Process Analytical Technology (PAT) is the usage of sensory data in any process. PAT was initially developed for telemetry. Telemetry is the transmission of measured sensory data via wire, cable, telephone, radio, or wireless technology. Sensor telemetry has been implemented and employed extensively by NASA for over 45 years. Remote sensing telemetry in NASA entails everything from the complete operational status of a spacecraft to an individual astronaut’s heartbeat. PAT is the usage of on-line, in-line, on-stream, in-stream, real-time, or near real-time sensors for monitoring continuous and episodic operations.

1 “Pharmaceutical Manufacturing,” Spring 2003 2 “National Formulary,” Supplement 5, United States Pharmacoepia, USP23–NF #5, (November, 1997) pp. 3464–3467.

The pharmaceutical industry has relied on laboratory testing methods in pharmaceutical manufacturing for the past 100 years. A “Laboratory Centric” view of pharmaceutical manufacturing became the norm during the last century. All manufacturing processes, product, and quality assurance issues were resolved, approved or rejected via laboratory testing. The lag time for laboratory’s issuance of test data, approvals, and product releases was hindered by the testing bottleneck in the laboratory itself. The lab tests and preparations were arduous, time-consuming, with the need for repetitive testing and sampling. PAT removes laboratory testing from the manufacturing process.

The spring 2003 issue of “Pharmaceutical Manufacturing” magazine mentions the FDA’s interest in PAT. Dr. Ajaz S. Hussain, deputy director of the Office of Pharmaceutical Science within CDER presented his views of PAT during the 17th International Forum on Process Analytical Chemistry (IFPAC/2003). Dr. Hussein offered a regulator’s perspective of PAT. Emphasis was placed on the following comments: “Quality cannot be tested in pharmaceutical products. Rather, it results from a quality-oriented process design...without specific on-stream analytical instruments, final product quality is neither predictable nor controllable.”¹

Dr. Carmel Egan was a speaker at the same conference as Dr. Hussain. Dr. Egan commented on how “PAT can improve and possibly revolutionize drug development and manufacturing” and she noted, conversely, the laboratory testing bias for quality control by elucidating the following often heard comments: “On-stream measurement is not as good as in the laboratory; on-stream measurements cannot be validated; on-stream analyzer reliability is inadequate; a small skill-base exists for this highly specialized technology.”

The statements above do not reflect the truth of the matter. PAT can and is validateable, verifiable, accurate, and repeatable with less drift and less frequent calibrations than most laboratory instrumentation.

Historical Development and Introduction of PAT

The advent of sensors with telemetric capabilities harbored the beginning of PAT. Thermometers are not PAT devices. Thermometers are indicators of temperature but without telemetry. The thermometer reading cannot be transmitted. Temperature sensors are indicators of temperature with telemetry. An analog signal is transmitted from the temperature sensor to a controller, indicator, or display. The development of microprocessor-based Programmable Logic Controllers (PLCs) in the 1970s bridged the final gap for the deployment of PAT. Before the advent of PLCs, sensory data was displayed with no proactive action. PLCs instigated control schemes using feedback loops to monitor or initiate actions based on an analog value or a digital status. As real-time conditions changed, controllers could react to the changing conditions, in real-time to prevent excursions in values, tolerances, or limits.

Distributed Control (DCS) and Supervisory Control and Data Acquisition (SCADA) systems became the harbingers of integrated sensory data and control systems used in large process industries such as petrochemical, pulp and paper, and nuclear power plants. During the early 1980s, a new type of device was introduced called Process Analytical Instrumentation (PAIs). These PAIs were on-line microprocessor-based instruments measuring single and multiple parameters with serial communications ports to export the multi-stream data. PAIs noted as on-line Total Organic Carbon (TOC) analyzers, conductivity/resistivity sensors, and particle counters with ultra-sensitive detection limits became instrumentation standards in the semiconductor industry 10 -15 years before introduction and acceptance in the pharmaceutical industry. All continuous 24/7 utilities and processes in a semiconductor production facility use PAT and PAI technology. No laboratory tests administered.

Only as recently as 1997 did the US Pharmacoepia publish in USP 23 addendum 5 the first PATs for on-line or laboratory usage.² USP <643> and USP <645> monographs were specifically written for the measurement of TOC and conductivity in USP Purified and WFI waters. This was the first time the same test method was authorized for both on-line and laboratory applications.

Pharmaceutical Manufacturing Today

Pharmaceutical manufacturing, today, employs PAT sensors, PLCs, feedback loops, controllers, displays, man-machine interfaces (MMI) with sensitive calibrated sensors in continuous and batch processes with 24/7 uninterruptible operations. In addition web-based devices allow the usage of an internal network to transmit the data to reception devices in the facility, to a central location remotely, or to any location worldwide. PAT has improved product quality, throughput, and the product uniformity. These highly controlled and real-time monitored processes produce excellent and repeatable products. Scrap and product destruction due to laboratory testing is virtually non-existent. Previously, laboratory tests could fail a production lot for any reason.

In the near term, laboratory testing will remain a fixture in the pharmaceutical industry. However, the amount of tests and the types of tests are diminishing as more sophisticated PAT and PAI devices are deployed.

Future PAT Applications

Many of the exclusive laboratory tests performed routinely for pharmaceutical manufacturing today, will be eliminated in the future. Bacterial Endotoxin Testing (BET), microbial growth and presence testing, and ion chromatography will be converted to on-line or at-line testing methods with no human intervention. Labor-intensive laboratory preparation and testing will be outmoded as the automation sequencing is refined and standardized.

The new sciences of micromachining, nanobots, and engineering at the atomic level will leapfrog the in-situ process environment and redefine Process Analytical Technology. In the future, microdesigned machines, a few micrometers or less in size, will be able to fabricate, synthesize, and produce genetic components in microproduction facilities enabling vast quantities of pharmaceuticals to be produced in 24/7/365 non-stop manufacturing environments.

Summary

Process Analytical Technology is a vast pool of sensors and technology allowing immediate feedback and control of any given process. PAT sensors range from single channel output temperature, humidity, and flow sensors up to and including sophisticated Process Analytical Instruments offering many channels of information through a single communications port. PAT sensors can be validated, calibrated, and employed in the pharmaceutical manufacturing environment.

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