After a product has been authorized for marketing, the manufacturer will often wish to make changes (variations) for a number of reasons. The two common areas for change are pharmaceutical aspects of the product (quality control, manufacturing, shelf-life, etc.) and product information.

Changes should not be discouraged on principle, because they are often intended to improve quality (e.g. stability, batch-to-batch consistency, analytical methodology) or product information (e.g. updates to information on adverse reactions). In an application to vary, the company advises the DRA of an intended change and submits appropriate validation data. To encourage companies to give prior advice of such changes, variations should be processed as quickly as possible. If feasible, the DRA should have a separate unit for processing changes. A balance must be maintained between not placing the company at a disadvantage because it has made the application and yet ensuring that the change has been adequately validated.

Even well resourced agencies find it impossible to evaluate all pharmaceutical changes made to all products. It is necessary, therefore, to define those changes that can be made without the DRA’s involvement and those that require prior approval. Some authorities establish an intermediate category of changes which do not require prior approval but which must be notified (“notifiable” changes).

Some DRAs find difficulty in getting the industry to comply with the requirement to apply in advance to make pharmaceutical changes. Better compliance can be achieved by these means:

X Definition of minor changes which do not require prior approval or are notifiable;

X A policy that a complete evaluation of the product will not be routinely triggered whenever a company applies to make a change (though if an application discloses a major defect, the DRA must take action);

X Where prior approval is required, definition of data requirements in published guidelines so that companies can plan ahead;

X Rapid turn-round of evaluations of applications to make changes;

X Random review, during GMP inspections, of company documentation for consistency with information submitted for marketing authorization purposes;

X A strong and effective system of enforcement of legislation when unauthorized changes are detected.

A model list of variations (changes) that do not need prior approval appears in Annex 10.

Some changes are so major that they constitute a new pharmaceutical product. These should be considered to be an application for a new product and should not be accepted as a variation. Such changes include:

X A change of the API to a different API;

X Inclusion of an additional API, or removal of one API from a multi-component product;

X A change in the dose of one or more of the APIs;

X A change in dosage form, including:

X Change from an immediate-release product to a slow- or delayed-release dosage form, or vice versa;

X Change from a liquid to a powder for reconstitution, or vice versa;

X Change in the route of administration.

It should be noted that a change in the recommendations for use (e.g. indications or patient population) would make the product not interchangeable with other brands and hence would not be acceptable unless the product information of all other brands were changed in the same way. However, as mentioned previously, differences in product information may have to be tolerated where local legislation allows new uses to be patented (e.g. new indications in the case of pharmaceuticals) or where market exclusivity arrangements apply.