A

Minor project
on

REVIEW ON DOCUMENTATION REQUIREMENT FOR

VARIATION PROCEDURES
– EUROPEAN UNION PERSPECTIVE

Guided by: Mr. S. M. Pathak Prepared by: Chirag k. Patel

Lecturer, M.Sc. PRA - Part II,
Dept. of PQA, Reg. No. – 081705015,
MCOPS, Manipal Dept. of Advance Pharmaceutical Studies,
Manipal University,
Manipal – 576 104
 Introduction
 Steps for drug marketing authorisation:

Drug dossier filing (New drug/generic)

Regulatory authority review Change in dossier

Marketing approval Update filing

Variation filing

Re-registration (upon expiry of registration)

 Types of MA procedures:
1. Centralise Procedure (CP)
2. Decentralise Procedure (DCP)
3. Mutual Recognition Procedure (MRP)
4. National Procedure (NP)
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 Variation:
“An amendment to the content of the documents such as they existed at the
moment the product was listed as approved”
 Types of variation:
Type ΙA
Type IB
Type ΙΙ
Urgent Safety Restriction (USR)
 Classification of variation
1. Consequential variation
2. Parallel variation
 Variation regulation shall not apply to:
1. Extensions of MA ;
2. Transfer of a MA to a new holder;
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 Dossier requirement for Type IA and IB notifications
For example:
Minor change in the manufacturing process of the active substance
Conditions:
1. No change in qualitative and quantitative impurity profile or in physico-
chemical properties.
2. The active substance is not a biological substance.
3. The synthetic route remains the same, i.e. intermediates remain the same.
Documentation:
1. Amendment to relevant sections part IIC or equivalent in the CTD format and
of the approved drug master file (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.
 Variation regulations

 EMEA
 Eudralex
 EC No. 1084/2003 (for MRP & DCP)
concerning the examination of variations to the terms of a marketing
authorisation for medicinal products for human use and veterinary medicinal
products granted by a competent authority of a MS

 EC No. 1085/2003 (for CP)

concerning the examination of variations to the terms of a marketing
authorisation for medicinal products for human use and veterinary medicinal
products falling within the scope of Council Regulation (EEC) No 2309/93

 Co ordination group for MRP & DCP (CMD) – CMDh & CMDv
 Provide guidance for submission related to MRP & DCP
 Procedure for variation through MRP

 Application form for variation to MA

 Allocation of the MR variation number

CC/D/nnnn/sss/X/vvv
where,
CC = Initial of the RMS
D = Domain (H or V)
nnnn = Medicinal product number
sss = Speciality number (for strength, pharmaceutical form)
X = Type of submission (IA, IB, II, X, R, E)
vvv = Chronological number
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Procedure for automatic validation of MRP for variations

For type IA notifications

MAH assigns MR
notification number

MAH submits notification

simultaneously to RMS
and CMS

MAH submits list of

despatch dates to RMS

RMS creates and

completes CTS
(EudraTrack) record
within 5 calendar days
CTS (EudraTrack) record
Should be backdated to
Date of receipt.
Procedure start date
Day 0
 For type IB notifications
MAH assigns MR
notification number

MAH submits notification

simultaneously to RMS and CMS

MAH submits list of

despatch dates to RMS

RMS creates CTS (EudraTrack) record within 5 working days

Additional 5 working days allowed for CMS

comment on submission

CMS: no comment CMS comments sent to RMS

- Non receipt
- Non payment of fees
Valid submission
Invalid submission
Procedure start date Day 0
Suspension of automatic validation
process - MAH requested to provide
missing information/fee

MAH submits missing

information/fee to CMS

CMS informs RMS of validity of

submission within 5 working
Days of receipt
 For type II variations
MAH assigns MR variation number

MAH submits variation

simultaneously to RMS and CMS

RMS creates CTS (EudraTrack) record

- CMS informed of submission

MAH submits list of despatch dates to RMS

RMS circulates proposed procedure start date

and variation timetable

10 working days allowed for CMS comment

on submission/timetable

CMS: acceptance CMS sent comments to RMS

(or no comment) concerning
- Non receipt
- Non payment of fee

- Objections to timetable

- Validity of content
 Valid submission Suspension of automatic
validation process

Procedure start date

Day 0

Timetable Validity
RMS/CMS MAH requested to
Agree timetable provide missing
information/fee

