Overview

Variations are either:

• an administrative change such as a change of company name and/or address
• a change to the characteristics of a product that can affect its quality, such as a change to its compositioncomposition, method of manufacture or how it is tested
• a change towhich may affect the safety, efficacy or pharmacovigilance requirements of the product

Changes are classed as major (type(Type II) or minor. Minor changes are either typeType 1AIA or 1B.IB.  These classifications are explained in Sections 5 and 6 below.

YouApplicants can apply for:

• a single change to one marketing authorisation (MA)
• multiple changes to one or more productsMAs and/or(refer MAsto Section 11)

  Marketing authorisationAuthorisation typesTypes

From 1 January 2021,2025, the following marketMarket authorisationAuthorisation (MA) types are possibleavailable in the UK:United Kingdom (UK):

PL

• UK-wide MA – these products are authorised for usesale inand UK
  supply throughout the United Kingdom
  • as a purely national UK-wide MA
  • as partregardless of anthe MR/DCroute procedureof involvingapplication: Northerndirect Irelandnational, asInternational CMS,Recognition butProcedure (IRP), Project Orbis, Access.
  • as a UK-wide MA

  PLGB –that authorisedwas forgranted useas inpart Greatof Britaina onlyMutual (England,Recognition/Decentralised Scotland(MR/DC) andprocedure Wales)

  • involving UK as aConcerned purelyMember Greatstate Britain(CMS) national
  • followingbefore conversion1 ofJanuary a2021.  centrallyThe authorisedMA productholder (CAP)
  • underhas the unfetteredoption accessto routecontinue (MAH needs to bemanage establishedthe MA in line with the MR/DC procedure with Northern Ireland and(NI) anyremaining productas musta accessCMS.  GreatNote Britainthat viaUK-wide NorthernMAs Irelandcan asno alonger qualifyingbe Northernapplied Irelandfor good)through EU procedures.

  PLNI -

• NI Only MAs (PLNI) – these products are authorised for usesale and supply in Northern Ireland only
  • as apart purelyof an MR/DC procedure including Northern Ireland nationalonly as a concerned member state (CMS).
  • asCentralised partMarketing ofAuthorisations anand MR/DCsubsequent procedurevariations includingceased to have validity in Northern Ireland onlyfrom 1 January 2025.

  SeeFor ourfurther guidanceinformation on applyingthese forauthorisation atypes licencerefer to marketguidance aon medicineUK-Wide inLicensing theof UKMedicines https://www.gov.uk/government/publications/uk-wide-licensing-for-human-medicines.

    UK Variations procedures

  The variation procedures followdetailed forunder Chapter IIa of the differentEU typesVariations Regulation (EC) No 1234/2008 regarding variations to the terms of marketing authorisations fromfor 1medicinal Januaryproducts 2021for arehuman essentiallyuse, which applies to variations to purely national Marketing Authorisations (MA) in the sameEuropean union (EU), were incorporated into UK law on 31 December 2020. They continue to apply to variations to purely national UK marketing authorisations as beforeset thatout date,in whereregulation relevant,65C coveredand bySchedule 10A to the appropriateHuman Medicines Regulations 2012 (as amended) “the HMRs”. 

  Commission Regulation 2024/1701 of 11 March 2024 amending the Variations Regulation (EC) No 1234/2008, has also been implemented in the UK. It entered into force on 7 July 2024 and became applicable on 1 January 2025.

  https://eur-lex.europa.eu/legal-content/EN/TXT/PDF/?uri=OJ:L_202401701

  Subsequent to that revision of the Variation Regulation applicable since 1 January 2025, the European orCommission national(EC) legislation.has Thepublished a communication which sets out guidance on the various categories of variations and operation of the procedures depend(Communication 2025/5045 dated 22 September 2025):

   https://eur-lex.europa.eu/legal-content/EN/TXT/?uri=OJ:C_202505045

  3.1  Implementation of new guidelines

  • The new guidance on whoprocedures and categories of variations applies from 15 January 2026.

  The application procedure which will be followed for the different types of UK Marketing Authorisations from 1 January 2025 is dependent on the regulatory authority responsible for leading the assessment:

  • MHRA for purely national variations
  • RMSvariations, the Reference Member State for MR/DCMutual Recognition (MR) variations or the Reference Authority for any worksharingEU variations
  work sharing variations. Therefore the MHRA guidance should be read in conjunction with guidance on the EMA and CMDh websites:

  Centralisedhttps://www.ema.europa.eu/en/human-regulatory-overview/post-authorisation/variations-including-extensions-marketing-authorisations

  https://www.hma.eu/human-medicines/cmdh/procedural-guidance/variation/amended-variation-regulation.html

  Type IB and Type II Variations

  Until 15 January 2026, marketing authorisationsauthorisation areholders authorisedshould forcontinue useto inrely Northernon Irelandthe onlycurrent Variations Guidelines and anyprocedures.  Variations submitted after this date should use the new variations guidance.  

