1995R0541 — EN — 06.06.1998 — 001.001 — 1
This document is meant purely as a documentation tool and the institutions do not assume any liability for its contents
►B COMMISSIONREGULATION(EC)No541/95
of10March1995
concerning the examination of variations to the terms of a marketing authorization granted by a
competentauthorityofaMemberState
(OJ L 55, 11.3.1995, p. 7)
Amended by:
Official Journal
No page date
►M1Commission Regulation (EC) No 1146/98 of 2 June 1998 L 159 31 3.6.1998
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COMMISSIONREGULATION(EC)No541/95
of10March1995
concerning the examination of variations to the terms of a
marketing authorization 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), aslas t amended
by Council Directive 93/39/EEC(2) of 14 June 1993, and in particular
Article 15 thereof,
Having regard to Council Directive 81/851/EEC of 28 September 1981,
on the approximation of legislation of the Member States relating toveterinary medicinal products(
3), aslas t amended by Council Directive
93/40/EEC(4), and in particular Article 23 thereof,
Whereas, appropriate provisions should be adopted for the examination
of variationsto the termsof a marketing authorization of medicinalproductswhich have benefited from the proceduresof mutual recogni-tion foreseen in Articles 7 and 7a of Council Directive 65/65/EEC of26 January 1965 on the approximation of provisions laid down by
law, regulation or administrative action relating to medicinal
products(
5), aslas t amended by Directive 93/39/EEC, in Article 9 (4)
of Council Directive 75/319/EEC or in Articles8, 8a and 17 (4) ofCouncil Directive 81/851/EEC, and medicinal productsfor which therehasbeen a referral to the proceduresfores een by Articles13 and 14 ofDirective 75/319/EEC or Articles21 and 22 of Directive 81/851/EEC;
Whereas, these provisions should also apply to the examination of
applicationsto vary the termsof a marketing authorization which had
been considered within the scope of application of Council Directive87/22/EEC of 22 December 1986 on the approximation of nationalmeasures relating to the placing on the market of high technologymedicinal products, particularly those derived from biotechnology(
6);
Whereas, it is appropriate to include a notification system or adminis-
trative procedures concerning minor variations for which it is necessary
to precisely define minor variations;
Whereas, moreover, it is necessary to distinguish from amongst those
variations which do not qualify as minor variations, those which mustbe considered to so fundamentally alter the marketing authorization,particularly from the point of view of the quality, safety or efficacy ofa medicinal product, that a new application for a marketing authoriza-
tion would be required;
Whereas, the provisions of this Regulation are in accordance with the
opinion of the Standing Committee on Medicinal Productsfor Humanuse and the Standing Committee on Veterinary Medicinal Products,1995R0541 — EN — 06.06.1998 — 001.001 — 2
(1) OJ No L 147, 9. 6. 1975, p. 13.
(2) OJ No L 214, 24. 8. 1993, p. 22.
(3) OJ No L 317, 6. 11. 1981, p. 1.
(4) OJ No L 214, 24. 8. 1993, p. 31.
(5) OJ No 22, 9. 2. 1965, p. 369/65.
(6) OJ No L 15, 17. 1. 1987, p. 38.
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HAS ADOPTED THIS REGULATION:
Scopeanddefinitions
Article 1
1. ThisRegulation laysdown the procedure for the examination of
applicationsfor variationsto the termsof a marketing authorization ofmedicinal products which have been considered within the scope of
application of Directive 87/22/EEC, of medicinal productshaving
benefited from the proceduresof mutual recognition fores een in Arti-cles7 and 7a of Directive 65/65/EEC, Article 9 (4) of Directive 75/319/EEC or Articles8, 8a and 17 (4) of Directive 81/851/EEC, andmedicinal productsfor which there hasbeen a referral to the proce-duresfores een by Articles13 and 14 of Directive 75/319/EEC or
Articles21 and 22 of Directive 81/851/EEC.
