GCC - New Variation Guideline

Version
6.2
Date of implementation 21/05/2023
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What is New in the GCC Guidelines for variation requirements version 6.2?
• 1 New variation related to adding electronic patient leaflet has been added.
(Variation 47 Page 55)
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Table of Contents
1. Introduction ............................................................................................................................8
2. General Notes ..........................................................................................................................8
3. Scope ........................................................................................................................................8
4. Objectives ................................................................................................................................9
5. Types of Variation ..................................................................................................................9
6. Appendix 1 Examples for some major changes and most common minor changes........11
I. Administrative Changes ...................................................................................................11
II. Quality Changes............................................................................................................15
II.1 Active substance .............................................................................................................15
a) Manufacture....................................................................................................................15
b) Control of active substance.............................................................................................21
c) Container closure system ................................................................................................24
d) Stability ..........................................................................................................................27
II.2 Finished product ............................................................................................................28
a) Description and composition ..........................................................................................28
b) Manufacture....................................................................................................................33
c) Control of excipients ......................................................................................................42
d) Control of finished product.............................................................................................46
e) Container closure system ................................................................................................49
f) Stability ..........................................................................................................................56
II.3 CEP/TSE/Monograph ...................................................................................................58
II.4 PMF/VAMF ...................................................................................................................62
II.5 Drug containing medical device ....................................................................................64
III. Safety, Efficacy, Pharmacovigilance Changes ...........................................................67
III. 1 Human and veterinary medicinal products ..............................................................67
III. 2 Veterinary medicinal product - Specific Changes ...................................................70
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IV. PMF/VAMF ..................................................................................................................72
7. Appendix 2: Changes that make a new application necessary .........................................80

8. Appendix 3: Requirements for addition/change to API suppliers: ..................................81
− Abbreviations ........................................................................................................................83
− References .............................................................................................................................84
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1. Introduction
These guidelines are adopted from the EMA Guidelines on the details of the various
categories of variations, Regulation (EC).
This document has been developed to assist applicants in the preparation and
submission of drug applications for variations.
2. General Notes
The following notes should be taken into consideration when submitting any variation
application:
An application for Variation to a Marketing Authorization should always be

submitted (please refer to latest edition of the framework).
Applicants should present a summary of the intended change in tabular form in

which the current state/situation and the situation after the intended change are
compared to outline the scope of the change in a transparent manner.
A justification for the introduction of the change should always follow.
− Some documents such as certificate of analysis (COA), specification sheet, and

approval letters from the country of origin …etc should be submitted when relevant.
It is important to note that the authority reserves the right to request any additional
information and data not specifically described in this document, in order to assess
adequately the safety, efficacy and quality of drug products. Authority is committed
to ensuring that such requests are justifiable and decisions are clearly documented.
Applicants should be aware that deficient documentation can lead to rejection of

the application. In addition, submitting redundant or irrelevant information may
delay approval procedures.
3. Scope
This document applies to change(s) made to drug products that have already received
a marketing authorization by GCC or any local authority within GCC.
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4. Objectives
To classify variations and to provide applicants with recommendations on the data
required for each type of variation; which may impact the safety, efficacy and
quality of drug products.
5. Types of Variations
The variation or post-marketing changes can be classified into two categories:
A. Minor variations:
− Type IA: Such minor variations do not require prior approval

before implementation (“Do and Tell” procedure). Type IAIN variations should
be submitted immediately, within 14 days following implementation. Other type
IA variations, however, can be compiled in a single variation application, to be
submitted to the GHC no later than January 31st of each year. The variation
application for every product should clearly indicate:
• All IA variations that have been implemented during the previous year.
• Date of implementation of each variation.
• Code of each variation, based on this guideline, and a proof that the conditions
of such variations have been met.
• All the corresponding documentation listed in this guideline for each
variation.
When one or more conditions established in this guideline for minor change of Type IA
are not met, the concerned change may be submitted as Type IB variation unless the change
is specifically classified as a major change variation of type II. While in the case of minor
variations of Type IA, failure to provide all necessary documentation in the application
will not necessarily lead to the immediate rejection of the variation if the holder provides
any missing documentation immediately upon the request of the authority, it should be
highlighted that a minor variation of Type IA may in specific circumstances be rejected
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with the consequence that the holder must immediately cease to apply already implemented
variations concerned. Editorial changes and typos are to be treated as Type IA changes
unless otherwise stated.
− Type IB: Such minor variations must be sumbitted to the authority by the
Marketing Authorization Holder (MAH) before implementation, but do not
require a formal approval. However, the MAH must wait a period of time
(please refer to latest edition of the framework) to ensure that the application is
deemed acceptable before implementing the change (“Tell, Wait and Do”
procedure).
B. Major variations:
Type II: Such major variations, which may have a significant impact on the
Quality, Safety or Efficacy of a medicinal product and require prior approval
before implementation.
In order to facilitate the classification of variation or post-market changes, examples

and appendices listed below are explicitly define the various types of changes:
Appendix 1; example of some major changes and most minor changes; which are
classified by the type of change. When the conditions are not met, the change may
classified as either a major change or may make a new application is necessary.
Appendix 2 list the types of changes that make a new application necessary.
Appendix 3 Requirements for addition/change to an API suppliers.
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6. Appendix 1 Examples for some major changes and most common
minor changes
I. Administrative Changes
1. Change in the marketing authorization holder Conditions
Documentation Procedure
to be
to be supplied type
fulfilled
a) Change in the name and/or address of the IAIN

1 1, 2, 4
marketing authorization holder
b) Transfer the product to new marketing

authorization holder (different legal 1, 2 , 3 ,4 , 5 IB
entity)
Conditions
1) The marketing authorization holder (MAH) shall remain the same legal entity.
Documentation
1) A formal document from a relevant official body (e.g. chamber of commerce, national drug
regulatory authority…etc) in which the new name or new address is mentioned.
2) Replacement of the relevant pages of the dossier that are affected by the variation.
3) Copy of the agreement
4) Certificate of a Pharmaceutical Product (CPP)
5) A recent and official price certificate by the company and legalized by the Saudi Embassy in the
country of origin.
2. Remove agent name from the artwork (Mock-up) Conditions

to be
to be supplied type
fulfilled
1 1, 2 IA
Conditions
1) The proposed artwork should comply with the GCC guidelines for Presenting the SPC, PIL and
Labeling Information.
Documentation
1) Samples of the artwork.
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3. Change in the (invented) name of the medicinal Conditions Documentation Procedure
product to be to be supplied type
fulfilled
1, 2 IB
Documentation
1) A formal document from the national drug regulatory authority in which the new name is
approved, if applicable.
4. Change in name of the active substance Conditions Documentation Procedure

to be to be supplied type
fulfilled
1 1, 2 IAIN
Conditions
1) The active substance shall remain the same.
Documentation
1) Proof of acceptance by WHO or copy of the INN list.
5. Change in the name and/or address of a Conditions Documentation Procedure

manufacturer or supplier of the active substance, to be to be supplied type
starting material, reagent or intermediate used in fulfilled
the manufacture of the active substance (where
specified in the product dossier) where no
Certificate of Suitability is available
1 1, 2, 3 IA
Conditions
1) The manufacturing site and all manufacturing operations shall remain the same.
Documentation
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1) A formal document from a relevant official body (e.g. chamber of commerce, national drug
regulatory authority…etc) in which the new name and/or address is mentioned.
3) In case of a drug master file (DMF), an updated “letter of access”.
6. Change in the name and/or address of a Condition Documentatio Procedure

manufacturer of the finished product, including s to be n to be type
quality control sites fulfilled supplied
a) Manufacturer responsible for batch release 1 1, 2 IAIN
b) All other 1 1, 2 IA
Conditions
1) The manufacturing site and all manufacturing operations shall remain the same.
Documentation
1) Copy of the modified manufacturing authorization, if available; or a formal document from a

relevant official body (e.g. chamber of commerce, national drug regulatory authority… etc) in
which the new name and/or address is mentioned.
7. Change in ATC Code /ATC Vet Code Conditions Documentation Procedure

fulfilled
1 1, 2 IA
Conditions
1) Change following granting of or amendment to ATC Code by WHO/ATC Vet Code.
Documentation
1) Proof of acceptance (by WHO) or copy of the ATC (Vet) Code list.
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8. Deletion of a manufacturing sites (including for an Condition Documentatio Procedure
active substance, intermediate or finished product, s to be n to be type
packaging site, manufacturer responsible for batch fulfilled supplied
release, site where batch control takes place, or
supplier of a starting material, reagent or excipient,
when mentioned in the dossier).
1, 2 1, 2 IA
Conditions
1) There should at least remain one site/manufacturer, as previously authorized, performing the same
function as the one(s) concerned by the deletion.
2) The deletion should not be due to critical deficiencies concerning manufacturing.
Documentation
1) The submitted documents should clearly outline the “present” and “proposed” manufacturers.
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II. Quality Changes
II.1 Active substance

a) Manufacture
9. Change in the manufacturer of a starting Conditions Documentation Procedure

material/reagent/intermediate used in the to be to be supplied type
manufacturing process of the active substance or fulfilled
change in the manufacturer of the active
substance, where no Certificate of Suitability is
available
a) The proposed manufacturer is part of the 1, 2, 3, 4, 5, 6, 7 IB

same organization as the currently approved
manufacturer.
b) Introduction of a manufacturer of the active II

substance supported by an DMF.
c) The proposed manufacturer uses a II

substantially different route of synthesis or
manufacturing conditions, which may have a
potential to change important quality
characteristics of the active substance, suchas
qualitative and/or quantitative impurity
profile requiring qualification, or physico-
chemical properties impacting on
bioavailability.
d) New manufacturer of material for which an II

assessment is required of viral safety and/or
TSE risk
e) The change relates to a biological active II

substance or a starting
material/reagent/intermediate used in the
manufacture of a biological/immunological
product
f) Changes to quality control testing 1, 2 1, 5 IA

arrangements for the active substance-
replacement or addition of a site where batch
control/testing takes place
g) Addition of an alternative sterilisation site for 1, 2, 4, 5, 8 IB

the active substance using a pharmacopeial
method
h) Introduction of a new manufacturer of the II

active substance that is not supported by an
DMF and requires significant update to the
relevant active substance section of the dossier
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i) Introduction of a new site of micronisation 1, 3 1, 4, 5, 6 IA
j) Changes to quality control testing II

arrangements for a biological active
substance: replacement or addition of a site
where batch control/testing including a
biological/immunological/immunochemical
method takes place
k) New storage site of Master Cell Bank and/or 1, 5 IB

