Commission Regulation (EC) No 1146/98 of 2 June 1998 amending Regulation (EC) No 541/95 concerning the examination of variations in the terms of a marketing authorisation granted by a competent authority of a Member State
Date: 1998-06-02
Institutions: European Commission
Subjects: exchange of information, marketing, marketing standard, medicinal product, pharmaceutical legislation, public health

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L 159/31

COMMISSION REGULATION (EC) No 1146/98

of 2 June 1998

amending Regulation (EC) No 541/95 concerning the examination of variations
in the terms of a marketing authorisation granted by a competent authority of a
Member State

THE COMMISSION OF THE EUROPEAN COMMUNITIES,

Having regard to the Treaty establishing the European
Community,

Having regard to Council Directive 75/319/EEC of 20
May 1975, on the approximation of provisions laid down
by law, regulations or administrative action relating to
medicinal products (1), as
last amended by Directive
93/39/EEC (2), and in particular Article 15 thereof,

Having regard to Council Directive 81/851/EEC of 28
September 1981, on the approximation of legislation of
relating to veterinary medicinal
the Member States
products (3), as last amended by Directive 93/40/EEC (4),
and in particular Article 23 thereof,

Whereas, following practical experience in the application
of Commission Regulation (EC) No 541/95 (5) appropriate
provisions should be made to the terms of this Regula-
tion;

Whereas it is appropriate to provide for a procedure to be
followed in the case where national competent authority
imposes urgent safety restrictions;

the marketing authorisation
authorisation holder,
holder shall be obliged to submit an application for a
variation taking account of
the safety restrictions
imposed by the national authorities. This application
shall be submitted without delay to the national
competent authorities concerned for the application of
the procedures set out in Articles 6 and 7 of this Regu-
lation. This paragraph is without prejudice to Article
15a of Directive 75/319/EEC and Article 23a of Direc-
tive 81/851/EEC’.

2. In Article 4, paragraph 2 is replaced by the following

text:

The reference Member State shall

‘2.
forthwith
inform all other concerned Member States about the
the procedure. The reference
date of
Member State shall also inform the marketing author-
isation holder(s) about the date of the start of the pro-
cedure’.

the start of

3. After Article 7, Article 7a and Article 7b are added:

Whereas, moreover, it is necessary to simplify the notifi-
cation procedure for minor variations and to introduce
some changes to the annexes to this Regulation;

‘Article 7a

the provisions of

Whereas,
this Regulation are in ac-
cordance with the opinion of the Standing Committee on
Medicinal Products for Human Use and the Standing
Committee on Veterinary Medicinal Products,

HAS ADOPTED THIS REGULATION:

Article 1

Regulation (EC) No 541/95 is amended as follows:

1. In Article 1 the following paragraph 3 is added:

‘3. Where national competent authorities impose
urgent provisional safety restrictions on the marketing

(1) OJ L 147, 9. 6. 1975, p. 13.
(2) OJ L 214, 24. 8. 1993, p. 22.
(3) OJ L 317, 6. 11. 1981, p. 1.
(4) OJ L 214, 24. 8. 1993, p. 31.
(5) OJ L 55, 11. 3. 1995, p. 7.

Because of the specificities inherent in the manufac-
turing of human influenza vaccines,
the following
dispositions are applicable:

1. Within 30 days following the date of the start of the
procedure, the national competent authorities of the
reference Member State shall prepare an assessment
report on a pharmaceutical dossier and a draft de-
cision which shall be addressed to the other
national competent authorities concerned.

2. Within that period, the competent authority of the
reference Member State may send the marketing
authorisation holder a single request for information
in addition to that already supplied pursuant
to
inform the other competent
Article 6. It shall
authorities concerned.

3. Within 12 days of receipt of the draft decision and
the assessment report, the other competent national
authorities concerned shall accept this draft decision
and inform the competent national authority of the
reference Member State to this effect.

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3. 6. 98

4. The clinical data and, where appropriate,

those
concerning the stability of the medicinal product
shall be addressed by the applicant to the com-
petent authorities of the reference Member State
and to those of the other Member States concerned
at the latest 12 days following the end of the time
limit laid down in paragraph 3.

The reference Member State shall evaluate these
data and draft a final decision within seven days of
the reception of the data mentioned in the first
subparagraph. Each of the other national competent
authorities shall accept this draft decision and adopt
a decision in conformity with this project within the
seven following days.

