Key updates to Brazilian post-approval change requirements and use of Polysorbate 80 in China

The BioPhorum Post-Approval Strategy Team has been working hard in international regulatory environments over recent years and can now share intelligence on some significant breakthroughs in the key markets of Brazil and China.

Brazil is planning to reduce its data requirements for post-approval change submissions, which will make it aligned with other ICH countries. While China has issued new monographs for Polysorbate 80, which means that the international grade can now also be used for injectable products.

Post-approval changes in Brazil

The Brazilian Health Regulatory Agency, ANVISA, has confirmed that it will be reducing its data requirements for post-approval change submissions, with the new regulation being effective from the end of 2020.

Currently, stability data is required on three commercial batches made with the post-approval change, for half of the commercial shelf-life of the product. The new guidance is aligned to the requirements in place in other ICH countries, i.e. three to six months data (at the intended and accelerated stability conditions) to demonstrate that the change has no impact on product and stability performance. Manufacturing and stability data can also come from representative batches, not just those manufactured at commercial scale.

“I have been intimately involved with this incredible journey over the past four years,” said Kavita Ramalingam Iyer, Director in BioPharm Regulatory CMC at GSK. “It has been rewarding to see the team influence incremental improvements with the health agencies leading to a favorable revision of post-approval guidances. These changes will enable industry members to better manage post-approval change variations and potentially enhance the speed of quality medicines to patients.”

These benefits are in addition to other changes already put in place by ANVISA that had been recommended by BioPhorum. There are improved review timelines of post-approval submissions that are more aligned to WHO-recommended timelines, i.e. major changes reduced from three years to a target of six months. And the option to file a change approved in the US and Europe through an accelerated process that will take even less time. This accelerated review for biologics was piloted by the agency in 2019.

“We were able to work with ANVISA to tailor discussions that educated the agency on the problems we were seeing and to work on mutually beneficial outcomes,” said Mic McGoldrick, Associate Director CMC Vaccines and Biologics Policy at Merck. “After several in-person training sessions covering many topics, we have seen the effects of our work – post-approval changes have been better aligned with worldwide standards, approval timelines have decreased and stability guidances that reflect ICH standards are much closer to the major agency requirements, to name a few. A very successful collaboration that we hope will continue into the future.”

Polysorbate 80 in China

The Chinese Pharmacopeia committee has issued new monographs for Polysorbate 80, which means Polysorbate 80 Common Grade (similar to that used elsewhere in the world) can now also be used for injectable products.

The previous monographs only allowed the use of a Polysorbate 80 Injectable Grade for injectable products. This grade is only manufactured by one Chinese supplier and the Chinese Health Agency would not accept, on a routine basis, injectable products made with other grades of Polysorbate 80.

This led to a couple of options for manufacturers with products using Polysorbate 80. Either they didn’t register a product in China as it would not meet compendial requirements, or they had to reformulate an existing product exclusively for the Chinese market, which was hugely costly and led to a manufacturer being tied to that one Chinese supplier.

The new monographs mean that this blocker will be removed by the end of 2020. However, due to the Chinese complex registration system of excipients, it does not yet mean that drug products can be registered in China straight away as other registration requirements must be met. Polysorbate 80 Common Grade suppliers must ensure that the drug master file (DMF) for their excipient is registered on the Chinese DMF platform for use in injectables.

Also, three new specification tests must be registered for the new monographs of Polysorbate 80 Common Grade. The tests that will be implemented this year (color and pH) should not be an issue given the current quality of materials but will, nonetheless, require a change to Polysorbate 80 DMFs filed to the excipient DMF platform. However, a new specification for tri ethylene glycol content may be an issue for some of the suppliers, as this is intended to become mandatory in 2025.

“As China expands its entry into ICH membership, we have been poised to provide supporting information on a few key topics working with the Chinese R&D-based Pharmaceutical Association Committee,” added McGoldrick. “We have seen many new guidances published by the Chinese Center for Drug Evaluation that have helped resolve the uncertainty around registrations and post-approval changes. During this, the CDE has been receptive to industry feedback, which was not always the case. This is a good sign of our ability to provide much-needed medicines to the Chinese population.”

The Post-Approval Strategy team is working with the Polysorbate 80 suppliers that are members of BioPhorum (Avantor and Thermo Fisher) to coordinate activities to get their material updated onto the DMF platform (compliant with additional specification tests and the information required for excipients used in the composition of injectable products). Avantor uses Croda-manufactured material and will ensure the actions needed before the end of the year will also happen for the Croda material.

If you intend to register a product in China using Polysorbate 80 sourced from suppliers other than Avantor, Thermo Fisher or Croda, you should encourage them to modify the registration of their material on the Chinese DMF platform and consider further testing of current inventories.

Member organizations should identify opportunities to implement the new data requirements and monographs throughout their impacted functions so that the benefits can be realized as soon as the changes are in place.

For more information, contact Isabelle Lequeux, Facilitator for the DS PAS and Regulatory Governance Teams, via

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