2. ThisRegulation doesnot impede the marketing authorization
holder(s) from taking provisional urgent safety restrictions in the eventof risk to public or animal health. The holder(s) shall forthwith informthe national competent authorities. If the competent authorities have
not raised any objections within 24 hours, the urgent safety restrictions
may be introduced and the applicationsfor thisvariation s hall besubmitted to the national competent authorities for the application ofthe proceduress et out in Articles6 and 7 of thisRegulation.
3. Where national competent authorities impose urgent provisional
safety restrictions on the marketing authorisation holder, the marketingauthorisation holder shall be obliged to submit an application for avariation taking account of the safety restrictions imposed by the
national authorities. This application shall be submitted without delay
to the national competent authoritiesconcerned for the application ofthe proceduress et out in Articles6 and 7 of thisRegulation. Thispara-graph iswithout prejudice to Article 15a of Directive 75/319/EEC andArticle 23a of Directive 81/851/EEC.
Article 2
For the purposes of this Regulation, the following definitions shall
apply:
1. Variation to the termsof a marketing authorization:
— for medicinal productsfor human us e: an amendment to the
contentsof the documentsreferred to in Articles4 and 4a of
Directive 65/65/EEC, in the Annex of Directive 75/318/EECand in Article 2 of Directive 75/319/EEC, such as they existedat the moment of the decision on the marketing authorization orafter approval of any previousvariations ; except where a newapplication for a marketing authorization must be presented
pursuant to Annex II of this Regulation;
— for veterinary medicinal products: an amendment to the contents
of the documentsreferred to in Articles5, 5a and 7 of Directive81/851/EEC such as they existed at the moment of the decisionon the marketing authorization or after approval of any previousvariation; except where a new application for a marketing
authorization must be presented pursuant to Annex II of this
Regulation.
2. Reference Member State: the Member State which, for a given
medicinal product, has produced the assessment report which served
as the basis for the Community procedures foreseen in Article 1 ofthisRegulation or alternatively the Member State chos en in thisrespect by the authorization holder with a view to application ofthisRegulation.
3. Urgent safety restriction: an interim change to product information
by the marketing authorization holder restricting the indication(s),and/or dosage, and/or target species of the medicinal product; or1995R0541 — EN — 06.06.1998 — 001.001 — 3
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adding a contra-indication, and/or warning due to new information
having a bearing on the safe use of the product.
Article 3
1. (a) A ‘minor variation’ (type I) meansa variation asdefined in
Article 2 and listed in Annex I to this Regulation, provided theconditions for such variations laid down in the said Annex aremet.
(b) A ‘major variation’ (or type II) meansa variation asdefined in
Article 2 which cannot be deemed to be a type I variation withinthe meaning of the preceding paragraph.
2. For the purposes of this Regulation, transfer of marketing author-
ization to a new holder, except for the situations covered by point 3 of
Annex I to this Regulation shall not be considered as a variation in the
meaning of Article 2 (1).
Notificationprocedureforminorvariations
Article 4
1. (a) To obtain a type I variation, an identical application shall be
submitted simultaneously to the national competent authorities
of the different Member Stateswhere the medicinal product hasbeen authorized; it shall be accompanied by documents demon-strating that the conditions laid down in Annex I of thisRegulation for the requested variation have been met and alldocumentsamended asa res ult of the application.
(b) The abovementioned documents shall include the list of Member
Statesconcerned by the application for the variation and s hallidentify the reference Member State for the medicinal product
under consideration.
2. The reference Member State shall forthwith inform all other
concerned Member Statesabout the date of the s tart of the procedure.The reference Member State shall also inform the marketing authorisa-
tion holder(s) about the date of the start of the procedure.
3. An application within the meaning of paragraph 1 shall not
concern more than one variation in the marketing authorization. Where
several variations are to be made to a single marketing authorization,
an application shall be submitted within the meaning of paragraph 1in respect of each variation sought; each such application shall containa reference to the other application(s).