Working Cell Banks
Conditions
1) The active substance is not a biological/immunological substance or sterile.
2) Method transfer from the old to the new site has been successfully completed.
3) The particle size specification of the active substance and the corresponding analytical method
remain the same.
Documentation
2) A declaration from the marketing authorization holder that the synthetic route (or in case of herbal
products, where appropriate the method of preparation, geographical source, production of herbal
drug and manufacturing route) quality control procedures and specifications of the active
substance and of the starting material/reagent/intermediate in the manufacturing process of the
active substance (if applicable) are the same as those already approved.
3) Either a TSE Certificate of Suitability for any new source of material or, where applicable,
documentary evidence that the specific source of the TSE risk material has previously been
assessed by a national drug regulatory authority of the ICH region and associated countries and
shown to comply with the current Note for Guidance on FMinimising the Risk of Transmitting
Animal Spongiform Encephalopathy Agents via Human and Veterinary Medicinal Products or
an equivalent guideline of the ICH region and associated countries. The information should
include the following: Name of manufacturer, species and tissues from which the material is a
derivative, country of origin of the source animals, its use and previous acceptance.
4) Batch analysis data (in a comparative tabular format) for at least two batches (minimum pilot
scale) of the active substance from the current and proposed manufacturers/sites.
6) A declaration by the Qualified Person (QP) at the site responsible for batch release that starting
material/reagent/intermediate used in the manufacturing of the active substance and the active
substance are manufactured in accordance with the good manufacturing practice (GMP)
guidelines.
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7) Where relevant, a commitment of the manufacturer of the active substance to inform the MA
holder of any changes to the manufacturing process, specifications and test procedures of the
active substance.
8) Proof that the proposed site is appropriately authorized for the pharmaceutical form or product
or manufacturing operation concerned.
10. Changes in the manufacturing process of the Conditions Documentation Procedure

active substance to be to be supplied type
fulfilled
a) Minor change in the manufacturing process 1, 2, 3, 4, 5, 1, 2, 3 IA

of the active substance. 6, 7
b) Substantial change to the manufacturing II

process of the active substance which may
have a significant impact on the quality,
safety or efficacy of the medicinal product.
c) The substance is a biological/immunological II

substance.
d) The change relates to a herbal product and II

there is a change to any of the following:
geographical source, manufacturing route or
production.
e) Minor change to the restricted part of drug 1, 2, 3, 4 IB

master file (DMF).
Conditions
1) No change in qualitative and quantitative impurity profile or in physicochemical properties.
2) The product concerned is not a biological /immunological medicinal product.
3) The synthetic route remains the same, i.e. intermediates remain the same and there are no changes
to the reagents, catalysts or solvents used in the process. In the case of herbal products, the
geographical source, production of the herbal substance and the manufacturing route remain the
same.
4) The specifications of the active substance or intermediates are unchanged.
5) The change is fully described in the open (“applicant’s”) part of drug master file (DMF), if
applicable.
6) The change does not refer to the geographical source, manufacturing route or production of a
herbal medicinal product.
7) The change does not refer to the restricted part of an Active Substance Master File.
Documentation
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1) Replacement of the relevant pages of the finished product dossier and drug master file (DMF)
(where applicable), including a direct comparison of the present process and the new process.
2) Batch analysis data (in comparative tabular format) of at least two batches (minimum pilot scale)
manufactured according to the currently approved and proposed process.
3) Copy of approved specifications of the active substance.
4) A declaration from the marketing authorisation holder or the DMF Holder, where applicable, that
there is no change in qualitative and quantitative impurity profile or in physico-chemical
properties, that the synthetic route remains the same and that the specifications of the active
substance or intermediates are unchanged.
Note: for 10.b), for chemical active substances, this refers to substantial changes to the synthetic route or
manufacturing conditions which may have a potential to change important quality characteristics of the
active substance, such as qualitative and/or quantitative impurity profile requiring qualification, or
physico-chemical properties impacting on bioavailability.
11. Change in batch size (including batch size ranges) Conditions Documentation Procedure
of active substance or intermediate used in the to be to be supplied type
manufacturing process of the active substance fulfilled
a) Up to 10-fold increase compared to the 1, 2, 3, 4, 1, 2 , 5 IA
currently approved batch size 6, 7, 8
b) Downscaling down to 10-fold 1, 2, 3, 4, 5 1, 2 , 5 IA
c) The change requires assessment of the II
comparability of a biological/immunological
active
substance
d) More than 10-fold increase compared to the 1, 2, 3, 4 IB
currently approved batch size
e) The scale for a biological/immunological 1, 2, 3, 4 IB

active substance is increased/decreased
without process change (e.g. duplication of
line)
Conditions
1) Any changes to the manufacturing methods are only those necessitated by scale-up or
downscaling, e.g. use of different-sized equipment.
2) Test results of at least two batches according to the specifications should be available for the
proposed batch size.
3) The product concerned is not a biological/immunological medicinal product.
4) The change does not affect the reproducibility of the process.
5) The change should not be the result of unexpected events arising during manufacture or because
of stability concerns.
6) The specifications of the active substance/intermediates remain the same.
7) The active substance is not sterile.
8) The currently approved batch size was not approved via a Type IA variation.
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Documentation
2) The batch numbers of the tested batches having the proposed batch size.
3) Batch analysis data (in a comparative tabulated format) on a minimum of one production batch
manufactured to both the currently approved and the proposed sizes. Batch data on the next two
full production batches should be made available upon request and reported by the marketing
authorization holder if outside specification (with proposed action).
4) Copy of approved specifications of the active substance (and of the intermediate, if applicable).
5) A declaration from the marketing authorisation holder or the DMF holder as appropriate that the
changes to the manufacturing methods are only those necessitated by scale-up or downscaling,
e.g. use of different-sized equipment, that the change does not adversely affect the
reproducibility of the process, that it is not the result of unexpected events arising during
manufacture or because of stability concerns and that the specifications of the active
substance/intermediates remain the same.
12. Change to in-process tests or limits applied during Conditions Documentation Procedure
the manufacture of the active substance to be to be supplied type
fulfilled
a) Tightening of in-process limits 1, 2, 3, 4 1, 2 IA
b) Addition of a new in-process test and limits 1, 2, 5, 6 1, 2, 3, 4, 6 IA
c) Widening of the approved in-process control II
(IPC) limits, which may have a significant
effect on the overall quality of the active
substance
d) Deletion of an in-process test which may have II
a significant effect on the overall quality of the
active substance
e) Addition or replacement of an in-process test 1, 2, 3, 4, 6 IB
as a result of a safety or quality issue
f) Deletion of a non-significant in-process test 1, 2, 7 1, 2, 5 IA
Conditions
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 authorization 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) Any change should be within the range of currently approved limits.
4) The test procedure remains the same.
5) Any new test method does not concern a novel non-standard technique or a standard technique
used in a novel way.
6) The new test method is not a biological/immunological/immunochemical method or a method
using a biological reagent for a biological active substance (does not include standard
pharmacopoeial microbiological methods).
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Documentation
2) Comparative table of current and proposed in-process tests.
3) Details of any new Non pharmacopoeial analytical method and validation data.
4) Batch analysis data on two production batches (3 production batches for biologicals, unless
otherwise justified) of the active substance for all specification parameters
5) Justification/risk-assessment showing that the parameter is non-significant.
6) Justification for the new in-process test and limits.
13. Changes to the active substance of a seasonal, Conditions Documentation Procedure

prepandemic or pandemic vaccine against to be to be supplied type
human influenza fulfilled
a) Replacement of the strain(s) in a seasonal, II

prepandemic or a pandemic vaccine against
human influenza
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b) Control of active substance
14. Change in the specification parameters and/or Conditions Documentation Procedure

limits of an active substance, starting to be to be supplied type
material/intermediate/reagent used in the fulfilled
manufacturing process of the active substance
a) Tightening of specification limits 1, 2, 3, 4 1, 2 IAIN
b) Addition of a new specification parameter to 1, 2, 5, 6, 7 1, 2, 3, 4, 5, 7 IA

the specification with its corresponding test
method
c) Change outside the approved specifications II

limits range for the active substance
d) Widening of the approved specifications II

limits for starting
materials/reagents/intermediates, whichmay
have a significant effect on the overall quality
of the active substance and/or the finished
product
e) Deletion of a specification parameter which II

may have a significant effect on the overall
quality of the active substance and/or the
finished product
f) Addition or replacementt (excluding 1, 2, 3, 4, 5, 7 IB

biological or immunological substance) of a
specification parameter as a result of a safety
or quality issue
g) Deletion of a non-significant specification 1, 2, 8 1, 2, 6 IA

parameter (e. g deletion of an obsolete test
e.g. organoleptic test)
h) a change in specification from in-house to a 1, 2, 3, 4, 5, 7 IB

non-official Pharmacopoeia
Conditions
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6) The test method is not a biological/immunological/immunochemical method or a method using

a biological reagent.
7) For any material, the change does not concern a genotoxic impurity. If it involves the final active
substance, other than for residual solvents which must be in line with ICH/VICH limits, any
new impurity control should be in line with the official Pharmacopoeia
8) The specification parameter does not concern a critical parameter, for example any of the
following: assay, impurities (unless a particular solvent is definitely not used in the manufacture
of the active substance), any critical physical characteristics, e.g. particle size, bulk or tapped
density, identity test, water, any request for skip testing.
Documentation
2) Comparative table of current and proposed specifications.
3) Details of any new analytical method and validation data.
otherwise justified) of the relevant substance for all specification parameters.
5) Where appropriate, comparative dissolution profile data for the finished product on at least one
pilot batch containing the active substance complying with the current and proposed
specification. For herbal products, comparative disintegration data may be acceptable.
6) Justification/ risk-assessment showing that the parameter is non-significant.
7) Justification of the new specification parameter and the limits.
15. Change in test procedure for active substance or Conditions Documentation Procedure
starting material/reagent/intermediate used in the to be to be supplied type
manufacturing process of the active substance fulfilled
a) Minor changes to an approved test procedure 1, 2, 3, 4 1, 2 IA
b) Change (including replacement or addition) II

to a
test method or a method using a biological
reagent for a biological active substance.
c) Other changes to a test procedure (including 1, 2 IB

replacement or addition) for the active
substance or a starting material/intermediate
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d) Other changes to a test procedure (including 1, 2, 3, 5, 6 1, 2 IA
replacement or addition) for a reagent, which
does not have a significant effect on the
overall quality of the active substance
e) Deletion of a test procedure for the active 7 1 IA

substance or a starting
material/intermediate, if an alternative test
procedure is already authorized
Conditions
1) Appropriate validation studies have been performed in accordance with the relevant guidelines
and show that the updated test procedure is at least equivalent to the former.
2) There have been no changes of the total impurity limits; no new unqualified impurities are
detected
3) The method of analysis should remain the same (e.g. a change in column length or temperature,
but not a different type of column or method).
4) The test method is not a biological/immunological/immunochemical method, or a method using

6) The active substance is not biological/immunological.
7) An alternative test procedure is already authorised for the specification parameter and this
procedure has not been added through IA variation.
Documentation
1) Replacement of the relevant pages of the dossier that are affected by the variation, which
includes a description of the analytical methodology, a summary of validation data, revised
specifications for impurities (if applicable).
2) Comparative validation results, or if justified comparative analysis results showing that the
current test and the proposed one are equivalent. This requirement is not applicable in case of
an addition of a new test procedure.
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c) Container closure system
16. Change in immediate packaging of the active Conditions Documentation Procedure

substance to be to be supplied type
fulfilled
a) Change in the qualitative and quantitative 1, 2, 3 1, 2, 3, 4, 5, 6 IA

composition.
b) Qualitative and/or quantitative composition II

for sterile and non-frozen
biological/immunological active substances
c) Liquid active substances (non-sterile) 1, 2, 3, 4, 5, 6 IB
Conditions
1) The proposed packaging material must be at least equivalent to the approved material in respect
of its relevant properties.
2) Satisfactory results of the Relevant stability studies that have been started according to the GCC
stability guidelines and relevant stability parameters have been assessed in at least two pilot
scale or production scale batches for at least three months.
3) Sterile and biological/immunological active substances are excluded.
Documentation
2) Appropriate data on the new packaging (comparative data on permeability e.g. for O2, CO2
moisture), including a confirmation that the material complies with relevant pharmacopeial
requirements.
3) Proof must be provided that no interaction between the content and the packaging material
occurs (e.g. no migration of components of the proposed material into the content and no loss
of components of the product into the pack).
4) The results of stability studies that have been carried out according to the GCC stability
guidelines, on the relevant stability parameters, on at least two pilot or production scale batches
for at least three months.
5) A letter of commitment to finalize the stability studies and the data must be submitted
immediately to the authority only in case of any out-of-specifications (OOS) results or
potentially outside specifications at the end of the approved shelf life along with the proposed
action(s).
6) Comparative table of the current and proposed specifications, if applicable.
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limits of the immediate packaging of the active to be to be supplied type
substance fulfilled
a) Tightening of specification limits 1, 2, 3, 4 1, 2 IA
b) Addition of a new specification parameter to 1, 2, 5 1, 2, 3, 4 , 6 IA

method
c) Addition or replacement of a specification 1, 2, 3, 4 , 6 IB

parameter as a result of a safety or quality issue
d) Deletion of a non-significant specification 1, 2 1, 2, 5 IA

parameter (e.g. deletion of an obsolete test)
Conditions
or a type II variation procedure) unless it has been previously assessed and agreed as part of a
follow-up measure.
2) The change does not result from unexpected events arising during manufacture of the packaging
material or during storage of the active substance.
Documentation
4) Batch analysis data on two batches of the immediate packaging for all specification parameters.
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Conditions
Change in test procedure for the immediate Documentation Procedure
18. to be
packaging of the active substance to be supplied type
fulfilled
a) Minor changes to an approved test

