Process Analytical Technology
Encyclopedia
Process analytical technology (PAT) has been defined by the United States Food and Drug Administration
(FDA) as a mechanism to design, analyze, and control pharmaceutical manufacturing processes through the measurement of Critical Process Parameters (CPP) which affect Critical Quality Attributes
(CQA).
The concept actually aims at understanding the processes by defining their CPP's, and accordingly monitoring them in a timely manner (preferably in-line or on-line) and thus being more efficient in testing while at the same time reducing over-processing, enhancing consistency and minimizing rejects.
The FDA has outlined a regulatory framework for PAT implementation. With this framework – according to Hinz – the FDA tries to motivate the pharmaceutical industry to improve the production process. Because of the tight regulatory requirements and the long development time for a new drug, the production technology is "frozen" at the time of conducting phase-2 clinical trials.
Generally, the PAT initiative from FDA is only one topic within the broader initiative of "Pharmaceutical cGMPs for the 21st century – A risk based approach".
This mechanism for producing consistent product quality & reducing waste presents a good case for utilising continuous manufacturing technologies. The control of a steady state process when you understand the upstream & downstream effects is an easier task as common cause variability is easier to define and monitor.
With this in mind the PAT drive is to have a dynamic manufacturing process that compensates for variability both in raw materials & equipment to produce a consistent product.
The following criteria serve as a basic framework for successful PAT roll-outs: (From A PAT Primer)
Currently NIR spectroscopy applications dominate the PAT projects. A possible next-generation solution is Energy Dispersive X-Ray Diffraction (EDXRD). For a detailed review of PAT tools see Scott, or Roggo. For an example of application see Gendre.
(MVDA) and design of experiments
(DoE). This is because analysis of the process data is a key to understand the process and keep it under multivariate statistical control.
Food and Drug Administration
The Food and Drug Administration is an agency of the United States Department of Health and Human Services, one of the United States federal executive departments...
(FDA) as a mechanism to design, analyze, and control pharmaceutical manufacturing processes through the measurement of Critical Process Parameters (CPP) which affect Critical Quality Attributes
Critical to quality
Critical to Quality is an attribute of a part, assembly, sub-assembly, product, or process that is literally critical to quality or more precisely, has a direct and significant impact on its actual or perceived quality.-See also:* Business process...
(CQA).
The concept actually aims at understanding the processes by defining their CPP's, and accordingly monitoring them in a timely manner (preferably in-line or on-line) and thus being more efficient in testing while at the same time reducing over-processing, enhancing consistency and minimizing rejects.
The FDA has outlined a regulatory framework for PAT implementation. With this framework – according to Hinz – the FDA tries to motivate the pharmaceutical industry to improve the production process. Because of the tight regulatory requirements and the long development time for a new drug, the production technology is "frozen" at the time of conducting phase-2 clinical trials.
Generally, the PAT initiative from FDA is only one topic within the broader initiative of "Pharmaceutical cGMPs for the 21st century – A risk based approach".
The Basics
PAT is a term used for describing a broader change in pharmaceutical manufacturing from static batch manufacturing to a more dynamic approach. It involves defining the Critical Process Parameters (CPPs) of the equipment used to make the product, which affect the Critical Quality Attributes (CQAs) of the product and then controlling these CPPs within defined limits. This allows manufacturers to produce products with consistent quality and also helps to reduce waste & overall costs.This mechanism for producing consistent product quality & reducing waste presents a good case for utilising continuous manufacturing technologies. The control of a steady state process when you understand the upstream & downstream effects is an easier task as common cause variability is easier to define and monitor.
The Variables
It would be acceptable to consider that raw materials used to manufacture pharmaceutical products can vary in their attributes e.g. moisture content, crystal structure etc. It would also be acceptable to consider that manufacturing equipment does not always operate in exactly the same fashion due to the inherent tolerance of the equipment and its components. It is therefore logical to say that variability in raw materials married with a static batch process with inherent variability in process equipment produces variable product. This is on the basis that a static batch process produces product by following a fixed recipe with fixed set-points.With this in mind the PAT drive is to have a dynamic manufacturing process that compensates for variability both in raw materials & equipment to produce a consistent product.
PAT implementation
The challenge to date with PAT for pharmaceutical manufacturers is knowing how to start. A common problem is picking a complex process and getting mired in the challenge of collecting and analyzing the data.The following criteria serve as a basic framework for successful PAT roll-outs: (From A PAT Primer)
- Picking a simple process. (Think Water for Injection (WFI) or Building Monitoring System (BMS)
- All details and nuances are well understood and explained for that process.
- Determine what information is easily collected and accessible through current instrumentation.
- Understanding the appropriate intervals for collecting that data.
- Evaluating the tools available for reading and synchronizing the data.
PAT Tools
In order to implement a successful PAT project, a combination of three main PAT tools is essential:- Multivariate data acquisition and data analysis tools: usually advanced software packages which aid in design of experimentsDesign of experimentsIn general usage, design of experiments or experimental design is the design of any information-gathering exercises where variation is present, whether under the full control of the experimenter or not. However, in statistics, these terms are usually used for controlled experiments...
, collection of raw data and statistically analyzing this data in order to determine what parameters are CPP. - Process analytical chemistry (PAC) tools: in-line and on-line analytical instruments used to measure those parameters that have been defined as CPP. These include mainly near infrared spectroscopyNear infrared spectroscopyNear-infrared spectroscopy is a spectroscopic method that uses the near-infrared region of the electromagnetic spectrum...
(NIRS); but also include biosensors, Raman spectroscopyRaman spectroscopyRaman spectroscopy is a spectroscopic technique used to study vibrational, rotational, and other low-frequency modes in a system.It relies on inelastic scattering, or Raman scattering, of monochromatic light, usually from a laser in the visible, near infrared, or near ultraviolet range...
, fiber optics and others. - Continuous improvement and/or knowledge managementKnowledge managementKnowledge management comprises a range of strategies and practices used in an organization to identify, create, represent, distribute, and enable adoption of insights and experiences...
tools: paper systems or software packages which accumulate Quality Control data acquired over time for specific processes with the aim of defining process weaknesses and implementing and monitoring process improvement initiatives. These products may be the same or separated from the statistical analysis tools above.
Long-term goals
The long term goals of PAT are to:- reduce production cycling time
- prevent rejection of batches
- enable real time release
- increase automation
- improve energy and material use
- facilitate continuous processing
Currently NIR spectroscopy applications dominate the PAT projects. A possible next-generation solution is Energy Dispersive X-Ray Diffraction (EDXRD). For a detailed review of PAT tools see Scott, or Roggo. For an example of application see Gendre.
MVA in PAT
Fundamental to process analytical technology (PAT) initiatives are the basics of multivariate analysisMultivariate analysis
Multivariate analysis is based on the statistical principle of multivariate statistics, which involves observation and analysis of more than one statistical variable at a time...
(MVDA) and design of experiments
Design of experiments
In general usage, design of experiments or experimental design is the design of any information-gathering exercises where variation is present, whether under the full control of the experimenter or not. However, in statistics, these terms are usually used for controlled experiments...
(DoE). This is because analysis of the process data is a key to understand the process and keep it under multivariate statistical control.
- Multivariate Analysis in Process Analytical Technology
- PharmaMV from Perceptive Engineering is one example of the commercially available tools for deployment of MVA techniques and process optimisation in a PAT scenario.