Commission Regulation (EC) No 1069/98 of 26 May 1998 amending Regulation (EC) No 542/95 of 10 March 1995 concerning the examination of variations to the terms of a marketing authorisation falling within the scope of Council Regulation (EEC) No 2309/93
Date: 1998-05-26
Institutions: European Commission
Subjects: marketing, marketing standard, medicinal product, pharmaceutical legislation

27. 5. 98

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Official Journal of the European Communities

L 153/11

COMMISSION REGULATION (EC) No 1069/98

of 26 May 1998

amending Regulation (EC) No 542/95 of 10 March 1995 concerning the
examination of variations to the terms of a marketing authorisation falling
within the scope of Council Regulation (EEC) No 2309/93

THE COMMISSION OF THE EUROPEAN COMMUNITIES,

Having regard to the Treaty establishing the European
Community,

Having regard to Council Regulation (EEC) No 2309/93
of 22 July 1993 laying down Community procedures for
the authorisation and supervision of medicinal products
for human and veterinary use and establishing a European
Agency for the Evalutaion of Medicinal Products (1), as
amended by Commission Regulation (EC) No 649/98 (2),
and in particular Articles 15(4) and 37(4) thereof,

Whereas following practical experience in the application
of Commission Regulation (EC) No 542/95 of 10 March
1995 concerning the examination of variations to the
terms of a marketing authorisation falling within the
scope of Council Regulation (EEC) No 2309/93 (3), appro-
priate adaptations should be adopted to the terms of this
Regulation;

Whereas, it is appropriate to provide for a procedure to be
followed in the case that the Commission imposes urgent
safety restrictions;

Whereas, moreover,
it
changes to the Annexes to this Regulation;

is necessary to introduce some

Whereas, the measures provided for in this Regulation are
in accordance with the opinion of
the Standing
Committee on Medicinal Products for Human Use and
the
on Veterinary Medicinal
Products,

Standing Committee

HAS ADOPTED THIS REGULATION:

Article 1

Regulation (EC) No 542/95 is hereby amended as follows:

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

‘3. Where the Commission imposes provisional
urgent safety restrictions on the marketing authorisa-

tion holder, the marketing authorisation holder shall
be obliged to submit an application for a variation
taking account of the safety restrictions imposed by
the Commission. This application shall be submitted
without delay to the Agency for the application of the
procedures set out in Articles 6 and 7 of this Regula-
tion. This paragraph is without prejudice to Article 18
of Regulation (EEC) No 2309/93.’;

2. paragraphs 1 and 2 of Article 8 are replaced by the

following:

the Agency shall

‘1. Where the competent Committee delivers an
opinion,
inform the marketing
authorisation holder and the Commission forthwith
and shall send to the Commission the amendments
to be made to the terms of the marketing authorisa-
tion accompanied by the documents set out in Article
9(3) and 31(3) of Regulation (EEC) No 2309/93.

Article 9(1) and (2) or Article 31(1) and (2) of
2.
Regulation (EEC) No 2309/93 shall apply to the
opinion adopted by the competent Committee.’;

3. in Annex I, point A is replaced by the following:

‘A. By derogation, the procedure set out in Articles 6,
7 and 8 of the present Regulation shall apply:

— to the minor variations Nos 11, 12, 13, 15
and 16 as referred to below and to minor vari-
ations Nos 24 and 25 if the test procedure
used is not a physico-chemical method for
medicinal products falling within the scope of
or
Council
for
89/381/EEC (**), or 90/667/EEC (***), or
medicinal products which had been consid-
ered as arising under Part A of the Annex to
Regulation (EEC) No 2309/93,

89/342/EEC (*),

Directive

— to any minor variation when a specific inspec-
tion of a manufacturing site needs to be
carried out.

(1) OJ L 214, 24. 8. 1993, p. 1.
(2) OJ L 88, 24. 3. 1998, p. 7.
(3) OJ L 55, 11. 3. 1995, p. 15.

(*) OJ L 142, 25.5.1989, p. 14.
(**) OJ L 181, 28.6.1989, p. 44.
(***) OJ L 373, 31.12.1990, p. 26.’;

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27. 5. 98

4. in Annex I, variation No 1 is replaced by the fol-

lowing:

‘10a. Addition or replacement of measuring device
for oral liquid dosage forms and other dosage
forms

‘1. — Change

following modifications(s) of

the

manufacturing authorization(s)

General condition:
the modified manufac-
turing authorization must be submitted to the
competent authority.

