These questions and answers have been developed by the Patient Information Quality (PIQ) Unit from our experience in answering a variety of enquiries that have been posted to the Patient Information Quality Unit mailbox.
These are intended to provide additional helpful advice to industry and to complement the guidance that MHRA has already published elsewhere.
1. How to submit
2. Fees
3. Multiple concurrent applications
4. Submission status
5. Implementation dates
6. Final printed samples
7. Compliance with Article 59(3)
8. Non-compliance with Article 59(3)
9. BGMA data-sharing scheme
10. Bridging to Nationally authorised leaflets tested in other Member States
11. Multiple product names and leaflets
12. Email addresses and website references
13. Self-certified changes
14. User testing of labels
15. Braille
16. Labelling of controlled drugs
17. Child-resistant packaging
18. Calendar packs
19. Over labelling
20. Tamper-evident seals
21. Sample packs
22. Joint marketed packs
23. Additional pack information
24. Additional leaflet information
25. Patient support materials
26. Invented names
27. Labelling of generic cephalosporin products
28. Revision date
29. Sunset clause
1. How to submit
How do we submit an Article 61(3) notification to Patient Information Quality (PIQ) for changes to labels and/or leaflets (including those supported by user testing data)?
All submissions must meet the requirements published in Special Mail 5.
For submission on CD please use:
- either the application form in Word format (i.e. 'Application for changes to labels and patient information leaflets'
(36Kb) (not accompanying a variation change)). - or the Portal form in Adobe PDF format (i.e. ‘Changes to the Marketing Authorisation’) can be used.
For submission via the Sentinel Portal, only the Portal Adobe PDF format of the form will be acceptable.
How do we submit a Better Regulation of Medicines Initiative (BROMI) Article 61(3) notification for self-certified changes to labels and/or leaflets?
For submission on CD please use:
- either the application form in Word format (i.e. 'Notification of changes to labels and patient information leaflets for self certification form' (128Kb)).
- or the Portal form in Adobe PDF format (i.e. an as an “Information Update” using the ‘General product licence submission’ form) can be used.
For submission via the Sentinel Portal, only the Portal Adobe PDF version of the form will be acceptable.
Where should we send a CD submission?
Please address it to:
Information Processing Unit
Area 9
Medicines and Healthcare products Regulatory Agency
151 Buckingham Palace Road
London
SW1W 9SZ
Can we submit changes to both labels and leaflet components at the same time?
Yes. Several changes to several components (of the same livery/entity) may be submitted in one application and therefore incur just one full fee. The application form should thereby reflect which from 'label', ‘leaflet’ and 'label/leaflet' the changes apply to.
What must we include in our Article 61(3) notification to PIQ for changes to labels and/or leaflets (including those supported by user testing data)?
You will need to submit the relevant completed application form (as detailed above), covering letter and a set of pdfs of the clean mock-up(s) (and user test or bridging data, as appropriate).
Can we submit changes to labels and leaflet components for several different liveries (Marketing Authorisation holder and own-label supplier) at the same time?
A separate application form is required for each livery. The submission must also include all affected Marketing Authorisations especially where a leaflet may be shared across several Marketing Authorisations.
How do we submit an Article 61(3) notification to PIQ for changes to labels and/or leaflets (including those supported by user testing data) for a Mutual Recognition Marketing Authorisation?
Until such time that the labelling and leaflet have been harmonised across all Member States concerned, the label and leaflet remains for National (UK) approval and should be submitted as an Article 61(3) notification to PIQ, as detailed above.
Where the applicant intends to harmonise the labelling and leaflet across Member States concerned then this should be as a part of a type II medical variation and must include data in compliance with Article 59(3) at that time. The usual variation application form (relevant to submission on CD or via the Sentinel Portal) should be used.
Where the labelling and leaflet have already been harmonised by Mutual Recognition or the Decentralised Procedure any further changes should be submitted in accordance with the CMD(h) guidance for Article 61(3) changes to patient information. Submissions on CD should be made on the notification form available on the Heads of Medicines Agencies (external link) website. Submissions made via the Sentinel Portal must use the Adobe format ‘Changes to the Marketing Authorisation’ application form.
2. Fees
We have a product available in several strengths and wish to make the same change to all of them at the same time: do the bulk fees for submission apply?
Yes.
What are the fees for a BROMI Article 61(3) notification (self-certified)?
From 1 April 2010 a new full fee of £201 for a BROMI Article 61(3) notification will be introduced. Bulk fee arrangements will continue to apply.