MAH submits missing

Information/fee to CMS

CMS informs RMS of valid

submission within 5 working
days of receipt
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 Processing of type IA notifications in the MRP:

Receive notification comprising of -

- Application form (with MR notification number).
- Supporting documentation.
- Checklist of the conditions specified for the proposed change(s) and
corresponding supporting documentation.
- Additionally, the RMS submission should include the list of dispatch dates
Day 0 - Within 5 days of receipt, set the procedure date to coincide with receipt of
the notification and inform CMS of start date
- Undertake a check to establish validity of the notification based on
submitted documentation
Day 14 – RMS will make a decision on validity of the whole notification on behalf of
all CMS
- Valid – acknowledgement of a valid notification is sent to the applicant
- Invalid – Applicant is informed of grounds for non-acceptance of the
notification
-- Inform CMS of outcome
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 Processing of type IB notifications in the MRP:
RMS
-10 W. days - Receive notification
-5 W. days - Within 5 working days of receipt inform CMS about the notification
and indicate the validity.
Day 0 - Inform Applicant and CMS of start date.
- Assess notification application.
Day 20 - Receive objections from CMS (if concerned by Notification No 2,No 41a2
or No 41b).
- Review objections.
Day 30 - Make a decision on behalf of all CMS:
- Approval
- Refusal
Notification with Grounds
- inform the Applicant about the deficiencies of the application
- stop the clock for the procedure
- Inform CMS of outcome.
Clock off - Applicant has 30 days to respond.
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End of Clock - No amendment received.
off period - formal refusal to Applicant on behalf of all CMS
- Inform CMS
- Amendment received by RMS and CMS.
- List of despatch dates for amendment received by RMS.
New Day 0 - Inform Applicant and CMS of new start date.
- Assess notification amendment.
New Day 20 - Receive objections from CMS (if concerned by Notification No
2,No 41a2 or No 41b).
- Review objections.
New Day 30 - Make a decision on behalf of all CMS:
- Approval
- Refusal
- Inform CMS of outcome.
Within 10 calendar - Applicant or CMS may request arbitration.
days of finalising
procedure
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 Processing of variation in MRP: Type II variation
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 Procedure for USR:
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 Variation concerns to human influenza vaccines:

Within 30 days - RMS shall prepare an AR on the basis of the quality

documents and a draft decision which shall be addressed to the CMS.
- RMS may request the holder to provide SI. It shall inform CMS.

Within 12 days - CMS shall recognise the draft decision and inform RMS to this
effect.

The clinical data and, where appropriate, data concerning the stability of the
medicinal product, shall be addressed by the holder to RMS and to CMS, at the
latest 12 days following the end of the time limit.

Within 7 days - RMS shall evaluate these data and draft a final decision
Within 7 days - CMS shall recognise the final draft decision and
- adopt a decision in conformity with the final draft decision.
 Procedure for variation through CP
 Procedure for type IA and type IB variations:
Application form is accompanied by:
- A copy of the relevant page(s) of the “Dossier requirements for type IA and IB
variations”.
- All required documentation as specified in the guideline. Where relevant, the
appropriate headings and numbering of the EU-CTD format must be used.
- Where relevant, the revised product information.
- Payment of the fee.

Application should be addressed and sent to the attention of the Central

Information Group (CIG) at the following address:
Central Information Group (CIG)
EMEA
7 Westferry Circus
Canary Wharf
London, E14 4HB
UK
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Type IA Variations
Within 14 days - EMEA will acknowledge the validity of a type IA variation
- There will be no interaction with MAH during the procedure,
and no request to provide missing information.
By day 14 - EMEA will inform MAH of the outcome of the validity check.

Type IB Variations
Before day 0 - EMEA will check whether the variation is correct and complete
(validation)
Within 30 days - EMEA will assess the submitted application.
If the agency is of the opinion that the application cannot be accepted it shall
inform the company within 30 days, allowing the company to amend the
application within 30 days.

Once the application is amended, it will be reviewed in 30 days. If no action is

taken by the applicant within 30 days of receipt of the grounds for non-
acceptance, the application shall be rejected.
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 Procedure for a type II variation:
Application form
A 60-day evaluation timetable shall apply. This period can be reduced having
regard to the urgency of the matter, particularly for safety issues. This period can
be extended to 90 days for variations concerning changes or additions to the
therapeutic indication.