1, 2, 3 1, 2 IA
procedure
b) Other changes to a test procedure

1, 3, 4 1, 2 IA
(including replacement or addition)
c) Deletion of a test procedure if an

alternative test procedure is already 5 1 IA
authorized
Conditions
2) The method of analysis should remain the same (e.g. a change in column length or
temperature, but not a different type of column or method).
4) The active substance/ finished product is not biological/immunological.
5) There is still a test procedure registered for the specification parameter and this procedure has
not been added through a IA variation.
Documentation
includes a description of the analytical methodology, a summary of validation data.
2) Comparative validation results or if justified comparative analysis results showing that the
an addition of a new test procedure
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d) Stability
Conditio
Change in the re-test period/storage period or storage Documentation Procedure
19. ns to be
conditions of the active substance to be supplied type
fulfilled
a) Retest period/storage period
1. Reduction 1 1, 2, 3 IA
2. Extension of storage period of a

biological/immunological active substance not in II
accordance with an approved stability protocol
3. Extension or introduction of a re-test period/storage

1, 2, 3 IB
period supported by real time data
b) Storage conditions
1. Change to more restrictive storage conditions of the

1 1, 2, 3 IA
active substance
2. Change in storage conditions of

biological/immunological active substances, when the
stability studies have not been performed in II
accordance with a currently approved stability
protocol
3. Change in storage conditions of the active Substance 1, 2, 3 IB
c) Change to an approved stability protocol 1, 2 1, 4 IA
Conditions
1) The change should not be the result of unexpected events arising during manufacture or because of
stability concerns.
2) The changes do not concern a widening of the acceptance criteria in the parameters tested, a removal
of stability indicating parameters or a reduction in the frequency of testing.
Documentation
1) Replacement of the relevant pages of the dossier that are affected by the variation. These must contain
results of appropriate recent real time stability studies; conducted in accordance with the GCC stability
guidelines on at least two (three for biological medicinal products) pilot or production scale batches of
the active substance in the authorized packaging material and covering the duration ofthe requested
re-test period or requested storage conditions.
2) Confirmation that stability studies have been done to the currently approved protocol. The studies
must show that the agreed relevant specifications are still met.
3) Copy of approved specifications of the active substance.
4) Justification for the proposed changes
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e) Design space:
Introduction of a new design space or Conditions
20. extension of an approved design space for the to be
to be supplied type
active substance, concerning: fulfilled
a) One unit operation in the manufacturing

process of the active substance including
1, 2, 3 II
the resulting in- process controls and/or
test procedures
b) Test procedures for starting

materials/reagents/intermediates and/or 1, 2, 3 II
the active substance
Documentation
1) The design space has been developed in accordance with the relevant scientific guidelines.
Results from product, process and analytical development studies (e.g. interaction of the
different parameters forming the design space have to be studied, including risk assessment
and multivariate studies, as appropriate) demonstrating where relevant that a systematic
mechanistic understanding of material attributes and process parameters to the critical quality
attributes of the active substance has been achieved.
2) Description of the Design space in tabular format, including the variables (material attributes
and process parameters, as appropriate) and their proposed ranges.
II.2 Finished product

a) Description and composition
21. Change or addition of imprints, bossing or other Conditions Documentation Procedure
markings including replacement, or addition of to be to be supplied type
inks used for product marking. fulfilled
a) Changes in imprints, bossing or other 1, 2, 3,4 1, 2 IAIN

markings
b) Changes in scoring/break lines intended to 1, 2, 3 IB

divide into equal doses
Conditions
1) Finished product release and end of shelf-life specifications have not been changed (except for
appearance).
2) Any ink must comply with the relevant pharmaceutical legislation.
3) The scoring/break lines are not intended to divide into equal doses.
4) Any product markings used to differentiate strengths should not be completely deleted.
28
Documentation
1) Replacement of the relevant pages of the dossier that are affected by the variation including a
detailed drawing or written description of the current and new appearance and including revised
product information as appropriate.
2) Samples of the finished product where applicable.
3) Results of the appropriate compendial tests demonstrating equivalence in characteristics/correct

dosing (i.e. results demonstrating that the proposed tablet breaks evenly).
29
22. Change in the shape or dimensions of the Condition Documentati Procedur
pharmaceutical form s to be on to be e type
fulfilled supplied
a) Immediate release tablets, capsules,

1, 2, 3, 4 1, 4 IAIN
suppositories and pessaries
b) Gastro-resistant, modified or prolonged release

1, 2, 3, 4, 5 IB
pharmaceutical forms and scored tablets
c) Addition of a new kit for a radiopharmaceutical

II
preparation with another fill volume
Conditions
1) If appropriate, the dissolution profile of the reformulated product is comparable to the old one.
For herbal products, where dissolution testing may not be feasible, the disintegration time of
the new product compared to the old one.
2) Release and end of shelf-life specifications of the product have not been changed (except for
dimensions).
3) The qualitative or quantitative composition and mean mass remain unchanged.
4) The change does not relate to a scored tablet.
Documentation
1) Replacement of the relevant pages of the dossier that are affected by the variation including a
detailed drawing of the current and proposed situation.
2) Comparative dissolution data on at least one pilot batch of the current and proposed
dimensions. For herbal product comparative disintegration data may be acceptable.
3) Justification for not submitting a new bioequivalence study.
4) Samples of the finished product where applicable.
5) Results of the appropriate compendial tests demonstrating equivalence in

characteristics/correct dosing.
23 Changes in the composition (excipients) of the Conditions Documentati Procedur

finished product to be on to be e type
fulfilled supplied
a) Changes in components of the flavoring or coloring system
1. Addition , deletion or replacement 1, 2, 3, 4, 5, 1, 3, 4, 5, 6 IAIN

6, 7, 8, 9
2. Increase or reduction 1, 2, 3, 4, 9 1, 3, 4 IA
30
3. Biological veterinary medicinal products for II
oral use for which the coloring or flavoring
agent is important for the uptake by target
animal species.
b) Other excipients
1. The change relates to a II

biological/immunological product
2. Qualitative or quantitative changes in one or II

more excipients that may have a significant
impact on the safety, quality or efficacy of the
medicinal product.
3. Any new excipient that includes the use of II

materials of human or animal origin for which
assessment is required of viral safety data or
TSE risk.
4. Change that is supported by a bioequivalence II

study.
5. Replacement of a single excipient with a 1, 2, 4, 5, 6, 7, IB

comparable excipient with the same functional 8, 9, 10
characteristics and at a similar level
6. Any minor adjustment of the quantitative 1, 3, 4, 7, 8, IB

composition of the finished product with
respect to excipients
Conditions
1) No change in functional characteristics of the pharmaceutical form e.g. disintegration time,

dissolution profile.
2) 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 finished product formulation.
3) The finished product specifications have only been updated in respect of appearance/odor/taste
and if relevant, deletion or addition of an identification test.
4) Stability studies have been started according to the GCC stability guidelines and relevant stability
parameters have been assessed in at least two pilot scale or production scale batches for at least
three months. In addition, where relevant, photo-stability testing should be performed.
5) Any new proposed components must comply with the relevant guidelines for flavors or colors.
6) The new excipient does not include the use of materials of human or animal origin for which
assessment of viral safety or TSE risk is required.
7) Where applicable, the change does not affect the differentiation between strengths and does not
have a negative impact on taste acceptability for pediatric formulations.
8) The change is not the result of stability issues and/or should not result in potential safety concerns
i.e. differentiation between strengths.
31
9) For veterinary medicinal products for oral use, the change does not affect the uptake by target
animal species.
Documentation
1) Replacement of the relevant pages of the dossier that are affected by the variation including
identification method for any new colorant and if appropriate updated end of shelf-life
specifications.
for at least three months and a letter of commitment to finalize the stability studies and to submit
the data must immediately to the authority in case of any out-of-specifications (OOS) results or
action.
3) A declaration letter that stability studies will be finalized and that data will submitted immediately
to the authority in case of any out-of-specifications (OOS) results or potentially outside
specifications at the end of the approved shelf life along with the proposed action.
4) Sample of the new product, where applicable.
5) Either a TSE Certificate of Suitability for any new source of material or, where applicable,
documentary evidence that the specific source of the TSE risk material has previously been
assessed by a national drug regulatory authority of the ICH region and associated countries and
shown to comply with the current Note for Guidance on Minimising the Risk of Transmitting
Animal Spongiform Encephalopathy Agents via Human and Veterinary Medicinal Products or an
equivalent guideline of the ICH region and associated countries. The information should include
the following: Name of manufacturer, species and tissues from which the material is a derivative,
country of origin of the source animals, its use and previous acceptance.
6) Data to demonstrate that the new excipient does not interfere with the finished product
specification test methods, if appropriate.
7) Justification for the change/choice of excipients etc. must be given by appropriate development
pharmaceutics(including stability aspects and antimicrobial preservation where appropriate).
8) For solid dosage forms, comparative dissolution profile data of at least two pilot scale batches of
the finished product in the new and old composition. For herbal products, comparative
disintegration data may be acceptable.
10) For veterinary medicines intended for use in food producing, justification that the excipient does
not have pharmacological activity at the dose at which it is administered to the target animal.
24. Change in coating weight of oral dosage forms or Conditions Documentation Procedure
change in weight of capsule shells to be to be supplied type
fulfilled
a) Solid oral pharmaceutical forms. 1, 2,3, 4 IB
32
b) Gastro-resistant, modified or prolonged II
release pharmaceutical forms where the
coating is a critical factor for the release
mechanism.
Documentation
potentially outside specifications at the end of the approved shelf lif along with the
proposed action.
4) Comparative dissolution profile of at least two pilot scale batches of the finished product in the
new and old composition . For herbal products, comparative disintegration time may be
acceptable.
25. Change in concentration of a single-dose, total Conditions Documentation Procedure

use parenteral product, where the amount of to be to be supplied type
active substance per unit dose (i.e. the strength) fulfilled
remains the same
II
26. Deletion of the solvent/diluent container from the Conditions Documentation Procedure
pack to be to be supplied type
fulfilled
1, 2 IB
Documentation
1) Justification for the deletion, including a statement regarding alternative means to obtain the
solvent/ diluent as required for the safe and effective use of the medicinal product.
b) Manufacture
27. Replacement or addition of a manufacturing site Conditions Documentation Procedure

for part or all of the manufacturing process of the to be to be supplied type
finished product fulfilled
33
a) Secondary packaging site 1, 2 1, 2, 3, 4, 5, 6 IAIN
1, 2, 3, 4, 5, 6,
b) Primary packaging site 1, 2, 3, 4, 5 IAIN
8, 12, 15, 16
c) Site where any manufacturing operation(s)

take place, except batch release, batch
control and secondary packaging, for
biological/immunological medicinal II
products, or for pharmaceutical forms
manufactured by complex manufacturing
processes
d) Site where any manufacturing operation(s) 1, 2, 3, 4, 5, 6,

take place, except batch-release, batch 7, 8, 9, 10, 11,
IB
control primary and secondary packaging, 12, 13, 14, 15,
for non-sterile medicinal products. 16
e) Site, which requires an inspection by GHC. II
f) Site where any manufacturing operation(s)