5. If, in the course of the procedure foreseen in the
present Article, a competent authority raises a ques-
tion of public health which they consider poses an
obstacle to the mutual recognition of the decision to
be taken, reference shall be made without delay to
the provisions of Article 15,
last paragraph, of
Directive 75/319/EEC.

Article 7b

Notwithstanding Article 7a, in case of a pandemic situ-
ation duly recognised by the World Health Organisa-
tion, competent national authorities may exceptionally
and temporarily consider the variation to be accepted
after a complete application has been lodged and
before the end of the procedure foreseen in Article 7a’.

4. In Annex I:

— The text of point A is replaced by the following

text:

‘A. By derogation, the procedure set out in Articles
6 and 7 of the present Regulation shall apply:

— to the minor variations Nos 11, 12, 13, 15
and 16 as referred to below and to minor
variations 24 and 25 if the test procedure
used is not a physicochemical method for
medicinal products falling within the scope
of Council Directives 89/342/EEC (1), or
89/381/EEC (2), or 90/677/EEC (3), or
for
medicinal products which had been con-
sidered as arising under List A of Directive
87/22/EEC,

— to any minor variation when a specific
inspection of a manufacturing site needs to
be carried out’.

General condition: the modified manufacturing
authorisation must be submitted to the com-
petent authority.

— Change in the name of a manufacturer of

the medicinal product

Condition to be fulfilled: the manufacturing site
shall remain the same.

— Change of the manufacturing site(s) for part
or all of the manufacturing process of the
medicinal product

Condition to be fulfilled: no change either in
the manufacturing process or in the specifica-
tions, including test methods.

— withdrawal of the manufacturing authoriza-

tion for a site of manufacture’.

— The text of variation No 5 is replaced by the fol-

lowing text:

‘5. Change in the colouring system of the product (addi-

tion, deletion or replacement of colourant(s))

Condition to be fulfilled: Same functional
characteristics, no change in dissolution profile
for solid dosage forms. Any minor adjustment
to the formulation to maintain the total weight
should be made by
an excipient which
currently makes up a major part of the formula-
tion’.

— The text of variation No 6 is replaced by the fol-

lowing text:

‘6. Change in the flavouring system of

the product

(addition, deletion or replacement of flavour(s))

Condition to be fulfilled: proposed flavour must
be in accordance with Directive 88/388/EEC.
Any minor adjustment to the formulation to
maintain the total weight should be made by an
excipient which currently makes up a major
part of the formulation’.

— After variation No 10 the following text is added:

‘10a. Addition or replacement of measuring device for

oral liquid dosage forms and other dosage forms

Condition to be fulfilled: the size and, where
applicable,
the proposed
measuring device must be compatible with
the approved posology’.

the accuracy of

— After variation No 11 the following text is added:

— The text of variation No 1 is replaced by the fol-

lowing text:

‘11a. Change in the name of a manufacturer of the

active substance

‘1. Change following modification(s) to the manufac-

turing authorisation(s)

Condition to be fulfilled: the manufacturer of
the active substance shall remain the same.

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11b. Change in supplier of an intermediate compound
used in the manufacture of the active substance

change is introduced within six months of adop-
tion of the revised monograph’.

Condition to be fulfilled: the specifications,
synthetic route and quality control procedures
are the same as those already approved’.

— The heading of variation No 30 is replaced by the

following text:

— After variation No 12 the following text is added:

‘Alternative condition: “. . . or a certificate of suit-
ability
is
provided”.

from the European Pharmacopoeia

‘30. Change in pack size for a medicinal product’

A supplementary condition is added:
aging material remains the same’.

‘The pack-

— A new condition is added to variation No 31:

12a. Change in specification of starting material or
intermediate used in the manufacture of the active
substance

‘The change does not concern a fundamental
component of the packaging material which affects
the delivery or use of the product’.

Condition to be fulfilled: specification must
be tightened or addition of new test and
limits.’

— After variation No 15 the following text is added:

‘15a. Change in in-process controls applied during the

manufacture of the product

— The heading of variation No 32 is replaced by the

following text:

‘32. Change of

imprints, bossing or other markings
(except scoring) on tablets or printing on capsules,
including addition or change of
inks used for
product marking’.

— After variation No 33 variation No 34 is added:

Condition to be fulfilled: specification must
be tightened or addition of new test and
limits’.

