Slicing years off change implementation

Slicing years off change implementation

Harmonizing post-approval change regulations

As the first regulatory authority in Latin America to gain full membership of the International Council for Harmonization (ICH), the Brazilian Health Regulatory Agency (Anvisa) asked BioPhorum to support it in its review of national regulations relating to post-approval change (PAC) submissions.

Brazil’s regulations, RDC50 about the stability data required to support a PAC and RDC49 on other requirements for PAC submissions (including manufacturing, analytical and development data), typically delay implementation of changes by several years. Currently, the regulations require three full-scale batches to be stored for a minimum of half their shelf life.

This year saw BioPhorum assist Anvisa with its review of RDC49; the collaboration having looked at RDC50 in 2018.

The challenges

Anvisa wanted to understand how the industry would see its alignment to the World Health Organization (WHO) and ICH guidelines on this topic, given the absence of a global harmonization of PAC requirements on access to medicines and vaccines.

When a PAC needs to be implemented at a biomanufacturer and reviewed by a national regulatory agency (NRA), different guidelines and regulations are consulted. Usually, these are:

  • WHO Annex 3—Guidelines on procedures and data requirements for changes to approved biotherapeutic products, and WHO Annex 4—Guidelines on procedures and data requirements for changes to approved vaccine
  • International Council for Harmonization (ICH) guidelines when the national regulatory authority is a full member
  • National regulations.

The resulting concept paper, General recommendations for harmonization of local regulations for post-approval submissions with WHO and ICH guidelines, outlines BioPhorum’s considerations regarding the agency’s intention to adopt the WHO guidelines while meeting the related ICH guidelines.

“I think this is a great example of how collaborative work between an agency and the industry contributes to regulatory convergence,” said Denise Bonamici, Head of Regulatory Science & Policy – LATAM at Sanofi. “The WHO post-approval change guidance for biotherapeutic products has all the features that will facilitate the work related to lifecycle management. This material could be used to support the implementation in each LATAM country.”


The paper demonstrates how NRAs and biomanufacturers can make use of both guidelines and introduces the desired principles for national regulations.

BioPhorum’s recommendations allow flexibility and use of development data to understand the change and to mitigate the risks associated with that change.

The key recommendations are:

  • Keep general principles in the resolution, but consider referring to more detailed requirements, for example WHO Annexes 3 and 4


  • Allow the possibility of providing scientific justification if any supporting data outlines for a given change are not provided, are different or are not considered applicable, as well as the PAC management protocol, in accordance with WHO and ICH guidelines


  • Replace the current Brazilian framework specificities (such as the annual report, transport chain validation and implementation date) with the process defined by the WHO.


Next steps

It is expected that Anvisa will issue the new versions of RDC49 and 50 later this year, first for public consultation then for adoption.

A new version of the Regulation for Post-Approval Change for Biologic Products and Vaccines is seen to be a definitive mean for the agency to demonstrate its endorsement of ICH principles, delivering key benefits to the patient, the industry and the agency.

The paper also looked at the current national ancillary requirements (these are different to other ICH countries) and showed that they are not necessary for submission, because they are typically reviewed during site inspection.

This, together with the strong progress that the agency has made in the review process of biopharmaceutical post-approval submissions, is expected to shave months, or even years, off the time needed to implement a post-approval change.

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