Real Time Release Testing – Has its Time Come?

Generally, pharmaceutical manufacturing involves laboratory testing on product sampled at the end of the manufacturing process to assure the product quality as part of the product release.  However, traditional release testing is not the only acceptable approach used to assure the quality product prior to release.  On September 15, 2015, the European Commission published a revised draft Guidance, “Annex 17: Real Time Release Testing.” This draft document is intended to provide updated guidance on Real Time Release Testing (RTRT).  This draft guidance is currently available for comments and input from the industry and public until December 11, 2015.

So, what is Real Time Release Testing and what requirements does the draft Guidance describe regarding the implementation of this approach?

As defined by the draft Guidance, RTRT is “a combination of in-process monitoring and controls” throughout the entire manufacturing process that are deemed to provide sufficient quality assurance for batch release without the need to perform analysis of the final materials that are the product of the manufacturing process (drug substance, drug product, and specified biologics).

RTRT is not a new concept.  In July 2001, the European Commission published the original Annex 17 to the EU Guide to Good Manufacturing Practice, “Parametric Release.”  However, this first version only focused on the application of Parametric Release for the routine release of terminally sterilized products.  The proposed revised document reflects the advances in the application of process analytical technology, QbD, and quality risk management principles.  Since the original EU guidance, the following FDA Guidance documents have been published, indicating that an appropriate combination of process controls together with effective monitoring and verification throughout the manufacturing process can provide greater assurance of product quality than just a traditional testing of the final materials: (1) Guidance for Industry “PAT – A Framework for Innovative Pharmaceutical Development, Manufacturing, and Quality Assurance,” September 2004; (2) Guidance for Industry “Q9 – Quality Risk Management,” June 2006; and (3) Guidance for Industry “Q8 (R2) Pharmaceutical Development – Part II Pharmaceutical Development Annex,” August 2009.

The main criteria required for implementing an RTRT strategy are:

  1. Real time measurement and control of relevant in-process material attributes and process parameters should be demonstrated to be accurate predictors of the corresponding finished product attributes.
  2. The valid combination of relevant assessed material attributes and process controls as the surrogates of finished product attributes should be established with scientific evidence founded on material, product, and process knowledge.
  3. The combined process measurements (process parameters and material attributes) and any other test data generated/gathered during the manufacturing process should provide a robust foundation for RTRT and the batch disposition decision.

With the recent increased level of discussions regarding the use of continuous processing technology in the pharmaceutical industry, RTRT’s time likely has really arrived. However, it should be kept in mind that interaction with the relevant regulatory agency during the assessment process and prior to the implementation of an RTRT strategy should be considered because, like anything else new, you never know where the FDA or other regulatory authority will land on the issue.