Biomedical Engineering Reference
In-Depth Information
The final drug substance manufacturing process for a ready-to-use liquid drug
product is substantially complete at the end of the API (active pharmaceutical ingredient)
manufacture, which typically delivers the formulated material with the targeted concen-
tration of the active ingredient in combination with all of the excipients according to the
formulation recipe. The next steps in the manufacturing process for the ready-to-use
liquid, if no compositional adjustments are required, fill the bulk formulation into the
desired containers, vials, or syringes, according to the final presentation requirements of
dosing units, followed by inspection, labeling and packaging, if no delivery device is
required. The opportunities for PAT applications in the so-called “fill and finish”
operations of the ready-to-use liquid drug product are mainly linked to at-line controls
tomonitor themetered dosages (e.g., fill weight), automated visual inspections of the final
presentation for particles or cosmetic imperfections in the containers, closures and the
labeling that may have a product quality impact. If the “Control Strategy” for the
ready-to-use liquid incorporates the use of PAT tools to support final product release,
then the at-line testing of the filled vials and syringes would require nondestructive,
noninvasive tools for specific quality attributes, for example, identity by NIR. But the
greatest opportunity to measure key product quality attributes by PAT tools of the
ready-to-use liquid drug product as part of a control strategy is during the bulk
manufacturing of the formulated dosage form. On the contrary, themanufacturing process
for lyophilized solid dosage form is very amenable to the application of PAT tools (e.g.,
pressure, product temperature, shelf temperature, etc.) during process design, optimiza-
tion, scale-up, technology transfer, and full-scale commercial manufacturing execution.
13.5.7 Application of PAT Tools for Freeze-Drying
Manufacturing Processes
Designing a freeze-dried biologic formulation recipe and the freeze-drying cycle todeliver
the desired final dosage form presentation in a commercial manufacturing setting is a
multistep activity that requires both the formulation composition and the lyophilization
cycle to be in step with each other, as the two are interdependent, that is, the formulation
composition will dictate the optimum cycle design and the cycle design will influence the
formulation composition. The development and optimization of the freeze-dried product
start with the considerations of the liquid formulation requirements associated with
chemical degradation, for example, oxidation, deamidation, isomerization. Next is physi-
caldegradation, suchasunfolding,aggregation,precipitation,andsolutionconditions, such
aspHandionicstrength.Finally, stress, duetoforexample, photostability, temperature, and
freeze-thaw. In addition, to deliver the freeze-dried robust cake product, lyo-specific
excipients are needed such as cryoprotectants or lyoprotectants, for example, glycine,
mannitol, and surfactants to aid shock, freezing, and reconstitution, for example, polysor-
bate 20 or 80. Traditionally, to arrive at the best solution formulation recipe, the design of
experimental approaches is used to establish the least number of experiments that are
required to deliver formulation optimum and shortest lyo cycle.
In optimizing the freeze-drying process, the solid-state properties of the final dosage
form combination of API and excipients and water must be considered in conjunction
with the operating conditions of the freeze-dryer to deliver the desired product quality