What are the fees for a full application for assessment by Patient Information Quality?
From 1 April 2010 the full fee is £559. Bulk fee arrangements apply.
3. Multiple concurrent applications
Can we submit an application to change our packaging if there are already variations pending on the Marketing Authorisation?
In general, applications submitted on Marketing Authorisations where there are outstanding applications that also affect the label and/or leaflet will not be accepted as valid.
Where your submission is to comply with article 59(3) and you are submitting user test data an exception will be made and your application will be validated and processed. In this case please direct your enquiry to the Patient Information Quality Unit mailbox providing details of all relevant submissions in order for us to advise appropriately.
4. Submission status
Please can you provide us with an update on the status of our submission? We have received no communication from MHRA confirming validation.
Enquiries should be directed to the Variation Queries mailbox
Please can you provide us with an update on the status of our submission? We have received no communication from MHRA confirming receipt.
Enquiries should be directed to Area 6 of the Information Processing Unit (see postal address above) or to the Submissions Centre mailbox.
Please provide appropriate details of the submission to allow colleagues to locate your documentation.
If the submission was made via the Sentinel Portal and you have not received an email auto-receipt or it has not yet been uploaded then please direct your enquiry to the Portal mailbox.
We have submitted a simple administrative change to the labelling and/or leaflet: when might we receive a decision from MHRA as to whether this is approved?
Valid applications are triaged weekly by PIQ and it is likely that you will receive feedback much earlier than 90 days for very simple changes.
We have received confirmation of a valid submission (i.e. that it is ready for assessment) but we have not received any further feedback regarding assessment or approval.
Please direct your enquiry to the Patient Information Quality Unit mailbox.
We have submitted a BROMI self-certification notification for changes to labels and/or leaflets but 14 days have passed and we have not received the Notification of Acceptance.
Enquiries should be directed to the Variation Queries mailbox.
Please provide appropriate details of the submission to allow colleagues to locate your documentation.
5. Implementation dates
We have received approval of the changes to the labelling and / or leaflet but how long do we have to implement the change to our packaging?
Once new packaging components have been approved by the MHRA these must be introduced into packed stock being certified for release to the market by the Qualified Person in accordance with Directive 2001/83/EC (as amended) within three to six months, unless MAHs have been advised of the need for earlier introduction of the new components for safety reasons. The Qualified Person should not certify a medicinal product for release to the market if the packaging components, at the time of certification, have not been updated within three to six months following approval.
6. Final printed samples
PIQ has requested samples of the final printed packaging components in the past: do you still require them?
Yes, please. In the past we requested three copies but with the introduction of Sentinel we now only require one copy for our archives.
7. Compliance with Article 59(3)
We have a number of products that will not be marketed on 1 July 2008: do we need to user test the leaflet in order to comply with the legislation?
No. You are not required to update the Marketing Authorisations for non-marketed products at this time but must commit to provide the appropriate submission prior to marketing in the future. Please inform MHRA in writing as advised in MAIL 163.
For submission on CD please use:
- either the application form in Word format (i.e. ‘Notification of changes to labels and patient information leaflets for self certification form' (128Kb)).
- or the Portal form in Adobe PDF format (i.e. an as an “Information Update” using the ‘General product licence submission’ form) can be used.
For submission via the Sentinel Portal, only the Portal Adobe PDF version of the form will be acceptable.
8. Non-compliance with Article 59(3)
What should we do if we missed the MHRA’s 31 December 2007 deadline and still do not have the data ready to submit?
Please notify PIQ of those Marketing Authorisations that are affected and the prospective submission date by writing to the Patient Information Quality unit mailbox.
What will happen if our Marketing Authorisations do not comply on 1 July 2008?
We are currently in discussion with our colleagues in Enforcement and our legal advisors and will provide further advice on conclusion of these discussions.
9. BGMA data-sharing scheme
We are participating in the BGMA data sharing scheme and understand that MHRA have committed to expedite our submissions.
Applications for expedited assessment are those which appear on the list of "parent" products for the BGMA data sharing scheme. Other applications being submitted as a part of your portfolio update will be handled within the normal 90 day assessment timetable.
10. Bridging to Nationally authorised leaflets tested in otherMember States
We have an identical product licensed in another Member State and the leaflet has already been subject to user testing in another language. Can we use the same data for the National leaflet in the UK?
Yes. You will need to provide MHRA with the full set of data translated into English in support of your submission.