   Type IA variations

  The date of implementation of the change(s) in the quality management system of the marketing authorisation holder (MAH) should be used to thesedetermine productswhether willthe new  Variations Guidance applies (rather than the date of submission used for type IB/II variations).

  For Type-IA variations implemented before 15 January 2026 should be managedsubmitted bybefore 15 January 2026 either as an early annual update or as individual notifications. 

  For Type-IA variations implemented on or after as of 15 January 2026, the EMA.first type-IA variation implemented will start a new cycle for the annual update, unless one of the listed annual update exemptions applies to that variation (refer to Section 5).

    UK Variations Classification

  Until further notice thethe EU variations classification guideline, which isexplains athe fundamentaltype component of thevariation operation(Type ofIA, theType variationsIAIN, system,Type IB, Type II or Extension) to submit will continue to apply to all types of variations.

  Reliancevariations route

  Youin canthe presentUK variationsunless toand purelyuntil nationalthe MHRA  issues MAsany (PL,revised PLGBguidance.  andWhere PLNI)relevant, the guidance also explains conditions to thebe MHRAmet underand theany reliancerequired route:supporting followingdocumentation which is a fundamental component of the acceptanceoperation of the samevariations change(s)system.,

  The tonew aVariations relatedGuidelines oron the samedetails productof ascategories part of avariations Europeanand procedure.on Forthe example,documentation ato CAPbe variationsubmitted orwill anapply MR/DCfrom variation.

  If15 youJanuary are2026 takingunless thisthey approach,are youstrain/sequence needchanges to makeauthorised itCOVID clearvaccines.

  • Specific arrangements for changes to Covid vaccines in the applicationUK andare relevantexplained evidence,in declarationsSection and7.

  Any supportingchanges information.to Forthe example,product wherethat relevant,require providea copiesmarketing ofauthorisation assessmentextension reportsapplication toshould supportbe thesubmitted submission.in Weaccordance willwith publishthe procedures further infor duenew course.marketing authorisations.  

    Minor variations

  These are divided into 2two types: IA and IB.

  Type IA change

  Variations

  Type IA changes have little or no impact on the quality, safety or efficacy of the product, for example administrative modifications such as:

  • the manufacturer’s name
  • a minor change to a control method
  • deleting detailsinformation of where the product is packaged

  Type IA proceduresvariations are classed‘do-and-tell’ ‘do-and-tell’,procedures, where youthe shouldMA Holder must implement the change before younotifying notifythe MHRA,MHRA. ensuringNotification thatmust whereoccur relevantnot (non-immediatelater notification)than you12 submitmonths, theafter applicationimplementation. withinHowever, 12some months.Type IA changes require immediate notification (Type IAIN) and must be submitted immediately after implementation.

  If the implementation period passesfor any Type IA variation exceeds 12 months without a variation being made,submitted, you should submit a default Type 1B. IB variation must be submitted. The MHRA will take up to 30 days to process yourthe application.

  SeeType IA notifications may cover multiple changes across one or more Marketing Authorisations. These should be submitted as a Grouped Variation.  When more than one Marketing Authorisation is involved, all changes must apply to all Marketing Authorisations within the CMDhcollection.

  Implementation variationsis procedureconsidered guidanceto be when the company makes the change to its own quality system. For changes affecting product information it is when the company internally approves the revised product information for use in the detailsnext packaging run.

  The MA Holder must submit Type IA variations as follows:

  Type IA Annual Update Notifications

  Type IA variations that do not require immediate notification following implementation must be bundled and submitted as an annual update to each MA. The changes do not need to be related to each other.  These notifications must be submitted not earlier than 9 months from the first implementation but not later than 12 months of thisthe typefirst implementation.  They can be submitted outside the annual update if one of change. the following applies:

  (i) the change has already been submitted as part of an acceptable grouping of variations of other types (Type IB or Type IAINII or Type IA)

  (ii) the change (immediatehas notification)

  already been submitted as part of a Type IA grouping which included a Type IAIN change

  Type IAIN variations should be submitted immediately (see section on Type IAIN changes). They may only be added to an annual update if this is submitted immediately after the implementation of the Type IAIN changes.

