GMP Update - what was new in 2016?

"You get the impression that GMP is developing faster and faster" - this is how many articles on current changes in the GMP area began recently. During the past year, the world of GMP turned somewhat slower. Its developments remain interesting though. This also became apparent in a live webinar presented by Bernd Renger on 14 December (recording of the webinar available). You will find a short summary of its highlights here:

Directive 2011/62/EU, the so-called Falsified Medicines Directive and the resulting changes and adjustments in other areas are still reverberating.

The deadline is approaching: As of 2018, security features are mandatory on the packaging of all prescription drugs, but also on those of critical over-the-counter drugs. These security features will allow for their identification and unambiguous tracing. The outer packaging or, if not available, the immediate packaging of any medicinal product must have safety features that make it possible to verify its authenticity and identify individual packages. 

This will be implemented via a 2D matrix code that can be read by common scanners (it is recommended to use bar codes that comply with the requirements of the International Organization for Standardisation/International Electrotechnical Commission (ISO/IEC) 16022:2006). The technical and organisational details regarding the security features were published together with the Delegated Regulation (EU) 2016/161 on 9 February 2016.

Eventually, it is an end-to-end verification system. However, potential checks (and deactivations), also at wholesale level, are being discussed depending on the way of distribution.

The code itself should have no more than 50 characters and must be worldwide unique, which can be something of a challenge. This will require considerable efforts throughout the introduction and implementation stage, and some companies need to hurry up in order to meet the deadline.

Revision of ISO 14644-1

The new EN ISO 14644-1:2015-12 for clean rooms and associated clean-room areas (part 1: classification of air purity on the basis of particle concentration) was published on 1 November 2015 and came into force on 1 January 2016. The norm will be taken into account in the new Annex 1 of the EU GMP Guide and is considered as state of the art for particle measurement in clean rooms performed during qualification and during the recurrent measurements.

There is no transition period mentioned for the implementation of the changes, e. g. definition of the measuring points. In case of doubt, the responsible inspectorate might be contacted. Please also see ISO 14644 - Part 1: The Long-Awaited Final Version on Cleanroom Classification for a summary of the changes.

The specifications are fairly clear. It will be interesting to see to what extent a risk-based approach to determine the number of measuring points will still be possible in the revised Annex 1.

Annex 17 to EU GMP Guideline (Real Time Release Testing)

Annex 17 to the EU GMP Guide (Real Time Release Testing) is to be completely restructured. The revised document was published on 15 September 2015 and the consultation phase ended on 11 December 2015. The answers and some interesting comments during the public consultation were published in July 2016.

The name change is symbolic of a completely new orientation. Ultimately, the current Annex 17 "Parametric Release" is limited to the use in routine releases of products sterilized in their final containers without sterility tests based on sterility parameters. During the revision, the principles of the ICH Q8, Q9 and Q10 concepts are to be implemented. A real-time release approach is to be incorporated in future approvals. Then the approval and release of a batch can be based on the monitoring and control of critical process parameters and relevant material characteristics, a sufficient product and process knowledge and a combination of in-process monitoring and controls that provide sufficient data. Then a batch release could be justified without testing a sample of the finished product again.

The Qualified Person (QP) will then perform the certification based on the results of control and management of critical process parameters and relevant material characteristics. Data obtained in a final analytical quality control will then be almost negligible. This is a paradigm shift that many will find difficult. There is very little experience to fall back on and, as a consequence, great interest in corresponding case studies. The author of these lines would appreciate any feedback on this by the well-disposed reader (please contact

ICH Q3D Guideline for Elemental Impurities

The ICH Q3D Guideline for Elemental Impurities and the corresponding documents by other authorities have accompanied us for some time now. Now the EMA Guideline "ICH Q3D on Elemental Impurities" (EMA/CHMP/ICH/353369/2013) was published on 25 July 2016 (as Step 4 Document, already in December 2014). New approvals are immediately affected; approved medicinal products for human use will be affected as of December 2017. A notification of amendment is not required if the risk assessment indicates that neither additional controls, replacements, modifications of the material quality nor a change in the manufacturing process are required.

However, this risk analysis might be tricky, as it has to be supported by a multitude of analytical data. Companies invest much respectively too much effort in this regard unfortunately. During an ECA conferencet in 2016, an undisclosed authority representative put it very nicely:  "We created a monster".

And there was yet another EMA draft of a guideline on the topic: The EMA Draft Guideline "Implementation strategy of ICH Q3D" (EMA/404489/2016). The document is supposed to provide assistance in the implementation of ICH Q3D within the European context. Up to now, the CHMP Guideline "on the Specification Limits for Residues of Metal Catalysts or Metal Reagents" has been in force since September 2008. Now the European authorities need to coordinate this transition and harmonize the regulatory expectations.

Draft FDA Guide - Request for Quality Metrics

The US Food and Drug Administration (FDA) had started an initiative in order to use so-called quality metrics for the planning of their risk-based inspectionsin 2015. A first draft of a guideline was published for comments by associations and industry in July 2015. The FDA wishes that, after it has come into force, manufacturers will convey defined quality scores to the FDA via an electronic portal. The FDA will use these to calculate specific statistics which are supposed to allow for risk-based management and planning by the FDA. The changes were also described in the GMP News FDA's Quality Metrics Initiative starts with voluntary Phase.

In June 2016, the FDA Quality Metrics Technical Conformance Guide was published. It determines the structure and contents of the data to be reported. To that purpose, technical standards and fields will be defined. Generally, the FDA goes by the data standards that have already been established in other areas. The so-called Study Data Technical Conformance Guide of the FDA serves as a basis for this. XML shall be used to format the data exchange. This is a standard widely used throughout the industry and also used by the FDA and other authorities for data transfer in the area of approvals, e.g. with eCTD.

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