Submitting Changes to Labelling and Patient Information Leaflets for Medicines

1. Background

UK legislation under Regulation 267 of the Human Medicines Regulations 2012 requires marketing authorisation holders (MAHs) of UK marketing authorisations and article 126a authorisations to inform the competent authority of all changes to labelling and patient information leaflets (PILs) that are not connected with changes to the Summary of Product Characteristics (SmPC). https://www.gov.uk/government/publications/submitting-changes-to-labelling-and-patient-information-leaflets/submitting-changes-to-labelling-and-patient-information-leaflets Responsibility for the information on packaging and PILs rests solely with the MAH. The MHRA has expanded the notification scheme for such changes under Better Regulation principles, making it the default since July 2012 for rapid and efficient processing. https://www.gov.uk/government/publications/submitting-changes-to-labelling-and-patient-information-leaflets/submitting-changes-to-labelling-and-patient-information-leaflets Only changes defined in section 3 are eligible for full assessment by the Product Information Quality Unit (PIQU). This guidance applies to changes in packaging components for all medicines except parallel imported products, Traditional Herbal Registrations, and homoeopathic medicines. https://www.gov.uk/government/publications/submitting-changes-to-labelling-and-patient-information-leaflets/submitting-changes-to-labelling-and-patient-information-leaflets

2. General Guidance on Submissions

Most changes to labelling and/or PILs not connected with SmPC changes are subject to self-certification by the MAH followed by notification to the MHRA, with exceptions in section 3. https://www.gov.uk/government/publications/submitting-changes-to-labelling-and-patient-information-leaflets/submitting-changes-to-labelling-and-patient-information-leaflets These changes cannot be submitted for formal assessment and will not be accepted as full applications by the Data Assurance Quality team (DAQ). Notifications are "tell and do," accepted within 14 days of receipt, and changes can be introduced once the MHRA acceptance letter is received. https://www.gov.uk/government/publications/submitting-changes-to-labelling-and-patient-information-leaflets/submitting-changes-to-labelling-and-patient-information-leaflets Any applicable fees are defined in relevant statutory instruments. Full colour mock-ups of the proposed final packaging components must accompany notifications, in a consolidated artwork file including changed and unchanged elements. https://www.gov.uk/government/publications/submitting-changes-to-labelling-and-patient-information-leaflets/submitting-changes-to-labelling-and-patient-information-leaflets Acceptance relies on MAH declarations of supporting documentation; MHRA conducts audits via random and targeted sampling, with outcome reports published on the website. https://www.gov.uk/government/publications/submitting-changes-to-labelling-and-patient-information-leaflets/submitting-changes-to-labelling-and-patient-information-leaflets Changes requiring full PIQU application or variation (per section 3) cannot use notification and must be fully applied for. Invalid notifications identified in audits may be rescinded, requiring further applications and potential stock removal if public health risks exist. https://www.gov.uk/government/publications/submitting-changes-to-labelling-and-patient-information-leaflets/submitting-changes-to-labelling-and-patient-information-leaflets

3. Applications for Full Assessment by MHRA

First approval of full colour mock-ups for labelling and PILs typically occurs at marketing authorisation grant (but text versions may have been approved earlier). New artwork for SmPC-related changes is assessed during variation applications. https://www.gov.uk/government/publications/submitting-changes-to-labelling-and-patient-information-leaflets/submitting-changes-to-labelling-and-patient-information-leaflets Subsequent changes requiring full PIQU assessment include:

• P1: First approval of mock-ups post-marketing authorisation grant where only text versions were submitted and approved in the marketing authorisation application (MAA); required prior to marketing. https://www.gov.uk/government/publications/submitting-changes-to-labelling-and-patient-information-leaflets/submitting-changes-to-labelling-and-patient-information-leaflets
• P2: Changes to PILs with significant content, design, or layout alterations, supported by user testing data, bridging data (demonstrating patient understanding), or data for extra-statutory information; full details on user testing or bridging needs are in the Best Practice Guidance on Leaflets. https://www.gov.uk/government/publications/submitting-changes-to-labelling-and-patient-information-leaflets/submitting-changes-to-labelling-and-patient-information-leaflets
• P3/P3EX: Changes to pack design and layout, including layout, content, or graphics; always require an application. Pre-approval by third parties enables expedited review, assessed within 30 days of valid application. https://www.gov.uk/government/publications/submitting-changes-to-labelling-and-patient-information-leaflets/submitting-changes-to-labelling-and-patient-information-leaflets
• P4: Changes solicited by MHRA notification, requiring full application; or handled via variation if consequential to variation (e.g., artwork for new own-label supplier, product name change, significant new safety information post-expert committee, or amendments following patient safety complaints). Variation applications may be handled in PIQU. https://www.gov.uk/government/publications/submitting-changes-to-labelling-and-patient-information-leaflets/submitting-changes-to-labelling-and-patient-information-leaflets