  (iii) the change is submitted as part of a sub-typeType IA UK super-group application where one or more changes are being submitted across MAs held by multiple MA Holders belonging to the same legal group of typecompanies.

  (iv) the change is an exceptional case listed in CMDh guidance Chapter 6, section 2:  https://www.hma.eu/human-medicines/cmdh/procedural-guidance/variation.html.  Exceptions relying on the need to mitigate a predicted or actual shortage should be supported by evidence of this in the UK. 

  When submitting a Type IA variation earlier under the exceptional case criteria, the basis for the exception must be clearly specified in both the cover letter and alsothe classed‘Scope and Background for Change’ section of the application form.

  Type IA Immediate Notifications (IAIN)

  Type IA Immediate Notifications are a sub-type of Type IA variations and are also ‘do-and-tell’ procedureprocedure. whereType MHRAIAIN requireschanges ‘immediatemust notification’be withinsubmitted immediately after implementation, with a period of 2 weeks being considered as reasonable. They can be submitted as part of a grouped variation or as part of the changeannual beingupdate implemented.provided their submission is not delayed.  A minor change would usually be typeType IAIN if it interferes with MHRA’sthe ability to continuously supervise the product.

  All relevant conditions and documentation mustrequirements bespecified metin forthe aclassification Typeguideline IA/IAINfor andType confirmedIA invariations amust copybe ofmet. Complete the classificationapplication guidelineform (eAF  https://esubmission.ema.europa.eu/eaf/) with eitherrelevant checkboxes selected. If a tickcondition or wheredocumentation requirement is not relevant,applicable, Notspecify ApplicableN/A (N/A).and add justification under “Note”.

  No ‘requests for further information’ (RFIs)(RFI’s) applyare toissued for Type IA proceduresprocedures, andthe thereapplications are either accepted  or rejected. There is no application fee associated with a National Type IA/IAIN. A full fees list of fees and further information about feesfees, iscan availablebe found in the section fees for licence variation applications.

  See thealso the CMDh variations procedure guidance for for the details of this type of change.

  Type IB change

  If the change is more significant than a Type IA change but is not a typeType II change or an extension,extension application, it is considered a typeType IB change. MHRA must approve typeType IB changes before they are madeimplemented. Many of these are changes to module 3 on the product.manufacturing or testing procedures.

  See thealso the CMDh variations procedure guidance for for the details of this type of change.

  Once the MHRA has all the necessary documents, it takes up to 30 days to process yourthe initialvariation application. YouA couldfurther be30 givendays ais furtherpermitted 30for daysthe applicant to respond to any request-for-informationrequests for information letter, which for Type IB are calledreferred to as Notification with Grounds letters (NWG).

  These

  • NWGs are seen as a conditional determination of a typeType IB variation, where the applicant has one opportunity to address any deficiencies or omissions.

    There isIf athe 30-dayapplicant deadlinedoes tonot respondreply in full to ana NWG.NWG Otherwise,the wevariation will withdrawbe orrefused, refusethis the variation. This also applies if we have received only a partial response has been received by the 30-day deadline.

    Major variations (type(Type II)

  These changes are more complex and mayare anticipated to have a significant impact on the quality, safety and/or efficacy of the product.

  The MHRA needs to approve major variations before they are made.implemented. One example of a major change is adding a new therapeutic indication to a product or updating the current indication (the medical needs the product is used for).indication.

  See thealso the CMDh variations procedure guidance for for the details of this type of change.

  Once MHRA has all the documents, it will take 30,22-days, 90(reduced timetable), 60-days (standard timetable) or 12090-days days(extended complex timetable) to assess yourthe application,application depending on how urgent or complex the changes are, excluding time taken to answer questions.

  OnceWith MHRAa hasperiod allfor the documents,applicant itto willrespond take 22-days, (reduced timetable), 60-days (standard timetable) or 90-days (extended complex timetable) to assessany yourrequests applicationfor dependingfurther oninformation how(RFIs) urgentnecessary or complex the changes are, excluding time taken to answerreach questions.

  Witha questionsdecision, (RFIs), assessment timeframes become 30, 90 and 120 days respectively.