take place, except batch release, batch
control, and secondary packaging, for sterile 1, 2, 3, 4, 5, 6,
medicinal products (including those that are 7, 8, 9, 10, 11, IB
aseptically manufactured) excluding 12, 13, 15
biological/immunological medicinal
products
Conditions
1) Satisfactory inspection in the last five years.
2) Site appropriately authorized (to manufacture the pharmaceutical form or product concerned).
3) Product concerned is not a sterile product.
4) Where relevant, for instance for suspensions and emulsions, validation scheme is available or
validation of the manufacture at the new site has been successfully carried out according to the
current protocol with at least three production scale batches.
5) Product concerned is not a biological/immunological medicinal product.
Documentation
2) Proof that the proposed site is appropriately authorized for the pharmaceutical form or product
concerned.
3) A certificate of GMP compliance issued from the GHC, if available.
4) Registration of the new manufacturing site at the GHC, if not registered.
34
5) Certificate of a Pharmaceutical Product (CPP) or Electronic CPP (eCPP) stating the new
manufacturing site. When the manufacturer is not mentioned on the CPP, the approval of the
corresponding variation granted in the reference country can be provided instead.
6) The submitted documents should clearly outline the “present” and “proposed” finished product
manufacturers.
7) If the new manufacturing site uses the active substance as a starting material – A declaration by
the Qualified Person (QP) or qualified key person at the site responsible for batch release that
the active substance is manufactured in accordance with the detailed guidelines on good
manufacturing practice for starting materials.
8) Copy of approved release and end of shelf-life specifications for the product if relevant.
9) Batch analysis data on one production batch and two pilot-scale batches simulating the
production process (or two production batches) and comparative data on the last three batches
from the previous site; batch data on the next two production batches should be available on
request or reported if outside specifications (with proposed action).
10) Relevant stability studies have been started according to the GCC stability and relevant stability
parameters have been assessed in at least two pilot scale or production scale batches for at least
three months.
potentially outside specifications at the end of the approved shelf lif along with the proposed
action.
12) Where relevant the batch numbers, corresponding batch size and the manufacturing date of
batches (≥3) used in the validation study should be indicated or validation protocol (scheme) be
submitted.
13) For semisolid and liquid formulations in which the active substance is present in non-dissolved
form, appropriate validation data including microscopic imaging of particle size distribution
and morphology.
14) For solid dosage forms, data from comparative dissolution tests with demonstration of similarity
of dissolution profile, performed on the last three batches from the previous site and the first
three batches from the new site should be submitted.
15) A recent and official price certificate by the company and legalized by the Saudi Embassy in
the country of origin.
16) If the manufacturing site and the primary and/or secondary packaging site are different,
conditions of transport and bulk storage should be specified and validated.
28. Change to batch release arrangements and Conditions Documentation Procedure

quality control testing of the finished product to be to be supplied type
fulfilled
a) Replacement or addition of a site where batch 1, 2, 3 1, 2, 4 IAIN
control/testing takes place
35
b) Replacement or addition of a site where batch II
control/testing takes place for a
biological/immunological product and any of
the test methods performed at the site is a
biological/immunological method
c) Replacement or addition of a manufacturer responsible for batch release
1. Not including batch control/testing 1 1, 2, 3, 4 IAIN
2. Including batch control/testing 1, 2, 3 1, 2, 3, 4 IAIN
3. Including batch control/testing for a II

biological/immunological product and any
of the test methods performed at the site is a
biological/immunological method
Conditions
1) The site is appropriately authorized.
2) The product is not a biological/immunological medicinal product.
3) Method transfer from the old to the new site or new test laboratory has been successfully
completed.
Documentation
1) Attach copy of manufacturing authorization(s) or where no manufacturing authorization exists

a certificate of GMP compliance issued within the last 3 years by the relevant competent
authority.
2) The submitted documents should clearly outline the “present” and “proposed” finished product
manufacturers batch control/testing and batch release sites.
3) A declaration by the Qualified Person (QP) responsible for batch certification stating that the
active substance manufacturer(s) referred to in the marketing authorization operate in
compliance with the detailed guidelines on good manufacturing practice for starting materials.
29. Change in the manufacturing process of the Conditions Documentation Procedure

finished product to be to be supplied type
fulfilled
a) Substantial changes to a manufacturing II

process that may have a significant impact
on the quality, safety and efficacy of the
medicinal product.
b) The change relates to a II

biological/immunological medicinal product.
36
c) Introduction of a non-standard terminal II
sterilization method.
d) Introduction or increase in the overage that II

is used for the active substance.
e) Minor change in the manufacturing process 1, 2, 4, 6, 7, 8, 9 IB

of an aqueous oral suspension.
f) Minor change in the manufacturing process 1, 2, 3, 4, 1, 2, 3, 4, 5, 6, IA

5, 6,7 7, 8, 9
Conditions
1) No change in qualitative and quantitative impurity profile or in physicochemical properties.
2) Either the change relates to an immediate release solid oral dosage form/oral solution and the
medicinal product concerned is not a biological/immunological or herbal medicinal product; Or
the change relates to process parameter(s) that, in the context of a previous assessment, have
been considered to have no impact on the quality of the finished product (regardless of the type
of product and/or dosage form).
3) The manufacturing principle including the single manufacturing steps remain the same, e.g.
processing intermediates and there are no changes to any manufacturing solvent used in the
process.
4) The currently registered process has to be controlled by relevant in-process controls and no
changes (widening or deletion of limits)are required to these controls.
5) The specifications of the finished product or intermediates are unchanged.
6) The new process must lead to an identical product regarding all aspects of quality, safety and
efficacy.
7) Relevant stability studies have been started according to the GCC stability guidelines and
relevant stability parameters have been assessed in at least one pilot scale or production scale
batches for at least three months. Assurance is given that these studies will be finalised and that
the data will be provided immediately to the authority if outside specifications or potentially
outside specifications at the end of the approved shelf life (with proposed action).
Documentation
1) Replacement of the relevant pages of the dossier that are affected by the variation, including a
direct comparison of the present process and the new process.
2) For semi-solid and liquid products in which the active substance is present in non-dissolved
form: appropriate validation of the change including microscopic imaging of particles to check
for visible changes in morphology; comparative size distribution data by an appropriate method.
3) For solid dosage forms: dissolution profile data of one representative production batch and
comparative data of the last three batches from the previous process; data on the next two full
production batches should be available on request or reported if outside specification (with
proposed action). For herbal products, comparative disintegration data may be acceptable.
37
5) For changes to process parameter(s) that have been considered to have no impact on the quality
of the finished product, declaration to this effect reached in the context of the previously
approved risk assessment.
6) Copy of approved release and end of shelf-life specifications.
7) Batch analysis data (in a comparative tabulated format) on a minimum of one batch
manufactured to both the currently approved and the proposed process. Batch data on the next
two full production batches should be made available upon request and reported by the
marketing authorization holder if outside specification (with proposed action).
guidelines, on the relevant stability parameters, on at least one pilot or production scale batches
9) A letter of commitment to finalize the stability studies with indication of the batch concerned
and the data must be submitted immediately to the authority only in case of any out-of-
specifications (OOS) results or potentially outside specifications at the end of the approved shelf
life along with the proposed action.
30. Change in the batch size (including batch size Conditions to Documentation Procedure
ranges) of the finished product be fulfilled to be supplied type
a) Up to 10-fold compared to the currently 1, 2, 3, 4, 5, 7 1, 4 IAIN

approved batch size.
b) Downscaling down to 10-fold. 1, 2, 3, 4, 5, 6 1, 4 IA
c) The change relates to a II

product or the change in batch size
requires a new bioequivalence study.
d) The change relates to all other II

pharmaceutical forms manufactured by
complex manufacturing processes
e) More than 10-fold increase compared to 1, 2, 3, 4, 5,6, 7 IB

the currently approved batch size for
immediate release (oral) pharmaceutical
forms.
f) The scale for a biological/immunological 1, 2, 3, 4, 5, 6, 7 IB

medicinal product is increased/decreased
without process change (e.g. duplication of
line)
Conditions
38
1) The change does not affect reproducibility and/or consistency of the product.
2) The change relates to standard immediate release oral pharmaceutical forms or to non-sterile
liquid based pharmaceutical forms.
3) Any changes to the manufacturing method and/or to the in-process controls are only those
necessitated by the change in batch-size, e.g. use of different sized equipment.
4) Validation scheme is available or validation of the manufacture has been successfully carried
out according to the current protocol with at least three batches at the proposed new batch size
in accordance with the ICH guidelines.
5) The product concerned is not a biological/immunological medicinal product.
7) The currently approved batch size was not approved via a Type IA variation.
Documentation
2) Batch analysis data (in a comparative tabulated format) on a minimum of one production batch
manufactured to both the currently approved and the proposed sizes. Batch data on the next two
full production batches should be made available upon request and reported by the marketing
authorization holder if outside specifications (with proposed action).
3) Copy of approved release and end of shelf-life specifications.
4) Where relevant the batch numbers, corresponding batch size and the manufacturing date of
batches (≥3) used in the validation study should be indicated or validation protocol (scheme) be
submitted.
5) The validation results should be provided
guidelines , on the relevant stability parameters, on at least one pilot or production scale batches
action. For biologicals/immunologicals: a declaration that an assessment of comparability is not
required.
39
31. Change to in-process tests or limits applied Conditions Documentation Procedure
during the manufacture of the finished product to be to be supplied type
fulfilled
a) Tightening of in-process limits 1, 2, 3, 4 1, 2 IA
b) Addition of a new tests and limits 1, 2, 5, 6 1, 2, 3, 4, 5, 7 IA
c) Widening of the approved IPC limits, which II

quality of the finished product
d) Deletion of an in-process test which may II

have a significant effect on the overall
e) Addition or replacement of an in-process test 1, 2, 3, 4, 5, 7 IB

f) Deletion of a non-significant in-process test 1, 2, 7 1, 2, 6 IA
Conditions
6) The new test method is not a biological/immunological/immunochemical method or a method

using a biological reagent for a biological active substance.
7) The in-process test does not concern the control of a critical parameter, e.g.: assay, impurities
(unless a particular solvent is definitely not used in the manufacture) any critical physical
characteristics (particle size, bulk, tapped density, etc.) identity test (unless there is a suitable
alternative control already present) microbiological control (unless not required for the
particular dosage form)
Documentation
2) Comparative table of current and proposed in-process tests.
otherwise justified) of the finished product for all specification parameters.
40
pilot batch manufactured using the current and new in-process tests. For herbal products,
comparative disintegration data may be acceptable.
7) Justification of the new in-process test and limits.
41
c) Control of excipients

limits of an excipient to be to be supplied type
fulfilled

the specification

limits range
d) Deletion of a specification parameter which II

e) Addition or replacement (excluding biological 1, 2, 3, 4, 5, 6, 8 IB

or immunological product) of a specification
parameter parameter with its corresponding
test method, as a result of a safety or quality
issue
f) Deletion of a non-significant specification 1, 2, 8 1, 2, 7 IA

parameter (e. g deletion of an obsolete test e.g.
organoleptic test)
g) a change in specification from in-house to a non- 1, 2, 3, 4, 5, 6, 8 IB

official Pharmacopoeia
Conditions
specification limits (e.g. made during the procedure for the marketing authorization application or
a type II variation procedure).
6) The test method is not a biological/immunological/immunochemical method.
7) The change does not concern a genotoxic impurity.
8) The specification parameter does not concern the control of a critical parameter, e.g.:
impurities (unless a particular solvent is definitely not used in the manufacture of the excipient)
42
any critical physical characteristics (particle size, bulk, tapped density, etc.)
identity test (unless there is a suitable alternative control already present)
microbiological control (unless not required for the particular dosage form)
Documentation
4) Batch analysis data on two production batches (3 production batches for biological excipients,) of
the excipient for all specification parameters.
pilot batch containing the excipient complying with the current and proposed specification. For
herbal products, comparative disintegration data may be acceptable.
6) Justification for not submitting a new bioequivalence study, if appropriate.
33. Change in test procedure for an excipient Conditions Documentation Procedure

fulfilled
a) Minor changes to an approved test procedure 1, 2, 3, 4 1, 2 IA

to a
reagent

replacement or addition)
d) Deletion of a test procedure if an alternative 5 1 IA

test procedure is already authorized
Conditions
43
detected.

