The recent medicinal products newsletter (issue 61) published by the HPRA includes an article about batch-specific requests (BSRs) and safety features. This is an update on the Falsified Medicines Directive safety features information.
The Commission Delegated Regulation (EU) 2016/161 with detailed rules for the safety features appearing on the packaging of medicinal products for human use, came into force in Ireland on the 9th February 2019.
BSRs will be considered for medicines for the Irish market that come within the scope of the regulation but do not bear safety features (UI and ATD).
The article outlines the details the MAH must provide in the BSR application.
Furthermore, the MAH must confirm that safety features have already been registered with the HPRA and if not a simultaneous Article 61 (3) notification must be submitted with the BSR application.
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The European Union is arguably the world’s most powerful bloc and very soon it’s about to lose the United Kingdom, one of its biggest members. How and when the UK leaves the EU will have further implications that ripple around the globe.
So if you’ve heard about Brexit but haven’t been keeping up with every twist and turn of the developments, no worries! Ivowen team will provide you with everything you need to know to have your products designed for UK and Brexit affected markets authorised successfully.
What is happening?
EMA
The European Medicines Agency (EMA) will physically relocate to the Netherlands in early March 2019.
EMA will leave its premises in London on 1 March 2019.
It was confirmed that from 4 to 8 March, the Agency will operate on the basis of extended teleworking. During the course of the following week EMA staff will gradually move into the Spark building.
From 4 March 2019 onwards the official address of EMA will be that of the permanent building, located in Amsterdam Zuidas:
European Medicines Agency, Domenico Scarlattilaan 6, 1083 HS Amsterdam, The Netherlands
Meetings and visits will take place at the Spark building:
Orlyplein 24, 1043 DP Amsterdam, The Netherlands
UK guidance on Brexit
Following the outcome of the EU referendum, MHRA still feels responsible for playing a crucial role in medicines and devices regulations as well as vigilance and market surveillance.
As part of the MHRA response to exiting the EU the following Brexit guidance was issued:
If you need any clarification or support to complete variations to support changes needed as a result of Brexit, Ivowen will gladly assist you in a timely manner. Contact us for more information or to make an enquiry.
MHRA guidance on Brexit
Bearing in mind the worst-case scenario if the UK leaves the EU with no deal, the UK would no longer be part of the EU medicines and medical devices regulatory networks and consequently submissions related to human medicines would need to be submitted directly to the MHRA.
The webinar below is relevant for all pharmaceutical companies involved in making medicines regulatory submissions and vigilance activities. It also ensures that stakeholders can be informed of any IT plans and preparations. There is also a section on how all medicines related clinical trial sponsors will register and submit:
If you need any clarification or support to complete variations to support changes needed as a result of Brexit, Ivowen will gladly assist you in a timely manner. Contact us for more information or to make an enquiry.
UK legislation on medicines and medical devices
Legislation has been published which, in the event of the UK leaving the EU with no agreement, will cover the regulation of medicines, medical devices and clinical trials and allow for the continued sale. The Brexit guidance is available here:
The 2012 Regulations (as amended by the 2019 Regulations) make reference to various pieces of EU guidance, as that stood immediately before the exit day (29 March 2019).
If you need any clarification or support to complete variations to support changes needed as a result of Brexit, Ivowen will gladly assist you in a timely manner. Contact us for more information or to make an enquiry.
EU Commission and EMA Q&As
The EU Commission & EMA have published an updated list of questions and answers related to the UKs withdrawal from the EU on the 1st February:
This confirms that dual labelling between UK & Ireland is acceptable where the labels meet the requirements of the Directive and reflect the SPC in Ireland (see Q24).
The focus of this Q&A is on the regulation of medicinal products within the centralised procedure.
If you need any clarification or support to complete variations to support changes needed as a result of Brexit, Ivowen will gladly assist you in a timely manner. Contact us for more information or to make an enquiry.
