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| ![](media/image1.jpeg){width="1.875in"              |                |
| height="2.2291666666666665in"}**Process Analytical  |                |
| Technology and ASTM Committee E55**                 |                |
|                                                     |                |
| **by D. Christopher Watts, Ph.D. Ali M. Afnan,      |                |
| Ph.D.\                                              |                |
| Ajaz S. Hussain, Ph.D.**                            |                |
|                                                     |                |
| Using traditional manufacturing methods, the        |                |
| pharmaceutical industry has, without question,      |                |
| provided quality drug products to the American      |                |
| public. However, there are opportunities for        |                |
| improvements in efficiency, process control,        |                |
| safety, and ultimately product quality, based on    |                |
| innovative approaches to manufacturing and quality  |                |
| assurance. Unfortunately, the pharmaceutical        |                |
| industry has been hesitant to innovate in the       |                |
| production arena. The most prominent reason cited   |                |
| for this hesitance centers on the regulatory        |                |
| environment surrounding the manufacture of          |                |
| pharmaceutical products. The U.S. Food and Drug     |                |
| Administration took a proactive approach to remove  |                |
| this hesitance from the industry, and established   |                |
| the Process Analytical Technology Initiative, a     |                |
| collaboration between the Center for Drug           |                |
| Evaluation and Research, the Office of Regulatory   |                |
| Affairs, and the Center for Veterinary Medicine.    |                |
|                                                     |                |
| The initiative was first publicly discussed at the  |                |
| FDA Science Board,(1) where leaders from industry,  |                |
| academia, and the agency highlighted the importance |                |
| of innovation in pharmaceutical manufacturing and   |                |
| the associated benefits to public health, the FDA,  |                |
| and the pharmaceutical industry.                    |                |
|                                                     |                |
| Recognizing that broad cooperation between the      |                |
| agency, industry, and academia would ultimately     |                |
| determine the success of the initiative, the FDA's  |                |
| Advisory Committee for Pharmaceutical Science       |                |
| established its PAT Subcommittee (2) with           |                |
| representation from all sectors. The PAT            |                |
| Subcommittee discussed all aspects of the           |                |
| initiative to assist in establishing an agency      |                |
| strategy for the PAT Initiative, including policy,  |                |
| teamwork, and training.                             |                |
|                                                     |                |
| Discussions at various workshops and FDA Advisory   |                |
| Committee meetings identified several advantages of |                |
| implementing the PAT framework. These benefits      |                |
| include:                                            |                |
|                                                     |                |
| • Reducing production cycle times by using on-,     |                |
| in-, and/or at-line measurements and controls;\     |                |
| • Reducing or preventing rejects, scrap, and        |                |
| reprocessing;\                                      |                |
| • Real-time release of products;\                   |                |
| • Increasing automation to improve operator safety  |                |
| and reduce human errors;\                           |                |
| • Facilitating continuous processing to improve     |                |
| efficiency and manage variability;\                 |                |
| • Using small-scale equipment (to eliminate certain |                |
| scale-up issues) and dedicated manufacturing        |                |
| facilities;\                                        |                |
| • Improving energy and material use; and\           |                |
| • Increasing production capacity.                   |                |
|                                                     |                |
| Many similarities exist within the PAT Initiative,  |                |
| specifically: the risk-managed approach to          |                |
| regulation and innovation in pharmaceutical         |                |
| manufacturing, the facilitation and encouragement   |                |
| of new technology introduction and innovation in    |                |
| pharmaceutical manufacturing, and a team approach   |                |
| to review and inspection. Having this focus, the    |                |
| PAT Initiative was naturally enveloped in the much  |                |
| broader current good manufacturing practices        |                |
| initiative.(3) PAT is a system that uses process    |                |
| monitoring tools for designing, measuring,          |                |
| analyzing, controlling and integrating information  |                |
| on a manufacturing process to better understand     |                |
| processes and to continually improve product        |                |
| quality by reducing process output (product)        |                |
| variability.                                        |                |
|                                                     |                |
| Therefore, focusing on process monitoring and       |                |
