Unit operations
PharmTech: Compared with a simple solution or lyophilized formulation, what additional unit operations are required for ER injectables
and why?
(Herbert, Alkermes): Manufacture of ER injectables usually consists of a process to manufacture the ER injectable microspheres or crystals and
then the more traditional process of filling into vials or syringes. The steps required to produce a polymer particulate-based
ER injectable include: encapsulation, extraction of solvent from the particle, isolation of the particles—usually by filtration,
drying of the particles to remove residual solvent and ensure physical stability of the particle, and filling of the particles
and sealing in a sterile vial for storage prior to use. These steps are required in addition to compounding to avoid putting
stability and drug-release characteristics at risk All steps must take place within a "sterile core" to ensure the product
is in fact sterile, and each operation requires a sterile validation effort. The latter can be challenging when solid particles
are being made and manipulated.
(Thiel and Loffredo, Hospira): The additional unit operations depend on the type of ER formulation. In the case of PLGA microparticle formulations, these
have traditionally been prepared using a double-emulsion technique. Briefly, the active ingredient is dissolved in an aqueous
solution, and this solution is filter-sterilized. Separately, the PLGA polymer is dissolved in a water-immiscible organic
solvent, and this solution is also filter-sterilized. The two phases are then combined with high-shear mixing or homogenization
to prepare a water-in-oil (W/O) emulsion. This primary emulsion is diluted into a larger volume of another, outer aqueous
phase with high-shear mixing to form the secondary emulsion (W/O/W).
Then, there is a solvent-removal step to harden the newly-formed PLGA microspheres, and filtration (sieving) and rinsing steps
to isolate PLGA microspheres of the desired size distribution while rinsing away everything else. Finally, the microspheres
are dried (bulk lyophilization) and sterile powder filled. If this procedure is used, the additional unit operations compared
with traditional parenteral manufacturing are the sterile emulsification, solvent removal, and particle-harvesting operations.
Bulk drying and sterile powder filling are also specialized operations.
There are other methods for preparing PLGA microparticles (e.g., spray drying), that would have entirely different unit operations.
For in-situ gel forming ER formulations, the manufacturing operations are more traditional, but may require specialized filling to handle
viscous solutions.
Tipton (Evonik): Additional unit operations required are specific to the final dosage form. So for microspheres, commonly an emulsion step
as well as a sieving and drying step are required. For liposomes, either an extrusion or homogenization step is added. If
the product is a conjugate such as a PEGylated protein, an additional synthesis step is required. An implant will require
a melt extrusion.
Although these unit operations may be complex and add cost to individual products, they are the necessary steps to obtain
the ER as compared with the conventional dose. The additional manufacturing cost is more than made up in the additional benefit
and value of the resulting ER product.
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