Brexit Stakeholder Event
Brexit Stakeholder Event – Ivowen was there
Following the UK’s departure from the European Union, the HPRA, together with medicines agencies in Europe, is making preparations to ensure continuity to deliver on patient and animal health remits even if the UK fully exits the current systems as scheduled. There are potential implications for the European network as a whole and particularly for Ireland with its shared marketplace, see meeting agenda below:
Contact us if you would like some more information on this event or Brexit in general
Written by Karolina Dobrychłop
https://eureg.ie/wp-content/uploads/2019/02/Brexit3.jpg437625ERAadministratorhttps://eureg.ie/wp-content/uploads/2023/10/European-Regulatory-Affairs-Logo.svgERAadministrator2019-02-19 17:53:522023-11-06 11:15:36Brexit – because it affects you too…
Ivowen have provided some practical guidance and documents below, which may help you prepare for Brexit for products authorised by the DCP and MRP procedures.
Do you still need to change your MAH(s) in any of the EU Member States because of Brexit?
If so, refer to the following updated guidance issued in January 2019 which details the documentation and requirements to submit a Marketing Authorisation Holder transfer:
If you need any clarification or support to complete a Marketing Authorisation Holder transfer, Ivowen will gladly assist you in a timely manner. Contact us for more information or to make an enquiry.
Is the UK your current RMS?
If so, you need to initiate an RMS switch as soon as possible. The guidance issued in July 2018 along with the template issued in June 2018 is required to complete this process. This template needs to be completed and sent to a specific e-mail address at the proposed new RMS. The list of contacts points to send the completed template is provided below:
If you need any clarification or support a RMS switch, Ivowen will gladly assist you in a timely manner. Contact us for more information or to make an enquiry.
Do you need to change your UK batch release site, etc., if it currently within the UK?
If so, you can refer to the updated guidance document issued in December 2018, which provides information on the type of variation that is required to change functions such as batch release site(s), QC testing site(s), packaging site(s), deletion of site(s) for batch release and changes to the QP for Pharmacovigilance (QPPV) and PSMF where these functions still reside within the UK:
If you need any clarification or support to complete variations to support changes needed as a result of Brexit, Ivowen will gladly assist you in a timely manner. Contact us for more information or to make an enquiry.
Do you supply product to Cyprus?
If so, the Cypriot Competent Authority has issued a newsletter to Stakeholders on the 14 January 2019 which lists 105 products authorised via an exceptional marketing authorisation affected by Brexit which are considered critical. The Drugs Council in Cyprus recommends that pharmaceutical companies register these products via an exceptional marketing authorisation using another reference state other that the UK.
If you need any clarification or support to complete an Exceptional Marketing Authorisation to avoid no supply of these critical products on the Cypriot market, Ivowen will gladly assist you in a timely manner. Contact us for more information or to make an enquiry.
The Health Products Regulatory Authority (HPRA) of Ireland is geared up and ready to support MA holders as they prepare for Brexit.
What happens if UK leaves the EU with no deal?
The implications of Brexit with regard to the UK’s role in the licensing of medicines will be determined by the terms of the ongoing exit negotiations. However, in accordance with Directives 2001/82/EC and 2001/83/EC:
For marketing authorisations issued through the mutual recognition procedure (MRP) or decentralised procedure (DCP), the Reference Member State (RMS) must be based in the EU/EEA.
The marketing authorisation holder (MAH) must be located within the EU/EEA.
MAHs will need to ensure that their EU qualified person responsible for pharmacovigilance (QPPV) and their pharmacovigilance system master file (PSMF) are located within the EU/EEA.
The batch release/testing site must be located within the EU/EEA.
HPRA are working “extraordinarily” hard on preparing for all scenarios
HPRA are Brexit ready
– Willing to act as RMS for all products where Ireland (IE) is currently CMS and a change of RMS is required. No fees will apply to the process for changing RMS to IE. The HPRA commits to an efficient and simple process for handling these requests (for example allowing the inclusion of multiple products in one request where applicable).
