What are "complex manufacturing processes"? A recent reply from the EMA

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5/6 December 2023

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The Variations Regulation (EC) no. 1234/2008 of the European Commission defines the procedure for variations of existing marketing authorisations. The "detailed guidelines for the various categories of variations", which were published in the consolidated version in August 2013 in the European Official Journal, explain the interpretation and application of this Variations Regulation.

Although the "detailed guidelines" describe a number of scenarios of possible variations in some detail, there are formulations in the Guideline text which require clarification due to their blur. The EMA adopted such a case in a recent update of its questions and answers collection "Quality of Medicines Questions and Answers: Part 1" to concretise the case through a statement.

It is about the term "complex manufacturing processes", which is used in two scenarios associated with type II variations (found in the "detailed guidelines" p 40ff):

• Replacement or addition of a manufacturing site for part or all of the manufacturing process of the finished product (Guideline change code B.II.b.1)
  ...
  c) Site where any manufacturing operation(s) take place, except batch release, batch control, and secondary packaging, for biological/immunological medicinal products, or for pharmaceutical forms manufactured by complex manufacturing processes.
  
• Change in the batch size (including batch size ranges) of the finished product (Guideline change code B.II.b.4)
  ...
  d) The change relates to all other pharmaceutical forms manufactured by complex manufacturing processes .

The EMA now clarified this term as follows:

• Guideline Change Code B.II.b.1: Complex manufacturing processes are given when the understanding of the relation between quality characteristics of the product and its in vivo efficacy is lacking. This is often the case in innovative medicines such as products of nanomedicine.
• Guideline Change Code B.II.b.4: Complex manufacturing processes are those which contain one or more sub-steps, where a scale-up can lead to problems.

In both scenarios, the approving authority will decide on a case by case basis. If the applicant submits the variation as a Type IB, he must provide a valid justification that the production process is not "complex". However, in doubt the authority may upgrade the variation to a Type II. Therefore, the EMA recommends that the applicant clarifies the situation with the authority before submitting the variation.