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Final CHMP Guidance on 'Real Time Release Testing'

Thursday the 26th April 2012

In late March 2012 the EMA issued the final version of CHMP note for guidance (NfG) on Guideline on Real Time Release Testing (RTRT). This is new guidance replaces the previous guidance on parametric release (CPMP/QWP/3015/99) from 1 October 2012. The previous guidance only applied to the release of terminally sterilised products without performing a sterility test. The new guidance retains the previous guidance, as section 7, but extends the concept to other sorts of product along the lines described in ICH Q8, 9 & 10.

This guideline states in its introduction:

“Enhanced product knowledge and process understanding, the use of quality risk management principles and the application of an appropriate pharmaceutical quality system, as defined within ICH Q8,Q9 and Q10, provides the platform for establishing RTRT mechanisms for other applications, for new products as well as established marketed products. Release of a product can be a combination of a RTR approach for certain critical quality attributes (CQAs) and a more conventional evaluation for other CQAs (partial RTR).”

The scope of the guidance includes testing for active substances, intermediates and finished products. It does not include investigational medicinal products.

The guidance states that “The introduction of RTRT requires pre-authorization by the competent authority”; i.e. it must be submitted and approved as part of either a new Marketing Authorisation application or a type 2 Variation.

Even if RTRT is approved for routine use, a product specification has to be established and each batch of a product should comply with it if tested. This specification is also needed for stability testing.

A key point made in this guidance is that when RTR testing has been approved this should be routinely used for batch release and if the RTR testing fails or results are trending toward failure, RTR testing may not be substituted by end-product testing.

Attributes that are indirectly controlled by approved RTRT should still appear in the Certificate of Analysis for batches. 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”.

If RTRT is registered but you have an equipment breakdown that means you are unable to use this for a period of time you will need a contingency plan for alternative testing. This contingency plan has to be included in your RTRT submission.

With respect to re-testing of products imported into the EU from ‘third’ countries the draft guidance states the following:

“For products coming from third countries into the EU, it is a requirement in Directive 2001/83/EC “that each production batch has undergone in a Member State a full qualitative analysis, a quantitative analysis of at least the active substances and all the other tests or checks necessary to ensure the quality of medicinal products in accordance with the requirements of the marketing authorisation”. This normally means a complete re-analysis of the product according to the approved specifications. When a company has got approval for RTR testing for one or more tests in the specifications, these tests would not be considered a “necessary test or check to ensure the quality of the medicinal product in accordance with the requirements of the marketing authorisation”. Therefore a relief from this testing will be accepted.

The guidance gives the requirements for regulatory submissions in section 6.

Best regards,

Peter Gough, Partner

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