4. By derogation to paragraph 3, where a variation in the marketing
authorization entails one or more further changes, a single application
may cover all such consequential variations. The single application
shall describe the relation between the main variation and its conse-quential variations.
5. To be valid, an application within the meaning of paragraph 1
shall be consistent with the provisions of this Article and accompanied
by the relevant feesprovided for thispurpos e by the applicable
national regulations.
Article 5
1. If, within 30 daysof the date of the s tart of the procedure, the
national competent authority of the reference Member State hasnotsent to the marketing authorization holder, who submitted the applica-
tion, the notification provided for in paragraph 2 of thisArticle, the
variation requested is deemed accepted by all Member States whichhave received the application.
2. Where one of the national competent authoritiesconcerned cannot
accept the request for the variation, that authority shall send objectivegroundsfor non-acceptance to the reference Member State within a1995R0541 — EN — 06.06.1998 — 001.001 — 4
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period of 20 daysfollowing the date of the s tart of the procedure. The
reference Member State shall send, before the end of the period fore-seen in paragraph 1, a notification with grounds to the marketing
authorization holder who hass ubmitted the application;
(a) within 30 daysof receipt of the s aid notification, the marketing
authorization holder may amend on one occasion only the applica-
tion in order to take due account of the groundss et out in the
notification. In that case the provisions of this present Article applyto the amended application and all applicationsfores een by Article4 are deemed to have been modified in the same sense;
(b) if the marketing authorization holder doesnot amend the applica-
tion asprovided for in (a) above, all applicationsare deemed tohave been rejected. The national competent authority of the refer-
ence Member State shall forthwith notify the refusal to the
marketing authorization holder and to the other concerned nationalcompetent authorities.
3. Within 10 daysof the end of the procedure mentioned in para-
graph 2 of this Article, and in cases of divergent positions among thenational competent authoritiesof the concerned Member Statesleadingto a refusal, the marketing authorization holder may refer the matter tothe Agency for application of Article 15, last paragraph, of Directive75/319/EEC or Article 23, last paragraph, of Directive 81/851/EEC.
Approvalprocedureformajorvariations
Article 6
1. (a) To obtain a type II variation, an identical application shall be
submitted simultaneously to the national competent authorities
of the different Member Stateswhere the medicinal product has
been authorized. It shall be accompanied by the relevant particu-larsand s upporting documentsreferred to in Article 2 (1) of thisRegulation.
The application must also be accompanied by:— the supporting data relating to the variation applied for,
— all documentsamended asa res ult of the application,
— an Addendum to or updating of existing expert report(s) to
take account of the variation applied for;
(b) The abovementioned documents shall include the list of Member
Statesconcerned by the application for the variation and s hallidentify the reference Member State for the medicinal productunder consideration.
2. The Member Statesconcerned s hall forthwith notify the reference
Member Statesabout the receipt of the application. The referenceMember State shall inform the Member States concerned and themarketing authorization holder(s) about the date of the start of the
procedure.
3. An application within the meaning of paragraph 1 shall not
concern more than one variation in the marketing authorization. Where
several variations are to be made to a single marketing authorization,
an application shall be submitted within the meaning of paragraph 1in respect of each variation sought; each such application shall containa reference to the other application(s).
4. By derogation to paragraph 3, where a variation in the marketing
authorization entails one or more further changes, a single applicationmay cover all such consequential variations. The single applicationshall describe the relation between the main variation and its conse-quential variations.
5. To be valid an application within the meaning of paragraph 1
shall be consistent with the provisions of this Article and accompaniedby the relevant feesprovided for thispurpos e by the applicablenational regulations.1995R0541 — EN — 06.06.1998 — 001.001 — 5
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Article 7
1. Within 60 daysfollowing the date of the s tart of the procedure,
the national competent authority of the reference Member State shall
prepare an assessment report and a draft decision which shall beaddressed to the other national competent authorities concerned.
