Annexes, glossary, abbreviations and references are as those in the main text.

Subject to the general and specific conditions that follow, applicants may make certain changes to pharmaceutical aspects of products without prior approval from the DRA.

The following general conditions apply to all changes made without prior approval:

(a) The change should be listed below as one that may be made without prior approval.

(b) It must have been demonstrated (validated) that the change does not reduce the quality, safety or efficacy of the product, and that the pharmaceutical properties of the product -e.g. particle size of the API, dissolution rate of solid dosage forms - have not been altered. It is the responsibility of the marketing authorization holder to ensure that all necessary validation has been conducted. The validation requirements listed below under “additional conditions” are the minimum.

(c) If the DRA requests a copy of the validation data, they must be supplied within one month of the request.

(d) The DRA must be notified of the change if the list below indicates that notification is required. A date of implementation must be included in the notification. Notifications must be made either in advance of the change or not later than one month after implementation.

Changes that may be made without prior approval are listed below. Specific conditions apply in some cases as indicated. No other changes may be made without prior approval.

1. Analytical methodology for the finished product. On condition that (a) validation shows that the new method is equivalent to or better than the existing method, and (b) major changes (e.g. ultra violet assay to high-pressure liquid chromatography (HPLC)) are notified.

2. Additional tests and limits for starting materials or finished products. On condition that these do not reflect a change in processing, e.g. from a fine to microfine particle size.

3. Alteration of methods of manufacture and manufacturing equipment. On condition that (a) the product is not a slow or otherwise modified release product, and (b) a new stability study has been commenced on at least two batches of the altered product.

4. A change in the content of an excipient of up to ±5%.

5. Changes to flavours, perfumes or colours. On condition that (a) any new colours are permitted by the European Union’s “List of permitted food colours” (19) or FDA’s “Inactive ingredient guide” (21), (b) the change is notified, (c) stability data are available on two batches of the altered product for at least three months under accelerated conditions (as defined in Annex 11) or one year under non-accelerated conditions, and (d) a new stability study has been commenced on at least two batches of the altered product for the full duration of the shelf-life.

6. Alteration of the quantitative composition of a tablet or capsule coating amounting to less than 2% of the total weight of the tablet or capsule. On condition that (a) the coating has no modified-release properties, (b) there is no API in the coating, (c) any new colours are permitted by the European Union’s “List of permitted food colours (19) or by FDA’s “Inactive ingredient guide” (21), and (d) the change is notified.

7. Changes to the volume of granulating fluid of up to ±15%.

8. Changes in batch size. On condition that a stability study has been commenced on at least one full scale production batch.

9. Changes to the quantitative content of agents whose only function is to make the product viscous. On condition that (a) it has been demonstrated that any solid material present is at least equally well suspended, and (b) a stability study has been commenced on at least two batches of the altered product.

10. Changes to the container/closure system in immediate contact with the product, or additional types of container/closure. On condition that (a) the product is not a sterile product, (b) the new system offers equal or better protection to the product, (c) stability data are available on two batches of the product in the new container for at least three months under accelerated conditions (as defined in Annex 11) or one year under non-accelerated conditions, (d) a stability study has been commenced on at least two batches of the altered product for the full duration of the shelf-life, and (e) the change is notified. Changes may not be made to labelling without prior approval.

11. Changes to parts of the container not in contact with the product, but not including labelling - see 12 below.

12. Changes may not be made to labelling without prior approval, except for changes to layout without alteration of text or meaning. Pictures or diagrams may not be added without prior approval because they may imply an unapproved indication.

13. Changes in imprints or marks on solid dosage forms. On condition that (a) these do not imply an unapproved indication or patient population, (b) no unapproved colour (as defined above) is introduced, (c) any changes to scoring are consistent with the dose schedules in the approved product information, and (d) the change is notified.

14. [In some countries, depending on legislation.] Change to the marketing authorization holder (name, address and/or legal entity). On condition that there is no change to the product, including sites of manufacture.

New sites of manufacture require prior approval, because the DRA should see evidence of compliance with GMP, e.g. a WHO-type certificate (see Annex 2). Changes or additions to pack size also require prior approval, because the new size must be consistent with the approved uses of the product.

Notifications of variations, and applications to vary, should be accompanied by the statement

No variations have been made other than (1) those notified herewith and (2) changes which are permitted without notification or prior approval according to the guidelines of the drug regulatory authority of ...........