Process Analytical Technology (PAT) is a system for designing, analyzing, and controlling manufacturing processes based on an understanding of the scientific and engineering principals involved and identification of the variables which affect product quality. The PAT initiative is consistent with the current FDA belief that quality cannot be tested into products, but should be built-in or by design. According to the FDA draft guidance "PAT- A Framework for Innovative Pharmaceutical Manufacturing and Quality Assurance," the desired state of pharmaceutical manufacturing is that:
- Product quality and performance are ensured through the design of effective and efficient manufacturing processes.
- Product and process specifications are based on a mechanistic understanding of how formulation and process factors affect product performance.
- Quality assurance is continuous and real time.
- Relevant regulatory policies and procedures are tailored to accommodate the most current level of scientific knowledge.
- Risk-based regulatory approaches recognize both the level of scientific understanding and the capability of process control related to product quality and performance.
The primary goal of PAT is to provide processes which consistently generate products of predetermined quality. In so doing, improved quality and efficiency are expected from reduction of cycle times using on-, in-, or at-line measurements and controls, prevention of reject product and waste, real time product release, increased use of automation, and facilitation of continuous processing using small-scale equipment, resulting in improved energy and material use and increased capacity.
Effective PAT implementation is founded on detailed, science-based understanding of the chemical and mechanical properties of all elements of the proposed drug product. In order to design a process that provides consistent product, the chemical, physical, and biopharmaceutical characteristics of the drug and other components of the drug product must be determined. Although the science of analyzing for chemical characteristics such as identity and purity is mature, certain physical characteristics such as solid form, particle size, and particle shape are more difficult to analyze and control.
Once the properties of the drug product components are understood, the processing variables that control the relevant properties must be identified. Identification of these variables necessarily requires a multivariate approach. From a solid-state point of view, PAT implementation involves the design of manufacturing processes based on a thorough scientific understanding of the solid-state properties and stability of the components of the drug product at critical points throughout manufacturing. Then, measurement and control of the critical parameters integrates a broad spectrum of analytical technologies interfaced to production plant control networks and incorporated into standard procedures.
The particle sizes of active pharmaceutical ingredients (APIs) and excipients are of signficant importance in most solid dosage products and are traditionally monitored by thief sampling followed by laboratory analysis. For systems where particle size is critical, this method of control suffers from several limitations. A small sample may not be representative of bulk product. Time is required to sample, transport, measure, and report results. There is possibility of exposure to operators and lab personnel. The cost of rejected lots can be high. All these limiations make traditional control methods impractical for real time quality assurance.
PAT approaches to particle size measurement sample larger, more representative portions of bulk product and offer rapid analysis with immediate feedback directly into the control system. Because PAT is a closed system there is no exposure to personnel.
 Figure 1 - Without particle size control |
 Figure 2 - Tight particle size control |
Figures 1 and 2 are images of two tablets; one without particle size control and one with tight control. Without control, API particles are of varying sizes and distribution, potentially affecting stability, solubility, and efficacy. Tight PAT control of particle size produces a more uniform and predictable particle size for higher a quality product.
Control of the solid-state polymorphic form of an API can be of critical importance for stability and efficacy. Often the solid-state form is very sensitive to process and sampling conditions such as temperature, humidity, presence of dust or other "seed" material, and rate of temperature or humidity change.
A PAT approach toward controlling solid-state form allows rapid analysis and control under process conditions. On-line analysis means the sample is never removed from process conditions, minimizing the likelihood that sampling could influence analytical results. Feedback control can also maximize yield when processing conditions are critical to final form. In the example below, two solid forms are distinguishable by Raman spectroscopy and a critical control parameter is the temperature during crystallization. Temperature excursions cause form change, therefore careful control of the temperature is necessary to optimize yield.
A primary goal of blending is production of a uniform mixture of API and excipients in the final dosage form. Incomplete mixing is difficult to detect in the final dosage form because measurements of component identity and concentration are often not specific to distribution. Typically blend uniformity is assumed by blending for a set time and is actually monitored by release testing. This approach suffers from several limitations:
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Release testing on limited samples may not be representative of bulk.