  The table below tabulatesexplains the various stages for each type II timetabletimetables

  	Stage		30-day procedure		90-day procedure		120-day procedure
  Start assessment-clock on	Day 0	Day 0	Day 0
  Assessment done
  Approved, refused or withdrawn (procedure finalised)	Day 22	Day 60	Day 90
  or
  RequestRFI for further information (RFI) issued - clock off (procedure suspended)	Day 21	Day 59	Day 89
  Amended application for applications with an RFI step
  Timescale for receipt of response	10 days	60 days	90 days
  Response received-clock on completion of processing (excluding clock off time)	By day 30	By day 90	By day 120

  A reduced Type II procedure (reduced from 60 days to 30) is for variations concerning safety issues and is agreed between the MHRA and the Marketing Authorisation Holder (MAH) and in general will be changes to the SmPC, requested following the assessment of a Periodic Safety Update Report (PSUR) or at the request of the MHRA Pharmacovigilance Unit.

  YouRequests should make requests for a reduced timescale toshould be made to variationqueries@mhra.gov.uk.

  All other forms of submission will be rejected.

    Changes to Covid Vaccines

  Seasonal strain/sequence (COVID variant) changes to existing licensed COVID vaccines should be made to the MHRA via a line extension application (not a Type II variation), after requesting a new PL number. Additional strengths, pharmaceutical forms or presentations (e.g. vial or pre-filled syringe) for the new strain should be submitted as separate line extensions (refer to section 9, extension applications), although these can be submitted at the same time as a bulk submission.

  Where strain/sequence changes have been authorised in another region via a Type II variation, this can be submitted via IRP with the same supportive data and the relevant variation assessment report(s); however, the application should be submitted to the MHRA as a line extension.

    Common invalidation errors and pre-submission checklist

  WeFollowing stronglyanalysis adviseof yousubmissions, tothe useMHRA ouris developing a pre-submission checklist (PDF,for 26.9KB,variations 2 pages) which will reducebe published in due course.

  These are areas of common invalidation errors:

  • C.I.2.a Type IB Variations: where changes are made to the likelihoodSummary of Product Characteristics (SmPC), Labelling, or Package Leaflet of a generic/hybrid/biosimilar medicinal product, following assessment of the submittedsame applicationchange beingfor invalidatedthe reference product, specify the Reference Product used for the Marketing Authorisation Application (MAA). Use an alternative product, with justification, only if the original is cancelled or rejected.
    out of date.
  • Cover Letter Requirements for IRP Variations: Complete and include an IRP submission checklist with each Type IB or Type II IRP variation. The checklist can be downloaded from https://assets.publishing.service.gov.uk/media/66a8f0cb0808eaf43b50d9e7/IRP-PostLicensingSubmissionChecklistV1.2.pdf.
  • ASMF: Include a declaration that the ASMF Holder has submitted all parts of the ASMF, including approved variations and assessment reports. Include a letter for permission of access.
  • SmPC Fragments: Include tracked SmPC and SmPC fragments in the working document folder of the sequence. See section below for further information.
  • Grouped Type IB and Type II Variations: When grouping is not an example already covered in the Variation Regulation, obtain prior approval from the Customer Experience Centre. Submit grouping requests to variationsqueries@MHRA.gov.uk.

  The marketing authorisation holder (MAH) is responsible for ensuring that,that where relevant, all relevant conditions and documentation are met and the submission of this information and dossiers are the most recent and upup-to-date. to date. Deficient or incorrect documentation can lead to invalidation and/or rejection of the variation.

  Extensions

  AlthoughFurther extensionsdetail areon stillcertain consideredchanges ais typepublished ofhere:  variation,[add theirlink to supplementary guidance]

    Extension Applications

  In cases where the impact onof a proposed change to the product is so significant thatit you will need to followbe theapplied for as a line extension through a new MA application.  The application process to to apply for a new MA. Thewill formneed forto thisbe processfollowed.

  Examples hasof circumstances where a sectionnew onMA extensions.

  Extensionsis canrequired be:are:

  • changes to the active substance(s), including the salt/ester, isomer or biological active substance
  • changes to strength,strength or pharmaceutical form

  • ·       orchanges to the route of administration including different routes of parenteral administration

  • Note the UK position on changes to Covid vaccines explained in section 7 of this guidance.

  See See annex 1 of the variations regulations for for more information on extensions.extensions. 

  Revised labels, leaflets and/or packaging

  If yourthe variation (forapplied example,for change of manufacturer) affects details of the labels, leaflets and or packaging (alsoof calledthe livery)product, (e.g. a change of themanufacturer) product,updated youversions will need to includebe theincluded updated versions with yourthe variation submission to be assessed.

  However,A youvariation don’tis neednot toneeded submit a variation if there hasn’t been a change to the product and you only want to make style changes toare proposed for the labels, leaflets and/or packaging.