2. Within that period, the competent authority of the reference
Member State may send the marketing authorization holder a single
request for information supplementary to that already supplied pursuant
to Article 6. It shall inform the other competent authorities concerned.In this case the period shall be extended by a further 60 days. Thisperiod may be extended for a period to be determined by the competentauthority on itsown initiative or upon reques t of the marketing author-
ization holder.
3. Within 30 daysfollowing receipt of the draft decis ion and the
assessment report, the other national competent authorities concernedshall accept this draft decision and inform the national competentauthority of the reference Member State to thiseffect.
4. Each national competent authority concerned by the application
for the variation shall adopt a decision in conformity with the draftdecision foreseen in the preceding paragraph. The national decisionsshall take effect on the day agreed after discussion between thenational competent authority of the reference Member State and the
marketing authorization holder in consultation with the other national
competent authoritiesconcerned.
5. If within the period foreseen in paragraph 3, mutual recognition
by one or more national competent authoritiesof the draft decis ion ofthe national competent authority of the reference Member State isnot
possible, reference shall be made to the provisions of Article 15, last
paragraph, of Directive 75/319/EEC or Article 23, last paragraph, ofDirective 81/851/EEC.
Article 7a
Because of the specificities inherent in the manufacturing of human
influenza vaccines, the following dispositions are applicable:
1. Within 30 daysfollowing the date of the s tart of the procedure, the
national competent authoritiesof the reference Member State s hall
prepare an assessment report on a pharmaceutical dossier and a draft
decision which shall be addressed to the other national competentauthoritiesconcerned.
2. Within that period, the competent authority of the reference Member
State may send the marketing authorisation holder a single requestfor information in addition to that already supplied pursuant toArticle 6. It shall inform the other competent authorities concerned.
3. Within 12 days of receipt of the draft decision and the assessment
report, the other competent national authoritiesconcerned s hallaccept thisdraft decis ion and inform the competent nationalauthority of the reference Member State to thiseffect.
4. The clinical data and, where appropriate, those concerning the stabi-
lity of the medicinal product shall be addressed by the applicant tothe competent authoritiesof 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 nationalcompetent authorities shall accept this draft decision and adopt adecision in conformity with this project within the seven followingdays.
5. If, in the course of the procedure foreseen in the present Article, a
competent authority raises a question of public health which theyconsider poses an obstacle to the mutual recognition of the decision1995R0541 — EN — 06.06.1998 — 001.001 — 6
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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 situation duly recog-
nised by the World Health Organisation, competent national authorities
may exceptionally and temporarily consider the variation to be
accepted after a complete application hasbeen lodged and before theend of the procedure foreseen in Article 7a.
Article 8
ThisRegulation s hall enter into force on the third day following its
publication in the Official Journal of the European Communities .
ThisRegulation s hall be binding in itsentirety and directly applicable
in all Member States.1995R0541 — EN — 06.06.1998 — 001.001 — 7
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ANNEX I
MINORVARIATIONS(TYPEI)TOAMARKETINGAUTHORIZATION
ASREFERREDTOINARTICLE3(1)
Introductorystatements
A. By derogation, the procedure set out in Articles 6 and 7 of the present
Regulation shall apply:
— to the minor variationsNos11, 12, 13, 15 and 16 asreferred 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 productswhich had been cons idered 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.
B. Where a variation requirescons equential updating of the product informa-
tion (summary of product characteristics, labelling, package and/or leaflet),
thisiscons idered part of the variation and the time period for imple-
menting the consequential update must be agreed with the competent
authority at the time of the approval of the variation.
1.Change following modification(s) to the manufacturing authorisation(s)
General condition: the modified manufacturing authorisation must be
submitted to the competent 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 specifications, including test methods.
— withdrawal of the manufacturing authorization for a site of manufac-
ture.
2.Change in the name of the medicinal product (either invented name or
common name)
Condition to be fulfilled: confusion with names of other existing medicinal
productsor INN (International Non-proprietary Name) name mus t be
avoided; when the name isa common name, the change hasto be made
in the following order: from common name to pharmacopoeial name or
to INN.
