1/22

CMDh Recommendation for classification of unforeseen variations

according to Article 5 of Commission Regulation (EC) No 1234/2008

Section of the
Proposed
Classification Date issued Summary of the proposed change
classification
Guideline

A. ADMINSTRATIVE CHANGES

Change in the nomenclature of the container material for immediate

A.z 4/4/2016 IA
packaging of the finished product.

B. QUALITY CHANGES
B.I. ACTIVE SUBSTANCE
B.I.a) Manufacture

Re-arrangement and amendment of equipment in the plasma

B.I.a.z 5/26/2015 pooling line of the active substance which has already been included IA
in the approved dossier.

Deletion of one manufacturing process of the drug substance

B.I.a.2.z 12/17/2012 IA
manufacturing processes

B.I.a.4.z 4/9/2013 Minor change of an analytical procedure for an in-process control. IA

B.I.b) Control of active substance

737373Classified as internal/staff contractors by the European Medicines Agency

#
 2/22

Change in the specification parameters and/or limits of the active

substance, starting material, intermediate or reagent used in the
B.I.b.1.z 4/3/2023 manufacturing process of the active substance to more accurately IA
describe the appearance of active substance, starting material,
intermediate or reagent

Change in the testing frequency of specification parameter, from

B.I.b.1.z 9/23/2019 IB
routine testing to skip or periodic testing

737373Classified as internal/staff contractors by the European Medicines Agency

#
 3/22

If information on the level of testing performed by the finished

product manufacturer on receipt of the drug substance batches is
already present in the approved registration dossier, the applicant is
advised to apply for a type 1B (B.I.b.z) variation to remove this
information from the dossier.
The level of testing performed by the finished product manufacturer
on receipt of batches of the drug substance is considered to be a
GMP issue and therefore information on whether the finished
B.I.b.z 6/28/2010 IB
product manufacturer performs all of the tests listed in the approved
specifications or accepts some of the results based on the certificate
of analysis provided by the drug substance manufacturer should not
be included in the approved dossier. The level of testing performed
by the finished product manufacturer on receipt of batches of the
drug substance will be subject to review during a GMP inspection.
The drug substance specifications applied by the finished product
manufacturer should, however, continue to be stated in the dossier.

B.I.c) Container closure system

B.I.c.1 12/14/2016 Deletion of one of the authorised bulk or final containers IA

Change of a secondary packaging component of the drug substance

B.I.c.z 12/19/2018 IA
(including replacement or addition)

B.I.d) Stability

737373Classified as internal/staff contractors by the European Medicines Agency

#
 4/22

Change in storage conditions of the reference standard. The same

B.I.d.1.b. 6/28/2010
principles will apply as outlined for the active substance.

B.II. FINISHED PRODUCT

Relevant for biologicals only: The information in 3.2.A.1 has to be
changed as in the provided floor plans an indicated meeting room
B.II.z 7/27/2015 will be changed to a storage room. The proposed variation is not a IA
change in the manufacturing process because the storage is not
changed, only the storage area is expanded.

B.II.b) Manufacture

Change in the manufacturing process of the finished product: to

B.II.b.3.b 4/26/2010 II
move the sterilizing filtration from A/B to C.
Minor change in the manufacturing process of the finished product-
B.II.b.3.z 4/26/2010 IB
Change in the holding time of an intermediate.

Change in the packaging material of bulk product not in contact with

B.II.b.3.z 9/26/2011 IA
the bulk product formulation (including replacement or addition)

Minor change in the manufacturing process of a sterile finished

B.II.b.3.z 2/14/2012 IB
product after the primary packaging step.
Deletion of one manufacturing process of the drug product
B.II.b.3.z 2/27/2017 IA
manufacturing processes
Increase or downscale of the batch size up to 10-fold or down to 10-
B.II.b.4.a and b 10/17/2016 IB
fold for the pharmaceutical form medicinal gas.

The in-process limits for hardness are proposed to be widened from

B.II.b.5.z 9/27/2010 65-85 N to 45-85 N. The lower limits will be at 45N and therefore IB
closer to the limits in the finished product specifications (25-85 N).