  For example, if you’re changing the design of the leaflet and it has no relation to a change in the product, a variation application is not needed. See See patient information leaflets for for guidance on how to submit these types of changes.

  SubmitSubmitting groupedMultiple changes (grouping)Changes

  YouMultiple canChanges applyto multiplea single MA (grouping)

  Multiple changes to a single product can be made using the ‘grouping’ format, asif long as the changes are directly related.

  For example, you can make a change to the manufacturing site of the finished product, change in batch size and the manufacturing process to a single product. TheGrouping typeadvice ofis procedure (type IA, IB, II) depends on the extent of the change. You can see details of this in the the annex III of the variations Regulation and and Schedule 10A of the Human Medicines Regulations.

  YouRegulations canand submitin groupedMHRA changespublished toadvice: an MA with multiple product licences under the European procedure. https://assets.publishing.service.gov.uk/government/uploads/system/uploads/attachment_data/file/369000/Examples_of_groupings.pdf 

  If a typeType IA variation is included in a group with other types of variations,youvariations, shouldthe notMA makeholder themay typeconsider IAholding changerelease of batches until all changes forin that group have been approved.

  Youapproved.  canShould groupthe anyType type IA andvariation IAINbe changesdependent foron differentother marketingchanges authorisations,in as long as the group only contains IA and IAIN changes and the changesgroup areis

   rejected theimplementation same. All of thesethe changesType shouldIA bechange madewould beforehave youto notify MHRA.cease. 

  Grouping applications for national MAs

  ForThe groupingstype whereof MAs were granted in the UK through a national procedure only,(Type youIA, willIB, needII) todepends applyon forthe groupedextent changesof through the MHRA.

  Checkchange. theThe acceptableassessment groupingtime guidanceframe and theapplicable examplesfee ofare groupings (PDF,determined 2.5by MB,the 12variation pages)with tothe seehighest ifclassification yourin groupingthe is acceptable.group.

  If yourthe desiredproposed group of changes isn’t included in the guidance or the examples, you need to complete the the grouping template, copy and paste it into the main body of an email and send it to to variationqueries@mhra.gov.uk before beforesubmitting youthe submit your application. WeThe aimMHRA aims to confirm ifacceptability yourof the grouping is acceptable within 7 working days.

  Variations

  Applicants toshould multiplereference productsthe (worksharing)

  Ingrouping someapproval circumstances,in you canboth usethe cover letter and application form. Additionally, include a copy of the worksharingapproval formatemail iffrom you’reCEC submittingin the application.

  Same variation(s) to multiple products (bulk submissions)

  It is possible to submit the same typeType IB or typeType II change or group of changes to multiple MAs.MAs Asheld farby asthe anysame productMA whichholder isas authorised‘bulk’ inapplications. the Companies UKwithin isthe concerned,same onlylegal productsgroup whichor are authorisedlicensees inare Northernconsidered Irelandto eitherbe centrally,the purelysame nationallyMA inholder Northernfor Irelandthis only,purpose. or(Commission asCommunication part(98/C of299/03)). an If MR/DCthere procedureis cana begroup the subject of worksharing.changes Youthen shouldType sendIA proposalsvariations formay worksharingalso applicationsbe to:

  • theincluded Europeanwhere Medicinesthey Agencyare (EMA)consequential ifor anyrelated. ofBulking thedoes MAsnot youimpact wanton to change were granted under the centralised procedure
  timescale.
  • theTo Coordinationavoid Groupduplication forof Mutualeffort Recognitionfor applicants and Decentralisedthe ProceduresMHRA, (CMDh)a ifbulk thevariation MAsshould werebe grantedsubmitted underin thesituations mutualwhere recognitionthe and/orsame decentralisedvariation proceduresis andapplied theto referencemultiple memberMAs statesfrom were different
  • the referencesame memberMA stateholder.

  Supergrouping ifof theType authorisationsIA wereand grantedIAIN underVariations

  It theis mutualpossible recognitionto and/orbulk decentralised procedure and thesubmit referencea membersingle stateapplication isfor was the same forType eachIA MA

  • theand competentType authoritiesIAIN forvariation theor relevantgroup countriesof ifvariations theto MAsproducts wereheld grantedby underdifferent purelylicence nationalholders, procedures,providing emailthe mr-dcprocedures@mhra.gov.ukMA forHolders belong to the UK

  Oncesame wemother havecompany, allor thegroup necessaryof documents,companies itor willwhich usuallyare take‘licencees’.  60These dayscompanies are considered to assessbe applicationsthe althoughsame itMA couldHolder takeas upexplained toabove.  120 All daysof ifthese thechanges variation(s)should arebe moreimplemented complexbefore ornotifying upMHRA.