Within that period, the competent committee may send the holder RSI within a
time limit set by that committee. The procedure shall be suspended until such
time as the supplementary information has been provided.

As a general rule, a clock-stop of up to 1 month will apply. For clock-stops longer

than 1 month the MAH should send a justified request to the EMEA for
agreement by CPMP. Such requests should be sent after receipt of the assessment
report, and at the latest before the CPMP meeting at which the RSI will be
adopted.

In exceptional cases (e.g. in the case of new indications or where the variation
requires an inspection) a clock-stop of up to a maximum of 6 months may be
applied.
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The CPMP assessment of responses will take up to 30 or 60 days depending on
the complexity and amount of data provided by MAH.

Where the CPMP delivers a favourable opinion, the EMEA shall inform MAH and
the commission immediately, and shall send the commission, where appropriate,
the amendments to be made to the terms of the MA.

In case of a negative opinion, the following documents must be attached to the

CPMP opinion:
- The appended committee’s VAR stating the reasons for its negative
conclusions.
- Where appropriate, and upon members’ request, divergent positions of
committee members with their grounds.

Where the CPMP delivers an opinion (whether favourable or unfavourable), the

appeal procedure shall apply (i.e. the applicant may appeal within 15 days as from
the receipt of the opinion).
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 Procedure for USR:

MAH shall immediately notify the EMEA, the rapporteur, the co-rapporteur and
member states of the provisional restrictions introduced. If the EMEA has not
raised any objections within 24 hours, MAH shall implement the USR within a
time frame agreed with the agency. The corresponding variation application
reflecting the USR shall be submitted immediately and in any case no later than
15 days after the initiation of the USR. The corresponding variation application
should be handled for type II variations as described above.

Where the commission imposes USR, MAH shall be obliged to submit a variation
application taking account of the safety restrictions imposed by the commission.
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 Variation concerns to human influenza vaccines:

Within 45 days following the date of the receipt of a valid application, the agency
shall give its opinion on the quality documents based on an assessment report.
Within the period given above, the agency may request the holder to provide
supplementary information.

The clinical data and, where appropriate, those concerning the stability of the
medicinal product shall be addressed by the holder to the agency at the latest 12
days following the end of the time limit of 45 days.

The agency shall evaluate these data and shall give its final opinion within 10 days
of the reception of the data. The agency shall address the final opinion to the
commission and to MAH within the 3 following days. The community register of
medicinal products shall be updated as necessary.
 Variation fees exemptions
 50% reduction to the total applicable fee to variation in case of medicinal product
for paediatric use in the first year from granting of a marketing authorisation.

 Total exemptions shall apply to the type II pandemic variation that is submitted
once the human pandemic situation is duly recognised, has been authorised by
the community but, in any case, shall not apply after the five-year period from the
EC decision on the authorisation of the core dossier has elapsed.

 Multiple applications on usage patent grounds.

 Structure of dossier
 CTD format
 From 1 July 2008, the EMEA accepts electronic-only submissions, either in
eCTD format or NeeS (eCTD format is however the recommended electronic
format), with no additional requirement for paper copies.
 For each application, two electronic copies should be provided to the
rapporteur of EMEA on DVD or CDROM together with an original, signed cover
letter.
 Categorisation of EA Vs VA
 Changes to the active substance(s):
Replacement of the active substance(s) by a different salt/ester complex/derivative
(with the same therapeutic moiety) where the efficacy/safety characteristics are not
significantly different;
Replacement by a different isomer, a different mixture of isomers, of a mixture by an
isolated isomer (e.g. racemate by a single enantiomer) where the efficacy/safety
characteristics are not significantly different;
Replacement of a biological substance or product of biotechnology with one of a slightly
different molecular structure. Modification of the vector used to produce the
antigen/source material, including a new master cell bank from a different source where
the efficacy/safety characteristics are not significantly different;
A new ligand or coupling mechanism for a radiopharmaceutical;
Change to the extraction solvent or the ratio of herbal drug to herbal drug preparation
where the efficacy/safety characteristics are not significantly different.
 Changes to strength, pharmaceutical form and route of administration:
Change of bioavailability;
Change of pharmacokinetics e.g. change in rate of release;
Change or addition of a new strength/potency;
Change or addition of a new pharmaceutical form;
Change or addition of a new route of administration.
 New variation regulation (EC 1234/2008)

implementation from 1st January 2010

Following criteria added into regulation:

 An annual reporting system should be introduced for certain minor variations.

