The World Health Organizaton recently published a new Annex 10: WHO general guidance on variations to multisource pharmaceutical products.
The document is "intended to serve as a guide for establishing national requirements for the regulation of post-approval changes." Proposed categories and reporting procedures are provided. Modifications may be justified in light of risk-benefit and legal considerations specific to each national medicines regulatory authority (NMRA).
The guideline can be used with respect to changes to the quality sections of product dossiers and should be read in context with the Guidelines on submission of documentation for a multisource (generic) finished product: quality part as well as other related WHO guidelines or applicable national guidelines.
The guideline emphasizes that "even well-resourced agencies find it difficult to evaluate all the pharmaceutical changes that are made to all products." Therefore, "a shift towards increased self-assessment of changes by the marketing authorization (MA) holder" has been observed. In this context "it is necessary, to define those changes that can be made without the NMRA´s prior approval (self-assessable changes) and those that require prior approval based on an understanding of the risk and how best to manage the risk."
Description of the reporting categories are discussed in section 5 of the Annex:
Notifications: They can be made for changes to the product that may have no potential or minimal potential to have a negative impact on the quality, safety and efficacy (QSE) of a finished pharmaceutical product (FPP). Implementation of such variations may be possible without prior approval by the NMRA (e.g. submission of these variations as annual notifications).
Minor variations: Changes with moderate or negative impact on the QSE. Such changes must be submitted to the NMRA with all required documentation prior to implementation. The MA holder may implement the change if no objection has been issued within a specific time period by the NMRA.
Major variations: They have a significant potential to have a negative impact on the QSE. A major variation should be reviewed and approved by the NMRA prior to implementation of the change. To increase the efficiency NMRAs may accept grouping of variations under specific circumstances (see also FDA´s new policy regarding grouping of CMC changes).
Editorial changes: They typically need not to be submitted and can be included as a notification together with a subsequent variation concerning that part of the dossier.
Certain changes can be so fundemental that they require a submission of a new dossier. Examples of such changes are:
Change of the API to a different API,
Inclusion of an additional API in a multicomponent product,
Removal of one API from a multicomponent product,
Change in the dose and/ or strength of one or more APIs,
Change from an immediate-release product to an extended- or delayed-release dosage form or vice versa,
Change from a liquid to a powder for reconstitution or vice versa,
Changes in the route of administration.
For any change in the SmPC, patient information leaflet (PIL) and/or labels the NMRAS should be notified and submission of the revised product information and/or labelling is expected as per country-specific requirements.
Proposed recommendations on the regulatory procedures for the reporting of changes to the NMRA are discussed in section 8 of the Annex:
General: It is essential that different branches of the NMRA interact and exchange information effectively. They should, for example, discuss whether a change may require a GMP inspection or may be reviewed during the next routine inspection.
Presubmission meetings: Procedures should be established to allow MA holders the opportunity to obtain advice prior to submitting variations.
Proposed documentation for minor variations: Basic information like - covering letter, - application form, - a list of subsections of the current dossier affected by the change(s), - a list and description of each change, reason for change(s) and the date each change was implemented, - relevant summary of data from studies and tests performed, - copies of the updated subsections of the original dossier, should be included as part of the immediate or annual notification, where prior approval is not required.
Proposed documentation for variations requiring prior approval: Additionally to the documents mentioned under "minor variations": - replacement of the relevant subsections of the dossier in accordance with the acceptable dossier format for the NMRAs concerned, with the proposed changes clearly annotated, - copies of the SmPC, PIL and labels, if relevant, - registration status and date of the proposed change(s) in other countries and/or agencies that have already approved the variation(s), especially the country of origin and the reference agencies.
Review procedures: NMRA should adopt a risk-based review strategy for assessment, concentratiing most effort on those changes considered to carry the greatest risk. NMRA may consider whether it will rely on decisions and/or assessment reports made by other national authorities or prepare its own full assessment report or use a combination of those approaches.