The Indian pharmaceutical industry needs to step up its quality game if it wants to continue as one of the leading exporters for the US and European markets. As it has become evident with the FDA scrutiny and warnings, quality cannot be achieved at the final stages and needs to be built in at every step of development and manufacturing. The FDA has prescribed the Implementation of PAT (Process Analytical Technology) as one of the measures to integrate real-time quality as a part of process design, analysis and control.
Process Analytical Technologies (PAT) are used to provide and inform timely analysis of critical quality parameters with the end goal of improving final product quality as well as reducing manufacturing costs, thereby significantly benefiting the Pharmaceutical Industry in manufacturing area. The potential for improved operational control and compliance resulting from continuous real-time quality assurance was highlighted as a likely benefit that would result from PAT implementation.
The objective for PAT implementation of the following: -
PAT tools are routinely applied to develop a greater understanding of the process design space under a Quality-by-Design (QbD) framework. The use of PAT tools helps enable the development of robust processes, processes that are well-understood, with process set points that are controlled within design regions that are well-away from the edges of failure. As “quality cannot be tested into a product; it should be built-in or should be by design” well-designed and controlled processes may not require routine analytical measurements and feedback control during the manufacture.
A PAT tool that measures a critical quality attribute (CQA) may be implemented commercially for process control; however there are business drivers and regulatory aspects that will contribute to a final control strategy. Process Analytical Technology (PAT) can be defined as a new way of thinking validation. It is thereby not in itself a single technique or procedure, but rather a combination of techniques, procedures and technologies that enable online verification of key process parameters.
These parameters will vary depending on the process and the level of detail the measurements shall include. Some of the current problems regarding process cycle times in pharmaceutical manufacturing processes have been well documented in FDA meetings about PAT. A technique of PAT involves replacing laboratory testing with online monitoring. This may be done by using analysers like near-infrared spectroscopy to determine the drying endpoint during granulation, or using focused beam reflectance measurement for particle size determination.
Historically, pharmaceutical production involves the manufacture of the finished product, followed by laboratory analysis to verify quality. The disadvantages associated with this approach are continual process optimization, recurring manufacturing difficulties, and the possibility of failed batches. The Food and Drug Administration (FDA) is inviting discussions throughout the pharmaceutical industry concerning a new mode of operation, which will address these concerns. This mode of operation is known as Process Analytical Technology (PAT).
Process Analytical Technologies involve the use of raw material properties, manufacturing parameters, process monitoring, and chemometric techniques to produce finished products of acceptable quality. The central point of PAT is to generate product quality information in real-time. The advantages of PAT are many and varied. While process monitoring traditionally involved temperature, pressure, flows, pH and other physical parameters, PAT focusses on the use of in-line testing using near infrared, Raman, or other physiochemical techniques as a primary means of process monitoring. The data retrieved would provide information on the properties of blends, cores, and other stages in the process. Through the use of probes in the process, uniformity, drying, and mixing endpoints, and other targeted stages can be pinpointed to a high degree of certainty. Sampling error would be minimized with in-line probes placed strategically throughout the production process.
PCA is a technique of creating data models of previously produced and tested batches to verify similarity to newly created batches. One advantage this technique has over the commonly used f2 metric is that batches are now compared to a substantial compilation of batches included in a validated model. Trends could potentially be identified earlier than with an f2 comparison. This could help improvement of process consistency after scale up and post approval changes.
PLS is used to correlate data, such as finished product dissolution results, to raw material, process parameters, and in-line readings. Variables which affect the dissolution rate can be better understood and monitored. The effect of scale ups and post approval changes can be quantified. Critical parameters can be controlled, thereby creating high quality drug product, less level/stage 2 testing, and minimal product failure. When out of specification results do occur, drug products can be better investigated through the use of PLS to determine which underlying variables contributed to the failing drug product.
Pharmaceutical companies face many challenges and problems while implementing PAT into their new and pre- existing manufacturing processes. The PAT initiative was first proposed by the United States Food and Drug Administration’s (FDA), Centre for Drug Evaluation and Research (CDER) with the objective of achieving good health and cost benefits by application of modern process control and tests in pharmaceutical manufacturing industries. Quality-by-Design (QbD) is well-established in development and manufacture of pharmaceutical drug substance and drug product.The outcome of QbD is a well-designed and understood quality product that consistently delivers the continuous performance. The knowledge obtained during development helps in justify the establishment of a design space, (process) control strategy and set point within the (regulatory approved) design space.
Materials made within the design space will produce an acceptable product, and the changes within the design space are (regulatory) acceptable. These same principles and concepts have been applied to the development of analytical methods, and termed Analytical QbD (AQbD). Analogous to process QbD, the aim of AQbD is to design a well-understood, robust method that consistently delivers the necessary performance as described in the analytical target profile (ATP).
Sampling error would be minimized with in-line probes placed strategically throughout the production process. The first step away from off-line testing (laboratory separated from the production plant), would be at-line testing. This is the movement of process testing instrument to the production line to provide fast and quality results. One advantage is elimination of the transfer of samples which involving time delays. Along with traditional tests such as Dissolution, Assay, Friability, Hardness, and Thickness, this could also include accelerated dissolution rate analysis, and NIR tablet analyzers. One approach of process analytical chemistry is on-line testing, which either draws samples or monitors periodically. Another mode is known as in-line testing, which places probes in constant contact with drug product and formulation.
The advantage of on/in line testing is better controller of the process. Beyond data such as blending, or drying, the FDA has proposed creating on/at-line assurance of dissolution rates using analytical data correlations. Near infrared (NIR) is one of the techniques that has gained recent recognition as a means to add on or in-line analysis at the production level. The near-infrared light does not destroy or react with samples and is able to penetrate into and through solid samples. While NIR has gotten most of the attention, PAT is not limited to NIR but can include many other monitoring instruments, such as Raman, Mid-IR, acoustic emission signals, and other imaging techniques.
Dissolution is the first most important method for evaluating solid oral dosage form consistency, and uniformity. Using PAT, processes would be under such high control that the dissolution results could be accurately predicted well before the drug product and formulation are analyzed. Research on the correlation between dissolution results and measured process parameters would be performed so that the impact of process, raw materials, and finished product variables can be understood. The manufacturing process could be continuously monitored and adjustments made to ensure that the finished product would meet the desired specific quality and criteria. Measurements from these techniques have already been used successfully to give predictive values for dissolution, content uniformity, assay, moisture, and hardness. The data produced by these devices are valuable with information which is highly complex. In-situ analytics offers the potential for faster understanding of the process as compared to traditional off-line analyses. Development of chemometric models for quantitative analyses are required during process development, and the speed of data analysis is often more important. The ability to monitor in-situ and in near real time is invaluable during product development.
For example, the following detailed objectives are frequently requested: When does a product form, develop and at what rate? When does a reactant appear in less quantity or disappear? Does the reaction occur via a reactive intermediate? When does crystallization start and what factors control the rates? How does the homogeneity of a blend change with time? What polymorphic form(s) occur during processing? When does wet granulation reach an end point? How does the tablet potency change during a process run? Since one of the goals of QbD is to maintain control of the process to achieve the desired product attributes, process analytical technology (PAT) is an important tool for QbD.