 Classification of variations
 Recommendation on classification of unforeseen variation
 Grouping of variations
 Worksharing procedure
 Allocation of the variation numbers for grouped and worksharing applications
Flowchart for recommendation on unforeseen variations - Request to CMD(h)
Flowchart for recommendation on unforeseen variations - Request to EMEA
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 Grouping of variations
 Each variation should require a separate submission. Grouping of variations
should nevertheless be allowed in certain cases, in order to facilitate the review
of the variations and reduce the administrative burden. Grouping of variations to
the terms of several MA from the same MAH should be allowed only in so far as
all concerned MA are affected by the exact same group of variations.

 The same minor variations of type IA to the terms of one or several MA owned by
the same holder are notified at the same time to the same relevant authority, a
single notification may cover all such variations.

 For the purpose of handling a grouped application and worksharing procedure,

the following definition of a MA is used:
“all strengths and pharmaceutical forms of a certain product. For MRP/DCP
products this would imply that all products belonging to e.g. AT/H/1234/001-n
will be considered to belong to the same marketing authorisation.”
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Cases for grouping variations:
For example -
 One of the variations in the group is an extension of the MA.
 One of the variations in the group is a major variation of type II; all other
variations in the group are variations which are consequential to this major
variation of type II.
 One of the variations in the group is a minor variation of type IB; all other
variations in the group are minor variations which are consequential to this minor
variation of type IB.
 All variations in the group relate solely to changes of administrative nature to the
SPC, labelling and package leaflet or insert.
 All variations in the group are changes to ASMF, VAMF or PMF.
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 All variations in the group relate to a project intended to improve the
manufacturing process and the quality of the medicinal product concerned or its
active substance(s).
 All variations in the group are changes affecting the quality of a human pandemic
influenza vaccine.
 All variations in the group are consequential to a given USR.

The type of variation as well as the timetable of the grouped application is

dependent on the “highest” type of the single changes.
 Worksharing procedure
In order to facilitate the planning of the procedure, MAHs are advised to
announce an upcoming worksharing procedure to the co-ordination group 3-6
months in advance of the planned submission. Such pre-submission information
should contain the following information:
 List of concerned MAs.
 Explanation as to why all concerned MAs are considered to belong to the same
holder
 Description of the variation.
 Preferred RA.
 In case the preferred RA has not granted a MA for all concerned MAs, the MAH
should explain the choice of the preferred RA.
 Explanation as to why the holder believes that a worksharing procedure is
suitable.
 Planned submission date.

At the latest two weeks after the CMD(h) meeting, CMD(h) will inform the MAH
that the worksharing application has been accepted and which NCA will act as RA.
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The holder shall submit to all relevant authorities an application containing the
elements listed below, with an indication of the recommended RA.

 A list of all the MA affected by the notification or application.

 A description of all the variations submitted, including:

√ In the case of type IA, the date of implementation for each variation
described;

√ In the case of type IA which do not require immediate notification, a

description of all minor variations of type IA made in the last 12 months to
the terms of the concerned MAs and which have not been already notified.
 All necessary documents submitted.
 Where a variation leads to or is the consequence of other variations to the terms
of the same MA, a description of the relation between these variations.
 In the case of variations to centralised MA, the relevant fee provided.
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 In the case of variations to MA granted by the competent authorities of MS:
√ A list of those MS with an indication of the RMS if applicable;
√ The relevant fees
If the application fulfils the requirements laid down above, CMD shall chose a RA
and that RA shall acknowledge receipt of a valid application.

Where the chosen RA is the CA of a MS which has not granted a MA for all the
medicinal products affected by the application, CMD may request another
relevant authority to assist RA in the evaluation of that application.

The RA shall issue an opinion on the valid application within a period of 60 days
following acknowledgement of receipt of a valid application in the case of minor
variations of type IB or major variations of type II;

The RA may reduce the period regard to the urgency of the matter, or extend it to
90 days for variation concerning a change to or addition of therapeutic
indications.
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Within the period given above, the RA may request the holder to provide
supplementary information within a time limit set by the RA.
The RA sends its final opinion to all concerned MSs.

 In worksharing procedures in which the EMEA acted as RA, the concerned MSs
shall approve the final opinion, inform the EMEA and amend accordingly the MAs
concerned within 30 days, unless the referral is initiated within 30 days following
receipt of the opinion.

