A Minor project on

REVIEW ON DOCUMENTATION REQUIREMENT FOR VARIATION PROCEDURES EUROPEAN UNION PERSPECTIVE

Guided by: Mr. S. M. Pathak Lecturer, Dept. of PQA, MCOPS, Manipal

Prepared by: Chirag k. Patel M.Sc. PRA - Part II, Reg. No. 081705015, 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 Marketing approval Variation filing Re-registration (upon expiry of registration) Change in dossier Update filing

y

Types of MA procedures: 1. Centralise Procedure (CP) 2. Decentralise Procedure (DCP) 3. Mutual Recognition Procedure (MRP) 4. National Procedure (NP)

Continuey

Variation: An amendment to the content of the documents such as they existed at the moment the product was listed as approved

y

Types of variation: Type A Type IB Type Urgent Safety Restriction (USR)

y

Classification of variation 1. Consequential variation 2. Parallel variation

y

Variation regulation shall not apply to: 1. Extensions of MA ; 2. Transfer of a MA to a new holder;

Continuey

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 physicochemical 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 MRPy

Application form for variation to MA Allocation of the MR variation number CC/D/nnnn/sss/X/vvv where, CC D sss X vvv = Initial of the RMS = Domain (H or V) = Speciality number (for strength, pharmaceutical form) = Type of submission (IA, IB, II, X, R, E) = Chronological number

y

nnnn = Medicinal product number

Continue..Procedure for automatic validation of MRP for variations For type IA notificationsMAH 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 notificationsMAH 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 Valid submission Procedure start date Day 0

CMS comments sent to RMS - Non receipt - Non payment of fees

Invalid submissionSuspension 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 variationsMAH 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 (or no comment)

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

MAH submits missing Information/fee to CMS

CMS informs RMS of valid submission within 5 working days of receipt

Continue..y

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

Continuey

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 Day 20 - Inform Applicant and CMS of start date. - Assess notification application. - 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.

ContinueEnd of Clock off period - No amendment received. - 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 New Day 20 - Inform Applicant and CMS of new start date. - Assess notification amendment. - 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

Continuey

Processing of variation in MRP: Type II variation

Continue

Continue

Continuey

Procedure for USR:

Continue

Continue

Continuey

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 CPy

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

ContinueType 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 Type IB Variations Before day 0 - EMEA will check whether the variation is correct and complete (validation) - EMEA will inform MAH of the outcome of the validity check.

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 nonacceptance, the application shall be rejected.

Continuey

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.

ContinueThe 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).

Continuey

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.

Continuey

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 exemptionsy

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.

y

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.

y

Multiple applications on usage patent grounds.

Structure of dossiery y

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.

y

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 VAChanges 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. y 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.y

New variation regulation (EC 1234/2008)implementation from 1st January 2010 Following criteria added into regulation:

y y y y y y

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

Continue

Grouping of variationsy

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.

y

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.

y

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.

ContinueCases for grouping variations: For example y y

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.

y

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.

y

All variations in the group relate solely to changes of administrative nature to the SPC, labelling and package leaflet or insert.

y

All variations in the group are changes to ASMF, VAMF or PMF.

Continuey

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).

y

All variations in the group are changes affecting the quality of a human pandemic influenza vaccine.

y

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 procedureIn 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:y y

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.

y y y

y

y

ContinueThe holder shall submit to all relevant authorities an application containing the elements listed below, with an indication of the recommended RA.

y y

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.

y y

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.

y

In the case of variations to centralised MA, the relevant fee provided.

Continuey

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.

ContinueWithin 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.y

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 applicationsy

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.

y

y

y

ContinueThe 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)

ContinueIf 1 MA is included in grouping:y y

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:

y

y

y

y

y

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.

ContinueExamples:

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

DE/H/0113/002;

DE/H/0113/003;

(but not DE/H/0113/001)

Then the virtual variation numbers are:y y

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:y

DE/H/0110/001;

DE/H/0110/002;

DE/H/0113/001

Then the virtual variation numbers are:y y y

DE/H/0110/001/IA/0034/G DE/H/0110/002/IA/0034/G DE/H/0113/001/IA/0042/G

ContinueThe 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 fory

DE/H/0102/001;

DE/H/0113/001;

DE/H/0113/002

Then the virtual variation numbers are:y y y

DE/H/0102/001/WS/0072 DE/H/0113/001/WS/0059 DE/H/0113/002/WS/0059

Case studyHIV 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:

ContinueEffect of food:

y

y

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.

y

Conclusion

Referencesy

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 07 [cited 2009 Sept 15]; Available from: URL:http://ec.europa.eu/enterprise/ pharmaceuticals/eudralex/vol-2/c/var_type_1a1b_ guideline_06-2006.pdf Guideline on the categorisation of extension application versus variation application. [Online]. 2003 Oct [cited 2009 Sept 20]; Available from: URL:http://ec.europa.eu/enterprise/pharmaceuticals/eudralex/vol-2/c/v2c_ea_v_10_2003 .pdf Commission regulation (EC) No 1084/2003 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 member state. [Online]. 2003 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

y

y

y

y

y

y

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

y

y

y

y

y

???

Thank You