The current Variations Regulation, i.e. Commission Regulation (EC) No.1234/2008, was introduced in 2008 with the aim to simplify and introduce more flexibility to the process of post-approval changes to marketing authorisations (MA). A successful variations system must support innovation and timely access to medicines and encourage MA holders to introduce changes ultimately beneficial to patients, while reducing administrative burden for both MA holders and competent authorities. The Variations Regulation encompasses a risk-based approach to change, allowing minor Type IA changes to be first implemented then reported to the competent authorities, but requiring pre-approval for more extensive Type IB and Type II changes. All quality changes to biological medicinal products are currently classified as higher risk than comparable changes to non-biologics. The various Type IA categories for quality changes are not available for biologics, and almost all CMC changes to biologics are by default currently classified as Type II.
As part of the 2020 Pharmaceutical Strategy for Europe, a major update of the variations framework is underway. The European Commission has published a draft amendment to the Variations Regulation, and released an updated proposal for the Variations Guideline for stakeholder consultation. The updated Variations Regulation will come into effect in January 2025, and a transition period will apply for the implementation of the new Variations Guideline.
The proposed changes to the Variations Regulation and Guideline take into account the experience gained under the current variations framework, and represent a re-evaluation of the risks associated with the various categories of post-approval changes. Significantly, the Commission proposes a downgrading of the classification in many categories of quality variations to biologics. Decades of experience in their manufacture, combined with technical and scientific progress during this time, means that many classes of biologics are now very well characterised. Consequently they should not be considered as higher risk by default when compared to non-biologics, and a more risk-proportionate approach is now proposed. The proposed downgrading of certain variations will apply to all classes of biologics, including Advanced Therapy Medicinal Products.
A summary of the main categories of quality changes with their proposed classification under the updated system is provided below.
Manufacturing site changes:
Addition of a site responsible for manufacture of a biological starting material, reagent or intermediate is proposed to be downgraded to Type IB, unless the change is likely to have a significant impact on quality, safety or efficacy, or the material requires a viral safety or TSE risk assessment, in which case it remains as a Type II change. Addition of a site responsible for manufacture of a biological active substance is still proposed to be a Type II change. Addition of a site responsible for storage of the Master or Working Cell Bank is now proposed for submission as a Type IA notification, provided the storage conditions are unchanged. For finished biological products, addition of a manufacturing site is proposed to be downgraded to Type IB, and addition of a primary packaging site is now proposed to be permitted as a Type IA(IN) notification.
QC/batch testing and batch release site changes:
Addition of a QC testing site for a biological active substance (or its starting material or intermediate) is proposed to be downgraded to Type IB, provided there is no change to the analytical procedure. For finished biological products, addition of a batch release site, with or without QC testing, is proposed to be downgraded to Type IB.
Manufacturing process changes:
Minor change in the manufacturing process of a biological active substance (or its starting material, intermediate or reagent) is proposed to be permitted under a Type IA category, subject to the manufacturing steps, parameters and specifications remaining the same. Substantial changes to the biological active substance’s process will still be categorised as Type II. A change in batch size of a biological active substance will still be categorised as Type II, however, while a comparability assessment is currently required to support a batch size change, it is now proposed that a justification that a comparability assessment is not required can be provided by the applicant. For finished biological products, a minor change in the manufacturing process is now proposed to be permitted as a Type IA notification.
Specification and analytical procedure changes:
For biological active substances and finished products, it is proposed that the addition of a new specification parameter (with its analytical method), as well as the implementation of minor changes to an analytical method, may now be submitted under the appropriate Type IA categories. More substantial changes to the analytical methods will still require a Type IB or Type II variation. A new variation category is proposed which includes changes to, or replacement of, an in-house reference standard for a biological active substance or product. A Type IB variation is proposed for replacement of the reference standard where comparability results are available; where comparability results are not available a Type II variation is proposed.
Stability changes:
Reduction or extension of the retest period for a biological active substance is now proposed to be submitted under the applicable Type IA or IB category; currently these categories are available only to non-biological actives.
