Guidance

Variations to Marketing Authorisations (MAs)

How the MHRA processes variations to Marketing Authorisations (MAs)

The guidance describes the approach the MHRA takes to the processing of variations to marketing authorisations.

Update to this guidance on 29 December 2020

This guidance has been updated and supersedes the version published previously.

The updates are particularly relevant to variations for products that were approved under MR or DC procedures. For approved products, MA holders will have the option to maintain the authorisation within the MR or DC procedure in Northern Ireland, while maintaining a UK wide authorisation (Northern Ireland and Great Britain, which means England, Scotland and Wales).

As a consequence, importantly, variations to these MAs from 1 January 2021 may be submitted and managed as part of the relevant MR/DC procedure under Chapter II of Regulation (EC) No 1234/2008 with Northern Ireland as CMS, where the outcomes will be implemented UK wide. Note this when preparing and submitting any new variations, because if incorrectly submitted they will be rejected.

1. Variations Procedure

The procedures detailed under Chapter IIa of Variations Regulation (EC) No 1234/2008, which specifically applied to variations to purely national Marketing Authorisations, were incorporated into UK law from 11pm on 31 December 2020, and as such continue to apply to both pending and new variations to purely national UK Marketing Authorisations, from 1 January 2021 and can be found in new regulation 65C and Schedule 10A to the Human Medicines Regulations 2012 (“HMRs”).

In addition, unless specifically highlighted under section 3, the current variations classification guidelines, which explains the type of variation (Type IA, Type IAIN, Type IB, Type II or Extension) to submit and, where relevant, the conditions to be met and any required supporting documentation, will continue to apply

Any extension application should be submitted in accordance with the procedures for new Marketing Authorisations. The variations classification guidelines will continue to apply until the MHRA issues any revised guidance in the future.

The UK will recognise any Article 5 recommendation published by the Co-ordination group for Mutual recognition and Decentralised procedures – human (CMDh) before 1 January 2021. Any specific request from a Marketing Authorisation Holder (MAH), concerning the classification of a variation, which is still pending (no recommendation) on 1 January 2021 or is submitted after 1 January 2021 will need to be submitted directly to the MHRA, who will issue its own recommendation.

2. Variation of a UK marketing authorisation

Marketing Authorisations authorised in the UK by the MHRA before 1 January 2021 continue to have effect across the UK (Northern Ireland and Great Britain) . This includes those which are currently and will continue to be part of any MR/DC procedure.

For purely national Marketing Authorisations, any pending and new variations will be processed to conclusion after 1 January 2021 as national variations, where the relevant national procedures will be followed.

For Marketing Authorisations which were already authorised as part of MR/DC procedures before 1 January 2021, any pending and new variations will be processed to conclusion after 1 January 2021 as MR/DC variations using the relevant MR/DC procedures led by the RMS. This includes relevant worksharing variations.

Northern Ireland Protocol

Under the provisions of the NIP, medicinal products authorised for Northern Ireland continue to follow EU rules. The requirements of unfettered access will be respected for those products where the Marketing Authorisation Holder is established in Northern Ireland and the Great Britain marketing authorisation has been obtained as a qualifying Northern Ireland Good.

The Definition of Qualifying Northern Ireland Goods (EU Exit) Regulations 2020.

Community Marketing Authorisations

Under the Northern Ireland Protocol, Medicinal Products authorised via the centralised route will be directly authorised for use in Northern Ireland. Any variations to these Marketing Authorisations will be centrally managed by the EMA in accordance with relevant procedures. A separate MA will not need to be issued by the MHRA for Northern Ireland .

If the same product is separately authorised in Great Britain a separate variation application will need to be submitted to vary that authorisation. Type IA notifications can only be processed on the basis of what is actually submitted to the MHRA for Great Britain. However, for Type IB and Type II variations, if such a variation is submitted for the corresponding Great Britain authorisation, after approval of the identical changes by the EMA, and evidence of this is included with the submission, this will be taken into consideration according to the reliance route for variations. A lower fee will be charged. Further guidance will be issued in due course.

Products authorised under EU Decentralised or Mutual Recognition Procedures

See guidance concerning the handling of Decentralised and Mutual recognition procedures approved or pending.

