A variation is a change to the dossier of an authorized product.
In terms of Marketing Authorizations (MAs) a Variation is: “an amendment to the contents of the documents referred to in Articles 8 to 12 of Directive 2001/83/EC”
Once an MA has been granted, the Marketing Authorization Holder (MAH) has a legal obligation to ensure that the license is kept up to date as the approved particulars evolve over time. The key procedure for managing such changes is the EU Variations procedure.
A variation application basically details a proposed change to approved documentation, providing a formal means by which the approved license details held by the Member State Competent Authorities (CAs) for a given medicinal product can be updated.
Types of variation in Europe:
Three different variation types are defined by EC Regulation 1234/2008, with intrinsic varying implications for the type and complexity of the change(s) covered by each and the likely impact of the change upon the quality, safety or efficacy of the product:
Type IA/IAIN: these are so-called, “Do and Tell”, minor variations, which have only a minimal impact, or no impact at all, on the quality, safety or efficacy of the medicinal product concerned (N.B.: IAIN – Type IA change requiring ‘Immediate Notification’ to the CAs.). It should be noted that, by their very nature, these changes must have been implemented prior to notification of the change to the CAs;
Type IB: these are so-called, “Tell, Wait and Do”, and are minor variations which are not otherwise classified as minor Type IA variations or major Type II variations (or extensions). Type IB is now the ‘default’ category (superseding the ‘old’ Type II default);
Type II: Major variations, which are not an extension, and which may have a significant impact upon the quality, safety or efficacy of the drug product.
In summary, the core components of a variation package to be submitted to the CAs must include:
- A covering letter, stating details of the license to be amended plus the background to the proposed change(s), etc.
- A completed application form, describing amongst other information: the submission route (national/MRP/DCP/CP); MAH and license details; the appropriate variation type and category; a description of (and reason for) the change; a comparison of the ‘present’ license particulars with those ‘proposed’ for the change; the fee to be paid (if any); the MAH’s declaration that only those changes explicitly included with the variation application have been made; date of implementation of the change(s).
- Updated product information: SmPC, PIL, other labeling (packaging) details.
- Specification of the fee(s)/cost(s) for the application and proof of payment (if appropriate).
- Additional supporting documentation, where required, depending upon the nature of the change to be made, the variation type and category.
The above general list is not exhaustive and it should be noted that the overall submission content will be further defined by the type of variation to be submitted and the exact nature of the change(s) to be made.
Types of variation in USA:
A major change is a change that has a substantial potential to have an adverse effect on the identity, strength, quality, purity, or potency of a drug product as these factors may relate to the safety or effectiveness of the drug product. A major change requires the submission of a supplement and approval by FDA prior to distribution of the drug product made using the change. This type of supplement is called, and should be clearly labeled, a Prior Approval Supplement (§ 314.70(b)). An applicant may ask FDA to expedite its review of a prior approval supplement for public health reasons (e.g., drug shortage) or if a delay in making the change described in it would impose an extraordinary hardship on the applicant. This type of supplement is called, and should be clearly labeled, a Prior Approval Supplement – Expedited Review Requested (§ 314.70(b)(4)).5 FDA is most likely to grant requests for expedited review based on extraordinary hardship for manufacturing changes made necessary by catastrophic events (e.g., fire) or by events that could not be reasonably foreseen and for which the applicant could not plan.
A moderate change is a change that has a moderate potential to have an adverse effect on the identity, strength, quality, purity, or potency of the drug product as these factors may relate to the safety or effectiveness of the drug product. There are two types of moderate change. One type of moderate change requires the submission of a supplement to FDA at least 30 days before the distribution of the drug product made using the change. This type of supplement is called, and should be clearly labeled, a Supplement – Changes Being Effected in 30 Days (§ 314.70(c)(3)). The drug product made using a moderate change cannot be distributed if FDA informs the applicant within 30 days of receipt of the supplement that a prior approval supplement is required (§ 314.70(c)(5)(i)). For each change, the supplement must contain information determined by FDA to be appropriate and must include the information developed by the applicant in assessing the effects of the change (§ 314.70(a)(2) and (c)(4)). If FDA informs the applicant within 30 days of receipt of the supplement that information is missing, distribution must be delayed until the supplement has been amended to provide the missing information (§ 314.70(c)(5)(ii)). FDA may identify certain moderate changes for which distribution can occur when FDA receives the supplement (§ 314.70(c)(6)). This type of supplement is called, and should be clearly labeled, a Supplement – Changes Being Effected. If, after review, FDA disapproves a changes-being effected-in-30-days supplement or changes-being-effected supplement, FDA may order the manufacturer to cease distribution of the drug products made using the disapproved change (§ 314.70(c)(7)).
A minor change is a change that has minimal potential to have an adverse effect on the identity, strength, quality, purity, or potency of the drug product as these factors may relate to the safety or effectiveness of the drug product. The applicant must describe minor changes in its next Annual Report (§ 314.70(d)).