B.II.b.5.z 3/25/2013 Minor change of an analytical procedure for an in-process control IA

737373Classified as internal/staff contractors by the European Medicines Agency

#
 5/22

B.II.c) Control of excipients

Details on testing frequency for excipients are seen as a GMP issue,
therefore all the detailed information on testing frequency for
B.II.c.z 7/25/2011 IB
excipients in the chemical pharmaceutical dossier (Module 3) should
Addition
be deletedof via
an alternative supplier of the excipient Norflurane/HFA
a Type IB variation
resulting to some differences in the specification parameters and /or
B.II.c.1. z 5/25/2010 IB
limits of an excipient. between the approved manufacturer and the
new one due to the use of different test methods.
Change in source of excipient unlikely to present any risk of TSE
B.II.c.3.z 12/17/2012 IA
contamination

737373Classified as internal/staff contractors by the European Medicines Agency

#
 6/22

Deletion of one manufacturing process of a non-pharmacopoeial

B.II.c.4.z 2/23/2022 IA
excipient (when described in the dossier) or a novel excipient

B.II.d) Control of finished product Change in the microbiological purity specification parameters of the
finished product to comply with Ph.Eur. A change to the finished
products specifications in order to comply with Ph. Eur. could also
possibly be acceptable as a Type IA notification in certain
B.II.d.1.z 12/20/2010 IB
circumstances, taking into account the general acceptance that the
Reduction in the
new limits are testing frequency
acceptable of an analysis,
for the specific from routine
dosage forms. It is up to
B.II.d.1. z 12/20/2010 testing to skip or periodic testing (microbial testing of finished of the
the Applicant to provide all necessary data for the justification IB
product).
classification.
Change in the specification parameters and/or limits of the finished
B.II.d.1.z 12/20/2010 product to more accurately describe the appearance of the drug IA
product.

The introduction of Ph. Eur. 2.9.6 “Uniformity of content of single-

dose preparations” and/or Ph. Eur. 2.9.5 “Uniformity of mass of
B.II.d.1.z 4/30/2014 IA
single-dose preparations”, as appropriate, to replace the currently
registered Ph. Eur. 2.9.40 “Uniformity of dosage units (by CU)”

B.II.e) Container closure system

Details on testing frequency for packaging material are seen as a
GMP issue, therefore all the detailed information on testing
B.II.e.z 7/25/2011 IB
frequency for packaging material in the chemical pharmaceutical
dossier (Module 3) should be deleted via a Type IB variation

Addition of or change to a calendar package for a pack size already

B.II.e.z 6/30/2014 IAIN
registered in the dossier.

737373Classified as internal/staff contractors by the European Medicines Agency

#
 7/22

The specification parameter “total thickness” for the blister foil

(lidding aluminium foil) of the primary packaging material for a solid
B.II.e.2.z 3/28/2022 IA
dosage form is widened due to a difference in grammage of the
primer material.

Change in the name of a supplier of a packaging component. If the

B.II.e.7 a 11/22/2010 information is not needed in the dossier CMDh recommends deletion IA
of this information.

B.III.2.z) CEP/TSE/MONOGRAPHS

To reflect compliance with the Ph.Eur. and remove reference to the

internal test method and test method number for active substances,
B.III.2.z. 5/23/2011 IA
excipients, active substance starting materials and immediate
packaging materials (Updated on 23/11/2015)

Change from “novel excipient” (3.2.P.4.6) to EU Pharmacopoeial

B.III.2.z. 9/13/2022 IA
excipient (3.2.P.4.1)

B.IV MEDICAL DEVICES

737373Classified as internal/staff contractors by the European Medicines Agency

#
 8/22

Submission of the declaration of conformity, certificate of conformity

or notified body opinion to update the dossier of an already
approved medicinal product with an approved and unchanged
B.IV.z. 7/21/2021 IA
integral medical device prior to MRP/RUP, in order to meet the
requirements of Art. 117 of MDR provided no other changes to the
dossier are foreseen that affect the medical device part.

C. SAFETY, EFFICACY, PHARMACOVIGILANCE CHANGES

Change(s) in the Summary of product Characteristics, Labelling or

Package Leaflet intended to implement the outcome of a procedure
concerning PSUR or PASS, or the outcome of the assessment done
by the competent authority under Articles 45 or 46 of Regulation
C.I.3.z 7/29/2013 IB
1901/2006:
Implementation of wording agreed by the competent authority that
require additional minor assessment, e.g. translations are not yet
agreed upon.

Product Information update, for a medicinal product containing more

than one active substance, in order to include significant changes.
C.I.4 6/28/2010 Those changes were already assessed by a EU competent authority II
for a medicinal product containing one of the active substances, and
the same wording will be used for the combination product

Submission of additional clinical and non-clinical studies, including

C.I.13 9/20/2012 II
BE-studies.
Submission of results of assessments carried out on target patient
C.I.z 3/22/2010 groups in order to comply with Article 59(3) of Directive 2001/83/EC IB*
and any resulting change to the Package Leaflet.
Clarification of the temperature of use in section 4.2 of the SmPC
C.I.z 7/26/2010 and section 3 of the PL to ensure the correct handling of the IB
medicinal product

737373Classified as internal/staff contractors by the European Medicines Agency

#
 9/22

Inclusion of the statements of ADR reporting.