| control, instead of end product testing, requires   |                |
| process control standards, practices and guides.    |                |
| The pharmaceutical industry's current quality       |                |
| control practices are based on validated processes  |                |
| and endproduct testing to specifications.           |                |
|                                                     |                |
| The FDA recognizes that the success of these        |                |
| efforts is strongly dependent on active             |                |
| participation and input from manufacturing experts  |                |
| from industry, academia, government, and consumer   |                |
| groups. In order to engage these groups to the      |                |
| fullest extent possible, the FDA participated in    |                |
| the development of ASTM [[Technical Committee       |                |
| E5                                                  |                |
| 5]{.underline}](http://www.astm.org/COMMIT/E55.htm) |                |
| on Pharmaceutical Application of Process Analytical |                |
| Technology.                                         |                |
|                                                     |                |
| **Process Analytical Technology**                   |                |
|                                                     |                |
| The FDA defines PAT as a system for designing,      |                |
| analyzing, and controlling manufacturing through    |                |
| timely measurements (during processing) of critical |                |
| quality and performance attributes of raw and       |                |
| in-process materials and processes with the goal of |                |
| ensuring final product quality.(4) However, the     |                |
| unmistakable objective of PAT is to understand and  |                |
| control the manufacturing process, by integrating   |                |
| various efforts. Therefore, the term analytical in  |                |
| PAT must be viewed broadly to include chemical,     |                |
| physical, microbiological, mathematical, and risk   |                |
| analysis conducted in an integrated manner. Simply, |                |
| analytical is interpreted as "analytical thinking," |                |
| not only analytical chemistry.                      |                |
|                                                     |                |
| The focus on process understanding comes from the   |                |
| basic tenet of building --- not testing --- quality |                |
| into products. Other industrial sectors (e.g., food |                |
| and petrochemical) have recognized the futility of  |                |
| controlling product quality by testing the final    |                |
| product. A test of the final product should simply  |                |
| confirm the obvious, based on the direct            |                |
| measurement and control of critical quality         |                |
| attributes throughout the manufacturing process.    |                |
|                                                     |                |
| Considering any pharmaceutical unit operation in    |                |
| isolation from the entire manufacturing process     |                |
| would be ineffective in meeting the desired product |                |
| quality attributes, as each procedure in the        |                |
| manufacturing process should be directed at meeting |                |
| the needs of subsequent manufacturing operations,   |                |
| and ultimately, final product quality. For example, |                |
| what attributes of the raw materials are critical   |                |
| to obtaining the desired granulation? What          |                |
| attributes of the granulation are critical to       |                |
| compression, or capsule filling? Most important,    |                |
| what attributes of the tablets, granules, raw       |                |
| materials, and the manufacturing process are        |                |
| critical to final product quality? As such, the     |                |
| focus of PAT is on the process, from development to |                |
| production.                                         |                |
|                                                     |                |
| Additionally, understanding through innovation may  |                |
| not only come from strategies for measurement and   |                |
| control of traditional processes; novel approaches  |                |
| to pharmaceutical production itself may be          |                |
| developed as well.                                  |                |
|                                                     |                |
| **PAT Framework**                                   |                |
|                                                     |                |
| PAT has been described as a framework that focuses  |                |
| on understanding the manufacturing process. To that |                |
| end, a process is considered well-understood        |                |
| when 1) all critical sources of variability are     |                |
| identified and explained; 2) variability is managed |                |
| by the process; and 3) quality attributes of the    |                |
| granulation can be accurately and reliably          |                |
| predicted. Ultimately, the ability to accurately    |                |
| and reliably predict product quality attributes     |                |
| (via mathematical models) reflects a high degree of |                |
| process understanding. This level of process        |                |
| understanding is inversely proportional to the risk |                |
| of producing a poor quality product. Consequently,  |                |
| process understanding offers a risk-managed         |                |