3.Change in the name and/or address of the marketing authorization holder
(see Article 4a of Directive 65/65/EECor Article 5a of Directive 81/851/
EEC)
Condition to be fulfilled: the marketing authorization holder shall remain
the same person.
4.Replacement of an excipient with a comparable excipient (excluding adju-
vants for vaccines and biologically derived excipients)
Condition to be fulfilled: Same functional characteristics, no change in
dissolution profile for solid dosage forms.
5.Changeinthecolouringsystemoftheproduct(addition,deletion orrepla-
cement 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 makesup a major part of the formulation.
6.Change in the flavouring system of the product (addition, deletion or
replacement of flavour(s))1995R0541 — EN — 06.06.1998 — 001.001 — 8
(1) OJ No L 142, 25. 5. 1989, p. 14.
(2) OJ No L 181, 28. 6. 1989, p. 44.
(3) OJ No L 373, 31. 12. 1990, s. 26.▼M1
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Condition to be fulfilled: proposed flavour must be in accordance with
Directive 88/388/EEC. Any minor adjustment to the formulation to main-
tain the total weight should be made by an excipient which currently
makesup a major part of the formulation.
7.Change in coating weight of tablets or change in weight of capsule shells
Condition to be fulfilled: No change in dissolution profile.
8.Change in the qualitative composition of immediate packaging material
Conditions to be fulfilled: The proposed packaging material must be at
least equivalent to the approved material on relevant properties, and the
change does not relate to sterile products.
9.Deletion of an indication
Conditions to be fulfilled: The continued safety in use of the medicinal
product hasnot been the s ubject of concern from pharmacovigilance, pre-
clinical safety or quality data. Justification must be given.
10.Deletion of a route of administration
Condition to be fulfilled: The continued safety in use of the medicinal
product hasnot been the s ubject of concern from pharmacovigilance, pre-
clinical safety or quality data. Justification must be given.
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 accuracy of
the proposed measuring device must be compatible with the approved
posology.
11.Change in the manufacturer(s) of active substance
Condition to be fulfilled: the specifications, synthetic route and quality
control procedures are the same as those already approved or a European
Pharmacopoeia Certificate of suitability covering the active substance is
submitted.
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 of an intermediate compound used in the manufacture
of the active substance
Condition to be fulfilled: the specifications, synthetic route and quality
control procedures are the same as those already approved.
12.Minor change of manufacturing process of the active substance
Condition to be fulfilled: Specificationsare not advers ely affected; no
change in the physical properties, no new impurities or change in level of
impurities which would require further qualifications in safety studies.
Alternative condition: “… or a certificate of suitability from the European
Pharmacopoeia isprovided.
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.
13.Batch size of active substance
Condition to be fulfilled: Batch data must show that the change does not
affect consistency of production, or physical properties.
14.Change in specifications of active substance
Condition to be fulfilled: Specificationsmus t be tightened or addition of
new tests and limits.
15.Minor changes in manufacture of the medicinal product
Conditionsto be fulfilled: Medicinal product s pecificationsare not
adversely affected; the new process must lead to an identical product
regarding all aspects of quality, safety and efficacy.1995R0541 — EN — 06.06.1998 — 001.001 — 9
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15a.Change in in-process controls applied during the manufacture of the
product
Condition to be fulfilled: specification must be tightened or addition of
new test and limits.
16.Change in the batch size of finished product
Condition to be fulfilled: the change does not affect consistency of produc-
tion.
17.Change in specification of the medicinal product
Condition to be fulfilled: Specificationsmus t be tightened or addition of
new tests and limits.
18.Synthesis or recovery of non-Pharmacopoeial excipients which had been
described in the original dossier
Conditionsto be fulfilled: Specificationsare not advers ely affected, no
new impuritiesor change in level of impuritieswhich would require
further qualification in safety studies, no change in physico-chemical prop-
erties.
19.Change in specification of excipients in the medicinal product (excluding
adjuvants for vaccines)
Condition to be fulfilled: Specificationsmus t be tightened or addition of
new tests and limits.