– To encourage the use of multilingual labelling the HPRA will proactively work with other European regulators to help optimise opportunities for multilingual labelling. The HPRA ‘Guide to labels and leaflets of Human Medicines’ has been updated (Oct 2018) to give specific guidance on the development of multilingual labelling
– HPRA MAH transfer procedures have recently been changed to allow MAHs up to 6 months to implement packaging changes following issue of the transferred authorisation, for Brexit related transfers. In addition the HPRA no longer requires stock to be recalled from wholesaler level six months following the issue of the transferred authorisation/ licence/registration.
Timeline for changing RMS
Can be completed within a matter of days. The critical issue will be the timing of when the change in RMS should occur as it is required to occur when there are no open regulatory activities for a product.
Procedures for MAHs to transfer MAH to EU/EEA based MAH
The transfer procedure must be used where the legal entity of an authorisation/licence holder is changed as marketing authorisations are transferred to a new company number. It is possible to transfer the MAH while there are ongoing/open variations. If the transfer is processed/issued, the new MA holder details will transfer onto the open/ongoing variations
Bulk transfers are accepted by the HPRA for Brexit and reduced fees apply.
New PA number is provided in advance of application.
Word version of an updated package leaflet is acceptable.
If the only changes proposed relate to MAH details and a new PA number, an Article 61(3) application is not required. However, if there are additional changes to the labels and package leaflet an Article 61(3) application must be submitted. This can be submitted in parallel to the transfer.
Medical devices containing an ancillary medicinal substance
Transfers of medical devices containing a medicinal ancillary substance with a valid CE certificate are considered administrative only. Transfers typically take less than 30 days from validation of the submission to be completed. No fees will apply to this transfer process.
Parallel Product Authorisations
If the UK is listed as one of a number of source countries on a PPA, this will need to be removed by way of a type IA variation (category 4).
Where the holder of PPA is located within the UK, the authorisation will need to be transferred to holder located within the EEA.
Qualified person certification of repackaging activity must take place within the EEA. Variations to change the site of batch certification can be submitted using the PPA variation category No 9a and 9b.
Variations to Marketing Authorisations to change Qualified Person Responsible for Pharmacovigilance (QPPV), manufacturing site or/and batch release sites.
Any variations required for a marketing authorisation (MA), e.g change in location of QPPV or site of batch release, should be completed prior to the date of the UK’s departure from the EU (prior to the 29 March 2019).
Changes in the QPPV, including contact details (telephone, and fax numbers, postal address and email address) may, for medicinal products for human use, be updated through the Article 57 database only (without the need for a variation)
Changes to the location of the PSMF (street, city, postcode, country) may be updated through the Article 57 database only (without the need for a variation)
Are you in search of advice and support on Brexit?
Please contact us, Ivowen are available to offer advice and support on HPRA compliance.
Written by Nanda Naik
https://eureg.ie/wp-content/uploads/2018/11/IE-EU-flag.jpg285390ERAadministratorhttps://eureg.ie/wp-content/uploads/2023/10/European-Regulatory-Affairs-Logo.svgERAadministrator2018-11-21 16:10:012023-11-06 11:08:42HPRA’s support as you prepare for Brexit……
What do you want to do next? Do you want to continue to market your product in the EU only, or are you interested in both the EU and UK markets? Read on to find out what you need to do for both scenarios.
If you would like to continue to market your product in the EU there are a few things that need to be finalised before Brexit on the 29th March 2019:
Reference Member State (RMS transfer)
This should have been done yesterday(!) The time it takes depends on the requested RMS’s workload.
Since July 2018 the MHRA is no longer accepting new applications with UK as RMS. However there are some currently authorised products wherein the UK is still the RMS.
If you have products and the UK is currently the RMS then it is vital a RMS transfer is initiated immediately. If there is only one CMS then this CMS should become the RMS (submission required). If there is more than one CMS, the preferred CMS needs to be consulted and a request sent asking them to be RMS. It is the responsibility of the MAH to secure a new RMS. The timeline for such transfers are solely dependent on the workload of the requested RMS.
