Apply for changes to your marketing authorisation, including minor variations type IA and IB, major variations type II and extensions.

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 composition
  • a change to the safety, efficacy or pharmacovigilance of the product

Changes are classed as major (type II) or minor. Minor changes are either type 1A or 1B.

You can apply for:

  • a single change to one marketing authorisation (MA)
  • multiple changes to one or more products and/or MAs

Minor variations

These are divided into 2 types: IA and IB.

Type IA change

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 details of where the product is packaged

You should implement the change before you notify MHRA, ensuring you submit the application within 12 months. MHRA will take up to 30 days to process your application.

See the annex of the European guidance for the details of this type of change.

Type IAIN change (immediate notification)

Type IAIN is a sub-type of type IA where MHRA requires ‘immediate notification’, within 2 weeks of the change being implemented. A minor change would usually be type IAIN if it interferes with MHRA’s ability to continuously supervise the product.

See the annex of the European guidance for the details of this type of change.

Type IB change

If the change is more significant than a IA change but is not a type 2 change or an extension, it is considered a type IB change. MHRA must approve type IB changes before they are made to the product.

See the annex of the European guidance for the details of this type of change.

Once MHRA has all the necessary documents, it takes up to 30 days to process your initial application. You could be given a further 30 days to respond to any requests for information.

Major variations (type II)

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

MHRA needs to approve major variations before they are made. 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).

See the annex of the European guidance for the details of this type of change.

Once MHRA has all the documents, it will take 30, 90 or 120 days to assess your application depending on how urgent or complex the changes are, excluding time taken to answer questions.

Extensions

Although extensions are still considered a type of variation, their impact on a product is so significant that you will need to follow the application process to apply for a new MA. The form for this process has a section on extensions.

Extensions can be:

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

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

Revised labels, leaflets and/or packaging

If your variation (eg change of manufacturer) affects details of the labels, leaflets and or packaging (also known as livery) of the product, you will need to include the updated versions with your submission to be assessed.

However, you don’t need to submit a variation if there hasn’t been change to the product and you only want to make style changes to 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 patient information leaflets for guidance on how to submit these types of changes.

Submit grouped changes (grouping)

You can apply multiple changes to a single product using the ‘grouping’ format, as 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 1 product. The type of procedure (type IA, IB, II) depends on the extent of the change. You can see details of this in the annex of the EU guidelines.

You can submit grouped changes to an MA with multiple product licences under the European procedure.

If a type IA variation is included in a group with other types of variations, the type IA change should not be implemented until all changes for that group have been approved.

You can group any type IA and IAIN changes for different marketing authorisations, as long as the group only contains IA and IAIN changes and the changes are the same. All of these changes should be implemented before you notify MHRA.

Grouping applications for national MAs

For groupings where MAs were granted through a national procedure only, you will need to apply for grouped changes through that respective member state. For example, if 4 MAs (for 4 products) were granted in the UK, grouped changes such as a type IB with a type IA will need to be applied for through MHRA. If you have multiple products granted by Spain, for example, you would need to apply for grouped changes through their competent authority.

If you have multiple products and multiple MAs granted both nationally and at a European level, you may prefer to submit grouped changes using the worksharing process.

Check the acceptable grouping guidance and the examples of groupings (PDF, 2.5MB, 12 pages) to see if your grouping is acceptable.

If your desired group of changes isn’t included in the guidance or the examples, you need to complete the grouping template (MS Word Document, 26.5KB) , copy and paste it into the main body of an email and send it to variationqueries@mhra.gsi.gov.uk before you submit your application. We aim to confirm if your grouping is acceptable within 7 working days.

Variations to multiple products (worksharing)

You can use the worksharing format if you’re submitting the same type IB or type II change or group of changes to multiple MAs. Proposals for worksharing applications should be sent to:

Once MHRA have all the necessary documents, it will usually take 60 days to assess applications although it could take up to 120 days if the variation(s) are more complex or up to 30 days if urgent.

See the best practice guide on worksharing for details on how to submit an application this way.

Composite coordination collection (CCC) - national pilot scheme

If you want to apply for changes to one or more product licences (licence for each product under a marketing authorisation) that would affect the product information you can submit a composite coordination collection (CCC). Product information includes the summary of product characteristics, leaflets and labels.

With a CCC you can:

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

You shouldn’t use this scheme for:

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

You would pay for this scheme as though you were paying for individual variations. See the list of fees

To get your CCC proposal approved and to see how to apply, follow the guidance for CCC application (PDF, 700KB, 32 pages) .

Fees

Fees for variations.

Make a payment to MHRA before you apply if you haven’t already, and include proof of payment with your application.

Include your proof of payment as a labelled PDF in the working documents folder of your electronic Common Technical Document (eCTD). It should be either a:

  • BACS or CHAPS electronic confirmation form
  • photocopy of the cheque for the required sum (dated and signed)
  • MHRA iRIS email account receipt (preferred for iRIS account holders)
  • email confirmation from MHRA finance department

How to apply (all variation types except extensions)

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

Match the right change code to your specific variation by checking the annex in the European Commission’s guidelines. You will need to include this in your application form.

Submit the variation application form (MS Word Document, 970KB) along with the supporting documents via the MHRA Portal or for larger submissions (more than 100Mb zipped) via CESP.

If this is not possible MHRA will accept submissions on CD/DVD, however this may take longer to process. For more information read our guidance on submitting on CD/DVD.

You must submit your variation using the electronic Common Technical Document (eCTD). If you can’t use eCTD you can use the Non-eCTD electronic Submissions (NeeS) process.

We check that NeeS and eCTD submissions are technically valid using the Extedo Eurs is Yours (EiY) validation tool. We recommend that you use a validation tool to check your submission.

If you have any questions about submitting your variation email Area3-VARIATIONS-submission-queries@mhra.gsi.gov.uk.

Supporting documents

Send a dispatch date list (detailing when you intend to dispatch the products) to all member states before submitting your application if your MA was granted through the mutual recognition or decentralised procedures. Where the UK is your reference member state, email this list to Type1aDDL@mhra.gsi.gov.uk for type IA changes and MR-DCprocedures@mhra.gsi.gov.uk for type IB and II changes and include a copy in the ‘additional data’ section of the eCTD format.

Type IA and IB

For type IA and IB variation applications you need to include:

  • a cover letter with 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) acceptable groupings guidance and examples of groupings (PDF, 2.5MB, 12 pages) or the confirmation email from MHRA agreeing you can submit grouped variations
  • the supporting information required for specific variations as set out in the annex of the European Commission’s guidelines
  • present and proposed details of your product presented as a separate document if necessary
  • a contents page listing all documents included in your submission

Type II

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

  • relevant information to support your 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)

If relevant, the summary of product characteristic fragments (SPC) should be submitted to MHRA in the correct format using the templates below. If you do not use these templates your submission will be rejected.

These templates should not be altered in any way, other than inserting the relevant information. They should be saved using the following naming conventions in the ‘workingdocuments’ folder of your eCTD:

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

More information

The European Commission has published guidelines for submitting variation applications including the change codes needed. You may also find the common scenarios for submitting variations (PDF, 185KB, 8 pages) useful.

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

For help with completing the application form and groupings see the guidance by the coordination group for mutual recognition and decentralised procedures on the Heads of Medicines Agencies website.

Contact

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