Under the Northern Ireland Protocol, Medicinal Products authorised via the MR/DC procedure from 1 January 2021, where Northern Ireland is specifically included as a CMS may be authorised for use in Northern Ireland only, where a UK MA in respect of Northern Ireland (PL(NI)) will be issued by the MHRA, or as a UK wide MA (PL) with Northern Ireland as a CMS and Great Britain aligned with the decisions taken by the RMS, but not part of the DCP/MRP. Any variations to these Marketing Authorisations will be managed as part of the specific MR/DC procedure, according to the relevant procedures laid down in the Variations Regulation (EC/1234/2008 as amended), where worksharing will also be possible.

Where a UK wide MA is involved, since the MR/DC variation decision applies UK wide, it can be implemented unless the MHRA notifies the MAH within 30 days of the RMS decision that it cannot be accepted in Great Britain. In this case a separate MA for Great Britain will need to be issued.

Where a PL(NI) is issued, if the same product is separately authorised in Great Britain, a separate variation application will need to be submitted to vary that authorisation under domestic legislation. Type IA notifications can only be processed on the basis of what is actually submitted to the MHRA for Great Britain.

However, for Type IB and Type II variations, if such a variation is submitted for the corresponding Great Britain authorisation, after approval of the identical changes by the RMS, and evidence of this is included with the submission, this will be taken into consideration according to the reliance route for variations.

A lower fee will be charged and there will be no fee if the Great Britain authorisation was granted under the unfettered access route, based on a purely national Northern Ireland authorisation. Further guidance will be issued in due course.

2.1. Pending variations (no decision)

How variations that were pending (‘no final decision) on 1 January 2021 would be finalised:

Purely national Marketing Authorisations (not part of any worksharing procedure)

These will be processed to conclusion under the transitional provisions, using the same purely national procedures that were in place prior to 1 January 2021.

UK Marketing Authorisation covered under Chapter II of Regulation (EC) No 1234/2008 (variations to marketing authorisations granted in accordance with Chapter 4 of the 2001 Directive i.e. mutual recognition/decentralised variations (Type IA, Type IB or Type II)

These will be processed to conclusion after 1 January 2021 as MR/DC variations using the relevant MR/DC procedures led by the RMS, where NI will be a CMS.

Purely National Marketing Authorisations before 1 January 2021, but part of a worksharing procedure under Article 20 of Regulation (EC) No. 1234/2008 (Type IB or Type II)

Any worksharing variation involving purely national Marketing Authorisations will be processed to conclusion after 1 January 2021 as part of the existing worksharing procedures led by the relevant Reference Authority.

Action to take if the applicant does not wish to continue with the relevant variation as a national (UK) application

The applicant should notify the licensing authority in writing that they no longer want the application to proceed. A partial fee refund may be applicable in line with the current MHRA fees regulations.

2.2. Pending variations (decision made)

In the event that the UK is not the Reference Member State or Reference Authority for a variation procedure and a final decision has already been taken by the lead authority, but not finally processed in the UK before 1 January 2021, the MHRA will implement the agreed outcome of the procedure.

2.3. New variations submitted

All new variations submitted will either be processed as purely national variations, according to the same transposed procedures, as were in place prior to 1 January 2021 or those which were already part of MR/DC procedures prior to then, which will continue to be processed as MR/DC variations.

Northern Ireland Protocol

New variations submitted to Marketing Authorisations issued as a result of Northern Ireland’s involvement in European procedures will be managed in line with the base procedures.

All other new variations will be processed as purely national variations, according to the same transposed procedures, as were in place prior to 1 January 2021.

Worksharing will only be possible for purely national Marketing Authorisation authorised for use only in Northern Ireland. However, provided the identical Type IB or Type II variation has already been approved for a related European Marketing Authorisation and evidence of this is included with the submission, this will be taken into consideration during the assessment process according to the reliance route procedure.

A lower fee will be charged and there will be no fee if the Great Britain authorisation was granted under the unfettered access route, based on a purely national Northern Ireland authorisation. Further guidance will be issued in due course.

3. Points to note for specific changes submitted from 1 January 2021

3.1. Change to finished product manufacturer

A change in finished product manufacturing site, including as appropriate primary and/or secondary packaging site should be submitted under the relevant sub-change code under B.II.b.1 and be suitably supported. This includes the submission of a copy of the relevant Manufacturing Authorisation or as appropriate a valid good manufacturing practice (GMP) certificate issued by the UK, or a GMP certificate (or equivalent document) from the competent authority of a country on the approved country for batch testing list (currently EEA Member States, Australia, Canada, Israel, Japan, New Zealand, Switzerland and the USA).