Note: This variation covers the situation where the inclusion of ADR
C.I.z 6/7/2013 IAIN
reporting is not done as part of another regulatory procedure (e.g.
renewal or variation procedure affecting the product information).
Change(s) in the Summary of product Characteristics, Labelling or
Package Leaflet intended to implement the outcome of a PRAC
C.I.z 7/1/2013 IAIN
signal recommendation: implementation of wording agreed by the
competent authority that do not require any further assessment

737373Classified as internal/staff contractors by the European Medicines Agency

#
 10/22

Change(s) in the Summary of product Characteristics, Labelling or

Package Leaflet intended to implement the outcome of a PRAC
C.I.z 7/1/2013 signal recommendation: implementation of wording agreed by the IB
competent authority that require additional minor assessment, e.g.
translations are not yet agreed upon
Change(s) in the Summary of product Characteristics, Labelling or
Package Leaflet intended to implement the outcome of a PRAC
C.I.z 7/1/2013 signal recommendation: implementation of change(s) which require II
to be further substantiated by new additional data to be submitted by
the MAH in the SmPC, labelling or package leaflet of human
Change(s)
medicinal products in order to adapt to a recommendation of a
C.I.z 7/29/2013 competent authority , e.g. a Core SmPC, following the assessment IA
of an Urgent Safety Restriction etc.
-Change(s)
Implementation of wording
in the SmPC, agreed
labelling or by the competent
package leaflet ofauthority.
human
medicinal products in order to adapt to a recommendation of a
competent authority** , e.g. a Core SmPC, following the assessment
C.I.z 7/29/2013 of an Urgent Safety Restriction etc. IB
Implementation of wording agreed by the competent authority that
require additional minor assessment, e.g. translations are not yet
agreed upon.

Change(s) in the SmPC, labelling or package leaflet of human

medicinal products in order to adapt to a recommendation of a
competent authority , e.g. a Core SmPC, following the assessment
C.I.z 7/29/2013 II
of an Urgent Safety Restriction etc.
Implementation of change(s) which require to be further
substantiated by new additional data to be submitted by the MAH.

OTHER PROPOSED CHANGES NOT RELEVANT FOR CLASSIFICATION

Deletion of product name from list in PIL, following withdrawal of MA Article 61(3)
N/A 4/26/2010
in the relevant CMS. notification
NONE (to be
Change in dimensions of the secondary packaging of a medicinal
N/A 7/26/2010 considered on a
product
national level)

737373Classified as internal/staff contractors by the European Medicines Agency

#
 11/22

Changes to the suppliers of excipients without a TSE risk and

without changing any of the specifications. The current excipients No change
N/A 12/20/2010
suppliers are only specified in 3.2.P.4.1 section on the Certificate of necessary
Analysis of the excipients.

This is considered
not to be possible,
as the generic then
will be regarded as
Change of reference medicinal product before initiating a repeat use another medicinal
N/A 3/16/2012
procedure for a generic product product, and would
require a separate
Marketing
Authorisation
Application
Addition of a storage site which is separate from, but linked to a No variation as
N/A 5/25/2016 Change of the Reference standard material: Addition of
manufacturing site. covered by GMP
pharmacopeial reference standards (Ph. Eur. and/or USP) as No change
N/A 12/14/2016
replacement or alternative to the currently approved in-house necessary
reference standards (CTD Module 3.2.S.5, 3.2.P.6).

OTHER CHANGES - CLASSIFICATION TO BE CONFIRMED

To be confirmed 3/22/2010 Additional procedure for analysis of the breath test. II

* The EMA does not support the recommendation given by the CMDh. The EC has been informed accordingly.

737373Classified as internal/staff contractors by the European Medicines Agency

#
 12/22

ation of unforeseen variations

Regulation (EC) No 1234/2008

Proposed conditions, where relevant

The material of the container closure system must remain the same.