For practical reasons it is agreed that if a MS cannot approve the final opinion of
the RA, that MS should initiate referral within 10 days after distribution of the
final opinion, in order to leave 20 days for the amendment of the MAs concerned.
If a MS does not initiate referral within 10 days after distribution of the final
opinion, the final opinion is considered approved by the MS.
Allocation of the variation numbers for grouped and
worksharing applications
Principles:
 A grouped application or worksharing application is a single procedure for the
variation.

 Only for type IA variations, it is allowed to group variations over more than one MA.
If type IB or type II variations are grouped over more than one MA, then
worksharing needs to be followed.

 It is required to identify the specialities (pharmaceutical strength/form) of a MA

that were included in the group. This means that still specialities (strengths and
forms) of a MA need to be assigned when creating the grouping. In addition to the
grouping number a variation number for each speciality is allocated (so called
virtual variation number), and kept by the MAH.

 A product specific variation sequence number should to be recorded even for

grouped variations including > 1 MA and worksharing procedures. In these cases,
the variation sequence number appears in the allocated virtual variation numbers
as created for each speciality.
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The following scheme is used for grouped variations:

CC/D/nnnn/QQ/vvvv/g

Where: CC = two letter country code of the RMS

D = Domain (H)
nnnn = product counter (if 1 MA) / xxxx (if > 1 MA)
QQ = procedure qualifier (e.g. IA, IB, II, X )
vvvv = chronological number
If 1 MA: next available sequential variation counter
If > 1 MA: sequential variation grouping counter (for type IA only)
g = Grouping qualifier (G)
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If 1 MA is included in grouping:

 Number is composed of the RMS code, domain, product counter (nnnn) and the next
available variation sequence (vvvv) (e.g. DE/H/0450/IB/0070/G).
 This number can be allocated by the MAH itself.

If > 1 MA is included in grouping:

 For type IA variations, more than one MA may be grouped. In that case the product
counter is replaced by a placeholder (nnnn = xxxx), followed by a new variation
grouping counter and the grouping qualifier (G). (e.g. DE/H/xxxx/IA/0004/G).
 As the variation grouping counter (also worksharing procedure number) cannot be
allocated by the MAH, he has to contact the RMS prior to submission, since the
allocated number must be included in cover letter and application form.
 In addition to the grouped application number (also worksharing procedure number),
for each speciality included in the grouping a ‘virtual’ variation number is created and
maintained in CTS.
 The virtual numbers are not to be listed on the cover letter or application form, but
have to be kept by the MAH in order to know the next sequence counter for a ‘normal’
variation.
 Each grouped variation and worksharing procedure has a unique number.
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Examples:

If grouped variation DE/H/0113/IB/0058/G is for:

 DE/H/0113/002; DE/H/0113/003; (but not DE/H/0113/001)
Then the virtual variation numbers are:
 DE/H/0113/002/IB/0058/G
 DE/H/0113/003/IB/0058/G

If grouped variation (2 MAs) DE/H/xxxx/IA/0007/G is for:

 DE/H/0110/001; DE/H/0110/002; DE/H/0113/001
Then the virtual variation numbers are:
 DE/H/0110/001/IA/0034/G
 DE/H/0110/002/IA/0034/G
 DE/H/0113/001/IA/0042/G
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The following scheme is used for worksharing applications:
CC/D/nnnn/QQ/vvvv
Where: CC = two letter country code of the RA
D = Domain (H)
nnnn = the product counter is replaced by the placeholder: xxxx
QQ = procedure qualifier for worksharing procedure: WS
vvvv = sequential worksharing counter
Example:
If worksharing DE/H/xxxx/WS/0011 is for
 DE/H/0102/001; DE/H/0113/001; DE/H/0113/002
Then the virtual variation numbers are:
 DE/H/0102/001/WS/0072
 DE/H/0113/001/WS/0059
 DE/H/0113/002/WS/0059
 Case study
HIV protease inhibitor, saquinavir (Invirase), hard capsule (HC) formulation was
granted by the EC to Roche Registration Ltd on 04 October 1996 for the treatment
of HIV-1 infected adults.
This was followed by the MA of Fortovase, a soft gel capsule formulation (1998).
With the present 200 mg capsule strength, this dose regimen requires a total of
five saquinavir capsules and one ritonavir capsule per dose (a total of 12 daily).
Following variations are applied in INVIRASE:
Gender effect:
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Effect of food:

