Principles and Practice of Pharmaceutical Medicine

active substance, can be applied for as a Type II
variation.
In the United Kingdom, variation applications
are sent to the MHRA Variation Processing Divi-
sion.The applicationand supportingdata should be
submitted in a clearly laid out dossier applying
the headings and numbering of the CTD format.
There is a reduction in fees for bulk applications,
incorporating multiple changes (fees are published
on the RA’s web site).
The application documents for any variation are:

Cover letter – which clearly states the product
license numbers involved, the reason for the
change, for example if it has been requested or is
as a result of harmonization and whether the appli-
cation is national or a mutual recognitionvariation.

The list of dispatch dates – for mutual recogni-
tion applications where the United Kingdom is
the RMS.

Confirmation that the appropriate fee has been
paid.

A table of contents.

The variation application form dated and signed
by the official contact person. All changes pro-
posed should be clearly explained in the scope of
the variation.

Supporting data relating to the proposed varia-
tion.

Update orAddendum to qualitysummaries, non-
clinical overviews and clinical overviews (the
former ‘expert reports’) as may be relevant.
When nonclinical or clinical study reports are
submitted, their relevant summaries should also
be included in Module II.

In cases where the changes affect the SmPC,
labeling and/or PIL the revised product informa-
tion must be submitted. Mock-ups are required
of proposed labels and PILs, and both annotated,
old as well as the proposed, final versions of the
labeling are required.

‘Complex’ Type II variations require a higher fee,

as the review involved is more extensive; the time-

line is also longer. The following changes are

usually regarded as ‘complex’:

new or amended indication(s);

reformulation of the product introducing a novel

excipient that has previously not been included

in medicinal products;

a new route of synthesis that has not previously

been assessed and a Ph Eur Certificate of Suit-

ability is not available*;

new method of sterilization of a product*;

new container materials for a sterile product*;

new active ingredient manufacturer, not pre-

viously approved to manufacture the active

ingredient concerned, and who does not hold a

Ph Eur Certificate of Suitability for the substance

concerned;

for flu vaccine – new manufacturer or process;

reformulation of a product that is supported by

bioavailability studies;

change in the product’s preservative system;

change in excipients which significantly affect

the pharmaceutical or therapeutic properties.

If a company submits a variation application that

needs to be newly assessed because it is supported

by the results of clinical trials or other data (includ-

ing pharmacological and toxicological tests as well

as extensive evidence from post-marketing experi-

ence or publications), the RA will classify it as a

Type II complex variation. The calculation of fees

is complicated.

*Specific to the active ingredient

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