4. How to Submit Applications for Formal Assessment

MAHs must indicate on the application form (Word: Application for changes to labels and patient information leaflets; or portal form in Adobe PDF: [Changes to the Marketing Authorisation]) that the submission is for packaging changes without SmPC amendment, specifying category(ies) P1, P2, P3, and/or P4. https://www.gov.uk/government/publications/submitting-changes-to-labelling-and-patient-information-leaflets/submitting-changes-to-labelling-and-patient-information-leaflets Describe changes in a covering letter, include supporting data details. Reference changes on packaging components; multiple changes allowed if correctly referenced. Applications may include self-certified changes. Non-P1–P4 changes are rejected and must be resubmitted as notifications. Full colour mock-ups of proposed final components must accompany the submission. https://www.gov.uk/government/publications/submitting-changes-to-labelling-and-patient-information-leaflets/submitting-changes-to-labelling-and-patient-information-leaflets

5. Submissions for Self-Certification (Notification)

MAHs must state on the notification form (Word: Notification of changes to labels and patient information leaflets for self-certification; or portal form in Adobe PDF as Information Update via General Product Licence form) that the notification amends packaging without SmPC change, detailing precise changes and confirming no other changes introduced. https://www.gov.uk/government/publications/submitting-changes-to-labelling-and-patient-information-leaflets/submitting-changes-to-labelling-and-patient-information-leaflets Reference changes on packaging; multiple changes allowed if correctly referenced. Unnotified changes or those requiring formal application (per section 3) invalidate the notification. Full colour mock-ups must accompany the notification. https://www.gov.uk/government/publications/submitting-changes-to-labelling-and-patient-information-leaflets/submitting-changes-to-labelling-and-patient-information-leaflets

6. Mock-Ups

A mock-up is a full colour copy of the flat artwork design, presented to replicate outer and immediate packaging (including cutting and folding if necessary) in three-dimensional form, clearly showing labelling text. It is typically a paper copy, not necessarily in sales presentation material. https://www.gov.uk/government/publications/submitting-changes-to-labelling-and-patient-information-leaflets/submitting-changes-to-labelling-and-patient-information-leaflets

7. Timelines and Procedures

• Notifications: Accepted within 14 days; changes implementable post-acceptance letter. https://www.gov.uk/government/publications/submitting-changes-to-labelling-and-patient-information-leaflets/submitting-changes-to-labelling-and-patient-information-leaflets
• P3/P3EX Applications: Expedited review within 30 days if pre-approved by third parties and valid. https://www.gov.uk/government/publications/submitting-changes-to-labelling-and-patient-information-leaflets/submitting-changes-to-labelling-and-patient-information-leaflets
• Audits: MHRA conducts random/targeted audits; reports published. https://www.gov.uk/government/publications/submitting-changes-to-labelling-and-patient-information-leaflets/submitting-changes-to-labelling-and-patient-information-leaflets
• General: Changes not in section 3 are self-certified notifications only; full applications required for section 3 changes. https://www.gov.uk/government/publications/submitting-changes-to-labelling-and-patient-information-leaflets/submitting-changes-to-labelling-and-patient-information-leaflets

8. Variations and Self-Certification

• Self-certification applies to most non-SmPC changes (default since July 2012); "tell and do" procedure. https://www.gov.uk/government/publications/submitting-changes-to-labelling-and-patient-information-leaflets/submitting-changes-to-labelling-and-patient-information-leaflets
• Variations may incorporate artwork if consequential (e.g., supplier changes, name changes, safety updates). https://www.gov.uk/government/publications/submitting-changes-to-labelling-and-patient-information-leaflets/submitting-changes-to-labelling-and-patient-information-leaflets
• Invalid self-certifications (e.g., including section 3 changes) lead to rescission and required re-application. https://www.gov.uk/government/publications/submitting-changes-to-labelling-and-patient-information-leaflets/submitting-changes-to-labelling-and-patient-information-leaflets

9. Fees

Fees may apply to notifications, as defined in relevant statutory instruments; no specific fees detailed for applications. https://www.gov.uk/government/publications/submitting-changes-to-labelling-and-patient-information-leaflets/submitting-changes-to-labelling-and-patient-information-leaflets

10. Updates

Updated 22 December 2023. https://www.gov.uk/government/publications/submitting-changes-to-labelling-and-patient-information-leaflets/submitting-changes-to-labelling-and-patient-information-leaflets

11. Related Guidance

• Best Practice Guidance on Leaflets (for P2 user testing/bridging data). https://www.gov.uk/government/publications/submitting-changes-to-labelling-and-patient-information-leaflets/submitting-changes-to-labelling-and-patient-information-leaflets
• Audit outcome reports published on MHRA website. https://www.gov.uk/government/publications/submitting-changes-to-labelling-and-patient-information-leaflets/submitting-changes-to-labelling-and-patient-information-leaflets
• Links to forms and portal for submissions. https://www.gov.uk/government/publications/submitting-changes-to-labelling-and-patient-information-leaflets/submitting-changes-to-labelling-and-patient-information-leaflets