The PAT initiative: a real-time insight

Quality control is a major issue in pharmaceutical manufacturing. With the Process Analytical Technology initiative, the FDA is striving for greater efficiency and cost reduction.

The production of pharmaceutical products is a chain of different engineering processes – from setting up the formulation to granulating, drying, mixing, tabletting, coating and packaging the finished product. Only an absolute error-free progression through each single step guarantees a product of sufficient quality. The analytical control of all intermediates is another major issue in the pharmaceutical industry. Often classical offline analysis methods such as HPLC are used. However, this comes with major disadvantages; the most significant is the long time of analysis. The extent of utilization of the pharmaceutical production plants worldwide is far below what is technically feasible, due to non-specification grade batches and the long idle time prior to product release. In addition, in most cases laboratory quality control measurements permit no statement about the cause of a non-specification grade batch.

Quality control during the manufacturing
Quality control is no longer just exercised on finished products, but it can also be performed during the manufacturing process. U.S. Food and Drug Administration created the process analytical technology (PAT) initiative to utilize new scientific techniques for the process quality assurance. With direct in-line control, the effectiveness of pharmaceutical processes can be increased and the respective costs can reduced. It is intended to control specific quality parameters during the process and to predict them for the final product before its release. Monitoring every second and/or minute ensures that statistically significant data sets are produced. However, classical process variables such as pressure, temperature, pH or other physical parameters are not selective enough to make precise statements on relevant material properties. This can only be achieved with vibrational spectroscopy techniques like infrared, NIR or Raman spectroscopy.

Concentrating on NIR technology
The PAT initiative concentrates in particular on the near infrared spectroscopy as the most important analytical procedure for the in-line control, as NIR is unrivalled in the sum of its possibilities. The use of probes or flow cells permits a direct investigation of most relevant processes. This measuring technique is generally suitable to analyze substances that contain CH-, NH-, OH-, SH- or -C=O groups in a concentration range of approximately 1 percent and more. Both solid and liquid samples can be analyzed. With the development of modern probes and transmission cells, measurements can be accomplished even under extreme conditions (pressure 100 bar, temperature 300°C). All spectroscopic information can be transported by fiber optics, over long distances. The PAT initiative concentrates on the NIR technology as the most important analytical procedure for the in-line control. Bruker Optics offers MATRIXTM-F NIR spectrometer, which can be connected up to six probes. Utilizing the built-in and external 8 channel multiplexers, up to 48 reactions can be monitored by a single instrument.

Manifold applications
Since the near infrared spectroscopy permits a quantitative analysis of organic molecules in small concentrations, a monitoring of most pharmaceutical production processes is possible. Applications include:

• Quality control of incoming goods
• Formulation and reaction control
• Granulation and drying process
• Mixing
• Tabletting and packing

The NIR spectroscopy allows direct control of processes as demanded by the PAT initiative. Shorter cycle times, higher (and predictable during production) product qualities and the avoidance of non-specification grade batches are the result. Furthermore, with real-time analysis, many system parameters can be monitored and their meaning can be understood. Today, many users believe that the PAT initiative represents a paradigm shift in pharmaceutical analytics; meaning that the current ‘testing to document quality’ paradigm is shifted to a ‘continuous quality assurance’ paradigm. Therefore, analytical instruments get a complete new relevance: they don’t only serve for the examination, but can be used for the control. In this context the NIR technology represents the most valuable tool at present.