1 September 2023

EU and US variation requirements

One constant across the pharmaceutical industry is the requirement to keep dossiers updated and current. Post-approval lifecycle product management activities are the responsibilities of the marketing authorisation holders (MAHs).


Lifecycle management of pharmaceutical products varies between the EU and US in terms of different submission requirements and assessment timelines.

  • Post-approval variations: in the EU and US can be administrative in nature, simple changes requiring minor review, or major changes which are often complex.
  • Administrative variations: EU regulators go as far as to define ‘administrative’ as a category in their classification guideline, whreas in other regions they fall into the lowest variation category and have significant crossover with minor variations, eg new addresses. Many agencies accept that these changes can be implemented without the need for approval. Prior approval of administrative changes is time-consuming for agencies and costly for industry.
  • Minor variations: Minor variations are generally considered to have either no impact on the quality of the product or have a very low chance of impact and hence lower risk. Consequently, the level of agency review and hence the time required is reduced. As regulatory frameworks have developed, agencies have introduced means to allow the most minor variations to be implement before the review.
  • Major variations: Where notable alterations to product registration are required, these are expected to have an impact on a product’s quality and efficacy and as such are tightly controlled, requiring in-depth assessment and review. The MAH must demonstrate that the product will retain the same level of quality and efficacy. Comparative data is a significant requirement for such changes and must reliably show that the proposed changes do not impair product quality.


The below table shows the summary of variations and anticipated implementation dates in Europe and US


AR – Annual Report                                      CBE-0 – Changes Being Effected 0

CBE-30 – Changes Being Effected 30       PAS – Prior Approval Supplements


In EU there is also Line Extensions. In this classification are included certain changes which affect the fundamentals of the terms of the Authorisation and they cannot be granted via a variation and are submitted as an ‘extension application’. These changes are: changes to the active substance(s); changes to strenght, pharmaceutical form and route of administration. The invented name will remain the same for the ‘extension’.



Activities to improve international harmonisation of lifecycle management processes and guidelines allow agencies to share assessments and reduce individual workloads, improving their quality and speed of assessment. Such improvements are of considerable benefit to industry, seeing changes implemented faster and reducing the cost for many manufacturers.



CPD with Regulatory Rapporteur, Issue 1(1), i-iv, TOPRA 2017