In the autumn of 2002, the US Food and Drug Administration (FDA) announced a new initiative entitled Process Analytical Technology (PAT). The initiative is consistent with the FDA’s position that ‘Quality cannot be tested into products; it should be built-in or should be by design’.
PAT has been described as ‘systems for analysis and control of manufacturing processes based on timely measurements during processing of critical quality parameters and performance attributes of raw and in-process materials and processes to assure acceptable end product quality at the completion of the process’.
A major goal of the PAT framework is to develop processes that consistently generate products of predetermined quality. In so doing, improved quality and efficiency are expected to occur from:
- Reducing cycle times using on-, in-, or at-line measurements and controls.
- Preventing reject product and waste.
- Raising the possibility for real-time product release.
- Increasing the use of automation, which reduces operator error and increases operator safety.
- Facilitating continuous processing using small-scale equipment, resulting in improved energy and material use and increased capacity.
In order to build quality into a process, a primary step is to analyse the process, understand what the critical quality attributes are, monitor the factors that effect the critical quality attributes, and control those factors. PAT today is an important element of FDA’s ‘Quality by Design’ and cGMP’s for the 21st century.
Raman spectroscopy is a form of vibrational spectroscopy, much like infrared (IR) spectroscopy. The spectrum produced originates from energy transitions arise from molecular vibrations. However, the position and intensity can also be effected by physical factors. Thus a Raman spectrum can be analysed to yield information on both chemical and physical properties of the sample under investigation.
Raman spectroscopy is powerful tool for chemical analysis for several reasons: it exhibits high specificity, it is compatible with aqueous systems, the technique can be used to study solids, liquids, gels, and pastes without specialised sampling accessories, no special preparation of the sample is needed, the timescale of the experiment is short, and there are numerous sampling options including fibre-optics and microscope.
As can be seen from Table 1 Raman spectroscopy is in a very select group of identified PAT-capably techniques that can be initially applied in the early discovery stage and can still be applied in production.
This advantage allows for information and knowledge compounding and transfer between stages and groups as a material advances towards production.
Historically, R&D groups have utilised analytical tools in order to gain an insight into a molecule and to accomplish the tasks and goals of their departments.
However the tools employed and the tool-generated metrics were rarely able to be transferred to the next phase of development. This leads to inefficiencies in the scale-up stages as new tools, metrics, and models must be found, investigated, and refined.
Raman spectroscopy has the potential to shorten these phases by allowing the knowledge generated in earlier phases to be transferred forward employing similar analytical approaches but using analysers packaged and validated to the requirements of each group.
Raman is becoming a standard tool for PAT applications within the pharmaceutical industry. It can be used for automated rapid non-invasive high-throughput analysis of 96 well plates, generated information that can aid the mechanistic scientist determine the reactions mechanistic pathway. Following the successful production of the API, the API material is packaged and sent to the DP manufacturing facility. Raman has been demonstrated for raw material ID. Raman analysis allows detection of process induced transformations (PITs), understanding the types of species generated during PITs, information on the kinetics of the PIT and quantification of the species.