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Blending for longer than necessary increases cycle time.
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Variations in feed materials may alter blend time from batch to batch.
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Excessive blending may lead to 'de-mixing.'
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Failed release tests jeopardize the entire batch.
A PAT approach to blending provides process understanding and feedback to more precisely control blending.
Figure 3 - Blending carefully controlled
Figure 3 shows a Raman microscpectroscopic map of a tablet surface where blending was carefully controlled. The uniform distribution of API (red and yellow dots) confirms that blending was optimized for distribution. By measuring to an endpoint, blending could be discontinued when a desired distribution was reached, thereby minimizing cycle time. By careful selection of critical controls and measurement strategies, important properties of incoming materials could also be monitored to provide optimum conditions for blend uniformity.
Product drying, either after synthesis or during processing, is a necessary step that can have a dramatic impact upon the solid form of the final product. A drying step may be designed to simply remove excess solvent for subsequent processing, or it may be an integral part of solid-state form manipulation through dehydration or desolvation. Under most scenarios, drying is carried out for a set amount of time, which can lead to excessive cycle time and/or
undesireable form change if drying continues beyond the endpoint. Batch-to-batch variations in feed materials may cause uncompensated variations in drying time; failed release tests may jeopardize the entire batch.
A PAT approach provides the process understanding and measurement strategies to carefully control drying. By monitoring the product or the effluent, it is possible to determine the endpoint based either upon the rate of solvent removal or the amount of residual solvent in the product. In the simplest cases, endpoint may be determined when the solvent concentration falls below a given set-point. In a more complex process, such as that outlined above, the solid-state form can be monitored as a function of drying time. In the above example, the initial dihydrate goes through a hemihydrate and finally to the desired anhydrate. Prior to monitoring, the drying cycle took 40 hours, but real time monitoring cut the dry time closer to 20 hours. This type of process optimization and dynamic feedback is available when critical control parameters are understood, measured and used for process control.
Solid-state chemistry offers a significant analytical framework for PAT implementation. Given a compound of interest, SSCI scientists routinely determine the solid forms attainable and their relevance to manufacture and use, select the optimum solid form, and develop analytical methods to verify the presence of, and quantify the concentration of, the selected form in API. Solid-state methods can investigate the physical properties of the solid, such as particle size, particle shape, stability, ease of drying, filterability, solubility, and dissolution rate, and develop a manufacturing process that consistently provides the desired form of the API having the desired physical characteristics. Existing analytical and screening methodologies aid in setting API specifications, determining excipient compatibility, designing formulations , and developing drug product manufacturing strategies that are consistent with the solid properties of the API. Additionally, solid-state chemistry technologies can be used to detect and quantify API forms in solid mixtures and, thus, aid in setting drug product specifications.
"PAT- A Framework for Innovative Pharmaceutical Manufacturing and Quality Assurance" may be found at:
www.fda.gov/cder/guidance/5815dft.pdf
SSCI Inc. is a cGMP contract research laboratory that provides a wide range of research and analytical services focused on pharmaceutical and industrial chemical solids. We are experts in crystallization, characterization, and the chemistry of solid materials. SSCI operates at the forefront of technology in these areas:
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Polymorphism Studies and Salt Selection
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Production Control
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Development of Analytical Methods and Strategies (traditional and on-line)
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Amorphous Form Generation and Stabilization
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Solid-State Analytical Services
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Characterization of Small Molecule and Biological Solids
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Analysis of Drug Substance and Dosage Form
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Verification of Sameness for Clinical Trials
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Expert Services and Litigation Assistance
We invite your queries on these important developments in Process Analytical Technology and Quality by Design. We believe our extensive experience in cGMP solid-state research and analysis will help you meet the PAT challenges today and for the future. Please contact Dr. Dave Bugay, Dr. Mike Longmire, or Dr. Steve Byrn. For detailed information on SSCI's research, analytical, and consulting capabilities, and for upcoming conference presentations and short courses, visit the SSCI Web site: www.ssci-inc.com
SSCI Inc.
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West Lafayette, IN 47906-1076
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