| approach to regulatory scrutiny.                    |                |
|                                                     |                |
| Obtaining an increased understanding of the         |                |
| manufacturing process requires a multidisciplinary  |                |
| approach, combining expertise and scientific        |                |
| principles from several fields, such as             |                |
| engineering, chemistry, and statistics. Similarly,  |                |
| successful implementation of the PAT framework      |                |
| requires cooperation across divisions within an     |                |
| organization, including the manufacturing, research |                |
| and development, and quality units. Such            |                |
| cooperation within an organization is also          |                |
| necessary for regulation, hence, the FDA            |                |
| established a team approach to review and           |                |
| inspection for PAT.                                 |                |
|                                                     |                |
| **PAT Tools and Their Application**                 |                |
|                                                     |                |
| There are a variety of tools available to           |                |
| facilitate increased understanding and provide the  |                |
| integrated systems approach to measuring,           |                |
| analyzing, optimizing, controlling, and modeling    |                |
| the granulation process. Many of these tools were   |                |
| developed and employed in other industrial sectors, |                |
| but are beginning to find utility in the            |                |
| pharmaceutical industry. In its draft guidance for  |                |
| industry (*PAT -- A Framework for Innovative        |                |
| Pharmaceutical Manufacturing and Quality            |                |
| Assurance*), the FDA has categorized these tools as |                |
| follows:                                            |                |
|                                                     |                |
| • Multivariate data acquisition and analysis        |                |
| tools;\                                             |                |
| • Modern process analyzers or process analytical    |                |
| chemistry tools;\                                   |                |
| • Process monitoring, control, and endpoints; and\  |                |
| • Continuous improvement and knowledge management.  |                |
|                                                     |                |
| In addition to the PAT tools, other scientific      |                |
| principles constituting the PAT framework were      |                |
| outlined by the agency in the draft guidance for    |                |
| industry. These principles include:                 |                |
|                                                     |                |
| • Process understanding;\                           |                |
| • Risk-based approach;\                             |                |
| • Integrated systems approach; and\                 |                |
| • Real time release.                                |                |
|                                                     |                |
| In an effort to engage all stakeholders in          |                |
| delineating the PAT framework, ASTM Committee E55   |                |
| was established. Committee E55 will address the     |                |
| standards necessary for the application and         |                |
| implementation of the PAT framework, including the  |                |
| specific tools and principles described above.      |                |
|                                                     |                |
| **Committee E55 on Pharmaceutical Application of    |                |
| Process Analytical Technology**                     |                |
|                                                     |                |
| Working within ASTM affords the pharmaceutical      |                |
| industry the unique opportunity to learn from other |                |
| industrial sectors that have established similar    |                |
| frameworks. PAT represents the FDA's vision for     |                |
| future pharmaceutical product development and       |                |
| manufacture. As pharmaceutical development and      |                |
| manufacturing evolves from an art form to one based |                |
| on science and engineering, FDA will use the        |                |
| knowledge developed in PAT to establish product     |                |
| specifications and evaluate manufacturing           |                |
| processes. This is an opportunity to create         |                |
| improvements in the productivity of both the        |                |
| manufacturing and regulatory processes. FDA is      |                |
| partnering with other industry stakeholders in ASTM |                |
| Committee E55 as the most effective venue for       |                |
| developing science-based consensus standards for    |                |
| "process quality," which is the focus of the PAT    |                |
| Initiative. Committee E55 addresses issues related  |                |
| to process control, design, and performance, as     |                |
| well as quality acceptance/assurance for the        |                |
| pharmaceutical manufacturing industry.              |                |
|                                                     |                |
| Collaboration with ASTM provides the pharmaceutical |                |
| industry with opportunities to:                     |                |
|                                                     |                |
| • Learn from other industrial sectors, such as      |                |