  • This toprocedure 30is daysknown ifas urgent.

    Seesuper-grouping in the bestEU practice. guideUK onnationally worksharingauthorised forproducts detailscannot onbe howincluded toin submitsuper-grouping anprocedures applicationsubmitted thisto way.

    the EU

  Composite coordination collection (CCC)

  IfFor you want to apply for changes to one or more productpurely licencesnational (licenceMAs for each product under a marketing authorisation) that would affect the product information,information youthe canComposite submitCoordination aCollection composite(CCC) coordinationprocedure collectioncan (CCC).be used. Product information includes the summary of product characteristics, leaflets and labels. https://assets.publishing.service.gov.uk/media/5ff2f52dd3bf7f08a202459b/CCC__updated_guidance__29.12.20.pdf ,

  WithA a CCC youapplication can:can be used to:

  • submit only one consolidated mock-up of the leaflets and labels with all the changes proposedproposed.
  • submit a mixture of variations applications and Article 61(3) applications
  • apply for single or grouped changes, such as a typeType IB and/or typeType II variations (see (see groupings)

  YouThis scheme should not usebe thisused scheme for:

  • urgent variations relating to the safety of your product(s)
  • standalone typeType IA notifications
  • changes that don’t affect product information (summary of product characteristics, leaflets, labels)
  • changes to a product with a centralised licence

  YouApplicable fees are those that would payapply for thisthe schemechanges if applied for as thoughvariations youand wereArticle paying61(3) forchanges. 

  Variations individualto variations.MAs Seewhere Northern Ireland is a Concerned Member State

  For NI Only MAs granted through EU MR/DC (mutual recognition/decentralised) procedures, and cases where NI remains a Concerned Member State in a UK-wide MA, variations procedures will be led by the listReference Member State and managed as part of feesthe specific MR procedure.  In those cases EU procedural guidance should be followed:  Heads of Medicines Agencies: Variation.  

  ToThese getMAs yourcan CCCalso proposalbe approvedincluded andin toEU seeWorksharing howprocedures (where the same variations are submitted to apply,all followinvolved member states) which will be led by the Reference Authority.  Further guidance forcan CCCbe application (PDF,found 538in KB,Chapter 327 pages).here: Heads of Medicines Agencies: Variation

  • A UK-wide nationally authorised marketing authorisation cannot be submitted as part of an EU Worksharing procedure.

  Fees

  SeeA Feesfull list of fees and further information about fees, can be found in the section fees for variationslicence variation applications.. 

  UseThe theMHRA has also published a fees calculator:  Application Fees Calculator (mhra.gov.uk).  toThe workcalculator outcovers whatInitial theapplications fee(including marketing authorisation, extensions, herbal or homoeopathic applications) and Variation applications and is helpful for yourhighlighting submissionchanges willthat be.attract a complex fee.

  How to apply (all variation types except extensions)

  Specific variationsvariation changes are given unique change codes to include in the application form.

  MatchCheck and use the rightappropriate change code tofor yourthe specific variation by checkingreferring to the annex in the European Commission’s guidelines. Youthat willneeds need to includebe thisincluded in yourthe application form.

  Submitform: the EUR-Lex variation- application52025XC05045 form (MS- WordEN Document,- 970EUR-Lex

  For KB)cases alongwhere withNI theremains supportinga documentsConcerned viaMember theState MHRAin Portal.

  Youa canUK-wide nowMA, submitthe yourvariation application viacan thebe submitted via the Central European System Platform (CESP).

  Since JanuaryFor 2016other itvariation hasprocedures, becomethe mandatoryapplication formust newbe submitted through MHRA Submissions or MHRA Portal. https://www.gov.uk/guidance/mhra-portal-register-to-submit-forms

  New marketing authorisation, renewal and variation application submissions tomust be made using using electronic application forms (eAFs). This applieswill apply to all procedure types,types. including national procedures. If youapplicants are making a submission using the portal,MHRA Portal, you mustwill have to submit using the portal forms as well as submitting the eAF. If you are submitting youran application through CESP or or MHRA Submissions  youonly willthe onlyeAF needneeds to submit be the eAF.submitted.

  YouApplicants must submit yourvariations variation using the the electronic Common Technical Document format (eCTD).

  WeThe checkMHRA checks that eCTD submissions are technically valid using the Lorenz DocubridgeeValidator validation tooltool. whichIt strictlyis alignsrecommended validation against ICH international standards and eCTD 3.2 regional requirements. We recommend that youapplicants use a validation tool to check your submission.

