Analytical affairs
Forward-looking strategies in pharmaceutical industries: The growing importance of inline analysis

The FDA’s Process Analytical Technology (PAT) initiative brings opportunities for better process control and lower costs by taking critical process measurements in the line, not in the lab.

In pharmaceutical production processes there is a growing need for quality control procedures, prompted by—among other things—the US FDA’s PAT (Process Analytical Technology) initiative. PAT emphasizes the role of analytical technologies used directly in the production process (at-line, online or inline), rather than being confined to the laboratory.
Any widespread system of quality control must have a systematic basis. PAT enables risk assessment and quality control to be carried out during production in a way that is reliable, fast, direct and easy, and as a result it is being used more and more as a systematic quality control procedure in the production of pharmaceutical active ingredients.

Analysis within the process makes it easier to identify and control the many hazards inherent in every plant. From the synthesis or procurement of raw materials, to the packing of finished products, accurate measurements and well-thought-out procedures guarantee safety, productivity and profitability.
In its publication Guidance for Industry PAT the FDA defines the objectives of the initiative as:
-reducing production cycle times by using online, inline and at-line measurements and controls;
-preventing rejects, scrap, and re-processing;
-considering the possibility of real-time release;
-increasing automation to improve operator safety and reduce human errors; and
-facilitating continuous processing to improve efficiency and manage variability.
To achieve this, FDA has defined the following key technologies:
-multivariate data acquisition and analysis tools;
-modern process analyzers or process analytical chemistry tools;
-process and endpoint monitoring and control tools; and
-continuous improvement and knowledge management tools.
A typical analyzer for process control is a near infrared (NIR) spectrometer, which is uncomplicated to set up and can track rapid changes in concentration.
Seven steps to PAT
1. Identify hazardous properties, assess risks and determine preventive actions: Identification of hazards and assessment of the resulting risks is needed for every biological, chemical or physical property that could potentially harm end-users. Once the risks have been assessed, any necessary preventive actions can be decided.
2.Identify and document critical production steps: Critical production steps are those that could pose health
or safety risks for end-users. Once identified, these steps must be carefully
documented.
3. Define critical values for every step: Establish control measurements and define critical values for every production step.
4. Set up monitoring systems: Monitoring can be done by people or machines.
5. Establish corrective actions: Procedures must exist to guide the process back to its normal range when critical values are exceeded.
6. Implement verification procedures: It must be possible to confirm that the system is running properly.
7. Document everything: Documentation is necessary to record the decisions taken, to provide a record of process performance, as a management tool and as evidence for regulatory bodies.
Making it happen
The first step in implementing PAT is to convince the appropriate people in the company that the rewards will be worth the effort. Next, a trained and qualified PAT team must be nominated. This is not a job for one person; PAT must be the responsibility of a group of people in several senior positions. Once the people have been decided and the project’s other resources allocated, it is time to choose the tools to be used for risk analysis, and to apply them to the process. After the risks have been quantified, control procedures can be established. The criteria for choosing these include speed, flexibility, reproducibility and sensitivity.
The decisions made by the PAT team are then documented. The documentation should include a description of the product and its intended use; a flowchart showing the main production steps; a risk analysis that identifies all production-related risks and specifies analytical methods to minimize these risks; and control charts with threshold values, rules on how these are to be measured, and actions to be taken when they are exceeded.
Offline chemical analysis in labs can then be replaced by at-line analysis, using techniques including spectroscopy, fast chromatography, images and sensor arrays. Multivariate analysis enables data to be integrated to create a complete picture of the process. In some cases, at-line measurements can be used directly for control using MVI (multivariate identification) or MSPC (multivariate statistical process control), without reference to a central control system. Inline PAT techniques allow batch progress to be tracked and controlled using MSPC or BSPC (batch statistical process control).
The final step is to tie everything together.
Scope and liability
PAT has the potential to cover every aspect of pharmaceutical production. In active ingredient development, for instance, PAT can help in classifying, analyzing and documenting ingredients. Analytical tools for these tasks include chromatography and spectroscopy, especially IR and NIR spectroscopy.
On the production plant, PAT can provide the necessary rapid and accurate analysis of raw material as it enters the plant. NIR spectroscopy with customized glass fiber probes is useful here. Moving downstream, NIR spectroscopy can also be used in blenders and dryers to measure moisture and control endpoints. For the finished product, NIR spectrometers with custom probes can be fitted directly to filling machines to monitor the identity and concentration of the active ingredient, and to detect segregation in capsules.
NIR spectroscopy can document the dissolution behavior of tablets and check the identity and concentration of CIP solutions.
Risk assessment is central to every PAT initiative. The ability to measure process variables quickly and accurately, and the improved understanding of risk that is likely to accompany a PAT initiative, can add to manufacturers’ duty to avert, minimize or mitigate loss. PAT has a key role in quality assurance for the pharmaceutical industry. In November 2003, the Joint QWP/Ad Hoc GMP Inspectors Team for PAT was founded to create a forum for dialog between assessors and inspectors. The aim is to create a harmonized approach within the EU on the assessment and inspection of pharmaceutical plants and systems, including new approaches to manufacturing and controlling active sub-stances, medical products and packaging materials. Examples of specific objectives are:
-review the legal and procedural implications of the EU regulatory system;
-review and comment on documents produced by other organizations;
-review and assess licensing applications for processes using PAT;
-develop procedures for assessing
PAT-related applications to ensure co-ordination between assessors and inspectors;
-avoid conflicts with other regional approaches;
-identify training needs; and
-increase the scope and responsiveness of control through inline spectroscopy.