Marketing Authorisation Holder (MAH) transfer
Needs to be done immediately – the time it takes is dependent on where the application is submitted.
From the 29th March 2019 the MAH for a product licensed in an EU Member State (MS) other than the UK must be based in the EU. Therefore if the MAH is currently based in the UK there needs to be a MAH transfer to one based in the EU.
If this involves purely an address change (i.e. the marketing authorisation holder remains the same legal entity but they have an address in the EU) then this is a simple type IAin (A.1).
If the new MAH is a different legal entity then the MAH transfer must follow the guidelines of the currently registered RMS and CMS, at the very least documents such as transfer agreement, proof of establishment, , power of attorney(s), Pharmacovigilance (PV) update, etc., should be in place before submission of the request.
Batch release
Needs to be done within the next 4-8 weeks unless a product is a biological / immunological product in which case submission needs to be immediate.
Products that only have batch release and quality control testing sites for finished product in the UK will have to change the batch release and testing sites for their EU products. For products that have other batch release and testing sites the MAH may choose to delete the UK site(s) or may choose to replace them. For finished products manufactured in the UK an importation site (in EEA) will need to be introduced. In many cases, a single site can perform manufacturing, testing, importation and/or batch release activities.
Needs to be done asap and in association with any MAH transfers – usually a type IA or type IAin
The Qualified Person for Pharmacovigilance (QPPV) and Pharmacovigilance Site Master File (PSMF) must be based in the EU/EEA.
If you wish to continue to market the product in the UK in addition to the EU:
The MHRA have stated that after Brexit, all currently approved authorisations will be transferred into national procedures and will remain valid.
If an application is in-progress at the time of Brexit the application will need to be submitted to the MHRA again as a national application in the case of CP procedures and that for MR or DC procedures a transitional provision will be made. HOWEVER, this is contingent on a Brexit deal that allows for a transition period. This has not yet been agreed.
To ensure the product can remain on the market / licensed, the UK are proposing the following if there is a no-deal Brexit
a MAH should be established in the UK by the end of 2020. Until then, the MHRA will require a contact in the UK. A Change of Ownership will need to be submitted to MHRA to change from an EU MAH to a UK MAH for UK MAs
the Qualified Person for Pharmacovigilance (QPPV) should be established in the UK on day one, although those without a current UK presence will have until the end of 2020 at the latest to do so, but would nevertheless be required to make arrangements for providing the MHRA with access to the relevant safety data related to UK Marketing Authorisations (MAs) at any time. Companies may choose to have the EU QPPV take on responsibility for UK MAs until the UK QPPV can be established. A variation should be submitted to the MHRA to change QPPV. Exact details of this will be consulted upon
a Qualified Person (QP) for products manufactured in the UK or directly imported into the UK from outside a country on a designated country list (whitelist) must reside and operate in the UK. A QP for products manufactured in a country on a whitelist or manufactured in a third country and imported into the UK from a country on a whitelist can reside in a country on the whitelist.
As the date for the withdrawal of the UK (also known as Brexit) from the EU approached closer, it pays to hope for the best and prepare for the worst. With this in mind, the EMA have issued a guidance document on “Practical guidance for procedures related to Brexit for medicinal products for human and veterinary use within the framework of the centralised procedure, EMA, 19 June 2018” to prepare for the UK’s exit from the EU by the 30 March 2019.
For marketing authorisation applications (MAAs) that are expected to receive a Commission Decision (i.e. be approved) after 29 March 2019, the QPPV, PSMF (for medicines for human use), batch release sites, batch control sites, intended OMCL (if applicable) and nominated local representatives for Member States other than UK must be located in in the Union (EEA).
As published on the EMA website on the 10 July, a recent European Medicines Agency (EMA) survey shows that marketing authorisation holders for more than half (58%) of the 694 centrally authorised products (CAPs) with an important step in their regulatory processes in the United Kingdom (UK), are on track with their regulatory planning to ensure that their marketing authorisation remains valid once the UK leaves the European Union (EU).