‘34. Change in the manufacturing process of a non
component due to the subsequent

proteinaceous
introduction of a biotechnology step

— After variation No 20 the following text is added:

General remarks:

‘20a. Extension of the shelf life or retest period of the

active substance

Condition to be fulfilled:
stability studies
have been done to the protocol which was
approved at
the
the time of
the issue of
the studies must
marketing authorisation;
show that the agreed end of shelf life specifi-
cations are still met’.

— After variation No 24 the following text is added:

‘24a. Change in test procedure for a starting material
or intermediate used in the manufacture of the
active substance

Condition to be fulfilled: results of method
validation show new test procedure to be at
least equivalent
to the former procedure.
Specification not adversely affected’.

— The footnote of variation No 26 is changed as

follows:

‘In cases where the marketing authorisation holder
refers to the current edition of the pharmacopoeia,
no variation application is required provided the

This specific variation is without prejudice to
other variations in this Annex which can be
applied in this particular context.

Community legislation applicable to specific
groups of products (*) has to be complied with.

The medicinal products containing a proteina-
ceous component obtained through a biotech-
nology process fall within the scope of part A
of Council Regulation (EEC) No 2309/93 (**).

— Change

in the manufacturing process

for
components compliant with a European Phar-
macopoeia monograph and verified by means of
a certificate of suitability from the European
Pharmacopoeia

the specifica-
Conditions to be fulfilled:
tions and physicochemical properties and
all
component
of
characteristics
remain the same.

the

— Change

in the manufacturing process

for
components requesting a new impurities test
procedure

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3. 6. 98

the

characteristics

Conditions to be fulfilled:
the specifica-
tions and physicochemical properties and
all
component
of
remain the
same. The manufacturing
method is liable to leave impurities not
controlled in the pharmacopoeia mono-
graph, these impurities must be declared
and a suitable test procedure must be
described. This supplementary test must be
specified in a certificate of suitability from
the European Pharmacopoeia.

(*) Food and food ingredients compliant with
Regulation (EC) No 258/97 of the European
(OJ L 43,
Parliament and of the Council
14.2.1997, p. 1), colours for use in foodstuffs
within the
scope of Council Directive
94/36/EEC (OJ L 237, 10.9.1994, p. 13), food
additives within the scope of Council Direc-
tive 88/388/EEC (OJ L 184, 15.7.1988, p.
61), extraction solvents within the meaning
of Council Directive 88/344/EEC (OJ L 157,
24.6.1988, p. 28) as last amended by Direc-
tive 92/115/EEC (OJ L 409, 31.12.1992, p.
31) and foods or food ingredients derived
from a biotechnology step which has been
introduced in the manufacture/production
are not required to be notified as a variation
to the terms of the marketing authorisation.

(**) OJ L 214, 24.8.1993, p. 1.’

5. In Annex II:

— After the heading, the text of the first paragraph
and the following subheading are replaced as
follows:

‘Certain changes to a marketing authorisation have
to be considered to fundamentally alter the terms
of this authorisation and therefore cannot be con-
sidered as a variation in the meaning of Article 15
of Directive 75/319/EEC or in the meaning of

this Regulation. For

Article 23 of Directive 81/851/EEC and cannot be
granted following variation procedures foreseen in
Articles 4 to 7 of
these
changes,
listed below, any application has to be
considered within a complete scientific evaluation
procedure (as for
the granting of a marketing
authorisation). As the case may be, an authorisation
or a modification to the existing marketing authori-
sation will have to be issued by the competent
national authorities.

This Annex is without prejudice to the provisions
of Article 4 of Directive 65/65/EEC and Article 5
of Directive 81/851/EEC’.

— The text of variation No 1, paragraph (i) is replaced

by the following text:

‘(i) addition of one or more active substance(s)
including antigenic components for vaccines,
without prejudice
and 7b
concerning human influenza’,

to Articles 7a

— The text of variation No 4, paragraph (ii)

is

replaced by the following text:

‘(ii) shortening of the withdrawal period of a veter-
inary medicinal product if the change is not
linked to the establishment or a modification
in accordance
to a maximum residue limit
with Regulation (EEC) No 2377/90 (*).

(*) OJ L 224, 18.8.1990, p. 1.’

Article 2

This Regulation shall enter into force on the third day
following its publication in the Official Journal of the
European Communities.

This Regulation shall be binding in its entirety and directly applicable in all Member
States.

Done at Brussels, 2 June 1998.

For the Commission

Martin BANGEMANN

Member of the Commission