Process Analytical Technology (PAT) is a system for designing, analyzing, and controlling manufacturing processes based on 1) an understanding of the scientific and engineering principles involved and 2) 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 According to the FDA draft guidance, the desired state of pharmaceutical manufacturing is that: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
  • facilitation of continuous processing using small-scale equipment, resulting in improved energy and material use and increased capacity

Building Quality into Products

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 attributes such as identity and purity is mature, certain physical attributes such as solid form, particle size, and particle shape are more difficult to analyze and control. SSCI is uniquely experienced to address this aspect of PAT. Given a compound of interest, our scientists routinely:

  • determine the solid forms attainable and their relevance to manufacture and use
  • select the optimum solid form
  • develop analytical methods to verify the presence of, and quantify the concentration of, the selected form in API
  • investigate the physical properties of the solid such as particle size, particle shape, stability, ease of drying, filterability, solubility, dissolution rate, etc.
  • develop a manufacturing process that consistently provides the desired form of the API having the desired physical characteristics
  • aid in setting API specifications
  • determine excipient compatibility
  • aid in formulation design
  • develop drug product manufacturing strategies that are consistent with the solid properties of the API
  • develop analytical methods to verify the presence of, and quantify the concentration of, the selected form in drug product
  • aid in setting drug product specifications

SSCI scientists have extensive experience solving solid-state problems in drug products.

Process 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.

SSCI works with clients to establish specific process understanding and design process analytical control strategies. Building upon the current SSCI reputation for meticulous cGMP pharmaceutical research and analysis, SSCI can assist clients in all aspects of PAT implementation, including:

  • process understanding through advanced solid-state research
  • identification of critical control variables using multivariate techniques
  • development and validation of appropriate analytical methods for measuring critical control variables
  • transfer of analytical methods to on-, in-, or at-line use
  • consultation and assistance in method validation and use after transfer

Potential Regulatory Impact

FDA presentations indicate their anticipation that PAT implementation will eventually change the regulatory process. Documentation of quality by design during the pre-IND meeting, the end of phase II meeting, and in regulatory submissions will allow early review and analysis of the CMC section of an NDA by the FDA. Addressing issues of concern and further quality by design can result in classification of the drug substance and drug process manufacturing process as low-risk. In some cases, this approach is expected to result in a less comprehensive or eliminated preapproval inspection. While these procedural changes will not happen overnight, they present a possibility for more rapid regulatory approval and reduced time to market.

We invite your queries on this important development in the pharmaceutical industry. We believe our extensive experience in cGMP solid-state research and analysis will help you meet the PAT challenges today and for the future.