Condition to be fulfilled: the size and, where
applicable, the accuracy of the proposed mea-
suring
compatible with
approved posology.’;

device must

be

— Change in the name of a manufacturer of the

ations are added:

medicinal product

8. in Annex I, after variation No 11, the following vari-

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 author-

ization for a site of manufacture.’;

5. in Annex I, variation No 5 is replaced by the fol-

lowing:

‘5. Change in the colouring system of the product
(addition, deletion or replacement of colorant(s))

Condition to be fulfilled: same functional charac-
teristics, 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 formulation.’;

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

active substance

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

11b. Change

in supplier

compound used in the manufacture of
active substance

of an intermediate
the

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

9. in Annex I, after variation No 12 the following text is

added:

‘Alternative condition: “. . . or a certificate of suitabil-
ity from the European Pharmacopeia is provided.”

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

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

10. in Annex I, after variation No 15 the following vari-

ation is added:

6. in Annex I, variation No 6 is replaced by the fol-

lowing:

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

the manufacture of the product

‘6. Change in the flavouring system of the product
(addition, deletion or replacement of flavour(s))

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

in

Condition to be fulfilled: proposed flavour must
accordance with Council Directive
be
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.

11. in Annex I, after variation No 20 the following vari-

ation is added:

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

active substance

(*) OJ L 184, 15.7.1988, p. 61.’;

7. in Annex I, after variation No 10, the following vari-

ation is added:

Condition to be fulfilled: stability studies have
been done to the protocol which was approved
at the time of the issue of the marketing au-
thorisation;
the
agreed end of shelf life specifications are still
met.’;

the studies must show that

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12. in Annex I, after variation No 24, the following vari-

ation is added:

context, notably the variations Nos 4, 11,
12, 18, 19 and 26.

‘24a. Change in test procedure for a starting ma-
terial 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. Specifica-
tion not adversely affected.’;

13. in Annex I,

the footnote to variation No 26 is

amended as follows:

— Community

legislation applicable

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

products
component

containing
— The medicinal
obtained
proteinaceous
through a biotechnology process
fall
under the scope of Part A of Regulation
(EEC) No 2309/93.

‘In cases where the marketing authorisation holder
refers to the current edition of the pharmacopeia, no
variation application is required provided the change
is introduced within six months of adoption of the
revised monograph.’;

— Change in the manufacturing process for
compliant with a European
components
Pharmacopoeia monograph and verified by
means of a certificate of suitability from the
European Pharmacopoeia

14. in Annex I,

the heading of variation No 30 is

replaced by the following:

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

A supplementary condition is added: ‘The packaging
material remains the same.’;

15. in Annex I, a new condition is added to variation No

31:

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

16. in Annex I,

the heading of variation No 32 is

replaced by the following:

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

17. in Annex I, after variation No 33, the following vari-

ation is added:

‘34. — Change in the manufacturing process of a
non-proteinaceous component due to a sub-
sequent introduction of a biotechnology step

General remarks:

— This

specific variation is provided to
supplement the variations already existing
which can be applied in this particular

Conditions to be fulfilled: the specifications
and physcio-chemical properties
and all
characteristics of the component remain the
same.

— Change in the manufacturing process for
components requesting a new impurities test
procedure

Conditions to be fulfilled: the specifications
and physico-chemical properties
and all
characteristics of the component remain the
same. The manufacturing method is liable to
leave impurities not controlled in the phar-
macopoeia monograph, these impurites 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 Regula-
tion (EC) No 258/97 of the European Parliament
and of the Council
(OJ L 43 14.2.1997, p. 1).
Colours for use in foodstuffs within the scope of
European Parliament
and Council Directive
94/36/EEC (OJ L 237, 10.9.1994, p. 13), food addi-
tives of Directive 88/388/EEC, extraction solvents
within
of Council Directive
88/344/EEC (OJ 157, 24.6.1988, p. 28), as last
amended by Directive 92/115/EEC (OJ L 409,
31.12.1992, p. 31) and foods or food ingredients
derived from biotechnology step which has been
introduced in the manufacture/production shall
not require to be notified as a variation to the
terms of the marketing authorisation.’;

the meaning

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18. in Annex II, after the heading, the first paragraph and
the following subparagraph are replaced as follows:

19. in Annex II, variation No 4, paragraph (ii) is replaced

by the following:

‘Certain changes to a marketing authorisation have to
be considered to fundamentally alter the terms of this
authorisation and therefore cannot be considered as a
variation in the meaning of Article 15 paragraph 4 of
Regulation (EEC) No 2309/93 and cannot be granted
following a variation procedure. For these changes,
listed below, any new application has to be con-
sidered within a complete scientific evaluation pro-
cedure (as for the granting of a marketing authorisa-
tion). As the case may be, an authorisation of a modi-
fication of the existing marketing authorisation will
have to be granted by the Community.

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

if

(*) OJ L 224, 18.8.1990, p. 1.’

Article 2

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

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, 26 May 1998.

For the Commission

Martin BANGEMANN

Member of the Commission