Process Analytical Technology (PAT)

Process Analytical Technology (PAT) is defined as “a system for designing, analyzing, and controlling manufacturing through timely measurements (i.e. during processing) of critical quality and performance attributes of raw and in-process materials and processes, with the goal of ensuring final product quality.”¹¹ Process Analytical Technology (PAT) measurements may be of raw materials, intermediates, and products, and these measurements can provide significant data for understanding how process variables affect chemistry, bioprocess, or particle based systems. PAT provides an opportunity to measure previously unknown intermediates, mechanisms, endpoints and can be applied in R&D, Scale-up, and Manufacturing.

Insight For Every Experiment
PAT in research and development provides timely measurements that can reveal previously unknown process components and relationships. By collecting data rich experiments researchers gain an in-depth mechanistic insight to every formulation, fermentation, reaction or crystallization. A continuous stream of data throughout an experiment provides a link between process parameters and product quality or downstream process performance. Real-time data means researchers gain immediate insight into each experiment and can make fast, well informed decisions to improve each subsequent experiment.
View the Webinar: PAT for Flow and Batch Chemistry - GlaxoSmithKline

Transform Productivity
Researchers map the effect of experiment conditions, collect empirical data to validate predictive models, and gain confidence that a process will safely scale up. Data is collected 24 hours a day to accelerate the knowledge and confidence of each scientist. Process Analytical Technology (PAT) can also be used to provide proof of process understanding regulatory submission documentation.

Learn how Novartis used inline PAT to identify root cause of byproduct formation

Improving Laboratory Safety
In situ measurements are often more precise than offline measurements since they avoid the errors caused by sampling and sample preparation. The use of PAT in R&D minimizes personnel hazards associated with sampling hazardous materials for in-process testing especially when working with toxic or corrosive materials or experiments under high pressure.

See how PAT is applied where offline sampling had limits - Eli Lilly

Pilot Plant Fault Detection and Optimization
As a process is scaled up from the lab to pilot plant, PAT can ensure that each step is proceeding as intended. Researchers apply PAT to develop a “signature” or "fingerprint" to monitor process reproducibility during technology transfer. During scale-up, engineers often rely on PAT to verify consistent endpoint in batch processes or steady state operation in continuous processing. Inline monitoring provides continuous streams of data which does not require samples to be collected, prepared, and analyzed. This enables researchers to make decisions quickly without waiting for offline data. Thus, the knowledge-rich process information obtained with PAT allows for rapid troubleshooting, optimization, and fault detection. When an unexpected process deviation occurs, PAT can often be used to identify the root cause such as a variation in upstream process conditions, impurities, or raw materials. PAT improves safety by providing insight into progress of exothermic reactions, and where sampling may pose operator hazards.
Improving Scale-up with PAT - Roche Ireland

Troubleshooting and Control in Production
Ideally, a process is robust enough that it does not require monitoring when it reaches the manufacturing scale. However, many processes require close monitoring ensure consistency or improve downstream operations, especially when they first reach the manufacturing scale. PAT applications in manufacturing are often classified in two areas: a) Knowledge collection to improve the overall robustness of a process, including troubleshooting to identify the root cause of a process deviation; b) Process control for a batch or continuous process, especially where offline measurements are unstable, infrequent, time consuming, or hazardous.

Often, the return on investment for PAT is clear on the manufacturing scale since elimination of failures, increase in yield, and increase in cycle time can offer significant savings. Considerations of implementing PAT in manufacturing include: safety in a classified explosive environment, chemical compatibility, cGMP requirements, communication with a manufacturing control system, and mounting in with process equipment.

In Situ Process Analysis for Process Control - Lubrizol

Process Analytical Technology (PAT) provides key information for a wide range of applications, including:

• Quality by Design (QbD)
  
• Continuous Flow Chemistry
• Crystallization and Precipitation
• Raman Spectroscopy
• Downstream Processing

PAT tools may be in situ probe-based instruments, online measurements, software, or bulk measurements. Process Analytical Technology Spectroscopy tools, such as Mid-Infrared, Raman Spectrometer, UV-Vis, and NIR, are established techniques which provide continuous monitoring of key reaction species so researchers can understand and make informed decisions to optimize process design and quality.   

Inline particle size measurements offer direct measurement of changes to particle size, shape and count as they naturally exist in process, at full concentration, without the need to sample.  By understanding these changes, scientists can detect endpoints, ensure batch-to-batch consistency, and optimize downstream throughput and product quality.

Bulk measurements, such as heat flow calorimetry, allow researchers to minimize the risk of accidents by automatically controlling exothermic events. Confidence in scale-up is ensured by identifying the conditions that lead to heat release and altering them to create the safest possible process.

Below is a selection of Process Analytical Technology (PAT) in recent publications.

