly to ensure safety and appropriate dosing to the patient.
An increased use of lyophilization and the demand for more unit dose/unit of use packaging have created a requirement for new package forms. Lyophilizing in dual chamber packages eliminates the manual aseptic reconstitution step and greatly improves patient convenience and safety. However, lyophilizing a drug in dual chamber systems can be challenging compared with lyophilization in a standard vial due to differences in package configuration, heat flow, and lyophilizer trays. Appropriate considerations for the proper amount and fill for each chamber must be taken into account to produce a product designed to deliver the target label dose on use. One of the main benefits of dual chamber packaging is that the reconstitution step is built into the package and thereby improves patient convenience and safety.
Lyophilizing in dual chamber packages [e.g., dual chamber vial (DCV), dual chamber syringe (DCS) syringe, or dual chamber cartridge (DCC)] eliminates the manual reconstitution step and greatly improves patient convenience and safety.
Dual Chamber Cartridge
A DCC consists of a syringe barrel with two chambers that are separated by a middle plunger. The front chamber contains a lyophilized drug and is capped by an elastomeric closure part that is thin enough to be punctured by a doublesided needle (i.e., a pen needle). The rear chamber contains the diluent and is closed at the bottom with an elastomeric end plunger. A bypass exists between the two chambers to allow for liquid to flow from the rear chamber to the front chamber. The bypass may consist of either an external channel or internal grooves, where the grooves are cut into the inside of the glass.
A DCC is typically used in conjunction with a pen injector for reconstitution and delivery to the patient. Pen injectors are available in disposable and reusable formats. The DCC is preloaded in the pen injector for the disposable ready-to-use format. The user/patient must load the DCC into the pen injector for the reusable format. The first time the pen is utilized the user has to disinfect the rubber septum, attach a pen needle, reconstitute the cartridge, prime the pen to remove air, and set the dose. Additional uses for this system only require the user to disinfect the rubber septum, attach a pen needle, set the dose, and inject. The needle is removed after each injection. Thus, at time of use there are five steps prior to dosing.
Dual Chamber Syringe
A DCS is similar to a DCC except that the DCS is designed to be used without a device at time of use. Therefore, a DCS becomes equivalent to a prefilled syringe after reconstitution. A typical DCS includes aplunger rod and flange. Prior to reconstitution, the user affixes a needle to the DCS. This may be a pen needle or luer needle depending on the type of frontclosure. The plunger rod pushes liquid from the rear chamber through the bypass into the front chamber in a controlled fashion. This is typically performed by turning the plunger rod through a thread mechanism in the flange. There are approximately four steps prior to dosing the patient for the DCS. These steps include removing the tip cap or disinfection of the rubber disk, attaching the luer or pen needle, attaching the plunger rod, and pushing/turning the plunger rod to move diluent from the rear to the front chamber to reconstitute the lyophilized cake.
Formulation development for the active-containing chamber
It is critical to evaluate and gain an understanding of the fundamental relationships between the formulation, the process, and the package since all must work in unison for a successful product to be developed. Although formulation development activities for the lyophilized powder in the dual chamber package are similar to those for standard vial systems, there are some activities that are specific to package and process compatibility. Foremost, the formulator must consider the impact of moisture on product quality and ensure the cake mass is sufficient to withstand moisture ingress from the elastomer and diluent chamber. The formulator must also ensure the formulation is compatible with silicone and the selected elastomer. If the formulation is not compatible with silicone, either the formulation or the siliconization process needs to be optimized. The main concern for compatibility of the formulation with the elastomer is leachable release from the elastomer. This can be controlled with fluoropolymer coating of the elastomer or optimization of the formulation. Finally, the formulator should attempt to maximize product concentration in the formulation to minimize cake height since this significantly impacts overall lyophilization time.
Formulation development for the diluent-containing chamber
A key component of the dual chamber freeze-dried product is the selection of the appropriate diluent. The diluent chosen should enable rapid dissolution of the freeze-dried cake on transfer to the dry powder chamber, be compatible with the freeze-dried powder, and not negatively impact the chemical or physical stability of the reconstituted product. Typical diluents range from simple systems, such as water for injection, to tonicity modifying solutions, to water containing a preservative. Several of the dual chamber pen products have a preservative added to enable the reconstituted solution to be used in a multidose pen injector. Example preservatives used in several marketed dual chamber package systems include benzyl alcohol and m-cresol. If a multidose product is desired then appropriate compendial antimicrobial effectiveness testing (AET) must be preformed to assure that the correct preservative and concentration are chosen for the product. It should be noted that, depending on where the product is to be marketed, there may be different AET requirements. It is also important that the stability of the preservative is monitored over the product shelf life to assure that sufficient preservative is present to meet compendial AET.
The comparison of cost between a lyophilized product in a dual chamber package and a vial is complex due to the number of factors that need to be considered.
It is difficult to generalize this topic since many of the factors are dependent on specifics of the product. One of the foremost cost differentiators is related to decreased overfill in a dual chamber system. Consider the example of a 1-mL fill in vial versus dual chamber system. The USP suggests a 0.15-mL overfill for 1-mL fill vial products due to loss during withdrawal and administration (32), which equates to a 15% overfill. However, the overfill for a dual chambered system is only dictated by hold-up volumes between chambers and that caused by the delivery needle. This is typically 0.1 mL (i.e., 10% overfill) for a 1-mL dual chamber system. This consideration is especially important for biologics drugs where the drug itself is expensive.
Freeze-drying time and yield are specific to the formulation, primary package, and lyophilization parameters, but is generally less optimal for dual chambered systems. However, if a product in DCS has a relatively high collapse temperature and an efficient loading configuration in the lyophilizer, the overall difference in lyophilizer time and yield may not be much greater than for an identical product in vial. The number of accessories needed to reconstitute and deliver drug from a lyophilized drug in vial is much greater than for the lyophilized drug in a dual chamber system. This greater number of accessories must be taken into the overall cost of the final drug product. One exception is that drugs in DCCs must be delivered with a pen delivery system, which varies widely in cost.
Original article: "Freeze Drying/Lyophilization of Pharmaceutical and Biologics Products"