5) . An alternative test procedure is already authorised for the specification parameter and this
Documentation
34. Change in source of an excipient or reagent with Conditions Documentation Procedure

TSE risk to be to be supplied type
fulfilled
a) Change from TSE risk material to vegetable or synthetic origin:
1. For excipients or reagents used in the 1, 2 IB

manufacture of biological active substance or
a finished product containing a biological
active substance
2. For excipients or reagents not used in the 1 1 IA

manufacture of biological active substance or
a finished product containing a biological
active substance
b) Change or introduction of a TSE risk material II

or replacement of a TSE risk material from a
different TSE risk material, not covered by a
TSE certificate of suitability
Conditions
1) Excipient and finished product release and end of shelf-life specifications remain the same.
Documentation
1) Declaration from the manufacturer of the material that it is purely of vegetable or synthetic origin.
44
2) Study of equivalence of the materials and the impact on production of the final material and impact
on behavior (e.g. dissolution characteristics) of the finished product.
35. Change in synthesis or recovery of a non- Conditions Documentation Procedure

pharmacopeial excipient (when described in the to be to be supplied type
dossier) or a novel excipient fulfilled
a) Minor change in synthesis or recovery of a 1, 2 1, 2, 3, 4 IA

non-pharmacopeial excipient or a novel
excipient
b) The specifications are affected or there is a II

change in physicochemical properties of the
excipient which may affect the quality of the
finished product.
c) The excipient is a biological/immunological II

substance
Conditions
1) The synthesis and specifications are identical and there is no change in qualitative and
quantitative impurity profile (excluding residual solvents, provided they are controlled in
accordance with ICH / VICH limits), or in physicochemical properties.
2) Adjuvants are excluded.
Documentation
2) Batch analysis data (in a comparative tabulated format) of at least two batches (minimum pilot
scale) of the excipient manufactured according to the old and the new process.
3) Where appropriate, comparative dissolution profile data for the finished product of at least two
batches (minimum pilot scale). For herbal products, comparative disintegration data may be
acceptable.
4) Copy of approved and new (if applicable) specifications of the excipient.
45
d) Control of finished product

limits of the finished product to be to be supplied type
fulfilled

method

limits range
d) Deletion of a specification parameter which II

e) Addition or replacement(excluding biological 1, 2, 3, 4, 5, 7 IB

or immunological product) of a specification
parameter with its corresponding test method
f) Deletion of a non-significant specification 1, 2, 8 1, 2, 6 IA

parameter (e. g deletion of an obsolete
parameter such as odour and taste or
identification test for a colouring or flavouring
material)
g) Update of the dossier to comply with the 1, 2, 3, 4, 1, 2 IA

provisions of an updated general monograph of 7, 8
the Ph. Eur for the finished product
Conditions
specification limits (e.g. made during the procedure for the marketing authorization application or
a type II variation procedure).
6) The test method is not a biological/immunological/immunochemical method or a method using a

biological reagent for a biological active substance.
7) The change does not concern any impurities (including genotoxic) or dissolution.
46
8) The specification parameter or proposal for the specific dosage form does not concern a critical
parameter for example: assay, impurities (unless a particular solvent is definitely not used in the
manufacture of the finished product) any critical physical characteristics (hardness or friability for
uncoated tablets, dimensions, etc.) a test that is required for the particular dosage form in
accordance with the general monograph in an official pharmacopeia; any request for skip testing.
Documentation
otherwise justified) of the finished product for all specification parameters.
pilot batch complying with the current and proposed specification. For herbal products,
comparative disintegration data may be acceptable.
37. Change in test procedure for the finished product Conditions Documentation Procedure
fulfilled
a) Minor changes to an approved test 1, 2, 3, 4 1, 2 IA

procedure.

to a
reagent.

replacement or addition).
d) Deletion of a test procedure if an alternative 4 1 IA

method is already authorized.
e) Update of the test procedure to comply with 2, 3, 4, 5 1 IA

the updated general monograph in an official
pharmacopeia.
Conditions
47
and show that the updated test procedure is at least equivalent to the former test procedure.
detected.

a biological reagent. (does not include standard pharmacopoeial microbiological methods). -
5) The registered test procedure already refers to the general monograph of an official
pharmacopeia and any changes are minor in nature and require update of the technical dossier.
Documentation
current test and the proposed one are equivalent.; This requirement is not applicable in case of
38. Variations related to the introduction of real-time Conditions Documentation Procedure

release or parametric release in the manufacture of to be to be supplied type
the finished product fulfilled
II
48
e) Container closure system
39. Change in immediate packaging of the finished Conditions Documentation Procedure

product to be to be supplied type
fulfilled
a) Change in qualitative and quantitative composition
1. Solid pharmaceutical forms. 1, 2, 3 1, 2, 3, 4,5, 6 IAIN
2. Semi-solid and non-sterile liquid 1, 2, 3,4, 5, 6 IB

pharmaceutical forms.
3. Sterile medicinal products and biological/ II

immunological medicinal products.
4. The change relates to a less protective pack II

where there are associated changes in
storage conditions and/or reduction in shelf
life.
b) Change in the container type or addition of a new container
1. Solid, semi-solid and non-sterile liquid 1, 2, 3,4, 5, 6 , 7 IB

pharmaceutical forms.
2. Sterile medicinal products and biological/ II

immunological medicinal products.
3. Deletion of an immediate packaging that 4 1,8 IA

does not lead to the complete deletion of a
strength or pharmaceutical form
Conditions
1) The change only concerns the same packaging/container type (e.g. blister to blister).
2) The proposed packaging material must be at least equivalent to the approved material in respect
of its relevant properties.
3) Satisfactory results of the relevant stability studies have been started according to the GCC
stability guidelines and relevant stability parameters have been assessed in at least two pilot
scale or production scale batches for at least three months.
4) The remaining product presentation(s) must be adequate for the dosing instructions and
treatment duration as mentioned in the summary of product characteristics.
Documentation
49
2) Appropriate data on the new packaging (comparative data on permeability e.g. for O2, CO2
moisture).
3) Proof must be provided that no interaction between the content and the packaging material
occurs (e.g. no migration of components of the proposed material into the content and no loss
of components of the product into the pack). including confirmation that the material complies
with relevant pharmacopoeial requirements.
potentially outside specifications at the end of the approved shelf life with the proposed action.
6) Comparative table of the current and proposed immediate packaging specifications, if

applicable.
7) Samples of the new container/closure where applicable
8) Declaration that the remaining pack-size(s) is/are consistent with the dosage regimen and
duration of treatment and adequate for the dosing instructions as approved in the summary of
product characteristics.

limits of the immediate packaging of the finished to be to be supplied type
product fulfilled
a) Tightening of specification limits. 1, 2, 3, 4 1, 2 IA
b) Addition of a new specification parameter to 1, 2, 5 1, 2, 3, 4, 6 IA

the specification.
c) Addition or replacement of a specification 1, 2, 3, 4, 6 IB

parameter as a result of a safety or quality
issue.
d) Deletion of a non-significant specification 1, 2 1, 2, 5 IA

parameter (e. g deletion of an obsolete test).
Conditions
2) The change does not result from unexpected events arising during manufacture.
50
Documentation
4) Batch analysis data on two batches of the immediate packaging for all specification parameters.
5) Justification/risk-assessment showing that the parameter is non-significant or that it is obsolete.
41. Change in test procedure for the immediate Conditions Documentation Procedure
packaging of the finished product to be to be supplied type
fulfilled
a) Minor changes to an approved test procedure 1, 2, 3 1, 2 IA
b) Other changes to a test procedure (including 1, 3, 4 1, 2 IA

c) Deletion of a test procedure if an alternative 5 1 IA

Conditions
4) The active substance/finished product is not biological/immunological.
Documentation
includes a description of the analytical methodology and a summary of validation data.
51
an addition of a new test procedure .
42. Change in shape or dimensions of the container Conditions Documentation Procedure

or closure (immediate packaging) to be fulfilled to be supplied type
a) Non-sterile medicinal products 1, 2, 3 1, 2, 4 IA
b) The change in shape or dimensions concerns II

a fundamental part of the packaging
material, which may have a significant
impact on the delivery, use, safety or
stability of the finished product
c) Sterile medicinal products 1, 2, 3, 4 IB
Conditions
1) No change in the qualitative or quantitative composition of the container.
2) The change does not concern a fundamental part of the packaging material, which affects the
delivery, use, safety or stability of the finished product.
3) In case of a change in the headspace or a change in the surface/volume ratio, a satisfactory results
of the stability studies that have been started according to the GCC stability guidelines, and
relevant stability parameters have been assessed in at least two pilot scale or production scale
batches (three for biological/ immunological medicinal product) and at least three months (six
months for biological/immunological medicinal product).
Documentation
1) Replacement of the relevant pages of the dossier that are affected by the variation (including
description, detailed drawing and composition of the container or closure material).
2) Samples of the current and new container/closure where applicable .
3) Re-validation studies have been performed in case of sterile products terminally sterilized and
the summary of validation data is required.
4) In case of a change in the headspace or a change in the surface/volume ratio, the following should
be submitted:
• The results of stability studies that have been carried out according to the GCC stability
guidelines, on the relevant stability parameters, on at least two pilot or production scale
batches (three batches for biological/immunological medicinal product) for at least three
months (six months for biological/immunological medicinal product).
• A letter of commitment to finalize the stability studies and the data must be submitted
potentially outside specifications at the end of the approved shelf life with the proposed
action.
52
43. Change in pack size of the finished product Conditions Documentation Procedure
fulfilled
a) Change in the number of units (e.g. tablets, 1, 2, 3, 4, 5, 6, 7 IB

ampoules, etc.) in a pack
b) Deletion of a pack size(s) 1 1, 2 IA
c) Change in the fill weight/fill volume of sterile II

multi-dose (or single-dose, partial use)
medicinal products, and biological/
immunological multi-dose medicinal
products.
d) Change in the fill weight/fill volume of non- 1, 2, 3, 4, 5, 6, 7 IB

parenteral multi-dose (or single-dose, partial
use) products
Conditions
1) The remaining product presentation(s) must be adequate for the dosing instructions and
treatment duration as mentioned in the Summary of Product Characteristics.
Documentation
1) Replacement of the relevant pages of the dossier that are affected by the variation, including
revised product information as appropriate.
2) Justification for the new/remaining pack-size, showing that the new/remaining size is/are
consistent with the dosage regimen and duration of use as approved in the summary of product
characteristics.
3) Certificate of a Pharmaceutical Product (CPP) stating the new pack size.
5) A letter of commitment to finalize the stability study and to report any out-of-specification
results immediately to the authority.
6) A recent and official price certificate by the company and legalized by the Saudi Embassy in the
country of origin (indicating the new pack size).
7) Samples of the finished product.
Note: for 40.a), New pack size should be consistent with the posology and treatment duration as approved
in the summary of product characteristics, and the primary packaging material remains the same.
53
44. Change in any part of the (primary) packaging Conditions Documentation Procedure
material not in contact with the finished product to be to be supplied type
formulation (such as color of flip-off caps, color fulfilled
code rings on ampoules, change of needle shield
(different plastic used)
a) Change that affects the product information 1 1 IAIN
b) Change that does not affect the product 1 1 IA

information
Conditions
1) The change does not concern a part of the packaging material, which affects the delivery, use,
safety or stability of the finished product.
Documentation
45. Change in supplier of packaging components or Conditions Documentation Procedure

devices (when mentioned in the dossier) to be to be supplied type
fulfilled
a) Deletion of a supplier 1 1 IA
b) Replacement or addition of a supplier 1, 2, 3, 4 1, 2, 3 IA
c) Any change to suppliers of spacer devices II

for metered dose inhalers
Conditions
1) No deletion of packaging component or device.
2) The qualitative and quantitative composition of the packaging components/device and design
specifications remain the same.
3) The specifications and quality control method are at least equivalent.
4) The sterilization method and conditions remain the same, if applicable.
Documentation
2) For devices for medicinal products for human use, proof of CE marking.
3) Comparative table of current and proposed specifications, if applicable.
54
46. Change in the packaging design of the primary Conditions Documentation Procedure
and/or Secondary packaging not in contact with to be to be supplied type
the finished product formulation fulfilled
1,2,3 IB
Documentation
2) The submitted documents should clearly outline the “present” and “proposed” mock-up.
3) Sample of the artwork
47. Addition of the electronic patient leaflet Conditions Documentation Procedure