11. Multiple product names and leaflets
We have a number of licensed product names in section 1 of the Summary of Product Characteristics: can we have a single leaflet that includes all of these names?
No. Each licensed product name requires a bespoke leaflet presentation that meets the requirements of Article 59.
In the above situation, will each leaflet have to be the subject of a user test?
No. By the careful use of bridging studies, applicants (including own label suppliers/distributors) should be able to look across their portfolio and use tests carried out on similar or related medicines in a complementary manner to support the PIL drawn up for another product. Please refer to our bridging guidance for further information:
› Guidance for the Pharmaceutical Industry on the use of bridging studies to demonstrate compliance with article 59(3) of Council Directive 2001/83/EC [Consultation with Target Patient Groups]
(35Kb)
12. E-mail addresses and website references
Is it permissible to include the e-mail address of the Marketing Authorisation holder in a leaflet? If so, are there any restrictions on where the email address can appear? For example, my intention would be to position it with the address of the Marketing Authorisation holder.
Such non-statutory information should appear at the end of the 'Further Information' section of the leaflet. The e-mail address should not be placed in amongst the statutory information.
We want to add a reference to a website on the labelling and/or in the leaflet. Is this acceptable?
No. The current position of the European Commission is that any reference to a website on the labelling and packaging of medicines is not appropriate.
13. Self-certified changes
The change(s) we wish to make falls into the categories defined in the BROMI guidance but we cannot fulfil all of the criteria that accompany it. What should we do?
Please direct your enquiry to the Patient Information Quality Unit mailbox.
The BROMI guidance (81Kb) is a working document and is currently under review to simplify the criteria that must be met. Suggestions for amendment are always welcome, especially if they would encourage further uptake of this scheme.
14. User testing of labels
Does the legislation require us to test the labelling for our licensed products?
No, except where the outer labelling of the product also meets the leaflet requirements, in which case the labelling will also need to comply with Article 59(3).
15. Braille
Can we submit a BROMI self-certification notification to include Braille on the labelling?
Yes. Since the 1 April 2009 the MHRA has been accepting submission of this type to add Braille to the labelling in certain prescribed situations. Separate guidance is available covering this:
› Guidance on changes to labelling and patient information leaflets for self certification - compliance with article 56(a) - inclusion of Braille on the labelling (73Kb)
We can not fit the full name required in Braille on the front face of the carton, can we abbreviate it?
Braille can appear on more than one face of the carton provided that it is presented in a logical “reading” order (with the appropriate use of hyphenation). The use of abbreviated Braille is not acceptable.
We do not have enough space on the label to locate the Braille away from the printed text. What should we do?
Braille does not need to be on non-printed areas of the label but the legibility of any underlying printed text must not be compromised by the addition of Braille.
Which Braille alphabet should I use?
The European Blind Union (EBU) has worked with many blind organisations to provide an agreed Braille code and set of principles that can be used in many European countries. There is no intention to impose this on any European country and each Braille authority has the right to elect to allow the use of this code in their country or to require that the national Braille code is used.
The EBU pharma-braille website, developed and hosted by the Royal National Institute for the Blind (RNIB), is a subscription site giving details of the Braille code that has been agreed between many European blind organisations - the 'EBU Recommended Braille Code for Use on Pharmaceutical Packaging'. It also gives the EBU recommendations answering many frequently asked questions about how the Braille code should be implemented such as spacing, abbreviations, capitalisation and fitting Braille on the pack.
ls are also given relating to which countries have agreed to allow the use of this EBU code on pharmaceutical packaging. Each country's national code is also displayed where the information has been made available. As further countries respond we will update the contents and alert registered subscribers.
There is an annual subscription fee for commercial organisations of £250 + VAT, but some voluntary sector organisations may qualify for free subscriptions at EBU discretion.
To sign up, please register on the EBU Pharma - Braille site (external link) and then continue to either buy a subscription or email ebupharmabraille@rnib.org.uk to request a free subscription.
16. Labelling of controlled drugs
Please could you confirm if it is still a requirement to include CD in an inverted triangle on the labelling for Schedule 2 Controlled Drugs? This used to be a requirement but we cannot find any mention of it on the MHRA website.
The inclusion of CD in an inverted triangle has always been and still is a voluntary matter and we encourage Marketing Authorisation holders to adopt this approach. We would hope that you would continue to make reference to this on your medicines to which it applies.
17. Child-resistant packaging
We are trying to ascertain if there is an EU requirement/guideline on the need for child resistant packaging. We would like to know whether this is mandatory or whether it is at the discretion of the manufacturer.