Chemical Synthesis/Flow Chemistry

• Masahiro Hosoya, Shogo Nishijima, Noriyuki Kurose, “Management of the Heat of Reaction under Continuous Flow Conditions Using In-Line Monitoring Technologies, Org. Process Res. Dev. 2020, 24, 6, 1095–1103
  
  
• Chuntian Hu,  Christopher J. Testa,  Wei Wu,  Khrystyna Shvedova,   Dongying Erin Shen,  Ridade Sayin,   Bhakti S. Halkude,   Federica Casati,   Paul Hermant,   Anjana Ramnath,   Stephen C. Born,   Bayan Takizawa,   Thomas F. O’Connor,   Xiaochuan Yang,  Sukumar Ramanujam,  Salvatore Mascia, “An automated modular assembly line for drugs in a miniaturized plant”, Chem. Commun., 2020, 56, 1026-1029
  
  
• Dimitri Skliar, Jeffrey Nye, Antonio Ramirez, “Use of Process Analytical Technology (PAT) in Small Molecule Drug Substance Reaction Development”
  
  
• Peter Sagmeister, Jason D. Williams, Christopher A. Hone, C. Oliver Kappe, “Laboratory of the future: a modular flow platform with multiple integrated PAT tools for multistep reactions”, React. Chem. Eng., 2019, 4, 1571-1578

Bioprocessing/Biopharmaceuticals 

• Dhanuka P. Wasalathanthri, Matthew S. Rehmann, Yuanli Song, Yan Gu, Luo Mi, Chun Shao, Letha Chemmalil, Jongchan Lee, Sanchayita Ghose, Michael C. Borys, Julia Ding, Zheng Jian Li, Technology outlook for real‐time quality attribute and process parameter monitoring in biopharmaceutical development—A review. Biotech. & Bioeng. 2020; 117, 3182– 3198
  
  
• Dhanuka P. Wasalathanthri, Matthew S. Rehmann, Jay M. West, Michael C. Borys, Julia Ding, and Zhen Jian Li, “Paving the Way for Real Time Process Monitoring in Biomanufacturing”,  Amer. Pharma. Rev. 2020, 23(5)
  
  
• Carmen Mei, Sasmit Deshmukh, James Cronin, Shuxin Cong, Daniel Chapman, Nicole Lazaris, Liliana Sampaleanu, Ulrich Schacht, Katherine Drolet-Vives, Moriam Ore, Sylvie Morin, Bruce Carpick, Matthew Balmer, Marina Kirkitadze, “Aluminum Phosphate Vaccine Adjuvant: Analysis of Composition and Size Using Off-Line and In-Line Tools”, Comput. Struct. Biotech. J., 2019, 17, 1184-1194.
  
  
• Matthias Brunner, Philipp Brosig, Monika Losing, Marco Kunzelmann, Amandine Calvet, Fabian Stiefel, Jan Bechmann, Andreas Unsoeld, Jochen Schaub, “Towards robust cell culture processes — Unraveling the impact of media preparation by spectroscopic online monitoring”, Eng. Life Sci., 2019, 19 666-680.

Crystallization/Particle Characterization

• Chuntian Hu, Brianna T. Shores, Rachel A. Derech, Christopher J. Testa, Paul Hermant, Wei Wu, Khrystyna Shvedova, Anjana Ramnath, Liyutha Q. Al Ismaili, Qinglin Su, Ridade Sayin, Stephen C. Born, Bayan Takizawa, Thomas F. O’Connor, Xiaochuan Yang, Sukumar Ramanujam, Salvatore Mascia, “Continuous Reactive Crystallization of an API in PFR-CSTR Cascade with In-line PATs”, React. Chem. Eng., 2020,5, 1950-1962
  
  
• Marko Trampuž, Dušan Teslić, Blaž Likozar, “Process analytical technology-based (PAT) model simulations of a combined cooling, seeded and antisolvent crystallization of an active pharmaceutical ingredient (API)”,  Powder Tech., 2020, 366, 873-890
  
  
• Liang Zhong, Lele Gao, Lian Li, Hengchang Zang, “Trends-process analytical technology in solid oral dosage manufacturing”, European Journal of Pharmaceutics and Biopharmaceutics, 2020, 153 187-199
  
  
• Yiming Ma, Songgu Wu, Estevao Genito Joao Macaringue, Teng Zhang, Junbo Gong, Jingkang Wang, “Recent Progress in Continuous Crystallization of Pharmaceutical Products: Precise Preparation and Control”, Org. Process Res. Dev. 2020, 24, 10, 1785–1801
  
  
• N.Bostijn, W.Dhondt, C.Vervaet T.De Beer, “PAT-based batch statistical process control of a manufacturing process for a pharmaceutical ointment”, European Journal of Pharmaceutical Sciences, 2019, 136, 104946