(statement and barcode) to the outer package to be to be supplied type
artwork (Mock-up) fulfilled
1 1,2,3 IA
Conditions
1) This addition should have no impact to the artwork (Mock-up) design, size, shape, or color.
Documentation
2) The submitted documents should clearly outline the “present” and “proposed” mock-up.
3) Electronic patient leaflet certificate.
55
f) Stability
48. Change in the shelf-life or storage conditions of Conditions Documentation Procedure

the finished product to be to be supplied type
fulfilled
a) Reduction of the shelf-life of the finished product
1. As packaged for sale 1 1, 2, 3 IAIN
2. After first opening
3. After dilution or reconstitution
b) Extension of the shelf-life of the finished product
1. As packaged for sale (supported by real 1, 2, 3 IB

time data)
2. After first opening (supported by real

time data)
3. After dilution or reconstitution

(supported by real time data)
4. Extension of the shelf-life of a 1, 2, 3 IB

product in accordance with an approved
stability protocol
c) Change in storage conditions of the finished 1, 2, 3 IB

product or the diluted/reconstituted product
d) Change in storage conditions for biological II

medicinal products, when the stability studies
have not been performed in accordance with
an approved stability protocol
e) Change to an approved stability protocol 1, 2 1, 2, 4 IA
Conditions
2) The change does not concern a widening of the acceptance criteria in the parameters tested, a
removal of stability indicating parameters or a reduction in the frequency of testing.
Documentation
56
2) Recent real time stability studies (covering the entire shelf-life) conducted according to the GCC
stability guidelines and relevant stability parameters have been assessed on at least two pilot
scale batches* of the finished product in the authorized packaging material and/or after first
opening or reconstitution (in-use stability), as appropriate; where applicable, results of
appropriate microbiological testing should be included.
3) Copy of approved end of shelf life finished product specification and where applicable,
specifications after dilution/reconstitution or first opening.
4) Justification for the proposed change(s).
Note: for Documentation 2) Pilot scale batches can be accepted with a commitment to verify the shelf
life on production scale batches
g) Design Space:
Introduction of a new design space or Conditions
49. extension of an approved design space for the to be
to be supplied type
finished product, concerning: fulfilled
c) One unit operation in the manufacturing

process of the finished product including
1, 2, 3 II
the resulting in- process controls and/or
test procedures
d) Test procedures for

excipients/intermediates and/or the 1, 2, 3 II
finished product
Documentation
4) The design space has been developed in accordance with the relevant scientific guidelines.
Results from product, process and analytical development studies (e.g. interaction of the
different parameters forming the design space have to be studied, including risk assessment
and multivariate studies, as appropriate) demonstrating where relevant that a systematic
mechanistic understanding of material attributes and process parameters to the critical quality
attributes of the finished product has been achieved.
5) Description of the Design space in tabular format, including the variables (material attributes
and process parameters, as appropriate) and their proposed ranges.
57
II.3 CEP/TSE/Monograph
50. Submission of a new or updated certificate of Conditions Documentation Procedure
suitability or deletion of certificate of suitability: to be to be supplied type
fulfilled
• For an active substance.
• For a starting material/reagent/intermediate

used in the manufacturing process of the
active substance.
• For an excipient.
a) Certificate of Suitability
1. New certificate from an already approved 1, 2, 3, 4, 1, 2, 3, 4, 5 IAIN

manufacturer. 5, 8, 11
2. Updated certificate from an already 1, 2, 3, 4, 8 1, 2, 3, 4, 5 IA

approved Manufacturer.
3. New certificate from a new manufacturer 1, 2, 3, 4, 1, 2, 3, 4, 5 IAIN

(replacement or addition). 5, 8, 11
4. Deletion of certificates (in case multiple 10 3 IA

certificates exist per material)
5. New certificate for a non-sterile active 1, 2, 3, 4, 5, 6 IB

substance that is to be used in a sterile
medicinal product, where water is used in
the last steps of the synthesis and the
material is not claimed to be endotoxin free
b) TSE Certificate of suitability for an active substance/starting

material/reagent/intermediate/or excipient.
1. New certificate for an active substance from 3, 5, 6, 11 1, 2, 3, 4, 5 IAIN

a new or an already approved manufacturer.
2. New certificate for a starting 3, 6, 9 1, 2, 3, 4, 5 IA

material/reagent/intermediate/or excipient
from a new or an already approved
manufacturer.
3. Updated certificate from an already 7, 9 1, 2, 3, 4, 5 IA

approved manufacturer.
4. Deletion of certificates (in case multiple 10 3 IA

certificates exist per material)
5. New/updated certificate from an already II

approved/new manufacturer using
materials of human or animal origin for
which an assessment of the risk with respect
58
to potential contamination with
adventitious agents is required
Conditions
1) The finished product release and end of shelf-life specifications remain the same.
2) Unchanged (excluding tightening) additional specifications for impurities (excluding residual

solvents, provided they are in compliance with ICH/VICH) and product specific requirements
(e.g. particle size profiles, polymorphic form), if applicable.
3) The manufacturing process of the active substance, starting material/reagent/intermediate does

not include the use of materials of human or animal origin for which an assessment of viral
safety data is required.
4) For active substance only, it will be tested immediately prior to use if no retest period is included
in the Certificate of Suitability or if data to support a retest period is not already provided in the
dossier.
5) The active substance/starting material/reagent/intermediate/excipient is not sterile.
6) The substance is not included in a veterinary medicinal product for use in animal species
susceptible to TSE.
7) For veterinary medicinal products: there has been no change in the source of material.
8) For herbal active substances: the manufacturing route, physical form, extraction solvent and
drug extract ratio (DER) should remain the same.
9) If Gelatine manufactured from bones is to be used in a medicinal product for parenteral use, it
should only be manufactured in compliance with the relevant country requirements.
10) At least one manufacturer for the same substance remains in the dossier.
11) If the active substance is a not a sterile substance but is to be used in a sterile medicinal product
then according to the CEP it must not use water during the last steps of the synthesis or if it does
the active substance must also be claimed to be free from bacterialendotoxins.
Documentation
1) Copy of the current (updated) Certificate of Suitability.
4) Where applicable, a document providing information of any materials falling within the scope
of the note for guidance on minimizing the risk of transmitting animal spongiform
encephalopathy agents via human and veterinary medicinal products or an equivalent guideline
of the ICH region and associated countries including those which are used in the manufacturer
of the API. The following information should be included for each such material: name of
manufacturer, species and tissues from which the material is a derivative, country of origin of
the source animals and its use.
59
5) Where applicable, for active substance, a declaration by the Qualified Person (QP) of each of
the manufacturing authorisation holders listed in the application where the active substance is
used as a starting material and a declaration by the QP of each of the manufacturing authorisation
holders listed in the application as responsible for batch release. These declarations should state
that the active substance manufacturer(s) referred to in the application operate in compliance
with the detailed guidelines on good manufacturing practice for starting materials. The
manufacture of intermediates also require a QP declaration, while as far as any updates to
certificates for active substances and intermediates are concerned, a QP declaration is only
required if, compared to the previously registered version of the certificate, there is a change to
the actual listed manufacturing sites.
6) Suitable evidence to confirm compliance of the water used in the final steps of the synthesis of
the active substance with the corresponding requirements on quality of water for pharmaceutical
use.
51. Change to comply with reference pharmacopeia Conditions Documentation Procedure

fulfilled
a) Change of specification(s) of a former non-pharmacopeial substance to comply with

reference pharmacopeia
1. Active substance 1, 2, 3, 4, 5 1, 2, 3, 4 IAIN
2. Excipient/active substance starting material 1, 2, 4 1, 2, 3, 4 IA
b) Change to comply with an update of the 1, 2, 4, 5 1, 2 , 3, 4 IA

relevant monograph of the reference
pharmacopeia, or changing specifications from
in-house to reference pharmacopeia.
c) Change in specifications from a reference 1, 4, 5 1 , 2, 3, 4 IA

pharmacopeia to another reference
pharmacopeia.
Conditions
1) The change is made exclusively to comply with the pharmacopoeia. All the tests in the
specification need to correspond to the pharmacopoeial standard after the change, except any
additional supplementary tests.
2) Additional specifications to the pharmacopoeia for product specific properties are unchanged (e.g.
particle size profiles, polymorphic form).
3) No significant changes in qualitative and quantitative impurities profile unless the specifications
are tightened.
4) Additional validation of a new or changed pharmacopoeial method is not required.
5) For herbal active substances: the manufacturing route, physical form, extraction solvent and drug
extract ratio (DER) should remain the same.
60
Documentation
3) Batch analysis data (in a comparative tabulated format) on two production batches of the relevant
substance for all tests in the new specification and additionally, where appropriate, comparative
dissolution profile data for the finished product on at least one pilot batch. For herbal medicinal
products, comparative disintegration data may be acceptable.
4) Data to demonstrate the suitability of the monograph to control the substance, e.g. a comparison
of the potential impurities with the transparency note of the monograph.
61
II.4 PMF/VAMF
52. Inclusion of a new, updated or amended Plasma Conditions Documentation Procedure
Master File in the marketing authorization dossier to be to be supplied type
of a medicinal product. fulfilled
a) First-time inclusion Plasma Master File II

affecting the properties of the finished product
b) First-time inclusion of a new Plasma Master 1, 2, 3, 4 IB
File not affecting the properties of the finished
product
c) Inclusion of an updated/amended Plasma 1, 2, 3, 4 IB

Master File when changes affect the properties
of the finished product
d) Inclusion of an updated/amended Plasma 1 1, 2, 3, 4 IA

Master File when changes do not affect the
properties of the finished product
Conditions
1) The new, update or amended Plasma Master File has been granted a certificate of compliance from
the competent authority
Documentation
1) Letter declaring that:
• The PMF certificate, evaluation report and PMF are fully applicable to the authorized product,
• PMF holder has submitted the PMF certificate, evaluation report and PMF dossier to the
MAH (where the MAH is different from the PMF holder),
• The PMF certificate, evaluation report and PMF dossier replace the previous PMF
documentation for this Marketing Authorization.
2) Plasma Master File (PMF) certificate, evaluation report and PMF dossier (or amended parts).
3) An expert statement outlining all the changes introduced with the certified PMF and evaluating
their potential impact on the finished product.
4) The submitted documents should clearly outline the “present” and “proposed” PMF certificate.
62
53. Inclusion of a new, updated or amended Vaccine Conditions Documentation Procedure
Antigen Master File in the marketing to be to be supplied type
authorization dossier of a medicinal product. fulfilled
a) First-time inclusion Vaccine Antigen Master II

File affecting the properties of the finished
product
b) Inclusion of an updated/amended Vaccine 1, 2, 3, 4 IB

Antigen Master File when changes affect the
properties of the finished product
c) Inclusion of an updated/amended Vaccine 1 1, 2, 3, 4 IA

