Process monitoring is integral to manufacturing, as it monitors minute details of the process, product and equipment. It helps to keep track the process, enabling personnel to detect anomalies timely and initiate corrective & preventive actions.

For the pharma industry, process monitoring ensures quality in the manufacturing process and the output produced by monitoring every step and enabling personnel to mitigate deviation and prevent errors.

Inline process monitoring is an innovative way to monitor the process, where it measures, compares results, and makes decisions without halting the process. It is achieved by utilizing the latest sensing techniques and software systems, which are different from the traditional monitoring system and offer benefits that traditional can't.

What is inline process monitoring?

Inline process monitoring is a system where measuring / monitoring of the product is carried out without taking out or extracting the sample from the running production process in an equipment or machine. An inline sensor installed at an appropriate location automatically measures the current value and updates it in the recording system, which can later be retrieved. If required, the estimated value can also be used to adjust process variables to keep the process according to its design specifications.

The main advantage of this technique is its ability to take measurements without taking out samples from the production batch, taking this sample to the lab and waiting for results to be implemented.

Inline process monitoring enables monitoring quality parameters of the production process in a real-time manner. It enables manufacturers to adjust quality parameters in response to product deviations and can remove the erratic product from the batch. 

What is the traditional process monitoring method, and how does it differ from inline process monitoring?

The traditional process monitoring method involves taking samples from the production process and physically taking them to the lab to perform tests. During this process, the process/machine is stopped until the results are out. If the samples pass the test, the process is advanced to its next stage. Otherwise, the process is altered and again tested. If the results are satisfactory, then the process is allowed to move forward to its next stage

This method differs from the inline in many ways, such as 

● The process is halted throughout the testing process. Lab testing takes time, typically hours, depending upon the test type, and it can also take days to complete some tests. In this scenario, a batch takes more time to complete, increasing the time required for a product to market.

●The sample also requires safe handling throughout the testing procedure and appropriate storage conditions to prevent changing the sample characteristics.

● It requires resources, such as compliant humidity & temperature for safely storing the product during the time test results are awaited. Otherwise, it will change the product characteristics and eventually destroy the entire batch.

● There is a probability of human errors in the lab testing procedure. Although lab testing is performed through reliable and automated machines, human involvement cannot be eliminated, such as transferring samples from the production floor to the lab and preparing samples for testing. 

●Lab testing requires a series of tests, sometimes many tests in a day or per batch. Stopping the process or machine every time to take a sample makes the process time-consuming and tedious. Additionally, in the lab, some tests require various stages until the final result, making the process time-consuming.

On the other hand, the inline method does not suffer from the limitations mentioned above and can be used to increase the productivity and reliability of the testing procedure. 

How inline measurement is implemented in the Pharmaceutical industry

Inline measurement in the pharmaceutical industry is implemented with an accepted technology known as Process Analytical Technology - PAT. It is a system for measuring real-time process and product variables and is used to control the pharma manufacturing process to achieve high quality, efficacy, and safety. 

Among many advantages, it helps to prevent and correct variations in product characteristics by enabling manufacturers to keep an eye on the process and simultaneously correct them in a real-time manner. 

The heart of Process Analytical Technology is PAT sensors that make the desired process measurements in real-time. They are capable of detecting the relevant process parameters continuously without delay. They are specifically designed to monitor internal molecules, granules or crystalline structures, translating into the relevant overall product characteristics. 

A software system uses the data generated from these sensors to take appropriate actions to remove or reduce variation in the underlying process by altering different process, product or equipment parameters. The software system has pre-defined algorithms that best match the individual user requirements. 

The software system can also store historical data on batch processes. It can then be used to create optimum models containing recipes for each product to be used later during production. 

PAT can be applied to all components of the pharmaceutical manufacturing cycle, such as active pharmaceutical ingredients and commercial manufacturing of finished products. 

Example of PAT sensors being used in the Pharmaceutical industry

Let's discuss some examples of PAT sensors used in the pharmaceutical industry.