The need for child resistant packaging is a matter for national legislation and the relevant regulations in the UK are the Medicines (Child Safety) Regulations 2003 number 2317 [SI 2003/2317].
The following medicines must, by law, be provided in child resistant packaging:-
- Solid oral dose aspirin,
- Solid and liquid oral dose paracetamol and
- Solid and liquid oral dose iron, containing more than 24 mg elemental iron.
Two standards exist which apply to reclosable and non-reclosable packaging and these are BS EN ISO 28317 and BS EN 14375, respectively. These are European standards established under the CEN system ( Europe's equivalent to the BSi) but only become legal requirements if cited in national legislation.
The standards may be obtained from British Standards Online (external link).
Applications for new Marketing Authorisations or variations to the packaging on existing authorisations for the above medicines must be accompanied by evidence of compliance with these standards (as appropriate) at the time of the submission.
18. Calendar packs
We currently market a tablet/capsule product in blister packs and would like to introduce blister foils printed with days of the week (i.e. to create a ‘calendar’ pack). What should we do?
Calendar blisters are only appropriate for tablets or capsules that are taken as a single dose once (or twice) daily and that are packaged in blister strips that comprise multiples of seven.
If appropriate, a formal Article 61(3) notification should be submitted for assessment as detailed above.
19. Over labelling
We have discovered an error on the printed packaging for a specific batch of one of our products. Could you please confirm if it is permitted to over label the primary packs with the most up to date approved labelling?
All information on packaging (both primary and secondary) for any licensed medicinal product must be printed directly on to the relevant packaging element. It is not acceptable to present any information by means of an over label.
20. Tamper-evident seals
We wish to introduce a tamper evident seal to our pack. Does this fall to be considered by PIQ?
Where this involves a change in the closure system registered in section 6 of your Summary of Product Characteristics you should make a formal variation application in the normal manner.
No reference to the tamper evident nature of the packaging is permitted on the labelling of the medicine so no changes are required to be submitted to PIQ.
21. Sample packs
We wish to introduce a sample pack, how should we go about this?
The requirements for such packs are found in SI 1994/1932 (Schedule 4).
Sample packs must be registered on the Marketing Authorisation and have bespoke labelling agreed that is identical to the statutory approved labelling of the usual marketed packs. The additional requirement is that the outer packaging includes "Free medical sample - not for resale" (or similar wording). This information must be printed on to the pack - it is not acceptable to use stickers. Where a leaflet is supplied with the product, or is attached as a peelable label/leaflet, this must also be included on sample packs.
Such samples can only be supplied in response to a written request from persons qualified to prescribe or supply such products and the numbers supplied per annum should be limited. The sample packs must be no larger than the smallest presentation available for sale in the UK and are intended for healthcare professionals to familiarise themselves with the product. They must be accompanied by a copy of the approved SPC.
22. Joint marketed packs
We wish to market a common pack in the UK and another Member State. Is this acceptable and how can we achieve this?
In order for an applicant to register a common pack in the UK and another Member State the licence details for the relevant products must be sufficiently identical (this includes legal classification with regard to sale and supply to the relevant markets) with the exception of the Marketing Authorisation numbers.
The submission to update the packaging would be acceptable as a self-certified label and leaflet change (category number 6) provided the criteria are met.
23. Additional pack information
We wish to include additional statements on the packaging of our product, will this be acceptable?
Article 62 permits the inclusion of information that is compatible with the Summary of Product Characteristics and must not include elements that are promotional in nature.
It should also be noted that information which may be appropriate for one Marketing Authorisation holder’s product may not be relevant to a competitor product where the details of the Summary of Product Characteristics differ. Such non-statutory information must be subordinate in prominence and placement to the statutory information.
Lifestyle statements such as “suitable for vegetarians/vegans” are not acceptable whereas factual statements such as “sugar/gluten free” may be acceptable in the correct context.
24. Additional leaflet information
We wish to include additional statements in the PIL for our products, will this be acceptable?
Article 62 permits the inclusion of information that is compatible with the Summary of Product Characteristics and must not include elements that are promotional in nature.
It should also be noted that information which may be appropriate for one Marketing Authorisation holder’s product may not be relevant to a competitor product where the details of the Summary of Product Characteristics differ. Such non-statutory information must be subordinate in prominence and placement to the statutory information.
For further information please see attached guidance on:
› Signposting from the patient information leaflet to additional sources of information and other services (69Kb)
25. Patient support materials
We wish to provide patients prescribed our medicine with additional information. Do we need to gain MHRA approval for this material?