Antigen Master when changes do not affect
the properties of the finished product
Conditions
1) The new, update or amended Vaccine Antigen Master File has been granted a certificate of
compliance from the competent authority.
Documentation
1) Letter declaring that:
•
The VAMF certificate, evaluation report and VAMF are fully applicable to the authorized
product,
• VAMF holder has submitted the VAMF certificate, Evaluation report and VAMF dossier
to the MAH (where the MAH is different from the VAMF holder),
• The VAMF certificate, evaluation report and VAMF dossier replace the previous VAMF
documentation for this Marketing Authorization.
2) VAMF certificate, evaluation report and VAMF dossier (or amended parts).
3) An expert statement outlining all the changes introduced with the certified VAMF and
evaluating their potential impact on the finished products.
4) The submitted document should clearly outline the “present” and “proposed” VAMF certificate.
63
II.5 Drug containing medical device
54. Change of a measuring or administration device Conditions Documentation Procedure
fulfilled
a) Addition or replacement of a device which is

not an integrated part of the primary
packaging
1. Spacer device for metered dose inhalers II
2. Certified Device (for example with CE 1, 2, 3, 6, 7 1, 2 IAIN

marking)
3. Non certified Device for veterinary 1, 3 IB

products only
b) Deletion of a device 4, 5 1, 4 IAIN
c) Addition or replacement of a device which is II

an integrated part of the primary packaging
Conditions
1) The proposed measuring or administration device must accurately deliver the required dose for the product
concerned in line with the approved posology and results of such studies should be available.
2) The new device is compatible with the medicinal product.
3) The change should not lead to substantial amendments of the product information.
4) The medicinal product can still be accurately delivered.
5) For veterinary medicinal products, the device is not crucial for the safety of the person administering the product.
6) The medical device is not used as a solvent of the medicinal product.
7) If a measuring function is intended the certification should cover the measuring function.
Documentation
1) Replacement of the relevant pages of the dossier that are affected by the variation (including
description, detailed drawing and composition of the device material and supplier where
appropriate).
2) Proof of certification.
3) Data to demonstrate accuracy, precision and compatibility of the device.
4) Justification for the deletion of the device.
64
55. Change in specification parameters and/or limits Conditions Documentation Procedure
of a measuring or administration device for to be to be supplied type
veterinary medicinal products. fulfilled
b) Addition of a new specification parameter to 1, 2, 5 1, 2, 3, 4, 6 IA

the specification
c) Widening of the approved specifications II

limits, which has a significant effect on the
overall quality of the device
d) Deletion of a specification parameter that II

has a significant effect on the overall quality
of the device
e) Addition of a specification parameter as a 1, 2, 3, 4, 6 IB

result of a safety or quality issue
f) Deletion of a non-significant specification 1, 2 1, 2, 5 IA

parameter (e. g deletion of an obsolete test)
Conditions
specification limits (e.g. made during the procedure for the marketing authorizationapplication
2) The change should not be the result of unexpected events arising during manufacture.
Documentation
3) Details of any new analytical method and summary of validation data.
4) Batch analysis data on two production batches for all tests in the new specification.
6) Justification for the new specification parameter and the limits.
65
56. Change in test procedure of a measuring or Conditions Documentation Procedure
administration device for veterinary medicinal to be to be supplied type
products fulfilled
a) Minor change to an approved test procedure 1, 2, 1, 2 IA
b) Other changes to a test procedure (including 1, 3 1, 2 IA

c) Deletion of a test procedure if an alternative 4 1 IA

Conditions
2) The method of analysis should remain the same.
procedure has not been added through IA/IA(IN) notification.
Documentation
1) Replacement of the relevant pages of the dossier that are affected by the variation which includes
a description of the analytical methodology and a summary of validation data.
66
III. Safety, Efficacy, Pharmacovigilance Changes
III. 1 Human and veterinary medicinal products

57. Change in the summary of product characteristics, Conditions Documentation Procedure
labeling and patient information leaflet of a to be to be supplied type
generic/hybrid/biosimilar medicinal product fulfilled
following assessment of the same change for the
reference product.
a) Implementation of change(s) for which no new 1, 2 IB

additional data are submitted by the MAH
b) Implementation of change(s) which require to II

be further substantiated by new additional
data to be submitted by the MAH, or the
change has not been approved for the
reference product by thecompetent authority.
Documentation
1) Attached to the cover letter of the variation application: the competent authority
request, if available.
2) Revised product information.
58. Change(s) in the summary of product Conditions Documentation Procedure

characteristics, labeling and patient information to be to be supplied type
leaflet related to an urgent safety restriction, fulfilled
class labeling, a periodic safety update report,
risk management plan, or follow up
measure/specific obligation.
a) Implementation of change(s) requested by GCC or any local authority within GCC

following the assessment of an urgent safety restriction, class labeling, a periodic safety
update report, risk management plan, or follow up measure/specific obligation.
1. Implementation of agreed wording 1, 2 IB

change(s) for which no new additional
data are submitted by the MAH
2. Implementation of change(s) which II

require to be further substantiated by new
additional data to be submitted by the
MAH
b) Change(s) proposed by the MAH with II

submission of a periodic safety update
report, risk management plan, follow up
measures/specific obligations.
67
Documentation
1) Attached to the cover letter of the variation application: the competent authority request with
attached relevant assessment report, if available.
Note: MAHs are reminded that once new information becomes available (e.g. new study data) which might
entail the variation of the MA, this should be submitted as a variation.
59.Variations related to significant modifications of Conditions Documentation Procedure

the Summary of Product Characteristics due in to be to be supplied type
particular to new quality, pre-clinical, clinical or fulfilled
pharmacovigilance data
II
60. Change(s) to therapeutic indication(s) Conditions Documentation Procedure

fulfilled
a) Addition of a new therapeutic indication or II

modification of an approved one
b) Deletion of a therapeutic indication II
61. Deletion of: Conditions Documentation Procedure

fulfilled
a) a pharmaceutical form 1, 2 IB
b) a strength 1, 2 IB
Documentation
1) Declaration that the remaining product presentation(s) are adequate for the dosing instructions
and treatment duration as mentioned in the summary of product characteristics.
68
62. Change(s) to a PSMF following the assessment of Conditions Documentation Procedure
the same change(s) to the same DDPS in relation to to be to be supplied type
another medicinal product of the same MAH. fulfilled
1 1 IA
Conditions
1) The same changes to the PSMF are introduced for all medicinal products of the
same MAH (same final PSMF version)
Documentation
1) Latest approved version of the PSMF.
69
III. 2 Veterinary medicinal product - Specific Changes
63.Variations concerning a change to or addition of Conditions Documentation Procedure
a non-food producing target species. to be to be supplied type
fulfilled
II
64. Deletion of a food producing or non-food producing Conditions Documentation Procedure

target species. to be to be supplied type
fulfilled
a) Deletion as a result of a safety issue II
b) Deletion not resulting from a safety issue 1, 2 IB
Documentation
1) Justification for the deletion of the target species.
65. Changes to the withdrawal period for a Conditions Documentation Procedure

veterinary medicinal product to be to be supplied type
fulfilled
II
66.Variations concerning the replacement or Conditions Documentation Procedure

addition of a serotype, strain, antigen or to be to be supplied type
combination of serotypes, strains or antigens for a fulfilled
veterinary vaccine against avian influenza, foot-
and-mouth disease or bluetongue.
II
67.Variations concerning the replacement of a strain Conditions Documentation Procedure

for a veterinary vaccine against equine influenza. to be to be supplied type
fulfilled
II
70
68.Changes to the labeling or the package leaflet Conditions Documentation Procedure
which are not connected with the summary of to be to be supplied type
product characteristics. fulfilled
a) Administrative information concerning the 1 IAIN

holder’s representative
b) Other changes. 1 IB
Conditions
None
Documentation
69. Introduction of a new Pharmacovigilance system Conditions Documentation Procedure

fulfilled
a) Which has not been assessed by the II

relevant national competent authority for
another product of the same MAH
b) Which has been assessed by the relevant 1, 2 IB

national competent authority for another
product of the same MAH
Documentation
1) The new Detailed Description of the Pharmacovigilance System) DDPS(
2) Reference to the application/procedure and product in which the DDPS was assessed previously
71
IV. PMF/VAMF
70. Change in the name and/or address of the VAMF Conditions Documentation Procedure
certificate holder to be to be supplied type
fulfilled
1 1 IAIN
Conditions
1) The VAMF certificate holder must remain the same legal entity.
Documentation
1) A formal document from a relevant official body (e.g. Chamber of Commerce) in which the new
name or new address is mentioned.
71. Change in the name and/or address of the PMF Conditions Documentation Procedure
certificate holder to be to be supplied type
fulfilled
1 1 IAIN
Conditions
1) The PMF certificate holder must remain the same legal entity.
Documentation
1) A formal document from a relevant official body (e.g. Chamber of Commerce) in which the new
name or new address is mentioned.
72. Change or transfer of the current PMF certificate Conditions Documentation Procedure
holder to a new PMF certificate holder, i.e. to be to be supplied type
different legal entity fulfilled
1, 2, 3, 4, 5, 6 IAIN
Documentation
1) A document including the identification (name and address) of the current PMF Holder
(transferor) and the identification (name and address) of the person to whom the transfer is to be
granted (transferee) together with the proposed implementation date — signed by both
companies.
2) Copy of the latest PMF Certificate page ‘EMA Plasma Master File (PMF) Certificate of
compliance with Community legislation’.
72
3) Proof of establishment of the new holder (Excerpt of the commercial register and the English
translation of it) — signed by both companies.
4) Confirmation of the transfer of the complete PMF documentation since the initial PMF
certification to the transferee — signed by both companies.
5) Letter of Authorisation including contact details of the person responsible for communication
between the competent authority and the PMF holder — signed by the transferee.
6) Letter of Undertaking to fulfil all open and remaining commitments (if any) — signed by the
transferee.
73. Change in the name and/or address of a blood Conditions Documentation Procedure
establishment including blood/plasma collection to be to be supplied type
centers fulfilled
1, 2 1, 2, 3, IA
Conditions
1) The blood establishment shall remain the same legal entity.
2) The change shall be administrative (e.g. merger, take over); change in the name of the blood
establishment/ collection centre provided the blood establishment shall remain the same.
Documentation
1) Signed declaration that the change does not involve a change of the quality system within the
blood establishment.
2) Signed declaration that there is no change in the list of the collection centers.
3) Updated relevant sections and annexes of the PMF dossier.
74. Replacement or addition of a blood/plasma Conditions Documentation Procedure

collection establishment within a blood to be to be supplied type
establishment already included in the PMF. fulfilled
1, 2, 3 IB
Documentation
1) Epidemiological data for viral markers related to the blood/plasma collection centre covering the
last 3 years. For newly opened centre(s) or in case no data are yet available, a declaration that
epidemiological data will be provided at the time of the next annual update(s).
2) Statement that the centre is working under the same conditions as the other centers belonging to
the blood establishment, as specified in the standard contract between blood establishment and
PMF holder.
73
75. Deletion or change of status (operational/non- Conditions Documentation Procedure
operational) of establishment(s)/centre(s) used for to be to be supplied type
blood/plasma collection or in the for testing fulfilled
donations and plasma pools.
1, 2 1 IA
Conditions
1) The reason for deletion or change of status should not be related to a GMP issue.
2) The establishments(s)/centre(s) should comply with the legislation in terms of inspections in case
of change of status from non-operational to operational.
Documentation
76. Addition of a new blood establishment for the Conditions Documentation Procedure
collection of blood/plasma not included in the to be to be supplied type
PMF fulfilled
II
77. Replacement or addition of a blood centre for Conditions Documentation Procedure

testing donations and/or plasma pools within an to be to be supplied type
establishment already included in the PMF. fulfilled
1, 2 IB
Documentation
1) Statement that the testing site is performed following the same SOPs and/or test methods as the
already accepted.
78.Addition of a new blood establishment for testing Conditions Documentation Procedure