This also means that 42% are NOT ready… Are you one of the 42%
The EMA urges those companies who have not yet informed EMA of their Brexit preparedness plans to do so as soon as possible to mitigate any risks to the continuous supply of medicines for human and veterinary use within the EU.
We can help…
Ivowen can help Clients prepare to implement the required changes by providing the following services:
Provide practical guidance on what needs to be in place by the above date to address situations where the UK is the current MAH, batch release site, batch control sites, location of QPPV& PSMF, transfer of orphan designation, etc.
Act as a MAH in the EU
Provide Pharmacovigilance (QPPV) services in the EU
Provide Pharmacovigilance System Master File and backup services located in the EU
Assist Clients in selecting and transferring RMS to another EU member state where the UK is current MAH
Preparation of Brexit related variations to be ready for above timelines
Assistance in changes needed to Product Information to reflect changes such as new MAH, batch release site(s), amend names of local representatives
Please contact us for further information at any time.
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The updated Annex to “Excipients in the labelling and package leaflet of medicinal products for human use” guideline was published on the 09/10/2017. This updated Annex in all EU languages can be found here:
Marketing Authorisation (MA) Holders for approved products and Marketing Authorisation Applications for new MAs are required to list certain excipients in the labelling information, as outlined in Directive 2001/83/EC, as amended. These include all excipients for parenteral, ocular and topical products, and specific excipients in other products. These specific excipients are listed in the Annex for ease of access.
What’s new?
The newly added or updated specific excipients listed in the Annex include:
Aspartame (E 951)
Benzalkonium chloride
Benzoic acid (E 210) and benzoates
Benzyl alcohol
Boric acid (and borates)
Cyclodextrins
Fragrances containing allergens
Fructose
Phenylalanine
Phosphate buffers
Propylene glycol (E 1520) and esters of propylene glycol
Sodium
Sodium laurilsulfate (E 487)
Sorbitol (E 420)
Wheat starch (containing gluten)
What do you need to do?
For any of your currently approved products, you should use the first regulatory opportunity to revise any wording in line with the annex. This could be any when you are submitting any variation that involves changing the product information, for instance.
We can help…
Ivowen can advise you on the requirements and assist you with any of the updates and variations that you might have.
Please contact us for further information at any time.
All good (and bad) things, must come to an end. The NeeS (Non-eCTD electronic submissions) submission format, will no longer be accepted for any Marketing Authorisation applications (MAAs) or submissions in MRP or DCP from 1st January 2018. Centralised Procedure (CP) submissions have been mandatory in eCTD since 2010. All new MAAs submitted using either the Decentralised Procedure (DCP) or the Mutual Recognition Procedure (MRP), have had to be in eCTD format since the middle of 2015. As of 1st January 2018, all MRP submissions must be submitted in eCTD. Therefore, if your application/product is not in eCTD format and you need to submit an MRP variation, you have to transition to eCTD for the next submission.
What is the timetable?
Starting from 1st January 2018 it is mandatory for all CP, DCP and MRP submissions to be in eCTD format. For national procedures (NP) the deadline is currently set at 1st July 2018 for new MAAs.
Following quickly behind these requirements, all submissions in CP, DCP, MRP and NP will have to be in eCTD from January 2019. At this stage, the exact date is not confirmed, but you need to be ready.
We can help…
Ivowen can create a baseline dossier for any submission based on currently approved information. Currently, baselines are not mandatory but some Member States are requesting them. In addition, it is best practise to get your dossier into a baseline for all future submissions.
Ivowen can transition your application to eCTD at the next regulatory activity (variation, renewal, Article 61.3, etc.).
Ivowen can manage the eCTD lifecycle for you in-house and provide you with fully valid, submission-ready sequences.
Contact us for more information or for help with building your eCTD now.
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The submissions may concern national and European procedures (MRP, DCP) both for human and veterinary medicinal products.
Also from 3rd April 2017 the following submissions should be transmitted through CESP for Greece:
All submissions for Mutual Recognition/Decentralised Procedures (MRP/DCP)
national procedures relating to approvals, variations, renewals, PSURs, ASMFs etc., as well as any other documentation should be submitted using CESP.