If you signpost patients to this information from the statutory patient information leaflet, mock-ups of literature, DVDs, videos and other support material should be submitted to PIQ for review, prior to making these available to patients. For telephone helplines, details of the organisation providing the service should be provided as follows:
- the remit of the helpline;
- the qualification (e.g. nurse, pharmacist, lay-person) of those providing the information;
- any scripted Questions and Answers used.
Where you are introducing this service via a reference in your patient information leaflet the additional documentation will be considered during the assessment of the updated leaflet via a formal application.
Further guidance has been developed on the signposting to additional sources of information. The guidance is available at:
› Signposting from the patient information leaflet to additional sources of information and other services (69Kb)
26. Invented names
I have registered an invented name associated with a company name in section 1 of the summary of product characteristics (SPC). For the purposes of printing packaging components is it permissible within articles 56 and 59(1) of Council Directive 2001/83/EC [as amended] to
a) omit the company name portion of this name when applying Braille to packs or when printing patient information leaflets?
b) refer only to the common name of the active(s) contained within the medicine when applying Braille to packs or when printing patient information leaflets?
a). No. It is not permissible within the current policy to register a bespoke invented name encompassing a particular company name and thereafter introduce a “genericised” variant of the name on the leaflet or in the Braille representation since this does not meet with the legal requirements.
The requirement in the legislation is for all packaging components for a particular product to reflect the bespoke name registered in section 1 of the summary of product characteristics on the label, the patient information leaflet and in the Braille applied to the pack.
b). Similarly it is not permissible within the legislation to register a particular name in section 1 of the SPC and thereafter refer to a different name in the packaging components.
27. Labelling of generic cephalosporin products
Similarity in drug names is known to cause errors in drug prescription and selection. Recent medication errors have been reported concerning the mis-selection of generic cephalosporin products resulting in patients receiving the wrong product.
The MHRA and the National Patient Safety Agency have reviewed the errors and have agreed a labelling design mechanism which will help pharmacy staff more easily identify the correct medicine. To reduce the likelihood of errors occurring in the dispensing environment, use of Tallman lettering or other means of picking out key portions of the drug name will be required on the labelling of all medicines in this class.
Tallman lettering involves the use of capital letters (or the use of different coloured text) to highlight some unique aspect of the drug name. The particular string of letters to be highlighted in the cephalosporin range is set out below.
Applications for new or revised labelling for any medicine in this drug class submitted to assessment areas in the MHRA will be expected to comply with these provisions with immediate effect.
cefaCLOR
cefADROxil
cefALEXin
ceFIXime
cefoTAXime
cefPODOXime
cefRADine
cefTAZIDime
cefTRIAXone
cefUROXime
For further information please email the Patient Information Quality Unit, patient.information@mhra.gsi.gov.uk
28. Revision date
Article 59(1)(h) asks for the leaflet to include a "revision date". What date should I include on the leaflet when I submit an application to the MHRA? All applications which are accompanied by a leaflet mock-up should ensure that a revision date is included at the end of the PIL as required by article 59(1)(h).
This date should reflect the date of submission and should be in the format MM/YYYY.
If you are asked to revise the document following assessment you should amend the date to reflect the date of your response to the request for further information.
29. Sunset clause
My marketing authorisation (MA) was granted without mock-ups as there was no intention to market the product immediately following the application being granted. I now wish to submit an application to register mock-ups of all packaging components to enable the product to be marketed. What additional information is required?
Because the MA was granted on the basis of text only for the labelling and the patient information leaflets the marketing status was set as 'not marketed'. You should submit your full colour mock-ups of the labelling and the PILs according to the advice above in FAQ 1.
If you intend to market your product within one month of the grant of the full colour mock-ups you can notify the Patient Information Quality Unit (PIQU) during the assessment of the artwork components. The PIQU assessor will update the marketing status of the MA in line with your notification. You would not then need to make a separate notification to the MHRA in line with Article 23(a) of Directive 2001/83 and this will avoid any further action being taken against the MA as foreseen under Article 24(4-6) of Council Directive 2001/83/EC – the so-called 'sunset clause'.
Should you intend to market after one month, the marketing status will remain as ‘not marketed’ until such time as a separate notification is received via the sunsetclause mailbox, sunsetclause@mhra.gsi.gov.uk.
Further information can be found on the MHRA reminder of Article 23a obligations and the ‘Sunset Clause’ page.