| petrochemicals, where the use of process analyzers, |                |
| statistical principles, and risk management have    |                |
| been in practice for a number of years (and not     |                |
| "reinvent the wheel").\                             |                |
| • Focus our efforts on "process" and bring a        |                |
| much-needed (pharmaceutical) engineering            |                |
| dimension.\                                         |                |
| • Work toward international consensus.\             |                |
| • Involve all stakeholders and multidisciplinary    |                |
| expertise (FDA does not have the resources to do    |                |
| this).                                              |                |
|                                                     |                |
| **Conclusion**                                      |                |
|                                                     |                |
| Implementing the PAT framework and having a greater |                |
| understanding of the manufacturing process has      |                |
| obvious advantages to the pharmaceutical industry,  |                |
| regulators, and public health. Due to a change in   |                |
| the regulatory environment, pharmaceutical          |                |
| companies have been encouraged to innovate and      |                |
| employ the tools necessary to achieve an in-depth   |                |
| understanding of the manufacturing process. ASTM    |                |
| Committee E55 will facilitate the implementation of |                |
| the PAT framework through the active participation  |                |
| of industry, academia, and the FDA. This            |                |
| cooperation will be crucial as a drug quality       |                |
| system for the 21st century is developed. //        |                |
|                                                     |                |
| **References**                                      |                |
|                                                     |                |
| \(1\) [[FDA Science Board, Transcript, November     |                |
| 2001]{.underline}](http                             |                |
| ://www.fda.gov/oc/advisory/ sciboard111601. html).\ |                |
| (2)                                                 |                |
| [[Transcripts]{.underline}](http://www.fda.gov      |                |
| /ohrms/dockets/ac/cder02.htm#PharmaceuticalScience) |                |
| from the Advisory Committee for Pharmaceutical      |                |
| Science, Process Analytical Technology              |                |
| Subcommittee, February, June, and October 2002.\    |                |
| (3) In August of 2002, the FDA embarked on a major  |                |
| initiative to enhance the regulation of             |                |
| pharmaceutical manufacturing and product quality,   |                |
| "Pharmaceutical cGMPs for the 21st Century: A       |                |
| Risk-Based Approach." One goal of the initiative    |                |
| was to enhance the focus of the agency's cGMP       |                |
| requirements more squarely on potential risks to    |                |
| public health, by focusing regulatory attention and |                |
| agency resources on those aspects of manufacturing  |                |
| that pose the greatest potential risk. The second   |                |
| goal was to ensure that the establishment and       |                |
| enforcement of pharmaceutical product quality       |                |
| standards does not impede innovation and the        |                |
| introduction of new manufacturing technologies in   |                |
| the pharmaceutical industry. Finally, the third     |                |
| goal was to enhance the consistency and             |                |
| predictability of FDA's centers and field           |                |
| components.\                                        |                |
| (4) *FDA Draft Guidance for Industry, PAT --- A     |                |
| Framework for Innovative Pharmaceutical             |                |
| Manufacturing and Quality Assurance*, September     |                |
| 2003.                                               |                |
|                                                     |                |
| **About the authors**                               |                |
|                                                     |                |
| **Ali M. Afnan, Ph.D.**, and **D. Christopher       |                |
| Watts, Ph.D.,** are both members of the PAT Team in |                |
| the Office of Pharmaceutical Science at the Center  |                |
| for Drug Evaluation and Research at the U.S. Food   |                |
| and Drug Administration. Their responsibilities     |                |
| include developing agency policy and training       |                |
| pertaining to PAT, coordinating submissions and     |                |
| discussions with the pharmaceutical industry, and   |                |
| collaborating in research ventures with industry    |                |
| and academia.                                       |                |
|                                                     |                |
| **Ajaz Hussain, Ph.D.,** is deputy director, Office |                |
| of Pharmaceutical Science in the Center for Drug    |                |
| Evaluation and Research at the U.S. Food and Drug   |                |
| Administration. He also holds adjunct faculty       |                |
| appointments at Purdue University and the           |                |
| University of Michigan. Dr. Hussain has received    |                |
| several FDA- and CDER-level awards.                 |                |
|                                                     |                |
| Copyright 2004, ASTM International                  |                |
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