Handling Changes and Variations

Handling Changes and Variations

Copenhagen, Denmark

Course No 16579


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Dr Peter Bachmann, BfArM, Germany

Mariska de Kleijn, Janssen Biologics B.V., The Netherlands

Dr Josef Hofer, exdra GmbH, Germany

Dr Hiltrud Horn, Horn Pharmaceutical Consulting, Germany

Dr Wilhelm Schlumbohm, Berlin, Germany

Hilde Vanneste, Janssen Pharmaceutica NV, CMC Regulatory Affairs


This conference is intended to provide guidance on the provisions laid down in the EU variations regulation and the supporting guideline. You will get to know how the regulation works and you will learn about

  • How to efficiently submit and process variations
  • Which benefits the supporting guidelines provide and how to use them
  • What has to be considered during documentation of a variations procedure
  • How to handle changes in manufacturing procedures
  • How to handle changes in packaging material
  • How to manage changes in ASMFs and CEPs

Participants will have the opportunity to choose 1 out of 2 parallel workshops dealing with
  • Grouping of variations
  • Classification of variations


Since 1 January 2010 the Commission Regulation (EC) No. 1234/2008 is binding and directly
applicable in all EU member states. It defines the procedure for handling variations to the terms of marketing authorisations. Article 4 of this regulation calls for detailed guidelines explaining the different categories of variations types as well as procedural questions on the documents
to be submitted in each case. These Guidelines have been consolidated in one document and published as Chapter 5 of Eudralex Volume 2A (procedures for marketing authorization) in May 2013.

The variations regulation is intended to simplify the handling of the variations procedure and to provide more flexibility in the submission and processing of variations. However the provisions are of considerable complexity and it is important for API manufacturers and the pharmaceutical industry to be well informed about the latest status of the details of the provisions about handling changes and variations.

Additionally, the draft of the new ICH Q12 Guideline has been published for comment in December 2017. It introduces new concepts to facilitate the management of post-approval CMC changes in a more predictable and efficient manner. These new concepts include, for example, “Established Conditions” and “Post-Approval Change Management Protocols” to extent regulatory flexibility.

Finally, a lot of regulatory work (e.g. variations) will have to be managed due to the Brexit, which is expected to happen in March 2019.

Target Group

The conference is designed for all persons involved in the compilation of pharmaceutical dossiers for marketing authorisations who want to become familiar with the EU variations regulation, in particular for personnel from Regulatory Affairs. Furthermore, the course will be of interest to personnel from Quality Units, Quality Control and Production of the pharmaceutical and the API industry.


The European Variations Procedure – an Overview

  • Introduction and legal background
  • General provisions of the Commission Regulation (EC) No 1234/2008
  • Supporting Guidelines
  • Classification of variations
  • Procedural handling of variations
  • Grouping and worksharing of Variations
  • Impact of Brexit
  • Conclusion and Expectations
Submission and Processing of Variations – the CMDh Best Practice Guides and Explanatory Notes
  • Best practice guides for the processing of different types of variations
  • Best practice guides for the processing of grouped applications
  • Best practice guides on worksharing and recommendations on unforeseen variations
  • The explanatory notes on how to complete the Variation Application Form
How to document a Variations Procedure
  • Documentation requirements for different types of variations
  • Timelines
  • Why a Change Control System?
  • Major parts of a Change Control SOP
  • Efficient company internal communication
  • Hints and tips for lowering the workload
Grouping of Variations – Case Studies
  • Cases for grouping variations according to Article 7 in connection with Annex III
  • of the Commission Regulation
  • Possibilities to combine several changes into one single application
  • Examples
How to manage changes in a multi customer situation using ASMFs or CEPs
  • Specific issues for API manufacturers
  • Need for changes
  • How to inform your customers and get feed-back
  • Differences between ASMF and CEP
  • When can you implement the change
  • Conclusions
Handling National, European and Global Changes
  • Changes in national applications
  • Variations Project Management
  • Starting and processing the notification procedure within Europe
  • Changes and variations in the US
  • Handling global changes and variations
  • Impact of Q8, Q9, Q10 and PAT
How to handle Changes in Manufacturing Processes
  • Background
  • How to implement Changes
  • Changes in the Manufacture of APIs
  • Example: Minor change in the API synthesis
  • Example: Site change
  • Changes in the Manufacture of Drug Products
  • Example: Minor process change
  • Practical Example: Manufacturing Sites outside the EEA
  • Proof of GMP compliance of the new site
  • QP declarations
How to handle Packaging Changes
  • Background
  • Packaging information in Module 3
  • How to deal with these Changes
  • Key questions
  • Practical Examples
  • Change in supplier
  • Change in the foil composition
  • Change of packaging for sterile products
Variations and Lifecycle Management (Draft ICH Q12)
  • Reasons for variations
  • Procedures and classifications
  • Type II Variations: time scales
  • Extension of an existing marketing authorisation
  • Categorisation of new applications versus variation applications
  • Draft Q12: Established Conditions (ECs) and Post-Approval Change Management Protocols (PACMPs)

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