1) No changes to the manufacturing

process are applied
2) New equipment is identical in
construction and already listed in 3.2.A.1
3) Re-arranged pooling operations take
place in an area already approved for this
step (no new manufacturing site)
4) Demonstration of GMP approval of the
changes, which should be available at the
time of implementation

1. There should at least remain one manufacturing process, as

previously authorised.
2. The deletion should not be due to critical deficiencies concerning
manufacturing
See corresponding change for the active substance: B.I.b.2.a

737373Classified as internal/staff contractors by the European Medicines Agency

#
 13/22

1. The change is not a consequence of any commitment from previous

assessments to review specification limits (e.g. made during the
procedure for the marketing authorisation application or a Type II
variation procedure).
2. The change does not result from unexpected events arising during
manufacture e.g. new unqualified impurity; change in total impurity limits.
3. The change does not result from a change in the manufacturing
process and/-or packaging of the drug substance.
4. There should be no change to the quality of the active substance
material, intermediate, reagent.

N/A

737373Classified as internal/staff contractors by the European Medicines Agency

#
 14/22

N/A

The remaining packaging must be adequate for the storage of the bulk or
final active substance at the authorised conditions.

1. The secondary packaging does not play a functional role on the

stability of the active substance, or if it does, it is not less protective than
the approved one.
2. The changed packaging component must be adequate for the storage
of the active substance at the authorised conditions.
3. The change should not be due to critical deficiencies of the former
packaging component.
4. The change is not a result of any unexpected events arising during
manufacture or storage of the active substance.

737373Classified as internal/staff contractors by the European Medicines Agency

#
 15/22

Demonstration of GMP approval of the changes, which should be

available at the time of implementation.

N/A

N/A

The secondary packaging does not play a functional role on the stability
of the bulk product, or if it does, it is not less protective than the
approved one.

N/A
1. There should at least remain one manufacturing process, as
previously authorised;
2. The deletion should not be due to critical deficiencies concerning
manufacturing
As condition 2 is not fulfilled, the change should be submitted as a type
IB variation

N/A

See corresponding change for the finished product: B.II.d.2.a

737373Classified as internal/staff contractors by the European Medicines Agency

#
 16/22

N/A

Compliance with the conditions formulated in the EMA TSE Note for
Guidance has to be ensured.

737373Classified as internal/staff contractors by the European Medicines Agency

#
 17/22

1. There should at least remain one manufacturing process, as

previously authorised;
2. The deletion should not be due to critical deficiencies concerning
manufacturing

N/A

N/A

The change is not a result of any unexpected events arising during

manufacture or testing of the drug product.

In addition to conditions 1 and 2 under B.II.d.1, the following conditions

should also apply: –
1. The change does not result from any difficulties in complying with the
requirements of the currently registered content uniformity test method
(Ph. Eur.)
2. The proposed control is fully in line with the requirements of 2.9.5
and/or 2.9.6, as appropriate, for the specific dosage form.

1. “The primary packaging material remains the same”

#737373Classified as internal/staff contractors by the European Medicines Agency

 18/22

1.The material of the primer is not changed.

2.Relevant stability studies have been started under ICH conditions in at
least two pilot scale or industrial scale batches. These studies must be
finalised and the data will be provided immediately to the competent
authorities if outside specifications or potentially outside specifications at
the end of the approved shelf life.

1. The specification of the excipient fully complies with the Ph. Eur.
Monograph and all the tests in the
specification correspond to the pharmacopoeial standard
2. Additional specifications to the pharmacopoeia for product specific
properties are unchanged (e.g. particle size profiles, polymorphic form
or, e.g. bioassays, aggregates)
3. The excipient must remain the same
4. Additional validation of a new or changed pharmacopoeial method is
not required
5. The excipient was already considered not novel for the use in relation
to the specific route of administration.

737373Classified as internal/staff contractors by the European Medicines Agency

#
 19/22

1. The medical device remains unchanged

2. Submission is only needed in order to support an MRP or RUP

N/A

N/A

N/A

N/A

N/A

#737373Classified as internal/staff contractors by the European Medicines Agency

 20/22

The variation implements the wording requested by the authority, incl.

agreed national translations and it does not require the submission of
additional information and/or further assessment

737373Classified as internal/staff contractors by the European Medicines Agency

#
 21/22

1) The variation implements the wording requested by the Competent

Authority and it does not require the submission of additional information
and/or further assessment.

N/A

N/A

737373Classified as internal/staff contractors by the European Medicines Agency

#
 22/22

N/A

N/A

N/A
However, if the change also impacts any other section of Module 3 (e.g.
the actual description of the analytical method itself) then a suitable
variation application will need to be submitted

N/A

737373Classified as internal/staff contractors by the European Medicines Agency

#