  You can check the validationsame of your submission before making it using the LORENZ eValidator Basic validation software for eCTD and more. Your MHRA agent will use the Lorenz docuBridge eCTD tool to technicallycheck validate the submission against ICH international standards, eCTD 3.2 EU regional requirements, once we receive it.  submissions.

  For more information on the standards, see: 

  • ICH Official website

  • eSubmission: Projects (europa.eu)

  If youthere haveare any questions about submitting youra variation, email variationqueries@mhra.gov.uk.variationqueries@mhra.gov.uk].

  For submissions submissions via MHRA,MHRA seeSubmissions Registerplease to make submissions to the MHRAregister.

  You should use our eAF and cover letter tool to determine what information you need to include in your application. If you do not include the correct information your application will not be validated.

  Submissions through the Common European Submission Portal (CESP)

  This system is available from the Heads of Medicines Agencies (HMA) and provides a simple and secure mechanism for exchange of information between applicants and EU regulatory agencies.

  The purpose of the system is to:

  • provide a secure method of communicating with regulatory agencies via one platform
  • allow submission of an application once to reach all required agencies
  • reduce the burden for both industry and regulators of submittingsubmitting/handling and handling applications on CD-ROM and DVD

  IfFor youapplicants arewho aare  first time CESP userusers and wish to setsetup up an organisationorganisation/university or university or trust to manage multiple users on the system, system, register with CESP company registrationhere.

  IfFor youapplicants who are a standalone userusers and wish to upload for non-commercialNon useCommercial Use on yourtheir own behalf, behalf, register with CESP non-commercial user registrationhere.

  Once registered,registered youapplicants will receive credentials to access the portal tousing youra registered email address.

  General CESP training is available to all registered users via CESP’s training menu once logged into the system. Training-on-demandTraining on demand videos are available and youapplicants can also sign up to ourthe MHRA free online weekly live demonstrations. CESP encourage all users to attend training before using the system. Viewsystem and view FAQs.

  Supporting documents

  For CMS submissions applicants should send a dispatch date list (detailing when youapplicants intend to dispatch the products) to all member states before submitting youran applicationapplication. ifIf youran MA was granted through the mutual recognition or decentralised procedures. YouThe list should be emailed the list to to MR-DCprocedures@mhra.gov.uk for forType type IB and II changes and include a copy in the ‘additional data’ section of the eCTD format.

  Type IA and IB

  For typeType IA and IB variation applications youapplicants need to include:

  • a a cover letter with withthe your MA number, type of variation and reason for the variation
  • an explanation of your grouped variations if applicable, making specific reference to the Heads of Medicines Agencies (HMA) (HMA) acceptable groupings guidance and  and examples of groupings (PDF, (PDF, 2.5 2.5MB, 12 MB,pages) or 12 pages) or the confirmation email from the MHRA agreeing youapplicants can submit grouped variations
  • the supporting information required for specific variations as set out in the annex of the the European Commission’s guidelines
  • present and proposed details of yourthe product presented as a separate document if necessary
  • a contents page listing all documents included in yourthe submission

  Type II

  For type II applications, youapplicants must include all of the above and:

  • relevant information to support yourthe application such as publications and any cited references
  • a new or updated addendum to the ‘quality overall summary’, clinical and non-clinical overviews

  Summary of product characteristics (SPC)(SmPC)

  If relevant, you should submit the summary of product characteristic fragments (SPC)(SmPC) should be submitted to the MHRA in the correct format using the templates below. If youthese dotemplates are not useused thesethe templates your submission will be rejected.

  YouThese musttemplates should not alterbe thesealtered templates in any way, other than inserting the relevant information. YouThey should savebe themsaved using the following naming conventions in the ‘workingdocuments’‘working documents’ folder of yourthe eCTD: eCTD:

  m1 -3-1-01: -3-1-01: SPC section 1 – product name (MS (MS Word Document,Document, 22 22 KB)KB)

  m1 -3-1-02: -3-1-02: SPC section 2 – Qualitative and quantitative composition (MS (MS Word Document,Document, 21.5 21.5 KB)KB)

  m1 -3-1-03: -3-1-03: SPC section 3 - pharmaceutical form (MS (MS Word Document,Document, 19.5 19.5 KB)KB)

  m1-3-1-4.1: m1-3-1-4.1: SPC section 4.1 - therapeutic indications (MS (MS Word Document,Document, 19.5 19.5 KB)KB)