20.Extension of shelf life as foreseen at time of authorization
Conditionsto be fulfilled: Stability s tudieshave been done to the protocol
which was approved at the time of the issue of the marketing authoriza-
tion; the studies must show that the agreed end of shelf life specifications
are still met; the shelf life does not exceed five years.
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 time of the issue of the marketing authorisa-
tion; the studies must show that the agreed end of shelf life specifications
are still met.
21.Change in shelf life after first opening
Condition to be fulfilled: Studies must show that the agreed end of shelf
life specifications are still met.
22.Change in shelf life after reconstitution
Condition to be fulfilled: Studies must show that the agreed end of shelf
life specifications are still met for the reconstituted product.
23.Change in the storage conditions
Condition to be fulfilled: Stability studies have been done to the protocol
which was approved at the time of issue of the marketing authorization.
The studies must show that the agreed end of shelf life specifications are
still met.
24.Change in test procedure of active substance
Condition to be fulfilled: Results of method validation show new test
procedure to be at least equivalent to the former procedure.
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.
25.Change in the test procedures of the medicinal product
Conditionsto be fulfilled: Medicinal product s pecificationsare not
adversely affected; results of method validation show new test procedure
to be at least equivalent to the former procedure.
26.Changes to comply with supplements to pharmacopoeias (1)1995R0541 — EN — 06.06.1998 — 001.001 — 10
(1)►M1In cases where the marketing authorisation holder refers to the current edition of
the pharmacopoeia, no variation application isrequired provided the change isintro-
duced within six months of adoption of the revised monograph. ◄▼B
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Conditionsto be fulfilled: change ismade exclus ively to implement the
new provisions of the supplement.
27.Change in test procedures of non-pharmacopoeial excipients
Condition to be fulfilled: Results of method validation show new test
procedure to be at least equivalent to the former test procedure.
28.Change in test procedure of immediate packaging
Condition to be fulfilled: Results of method of validation show new test
procedure to be at least equivalent to the former test procedure.
29.Change in test procedure of administration device
Condition to be fulfilled: Results of method validation show new test
procedure to be at least equivalent to the former test procedure.
30.
Change in pack size for a medicinal product
Conditionsto be fulfilled: Specificationsof the medicinal product are not
affected, the new size is consistent with the dosage regimen and duration
of use as approved in the summary of product characteristics; the change
doesnot relate to parenteral preparations . ►M1The packaging material
remainsthe s ame ◄.
31.Change in container shape
Conditionsto be fulfilled: No change in the quality and in the s tability of
the product in the container, no change in the container-product interac-
tions.
The change doesnot concern a fundamental component of the packaging
material which affectsthe delivery or us e of the product.
32.Change of imprints, bossing or other markings (except scoring) on tablets
or printing on capsules,
Condition to be fulfilled: New markings do not cause confusion with other
tablets or capsules.
33.Change of dimensions of tablets, capsules, suppositories or pessaries
without change of quantitative composition and mean mass
Condition to be fulfilled: No change in dissolution profile.
34.Change in the manufacturing process of a non proteinaceous component
due to the subsequent introduction of a biotechnology step
General remarks:
Thiss pecific variation iswithout prejudice to other variationsin this
Annex which can be applied in thisparticular context.
Community legislation applicable to specific groups of products(1) hasto
be complied with.
The medicinal productscontaining a proteinaceouscomponent obtained
through a biotechnology process fall within the scope of part A of Council
Regulation (EEC) No 2309/93(2).
—Change in the manufacturingprocess forcomponents compliant with a
EuropeanPharmacopoeiamonographandverifiedbymeansofacerti-
ficate of suitability from the European Pharmacopoeia
Conditions to be fulfilled: the specifications and physicochemical prop-
erties and all characteristics of the component remain the same.
