Real Time Release Testing: Analytical Methods and Innovations

A roundtable moderated by Angie Drakulich.
Feb 02, 2011

As part of this month's special report on real time release testing [see full story here], Pharmaceutical Technology talked to experts at analytical companies throughout the industry to gain their perspective on how RTRT can be done on a practical basis. Participating in the virtual roundtable are: Richard Godec, new product development manager, and Jonathan Yourkin, global pharmaceutical product manager, both at GE Analytical Instruments; Alon Vaisman, applications manager of pharmaceuticals for Malvern Instruments; Terry Redman, product manager for particle-system characterization at Mettler-Toledo AutoChem; and Stuart Farquharson, president & CEO of Real-Time Analyzers.

Industry implementation

PharmTech: Where does the industry now stand in terms of understanding and applying real-time release testing (RTRT) for finished drug products? Would you say that real-time release of a finished drug product is still at a nascent stage or is it further along? What are the advantages and disadvantages in real-time release of finished drug products?

Godec and Yourkin (GE Analytical Instruments): They are just beginning to study the problem. Almost no older manufacturing facilities are doing RTRT and very few new facilities are implementing RTRT for the finished products. There is more activity on in-process measurements at critical points that can help prevent final product quality failures. It is company dependent, but in general, RTRT of finished drug products is still in the nascent stage. The main advantage is the cost-effective control of the manufacturing process to meet all quality and product specifications. The main disadvantage is that there is an initial investment required to achieve RTRT of finished drug products.

Vaisman (Malvern Instruments): In my opinion, RTRT is no longer treated as an unobtainable goal. Many companies in industry and at academic research centers are making significant inroads in implementing continuous manufacturing trains and RTRT. That said, RTRT is hardly the norm today and constitutes a very small percentage of quality-control activities.

Advantages of RTRT are in streamlining production, minimizing delays and potentially eliminating out-of-spec product. The downside is that implementing RTRT can be a costly and resource intensive process that requires the thorough understanding and control of production activities.

Redman (Mettler-Toledo AutoChem): It appears that industry is making real progress in the understanding and implementation of many of the core elements of RTRT. Various PAT tools are being used earlier in development to assist the principles of quality by design (QbD), and these are facilitating the adoption of process monitoring and control concepts throughout scale-up and manufacturing. QbD enables a more thorough understanding of the relationships and interactions between critical process parameters and critical quality attributes, and this in turn allows for more effective strategies to mitigate risk and produce quality product by design. This improved process understanding, in combination with improved process analytics, is necessary for identifying the critical quality attributes and developing the methods for at-line or in-line measurement.

Although there have been successful examples of real-time monitoring and control of specific quality attributes such as granule size at the outlet of a roller compaction, or nearinfrared (NIR) spectroscopy for monitoring tablet dosage uniformity, it seems there is still a lack of holistic solutions that can reproduce or replace all of the necessary quality-control (QC) tests that would ensure a safe and effective product in its final packaged consumable form.

The main advantage of RTRT is simply business efficiency. Real-time assurance of quality, and the avoidance of storage or quarantine of intermediates and drug product while awaiting test results, will enable much greater efficiency throughout the process.

Farquharson (Real-Time Analyzers): The pharmaceutical industry clearly understands the value of RTRT. However, there is risk in applying RTRT, the greatest being incorrect information supplied by PAT tools used to implement RTRT. And consequently, I believe that RTRT is still in the nascent stage.

One of the main advantages of RTRT is being able to monitor and control the quality of a drug during manufacturing (e.g., optimizing polymorph type during synthesis, crystallization, blending). This allows the manufacturer to: improve conformity of final product to specifications; minimize the need of testing every capsule, tablet, or vial of the finished product; and identify out-of-specification batches early and eliminate further manufacturing steps (e.g., tableting of out-of-specification powder).