Responses to deficiencies and any other additional information that can be requested from the EOF within the claims of assessment.
What does this mean for you?
To date in Poland, only submissions concerning initial MAAs were possible via CESP. There are still some national requirements in Poland, however. All documents that require an original signature can be either submitted
in electronic version with a valid electronic signature or
must be submitted in parallel to CESP in paper.
Documentation once submitted via CESP should be submitted via this channel throughout its whole lifecycle.
For submissions into Greece, additional CD/DVDs are no longer required. In addition, for each submission, a corresponding reference number will be automatically assigned and will be sent directly to the applicant.
Where can I find more information?
Full details are available on the Polish Ministry’s website (in Polish) here.
Ivowen are fully equipped to prepare and submit any applications on your behalf. Please contact us or our EuDRAcon partners for more information and for support of your dossier compilation or updates.
Written by Majella Ryan
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The ICH has introduced this new guideline to control the elemental impurities that may be present in drug products. It replaces EMEA guidance on Specification limits for residues of metal catalysts or metal reagents (EMEA/CHMP/SWP/4446/2000).
This guideline applies to new drug products (with a new drug substance) and to drug products containing existing drug substances. There are some exemptions, which you can find in the guideline.
It does not apply to drug products used during clinical research stages of development.
CHMP implementation dates for this guideline are
• New MA application for new products (new drug substance) – June 2016
• New MA application for products with existing drug substance – June 2016
• Marketed products including new MR applications of already approved products – Dec. 2017
What does this mean for you?
Elemental Impurities (EIs) in Drug Product (DP) may arise from several sources. They may be residual catalysts that were added intentionally or may be present as impurities (e.g., through interactions with processing equipment, container/closure systems or by being present in components of the drug product, i.e. drug substance, excipients or water).
Because EIs do not provide any therapeutic benefit to the patient, their levels in the drug product should be controlled within acceptable limits. These limits are outlined in the new guideline.
This guideline presents a process by which to assess and control EIs in the drug product using the principle of Risk Management as described in ICH Q9. This process provides a platform for developing a risk based control strategy to limit EIs in the DP.
The Risk Assessment (RA) should be based on scientific knowledge and principles. It should link to safety considerations for patients with an understanding of the product and its manufacturing process, and it should be focused on assessing the level of EIs in a DP in relation to the Permitted Daily Exposure (PDE) presented in the guidance.
The summary of RA and any measures taken, to ascertain compliance and the overall control strategy for EIs, including any specification as needed, should be provided in the Regulatory dossier.
The documentation of RA should be maintained in company’s quality system and should be kept for inspection (at the time of GMP inspection of the site by the competent authority).
If RA fails to demonstrate that an EI level is consistently less than the Control Threshold, then additional controls should be established to ensure that the EI levels does not exceed the PDE in the drug product. Approaches that an applicant can pursue include but are not limited to:
• Modification of the manufacturing steps that result in reduction of EIs,
• Implementation of in-process controls,
• Establishment of specification limits for excipients or drug substance or drug product,
• Selection of appropriate container closure systems.
For marketed products, if the RA concludes that additional controls are to be established then the regulatory impact of these additional controls should be evaluated to see whether it triggers a variation(s) to the existing MA.
Where can I find the relevant information…
The new guideline is available on the EMA website. You can find it by following this link.
We can help…
Ivowen are fully equipped to apply for any such variations on your behalf. Please contact us for more information and for support of your dossier compilation or updates.
Written by Nanda Naik
https://eureg.ie/wp-content/uploads/2017/03/ICH-elemental-imps.png498832ERAadministratorhttps://eureg.ie/wp-content/uploads/2023/10/European-Regulatory-Affairs-Logo.svgERAadministrator2017-03-16 12:08:342023-11-06 11:08:43New ICH guideline Q3D on elemental impurities (EMA/CHMP/ICH/353369/2013)