—Changeinthemanufacturingprocessforcomponentsrequestinganew
impurities test procedure1995R0541 — EN — 06.06.1998 — 001.001 — 11
(1) Food and food ingredientscompliant with Regulation (EC) No 258/97 of the European
Parliament and of the Council (OJ L 43, 14. 2. 1997, p. 1), colours for use in foodstuffswithin the scope of Council Directive 94/36/EEC (OJ L 237, 10. 9. 1994, p. 13), foodadditiveswithin the s cope of Council Directive 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) aslas t amended by Directive 92/115/EEC (OJ L 409, 31. 12.1992, p. 31) and foodsor food ingredientsderived from a biotechnology s tep which hasbeen introduced in the manufacture/production are not required to be notified asavariation to the termsof the marketing authoris ation.
(
2) OJ L 214, 24. 8. 1993, p. 1.▼M1
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Conditions to be fulfilled: the specifications and physicochemical prop-
erties and all characteristics of the component remain the same. The
manufacturing method isliable to leave impuritiesnot controlled in
the pharmacopoeia monograph, 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 Phar-
macopoeia.1995R0541 — EN — 06.06.1998 — 001.001 — 12
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ANNEX II
Changes to a marketing authorization leading to a new application as
referred toinArticle 2
Certain changes to a marketing authorisation have to be considered to funda-
mentally alter the termsof thisauthoris ation and therefore cannot be
considered as a variation in the meaning of Article 15 of Directive 75/319/
EEC or in the meaning of Article 23 of Directive 81/851/EEC and cannot begranted following variation proceduresfores een in Articles4 to 7 of thisRegu-
lation. For 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 authorisation will have to be issued by the competent
national authorities.
ThisAnnex iswithout prejudice to the provis ionsof Article 4 of Directive 65/
65/EEC and Article 5 of Directive 81/851/EEC.
1.Changes to the active substance(s):
(i) addition of one or more active substance(s) including antigenic compo-
nentsfor vaccines , without prejudice to Articles7a and 7b concerning
human influenza
(ii) deletion of one or more active substance(s) including antigenic compo-
nentsfor vaccines ;
(iii) quantitative change to the active substance(s);
(iv) replacement of the active substance(s) by a different salt/ester complex/
derivative (with the same therapeutic moiety);
(v) replacement by a different isomer, a different mixture of isomers, of a
mixture by an isolated isomer (e.g. racemate by a single enantiomer);
(vi) replacement of a biological substance or product of biotechnology with
one of a different molecular structure; modification of the vector used
to produce the antigen/source material, including a master cell bank
from a different source;
(vii) a new ligand or coupling mechanism for a radiopharmaceutical.
2.Changes to the therapeutic indications (
1):
(i) addition of an indication in a different therapeutic area, either treatment,
diagnosis or prophylaxis;
(ii) change of the indication to a different therapeutic area, either treatment,
diagnosis or prophylaxis.
3.Changes to strength, pharmaceutical form and route of administration (2):
(i) change of bioavailability;
(ii) change of pharmacokineticse.g. change in rate of releas e;
(iii) addition of a new strength;
(iv) change or addition of a new pharmaceutical form;
(v) addition of a new route of administration.
4.Other changes specific to veterinary medicinal products used in food-produ-
cing animals:
(i) addition or change of target species;
(ii) shortening of the withdrawal period of a veterinary medicinal product if
the change is not linked to the establishment or a modification to a
maximum residue limit in accordance with Regulation (EEC) No 2377/
90(3).1995R0541 — EN — 06.06.1998 — 001.001 — 13
(1) Therapeutic area isdefined asthe third level of the Anatomical Therapeutic Chemical
(A.T.C./A.T.C. Vet) code.
(2) For parenteral administration, it is necessary to distinguish between intraarterial, intra-
venous, intramuscular, subcutaneous, and other routes. For administration to poultry,respiratory, oral, ocular (nebulization) routes used for vaccination are considered to bethe equivalent routesof adminis tration.
(
3) OJ L 224, 18. 8. 1990, p. 1.▼M1
▼B
▼M1
▼B
▼M1