Important safety data received on 03 February 2005:

 In a clinical pharmacology study in healthy volunteers, 11/28 (39.3%) subjects
exposed to rifampicin 600 mg daily taken together with ritonavir 100 mg and
saquinavir 1000 mg given twice daily (ritonavir boosted saquinavir) developed
significant hepatocellular toxicity. Dosing was immediately interrupted and the
study discontinued immediately. Liver function tests in all affected subjects are
returning to normal following drugs discontinuation.
 As a result of these findings, Roche advises that Rifampicin should not be used in
patients also receiving saquinavir/ritonavir as part of combination antiretroviral
therapy (ART). The MAH has to submit Type II variations for all saquinavir containing
products with respect to the following SPC changes as soon as possible:

 SPC have to be updated in order to provide the relevant new information on

hepatotoxicty when rifampicin and saquinavir/ritonavir are given concomitantly.
Conclusion
 References
 Procedure for marketing authorisation – variation. [Online]. 2004 Feb [cited 2009 Sept 5];
Available from: URL:http://ec.europa.eu/enterprise/Pharmaceuticals/eudralex/vol2/a/v2a_
chap5_r1_2004-02_n.pdf
 Procedure for marketing authorisation – general information. [Online]. 2008 July [cited 2009
Sept 5]; Available from: URL: http://ec.europa.eu/enterprise/pharmaceuticals/
eudralex/vol2_en.htm
 Presentation and content of dossier – application form for variation. [Online]. 2009 Sept
[cited 2009 Sept 7]; Available from: URL:http://ec.europa.eu/enterprise/Pharmaceuticals/
eudralex/vol2_en.htm
 Guideline on dossier requirements for Type IA and Type IB notifications. [Online]. 2006 July
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 Guideline on the categorisation of extension application versus variation application.
[Online]. 2003 Oct [cited 2009 Sept 20]; Available from:
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2/c/v2c_ea_v_10_2003 .pdf
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June 27 [cited 2009 Sept 24]; Available from: URL:http://ec.europa.eu/enterprise/
pharmaceuticals/eudralex/vol-1/reg_2003_1084/reg_2003_1084_en.pdf
 Invirase – EPARs for authorised medicinal products for human use. [Online]. 2009 Apr 09
[cited 2009 Sept 30]; Available from: URL:http://emea.europa.eu/humandocs/Humans/
EPAR/invirase/invirase.htm
 CMD(h) Best Practice Guide for the submission and processing of variations in the mutual
recognition procedure. [Online]. 2008 Feb [cited 2009 Oct 02]; Available from
URL:http://www.hma.eu/fileadmin/dateien/Human_Medicines/CMD_h/procedural_guidan
ce/variations/2008_02_BPG_Variations_Rev5_chapter5_clean.pdf
 Request to CMD(h)/CMD(v)/EMEA for a recommendation on the classification of an
unforeseen variation under article 5 of commission regulation (EC) No 1234/2008. [Online].
2009 March [cited 2009 Oct 05]; Available from: URL:http://www.hma.eu/fileadmin/datein/
HumanMedicines/ CMD_h_Templates/variations/CMDh_137_2009_Rev0_Feb09.pdf
 Urgent safety restriction member state standard operating procedure. [Online]. 2005 Dec
[cited 2009 Oct 07]; Available from: URL: http://www.hma.eu/ fileadmin/dateien/
Human_Medicines/CMD_h/procedural_guidance/USR/2005_12_USR_SOP_Rev3_Clean.pdf
 Presentation and format of dossier – Common Technical Document. [Online]. 2006 May
[cited 2009 Oct 08]; Available from: URL:http://ec.europa.eu/enterprise/pharmaceuticals/
eudralex/vol-2/b/update_200805/ctd_05-2008.pdf
 Commission regulation (EC) No 1234/2008 concerning the examination of variations to the
terms of a marketing authorisation for medicinal products for human use and veterinary
medicinal products. [Online]. 2008 Dec 12 [cited 2009 Sept 27]; Available from: URL:
http://ec.europa.eu/enterprise/Pharmaceuticals/eudralex/vol-1/reg_2008_1234/reg_2008_
1234_en.pdf
???
Thank You…