Near Infrared  - NIR Spectroscopy

NIR spectroscopy is a standard technology and tool used as a PAT sensor during the processing of pharma powder for various applications. NIR region ranges from 780nm to 2526nm band of electromagnetic spectrum.

The NIR electromagnetics are induced into the desired product, and the product is monitored for absorption of these waves, which is then translated into specific product characteristics.

NIR spectroscopy allows detecting and measuring powder's chemical and physical characteristics, such as drug content, flowability and dissolution profile. These results can be used to determine the current state of powder quality and suggest improvements if required.

Raman Spectroscopy

Raman spectroscopy is also a technique used in PAT applications, to detect and identify materials. Raman spectroscopy ranges in the visible region, i.e. 400 to 700nm.

The powder is illuminated with a monochromatic laser light. The powder scatters the laser light with varying energy shifts, a function of a specific product characteristics. This scattered laser light provides valuable information about the molecule and determines the product characteristics.

Raman spectroscopy can be used as a PAT tool to monitor 

●The production process, specifically the biologics. The reference Raman spectrum is compared with the known spectrum of the production process to determine the execution of a process and the formation of a particular product stage.

●The Raw material to determine and quantify excipients and active substance in it. The Raman results of reference samples are compared with known material to determine the actual concentration of the raw material.

What is the view of the Food Drug & Administration - FDA for the implementation of PAT in the pharmaceutical industry?

The advantages offered by Process Analytical Technology – PAT are being accepted and acknowledged by many stakeholders, including different regulatory bodies such as the United States FDA. It encourages pharma and machine manufacturers to incorporate PAT in their production process. 

For this purpose, the FDA has also published a guideline titled "Guidance for Industry PAT — A Framework for Innovative Pharmaceutical Development, Manufacturing, and Quality Assurance." This guidance does not legally bind any manufacturer. However, it provides current thinking of FDA w.r.to Process Analytical Technology.  Some essential points are briefed below.

● The primary purpose of the PAT framework is designing, analyzing, and controlling manufacturing through timely measurements of raw, in-process materials and production processes to ensure quality in the final finished product.

●PAT Tools

PAT tools for pharmaceutical development, manufacturing, and quality assurance provide effective and efficient ways of acquiring information that can be categorized into 

●Multivibrate tools

●Process analyzers

●Process control tools

● Continuous improvement

● Risk-based Approach

The process understanding reduces the probability of producing poor-quality products. Risk-based decisions and innovations can achieve this.

●Integrated System Approach

Advancement in information systems and its implementation in the manufacturing section, especially the pharmaceuticals, is bringing development, manufacturing, quality assurance, and information/knowledge management closer, and must be coordinated in a practical scenario that requires the support of upper management, which must be present at all stages of PAT implementation and operation.

● Real-time release

It uses process data to evaluate and ensure the quality of the final product. Process data, combined with other data, can be used as a base for real-time release of the pharma process in establishing conformity with the regulatory regulations. 

When implementing real-time release, the agency's prior approval must be obtained. 

●Strategy for Implementation

The FDA's strategy in implementing PAT includes the following steps

●A team must be constituted to implement the PAT framework within the pharma organization, specifically reviewing  CMC and cGMP reviews.

● Training and certification of inspection and compliance staff for the successful implementation of PAT

● Scientific and technical support for inspection and compliance staff for the successful implementation of PAT

●The recommendation provided in this framework

● Advantages

Let's briefly discuss some advantages of Process Analytical Technology - PAT.

●They help to mitigate problems and deviations in the final product in real time, significantly reducing the time to market

● PAT helps to optimize the production process by knowing problems, defects and deviations that can be eliminated in the future

● Reducing the likelihood of defects and errors helps prevent recalls, which is a significant root cause for a pharma manufacturer in their increased expenditure

●Having PAT for real-time monitoring improves product quality.

About the Author:

Muhammad Asim Niazi

Muhammad Asim Niazi has a vast experience of about 11 years in a Pharmaceutical company. During his tenure he worked in their different departments and had been part of many initiatives within the company. He now uses his experience and skill to write interested content for audiences at PharmaSources.com.