Strategies in Parenteral Drug Manufacturing

A technical forum moderated by Patricia Van Arnum
May 01, 2011
By Pharmaceutical Technology Editors
Volume 35

Dual-chamber systems in parenteral drug delivery

Thomas Otto, managing director at Vetter Pharma-Fertigung.

Figure 1: (dual-chamber technology): Example of a dual-chamber syringes for various fill volumes with a tamper-evident closure system. (VETTER)
Biologics present a challenge to both the manufacturer and end-user. They usually must be formulated as parenterals. In liquid form, however, they often are unstable because of their complex structure and composition. In that case, they must be manufactured using highly specialized processes, such as lyophilization (i.e., freeze-drying), which nearly eliminates stability issues. Reducing a compound's sensitivity to temperature prolongs its shelf-life, but reconstitution can be cumbersome as it involves multiple steps that can increase the potential for error. Dual-chamber technology provides an effective alternative (see Figure 1 [Dual-chamber technology]) as it combines the lyophilized drug and diluent in a closed system, thereby enabling reconstitution in a few simple steps.

Traditional versus dual-chamber technology. Traditionally, users receive lyophilized drug product in a vial. To administer, the user meters the diluent into a syringe and adds the diluent to the lyophilized vial. Next, the reconstituted drug is withdrawn from the vial, and after changing the needle, the drug is administered to the patient. This process requires careful measuring of the diluent and the reconstituted drug, manual dexterity, and numerous steps for administration. This process is unwieldy for medical professionals in the clinic and especially for patients and their caregivers who self-administer in nonclinical settings.

Dual-chamber technology is one approach that can be used to resolve these problems in drug administration. The dual chamber is a closed system with the lyophilized drug residing in one chamber and liquid in the other. Before administration, the diluent is pushed through a channel between the two chambers to reconstitute the drug, which can then be injected.

Manufacturing process. Although the dual-chamber system is simple to use, its manufacture is more complex and requires lyophilization of the drug within the delivery system. The process begins by washing, siliconizing, and sterilizing the glass barrels, which are then each separated into two chambers by a middle stopper. Liquid drug is filled into the front chamber, and a closure is set in place. The drug is lyophilized to produce a stable lyocake after which the closure is sealed. The second chamber is filled with diluent, and the end stopper is put in place.

The primary packaging components, such as glass barrels, stoppers, and closure systems, must be carefully selected to withstand the manufacturing process to prevent adversely affecting the drug: During lyophilization, temperatures can reach as low as –60 °C under vacuum. Moreover, compounds can interact with the silicone and rubber formulations, so the drug must be precisely matched with the container components.

Benefits. The dual-chamber systems offer several benefits. They increase dosing precision because the drug and diluent are premeasured and sealed. They decrease risk of medication error by eliminating the use of multiple vials and needles. Moreover, because of their simplicity, dual-chamber systems allow patients or their caregivers to administer drugs at home. Dual-chamber syringes are used with single-dose drugs, but if medication is delivered in multiple doses, a dual-chamber cartridge with a pen system can be used. This versatility allows dual-chamber systems to be used in a life-cycle management strategy at initial launch or in later product generations.

Dual-chamber systems reduce overfill requirements. Vials require greater overfill to ensure that enough drug is available to manually draw the drug into a syringe. Because dual-chamber systems are closed and more efficient at dosing, they require less overfill.