Revised Annex 17: RTRT and Parametric Release

The revised Annex 17: Real Time Release Testing (RTRT) and Parametric Release of the EU GMP Guide has been published and will come into operation in five months on 26 December 2018. The Annex is intended to outline the requirements for application of an RTRT approach as an alternative to routine end-product testing and applies to finished products, active substances, and intermediates.

In addition, RTRT plays an important role for the implementation and authorization of continuous manufacturing processes, for which an upcoming ICH Q13 Guideline recently has been announced to be developed by the International Council for Harmonisation (ICH).

In 2015, a consultation was launched on a draft Annex 17. The document was open for consultation until 11 December 2015 and the responses to the public consultation have been published on the European Commission website. Following the comments received, the previous wording "RTRT master plan", for example, has been changed to "RTRT strategy". However, the now published final version of Annex 17 has not significantly been changed compared to the previous draft.

According to the document the reasons for the changes to Annex 17 are

  • the previous Annex 17 "only focused on the application of Parametric Release for the routine release of terminally sterilized products",
  • "advances in the application of process analytical technology (PAT), quality by design (QbD) and quality risk management (QRM) principles",
  • "combination of process controls together with timely monitoring and verification of pre-established material attributes" reveals greater assurance of product quality than the end-product testing alone,
  • amendments in other sections of the EU GMP Guide (e.g. Annex 1 and 15), ICH Q8, Q9, Q10, Q11 [and Q12], QWP Guideline on RTRT, and changes in manufacturing and analytical technology.

The document provides the following information on RTRT:

  • minimum criteria that are expected to be established and met when designing the RTRT strategy (e.g. valid combination of relevant assessed material attributes and process controls to replace finished product attributes, robust foundation for RTRT and the batch release decision based on combined process measurements).
  • information regarding the PQS (Pharmceutical Quality System) in which the RTRT strategy should be integrated and by which it should be controlled: 
    -  Change Control: Changes should be justified by the sound application of QRM principles, and fully documented.
    Control Strategy (CS): The CS should describe and justify the selected in-process controls (ICPs), material attributes and process parameters which are required to be routinely monitored. Since the CS is dynamic and may change this should be handled as a life cycle approach requiring the use of QRM and Knowledge Management (see also draft ICH Q12 Guideline on "Product Life Cycle Management"). The CS should also describe the sampling plan and acceptance/rejection criteria. The wording of the previous draft regarding Statistical methodologies / Operating Characteristic curve / Acceptable Quality Level (AQL) and Unacceptable Quality Level (UQL) associated with the sampling plan has been deleted. 
    - Personnel should be specifically trained on RTRT technologies, principles and procedures.
    - Validation and Qualification is an important part of the RTRT strategy, with particular reference to advanced analytical methods.
    - Deviations should be thoroughly investigated and any adverse trending indicating a change in the state of control should be followed up appropriately.
    - Continuous learning through data collection and analysis over the life cycle of a product should be part of the PQS.
    - An approved RTRT approach should be routinely used for batch release. If the results from RTRT fail or are trending toward failure, a RTRT approach may not be substituted by end-product testing. Trends should be followed up appropriately.
    - Certificate of Analysis (CoA): Attributes (e.g. content uniformity) that are indirectly controlled by approved RTRT should still appear in the CoA. The approved method for end-product testing should be mentioned and the results given as “Complies if tested” with a footnote: “Controlled by approved Real Time Release Testing”.

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