of donations and/or plasma pool not included in to be to be supplied type
the PMF fulfilled
II
74
79. Replacement or addition of a new blood Conditions Documentation Procedure
establishment or centre(s) in which storage of to be to be supplied type
plasma is carried out fulfilled
1, 2 IB
Documentation
1) Statement that the storage centre is working following the same SOPs as the already accepted
establishment.
80. Deletion of a blood establishment or centre(s) in Conditions Documentation Procedure

which storage of plasma is carried out to be to be supplied type
fulfilled
1 1 IA
Conditions
1) The reason for deletion should not be related to a GMP issues.
Documentation
81. Replacement or addition of an organization Conditions Documentation Procedure

involved in the transport of plasma. to be to be supplied type
fulfilled
1 IB
Documentation
1) Updated relevant sections and annexes of the PMF dossier, including a list of all the blood
establishments using this transport organization, a summary of the system in place to ensure that
the transport is performed under appropriate conditions (time, temperature and GMP compliance)
and confirmation that transport conditions are validated.
75
82. Deletion of an organization involved in the Conditions Documentation Procedure
transport of plasma to be to be supplied type
fulfilled
1 1 IA
Conditions
1) The reason for deletion should not be related to GMP issues.
Documentation
83. Addition of a CE-marked test kit to test individual Conditions Documentation Procedure
donations as a new test kit or as a replacement of to be to be supplied type
an existing test kit fulfilled
1 1, 2 IA
Conditions
1) The new test kit is CE-marked.
Documentation
1) List of testing site(s) where the kit is used.
2) Updated relevant sections and annexes of the PMF dossier, including updated information on
testing as requested in the "Guideline on the scientific data requirements for a PMF".
84. Addition of a non-CE marked test kit to test Conditions Documentation Procedure
individual donations as a new test kit or as a to be to be supplied type
replacement of an existing test kit fulfilled
a) The new test kit has not previously been II

approved in the PMF for any blood centre
for testing of donations
b) The new test kit has been approved in the 1, 2 IA

PMF for other blood centre(s) for testing
of donations
Documentation
1) List of testing centre(s) where the kit is currently used and a list of testing centre(s) where the kit
will be used.
2) Updated relevant sections and annexes of the PMF dossier, including updated information on
testing as requested in the "Guideline on the scientific data requirements for a PMF".
76
85. Change of kit/method used to test pools (antibody Conditions Documentation Procedure
or antigen or NAT test). to be to be supplied type
fulfilled
II
86. Introduction or extension of inventory hold Conditions Documentation Procedure

procedure. to be to be supplied type
fulfilled
1 1 IA
Conditions
1) The inventory hold procedure is a more stringent procedure (e.g. release only after retesting of
donors).
Documentation
1) Updated relevant sections of the PMF dossier, including the rationale for introduction or
extension of inventory hold period, the sites where the inventory hold takes place and for changes
to procedure, a decision tree including new conditions.
87. Removal of inventory hold period or reduction in Conditions Documentation Procedure

its length. to be to be supplied type
fulfilled
1 IB
Documentation
1) Updated relevant sections of the PMF dossier.
88. Replacement or addition of blood containers (e.g. Conditions Documentation Procedure

bags, bottles) to be to be supplied type
fulfilled
a) The new blood containers are CE- 1, 2 1 IA

marked
b) The new blood containers are not CE- 1 II

marked
Conditions
1) The container is CE-marked.
2) The quality criteria of the blood in the container remain unchanged.
77
Documentation
1) Updated relevant sections and annexes of the PMF dossier, including the name of container,
manufacturer, anticoagulant solution specification, confirmation of CE-mark and the name of the
blood establishments where the container is used.
89. Change in storage / transport Conditions Documentation Procedure

fulfilled
a) storage and/or transport conditions 1 1 IA
b) maximum storage time for the plasma 1, 2 1 IA
Conditions
1) The change should tighten the conditions and be in compliance with Ph. Eur. requirements for
Human Plasma for Fractionation.
2) The maximum storage time is shorter than previously.
Documentation
1) Updated relevant sections and annexes of the PMF dossier, including detailed description of the
new conditions, confirmation of validation of storage/transport conditions and the name of the
blood establishment(s) where the change takes place (if relevant).
90. Introduction of test for viral markers when this Conditions Documentation Procedure
introduction will have significant impact on the to be to be supplied type
viral risk fulfilled
assessment.
II
91. Change in the plasma pool preparation (e.g. Conditions Documentation Procedure
manufacturing method, pool size, storage of to be to be supplied type
plasma pool fulfilled
samples)
1 IB
Documentation
1) Updated relevant sections of the PMF dossier.
92. Change in the steps that would be taken if it is Conditions Documentation Procedure
found to be to be supplied type
fulfilled
retrospectively that donation(s) should have been
78
excluded from processing (“look-back”
procedure).
II
79
7. Appendix 2: Changes that make a new application necessary
Examples for changes that make a new application necessary include but are not
limited to the following:
1. Changes to the API, for example:
• Change of the API to a different API;
• Inclusion of an additional API in a multi-component product;
• Removal of one API from a multi-component product;
• Change in the dose of one or more APIs.
2. Changes to the pharmaceutical form/dosage form, for example:
• Change from an immediate-release product to a slow- or delayed-release dosage

form and vice versa;
• Change from a liquid to a powder for reconstitution, or vice versa.
• A change from multi-dose to single-dose or vice-versa (both for addition or

replacement).
3. Changes to the strength.
4. A change or addition of route of administration.
5. The addition or replacement of measuring or administration device being an integrated

part of the primary packaging that results in a change to the strength, pharmaceutical
form or route of administration of the product.
6. Other changes specific to veterinary medicinal products to be administered to food-

producing animals; change or addition of target species.
80
8. Appendix 3: Requirements for addition/change to API suppliers:
1. Addition/change to an API supplier that has already been submitted:
Requirements:
1. A declaration letter indicating that the DMF of the new API supplier has been
evaluated by GHC or SFDA during the last five years and no changes have
been made since that time.
2. Section (3.2.P) :
A letter of commitment to immediately initiate accelerated and long term
(covering shelf life) stability studies on at least one production batch of
the finished product according to the GCC guidelines using API from the
new supplier and submit stability data immediately to the authority only
in case of any out of specification results (OOS) or potentially outside
specifications at the end of the approved shelf life along with the proposed
action.
Where appropriate, comparative dissolution profile data for the finished
product on at least one pilot batch containing the active substance from
both the current and proposed sites. For herbal products, comparative
2. Addition/change to an API supplier where a Certificate of Suitability (CEP)

is available:
Requirements:
1. Section (3.2.S):
The applicant should submit:
- A valid Certificate of Suitability (CEP) (including any annexes) where
the declaration of access for the CEP should be duly filled out by the
CEP holder.
- written assurance that no significant changes in the manufacturing
method have taken place following the granting of certificate or its
last revision.
- 3.2.S.1.3 General properties.
- 3.2.S.3.1 Elucidation of structure and other characteristics.
- 3.2.S.4.1 Specification from both API manufacturer and the finished
product manufacturer.
81
- 3.2.S.4.4 Batch analysis from both API manufacturer and the finished
product manufacturer.
- 3.2.S.7 Stability.
2. Section (3.2.P):
action.
3. Addition/change to an API supplier where no Certificate of Suitability (CEP)

is available:
Requirements:
1. Section (3.2.S):
Full details of the chemistry, manufacturing process, quality controls
during manufacturing and process validation for the drug substance may
be submitted as DMF.
2. Section (3.2.P):
action.
82
− Abbreviations
API Active Pharmaceutical Ingredient.
ATC Anatomical Therapeutic Chemical (ATC) Classification.
CEP Certificate of Suitability.
DDPS Detailed Description of Pharmacovigilance System.
DER Drug Extract Ratio.
DMF Drug Master File.
ICH International Conference on Harmonization.
INN International Nonproprietary Name.
IPC In-Process Control.
MAH Marketing Authorization Holder.
PMF Plasma Master File.
QP Qualified Person.
SFDA Saudi Food and Drug Authority.
TSE Transmissible Spongiform Encephalopathy.
VAMF Vaccine Antigen Master File.
WHO World Health Organization.
NAT Nucleic Acid Testing.
Vet Veterinary.
VICH International Cooperation on Harmonization of Technical Requirements for
Registration of Veterinary Medicinal Products.
MA Marketing Authorization.
QPPV Qualified Person for Pharmacovigilance.
PSURs Periodic Safety Update Reports.
ICSRs Individual Case Safety Reports.
CV Curriculum Vitae.
GMP Good Manufacturing Practice.
SOPs Standard Operating Procedures.
GHC Gulf Health Council
83
− References
• Guidelines on the details of the various categories of variations, Regulation (EC) No

1234/2008 article 4(1)(a).
84

GCC - New Variation Guideline

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Date of implementation 21/05/2023

II. Quality Changes............................................................................................................15

II.1 Active substance .............................................................................................................15

b) Control of active substance.............................................................................................21

c) Container closure system ................................................................................................24

II.2 Finished product ............................................................................................................28

a) Description and composition ..........................................................................................28

c) Control of excipients ......................................................................................................42

d) Control of finished product.............................................................................................46

e) Container closure system ................................................................................................49

II.3 CEP/TSE/Monograph ...................................................................................................58

II.4 PMF/VAMF ...................................................................................................................62

II.5 Drug containing medical device ....................................................................................64

III. Safety, Efficacy, Pharmacovigilance Changes ...........................................................67

III. 1 Human and veterinary medicinal products ..............................................................67

III. 2 Veterinary medicinal product - Specific Changes ...................................................70

7. Appendix 2: Changes that make a new application necessary .........................................80

An application for Variation to a Marketing Authorization should always be

Applicants should present a summary of the intended change in tabular form in

A justification for the introduction of the change should always follow.

− Some documents such as certificate of analysis (COA), specification sheet, and

Applicants should be aware that deficient documentation can lead to rejection of

− Type IA: Such minor variations do not require prior approval

In order to facilitate the classification of variation or post-market changes, examples

Appendix 3 Requirements for addition/change to an API suppliers.

a) Change in the name and/or address of the IAIN

b) Transfer the product to new marketing

3) Copy of the agreement

4) Certificate of a Pharmaceutical Product (CPP)

2. Remove agent name from the artwork (Mock-up) Conditions

1) Samples of the artwork.

4. Change in name of the active substance Conditions Documentation Procedure

1) The active substance shall remain the same.

1) Proof of acceptance by WHO or copy of the INN list.

5. Change in the name and/or address of a Conditions Documentation Procedure

3) In case of a drug master file (DMF), an updated “letter of access”.

6. Change in the name and/or address of a Condition Documentatio Procedure

a) Manufacturer responsible for batch release 1 1, 2 IAIN

1) Copy of the modified manufacturing authorization, if available; or a formal document from a

7. Change in ATC Code /ATC Vet Code Conditions Documentation Procedure

1) Change following granting of or amendment to ATC Code by WHO/ATC Vet Code.

2) The deletion should not be due to critical deficiencies concerning manufacturing.

II.1 Active substance

9. Change in the manufacturer of a starting Conditions Documentation Procedure

a) The proposed manufacturer is part of the 1, 2, 3, 4, 5, 6, 7 IB

b) Introduction of a manufacturer of the active II

c) The proposed manufacturer uses a II

d) New manufacturer of material for which an II

e) The change relates to a biological active II

f) Changes to quality control testing 1, 2 1, 5 IA

g) Addition of an alternative sterilisation site for 1, 2, 4, 5, 8 IB

h) Introduction of a new manufacturer of the II

j) Changes to quality control testing II

k) New storage site of Master Cell Bank and/or 1, 5 IB

1) The active substance is not a biological/immunological substance or sterile.

10. Changes in the manufacturing process of the Conditions Documentation Procedure

a) Minor change in the manufacturing process 1, 2, 3, 4, 5, 1, 2, 3 IA

b) Substantial change to the manufacturing II