  m1 -3-1-4.2: -3-1-4.2: SPC section 4.2 - posology and administration (MS (MS Word Document,Document, 19.5 19.5 KB)KB)

  m1 -3-1-4.3: -3-1-4.3: SPC section 4.3 - contra-indications (MS (MS Word Document,Document, 19.5 19.5 KB)KB)

  m1 -3-1-4.4: -3-1-4.4: SPC section 4.4 - special warnings and precautions (MS (MS Word Document,Document, 19.5 19.5 KB)KB)

  m1 3-1-4.5: 3-1-4.5: SPC section 4.5 – interaction (MS (MS Word Document,Document, 19.5 19.5 KB)KB)

  m1 3-1-4.6: 3-1-4.6: SPC section 4.6 - fertility, pregnancy and lactation (MS (MS Word Document,Document, 23.5 23.5 KB)KB)

  m1 3-1-4.7: 3-1-4.7: SPC section 4.7 - driving and use machines (MS (MS Word Document,Document, 19.5 19.5 KB)KB)

  m1 3-1-4.8: 3-1-4.8: SPC section 4.8 - undesirable effects (MS (MS Word Document,Document, 19.5 19.5 KB)KB)

  m1 3-1-4.9: 3-1-4.9: SPC section 4.9 - overdose, emergency and antidotes (MS (MS Word Document,Document, 19.5 19.5 KB)KB)

  m1 3-1-5.1: 3-1-5.1: SPC section 5.1 – pharmacodynamics (MS (MS Word Document,Document, 19.5 19.5 KB)KB)

  m1 3-1-5.2: 3-1-5.2: SPC section 5.2 – pharmacokinetics (MS (MS Word Document,Document, 19.5 19.5 KB)KB)

  m1 3-1-5.3: 3-1-5.3: SPC section 5.3 - preclinical safety (MS (MS Word Document,Document, 19.5 19.5 KB)KB)

  m1 3-1-6.1: 3-1-6.1: SPC section 6.1 – excipients (MS (MS Word Document,Document, 19.5 19.5 KB)KB)

  m1 3-1-6.2: 3-1-6.2: SPC section 6.2 – incompatibilities (MS (MS Word Document,Document, 19.5 19.5 KB)KB)

  m1 3-1-6.3: 3-1-6.3: SPC section 6.3 - shelf life (MS (MS Word Document,Document, 19.5 19.5 KB)KB)

  m1 3-1-6.4: 3-1-6.4: SPC section 6.4 - special precautions (MS (MS Word Document,Document, 19.5 19.5 KB)KB)

  m1 3-1-6.5: 3-1-6.5: SPC section 6.5 – container (MS (MS Word Document,Document, 19.5 19.5 KB)KB)

  m1 3-1-6.6: 3-1-6.6: SPC section 6.6 – disposal (MS (MS Word Document,Document, 19.5 19.5 KB)KB)

  m1 3-1-07: 3-1-07: SPC section 7 - marketing authorisation holder (MS (MS Word Document,Document, 19.5 19.5 KB)KB)

  m1 3-1-08: 3-1-08: SPC section 8 - marketing authorisation number (MS (MS Word Document,Document, 19.5 19.5 KB)KB)

  m1 3-1-09: 3-1-09: SPC section 9 - date of the first authorisation or renewal (MS (MS Word Document,Document, 19.5 19.5 KB)KB)

  m1 3-1-10: 3-1-10: SPC section 10 - date of revision of the text (MS (MS Word Document,Document, 19.5 19.5 KB)KB)

  m1 3-1-11: 3-1-11: SPC section 11 – dosimetry (MS (MS Word Document,Document, 19.5 19.5 KB)KB)

  m1 3-1-12: 3-1-12: SPC section 12 – radiopharmaceuticals (MS (MS Word Document,Document, 19.5 19.5 KB)KB)

  More information

  The European Commission has published published guidelines for for submitting variation applications including the change codes needed. YouApplicants may also find the the common scenarios for submitting variations (PDF, (PDF, 171 171KB, 7 KB, 7 pages) useful.pages) useful.

  The European Commission’s Commission’s regulation1234/2008 as as updated by by regulation 712/2012 and Regulation 2024/1701 outlines the legislation for processing variations.

  External Publication Examples of groupings for variations October 25 (MS Word Document, 1.15 MB)

  Marketing Authorisation Variations – Supplementary Guidance October 25 (MS Word Document, 41.3 KB)

  Contact

  Email Email variationqueries@mhra.gov.uk with with any queries, or call 020 3080 7400.

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