EU implementation of ICH Q12

The ICH Q12 Guideline "Technical and regulatory considerations for pharmaceutical product lifecycle management"  has been signed off as Step 4 document on 20 November 2019. Following Step 4, the document has now to be implemented by the ICH Regulatory Members (Step 5). On 4 March 2020 the EMA published the ICH Q12 Step 5 Guideline and its annexes - which were adopted by CHMP in January 2020 - together with an Explanatory Note.

According to the Explanatory Note, "the ICH Q12 guideline provides regulatory tools and enablers with associated guiding principles, which are intended to harmonize globally the management of quality related post-approval changes. Some of its principles have been inspired by the current EU legal framework on variations".

ICH Q12 Guideline Scope

The scope of ICH Q12 covers:

  • Pharmaceutical drug substances (APIs) and products (both chemical and biological) that require a marketing authorization,
  • Drug-device combination products,
  • Analytical methods.

It does not include changes needed to comply with Pharmacopoeial Monographs.

Key Principles of ICH Q12

Key principles of ICH Q12 include:

  • management of postapproval CMC changes in a more predictable and efficient manner,
  • regulatory tools and enablers (e.g. Established Conditions (ECs), Product Lifecycle Management (PLCM) Document, Post-Approval Change Management Protocol (PACMP)) with associated guiding principles,
  • demonstration on how increased product and process knowledge can contribute to a more precise and accurate understanding of which post-approval changes require regulatory submission,
  • the importance of an effective pharmaceutical quality system (PQS) in the management of changes and the relationship between Regulatory Assessment and Inspection,
  • structured approaches for frequent CMC Post-Approval Changes and Stability Data Approaches to support the evaluation of CMC Changes.

ICH Q12 Annexes

The two ICH Q12 Annexes include:

Illustrative Examples (Annex I) for

  • Identification of ECs for the Manufacturing Process (Chemical Medicinal Product & Biological Medicinal Product) and for Analytical Procedures,
  • PACMPs,
  • PLCM Document.

Structured Approaches to Analytical Procedure Changes (Annex II)

Potential Benefits of ICH Q12

According to ICH the potential benefits of ICH Q12 are:

  • reduction of unnecessary cost and time burdens on industry and regulators,
  • support of continual improvement, which can result in decreased product variability and increased manufacturing efficiency,
  • mitigation of drug shortages related to manufacturing and quality issues,
  • easier introduction of innovations in manufacturing (and analytical techniques).

Implementation of ICH Q12

MAHs (Marketing Authorization Holders) wishing to use the tools and enablers described in ICH Q12 should consult publicly available information provided by regulatory authorities about the implementation of ICH Q12 in their region. In this context, the EMA notes that "there are some conceptual differences between ICH Q12 and the EU legal framework which have an impact on how the full operational and regulatory flexibility as laid down in the ICH Q12 guideline can be implemented in the EU". The ICH Q12 guideline refers to required or necessary information as ECs. While this term does currently not exist in the EU variation legal framework, "ECs mirror information and quality characteristics that are subject to a variation, as described in the EU Variation Regulation and associated EU Variation Guidelines".

However, ECs (and associated reporting categories) and the PLCM Document are currently not considered compatible with the existing EU legal framework on variations:

  • the definition of ECs and their reporting categories must follow the requirements laid down in the current EU Variations Regulation and associated EU Variations Guidelines,
  • in case a PLCM document is submitted, it can currently not be recognized in the EU due to the fact that it is not referred to in the EU legal framework.

In addition, the two topics "PQS & Change Management" and “Relationship between regulatory assessment and inspection” will require some additional clarification regarding demonstration and evaluation of PQS effectiveness and communication between regulators during implementation of the ICH Q12 guideline.

The agency states: "It is important to note that the legal framework always takes precedence over technical and scientific guidelines". However, the tools and concepts of ICH Q12 that are currently not foreseen in the EU legal framework will be considered when this framework will be reviewed. "In the meantime, the European Commission, together with the EMA and the National Competent Authorities, will continue to work on the implementation of the ICH Q12 guideline within the existing EU legal framework".

Please refer to the Note on EU implementation of ICH Q12 for further details on the implementation of ICH Q12 in the EU.

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