More information about batch testing including a list of approved countries for authorised human medicines from.

Where relevant reference to the EudraGMP database will suffice.

3.2. Change to importer/batch release site/quality control site

A change in importer/batch release site and/or quality control site should be submitted under the relevant change code under B.II.b.2 and be suitably supported.

3.2.1. Importer/batch release

The change should be supported by including a copy of the relevant Manufacturing Authorisation or a valid GMP certificate issued within the last 3 years (as issued by the UK or a country included on the approved country for import list (currently EU/EEA Member States).

Where relevant reference to the EudraGMP database will suffice.

3.2.2. Quality control site

The change should be supported by including a copy of the relevant Manufacturing Authorisation or a valid GMP certificate (as issued by the UK or a country included on the approved country for batch testing list (currently EEA Member States, Australia, Canada, Israel, Japan, New Zealand, Switzerland and the USA). However, see separate guidance considering any specific exclusions.

Where relevant reference to the EudraGMP database will suffice.

3.3. Change of Marketing Authorisation Holder (MAH)

A change of MAH, such as from a company outside the UK to one established in the UK, cannot be done as a variation. That change requires the submission of a Change of Ownership application.

A change to the name/address of the MAH can be submitted as a Type IA IN under change code A.1, provided that it is not a change to the legal entity.

3.4. Change to the location of the Pharmacovigilance Systems Master File (PSMF) or the Qualified Person for Pharmacovigilance (QPPV)

Any change to the QPPV or location of the PSMF should be submitted under change code C.I.8.a (Type IA IN), provided the conditions and documentation requirements can be fully met.

The QPPV for UK authorised products must be established in the EU/EEA or UK on day one, and the PSMF for UK authorised products must be accessible electronically from the UK at the same site at which reports of suspected adverse reactions may be accessed.

Please see separate guidance on submission of pharmacovigilance details.

3.5. Implementation of the outcome of referrals and procedures concerning PSUR or PASS

Where the procedure has been finalised before 1 January 2021, the outcomes in relation to any required variations will be processed according to the EU decision. Depending on the nature of the required changes, the variations should be submitted under the relevant main change codes of C.I.3 or B.V.b (usually type IA). The actual submission category will depend on the specific nature of the required changes, taking into consideration if further assessment is required

Where the procedure is ongoing, the outcome of the procedure should be implemented via the appropriate route.

Outcomes of these procedures should be implemented as appropriate and where a variation is required it will usually be a Type IA.

3.6. Submission of protocols and study reports for post authorisation safety studies (PASS)

Although not actually variations, whether or not carried out in relation to a condition of the MA or voluntarily, the protocol and final study reports from safety studies should be submitted to the MHRA within 12 months of the end of data collection.

The most effective way of processing these is according to the Type II variations procedure, and they should be submitted under change code C.I.13. The submission should be accompanied by the appropriate fee, which is the same as that of a Type II or Type II complex variation. . See also guidance on our approach to pharmacovigilance procedures from 1 January 2021.

3.7. Submission of paediatric study reports for assessment

Holders of a UK marketing authorisation who sponsor a paediatric study (which involves the use in the paediatric population of a medicinal product to which that authorisation relates), must submit the results of this study to the MHRA within the period of six months from the end of the study. MHRA has issued guidance setting out the submission requirements and procedures for assessment of completed paediatric studies.

In cases where an initial appraisal indicates that an assessment is required, the MAH will be asked to submit the paediatric data as a Type II complex variation to the MHRA under change code C.I.13.

If the results of a paediatric study have been submitted for assessment to EMA or CMDh under Article 46 of Reg.1901/2006/EC prior to 1 January 2021 MHRA will request MAHs to submit a Type IB variation to update the product information (PI) if there are proposed changes to the PI that can be directly implemented to relevant UK products following the completion of the EU procedure.

Contact

For further information, please email our Customer Services Centre at info@mhra.gov.uk or call 020 3080 6000. Alternatively, contact your Trade Association by emailing:

Published 31 December 2020