Debanjan (Deb) Das, is a pharmaceutical scientist with over 10 years of experience in formulation development of a variety of dosage forms. In his current position as an Application Development Manager with Dow Chemicals, Deb is focusing on Advanced Delivery Technology platform for hard-to-formulate actives and fast tracking commercial development.
Process analytical technology (PAT) tools are a regulatory requirement with the Food and Drug Administration, the International Conference on Harmonisation, and the European Medicines Agency. Although many sophisticated PAT tools are currently available, recent advances of on line, at line, near line, and remote methods of analysis during process development of semisolids seem to be based on the principles of infrared (IR), mostly by mid-IR and near-IR (NIR) and by acoustic resonance spectroscopy (ARS). IR spectroscopy is advantageous because virtually all final and intermediate forms of semisolids (such as liquids, emulsions, foams, slurries, dispersions, etc.) can be directly monitored without elaborate sample preparation. Examples of direct determination of drug content in finished formulation is shown in a study where Fourier transform infrared spectroscopy was combined with a sensitive photoacoustic detection to achieve superior spectral depth profiling and detection of weakly absorbing components in the presence of a strongly absorbing matrix, thus providing the ability to find trace concentrations of a drug without any sample preparation.
In another report, ARS outperformed NIR spectrometry in detection of drug molecules by directing the waveguide deeper into the drug product and achieving a faster analysis than NIR methods. In ARS (also called ultrasonic spectroscopy depending on the frequency of wave used), an acoustic wave is applied to a process, and its attenuation and velocity are measured following its interaction with the sample. Ultrasonic spectroscopy, coupled with NIR, can thus be used as a powerful quality control tool for finished products such as drug content and particle size measurements (0.01–1000 nm) on highly viscous materials such as ointments or creams.
Although there is more implementation of PAT tools in the realm of solid dose manufacturing, process development and scaling-up of semisolids present their unique set of challenges. Adding to this woe, there is a clear paucity of published literature and dearth of industrial reports on current innovative uses of PAT tools for manufacturing of semisolids due to protection of competitive intelligence. Many semisolid manufacturers, even with the advancement of PAT technologies, tend to use empirical trial-and-error methodology to address scale-up issues. Wide usage of IR and acoustic spectroscopic methods along with implementation of innovative PAT technologies, such as integrated chemometric sensors for real-time multidimensional analysis, will rest largely on the free scientific exchange of information within the industry and more sponsored research in academia.
In my opinion, the biggest challenge in the widespread implementation of PAT for manufacturing of semisolids has been the high initial installation cost. Semisolid dosage forms do not serve blockbuster molecules to net return of investment. Most of the time, branded products (as well as generic products) are made by contract manufacturers for cost cutting measures, which again is a deterrent for implementation of sophisticated PAT tools. However, some manufacturers (both branded and contractors) do adopt some form of PAT philosophy for their own sake and that is to identify and control key process parameters. Addressing this need, some large-scale commercial equipment is made with preinstalled sensors in their reaction vessels as value-added options. Widespread use of PAT would be thus contingent upon stronger regulatory enforcements and economical use of technology.