Regulatory Affairs Archives - European Industrial Pharmacists Group (EIPG)

PIC/S Annual Report 2021


by Giuliana Miglierini The Annual Report of the Pharmaceutical Inspection Co-operation Scheme (PIC/S) resumes the many activities and results achieved in 2021, despite the ongoing pandemic that required remote coordination and on-line virtual meetings. To this regard, a written procedure Read more

Joint implementation plan for the IVDR regulation


by Giuliana Miglierini Regulation (EU) 2017/746 (IVDR), establishing the new legislative framework for in vitro diagnostic medical devices (IVDs), will entry into force on 26 May 2022. The Medical Device Coordination Group (MDCG) has published an updated version of the Read more

Key issues in technical due diligences


by Giuliana Miglierini Financial due diligence is a central theme when discussing mergers and acquisitions (M&A). Not less important for the determination of the fair value of the deal and the actual possibility to integrate the businesses are technical due Read more

Joint implementation plan for the IVDR regulation

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by Giuliana Miglierini

Regulation (EU) 2017/746 (IVDR), establishing the new legislative framework for in vitro diagnostic medical devices (IVDs), will entry into force on 26 May 2022. The Medical Device Coordination Group (MDCG) has published an updated version of the Joint implementation and preparedness plan, discussing the priority actions to be implemented and monitored at the level of member states, Commission and MDCG.

The implementation of the IVDR is highly complex, as it requires a strict coordination between all the different stakeholders, including manufacturers, notified bodies, authorised representatives and laboratories. The IVD regulation has introduced a completely new device classification system for in vitro diagnostics, as well as a greater involvement of notified bodies in conformity assessment and new regulatory structures such as the EU reference laboratories and expert panels.

The Joint implementation plan is aimed to support the harmonised implementation of the new framework, a process led by the Commission and where member states are called to ensure the new provisions are effectively applied and enforced at national level.

Ongoing actions and future goals

As of January 2022, six notified bodies were already designated and the examination of other applications is undergoing. The Unique Device Identifier system that will support the punctual tracing of the devices has also been set up, while the Eudamed database is still under development. From the regulatory perspective, a number of new common specifications are being drafted; some guidance documents are already available while others are under development.

To smooth the impact of the transition and to prevent disruption in the supply of essential IVDs, Regulation (EU) 2022/112 has established the calendar for the transition of different classes of devices, i.e. 26 May 2025 for IVDs that fall in class D under the IVDR, 2026 for class C, 2027 for class B and A sterile.

The Joint implementation plan identifies two sets of priorities to be tackled by the stakeholders, on the basis of public health’s goals, patient safety and transparency. Set A includes essential actions to enable IVDs to maintain access to the market. Set B includes the development of other new pieces of legislation and guidance documents needed to better support the transition and the designation of EU reference laboratories for high-risk IVDs.

Set A, essential actions

Contingency planning and monitoring are the first priority to be met under Set A essential actions, in order to anticipate possible risks of IVDs’ shortages arising from the transition to the new framework. The MDCG will closely follow this process to monitor its progress and identify systemic risks and mitigation actions, with a particular attention to the availability of particularly critical IVDs.

Regular updates are also expected from the industry and notified bodies to inform member states and the Commission about the need of specific actions. This type of activity would also support the identification of barriers that could result in shortages of devices, e.g. with reference to the designation of notified bodies or the certification process. Stakeholders are also requested to be ready to manage some uncertainty in areas where guidance is still not available, thus requiring the provision of sound justifications to maintain critical IVDs on the market.

The second highest priority is the availability of a sufficient number of notified bodies to support the expected very high volume of applications for the certification of medium and high-risk IVDs. The plan indicates the need to make available national experts for the joint assessment of notified bodies. Member states should also address the need to improve the notified body capacity, discussing this issue within the MDCG and its specialised working groups as well as with the Commission. According to the Joint plan, the percentage of IVDs requiring certification under the new IVDR will rise up to 80-90%, from approx. 10% devices requiring involvement of a notified body under Directive 98/79/EC.

To facilitate this part of the transition, Regulation (EU) 2022/112 establishes that certificates issued under the Directive 98/79/EC are valid, under certain conditions, until May 2025. Renewals of existing certificates by a set of nineteen notified bodies designated under the current Directive is possibile, if necessary, up to 26 May 2022.

The plan also takes into consideration the possible occurrence of new Covid-19 restrictions, that may highly impact the work of the notified bodies (for example, due to the need to run first-time audits of many manufacturers). The Commission and the MDCG are thus called to consider how notified bodies can perform conformity assessment activities in such circumstances.

Set B, high priority actions

Actions included in set B are not essential for manufacturers to market their IVDs, but their implementation would support a smoother transition.

The EU reference laboratories are a new type of independent scientific body designated by the Commission to carry out additional tests on the performance and compliance with any common specifications of class D devices, before placing them on the market. If the Commission would not designate a EU reference laboratory for a particular device in class D, those requirements are not applicable. According to the Joint plan, a call for application to member states and the Joint Research Centre shall be issued by the Commission to nominate candidate laboratories. New implanting acts on tasks and criteria and on fees to be levied by the EU reference laboratories are also expected.

According to the IVDR, the adoption of common specifications (CS) is optional; nevertheless, the Joint plan indicates the intention of the Commission to propose some sets of common specifi cations and reach an agreement on the text that should enter the first adoption round. This should also lead to the adoption of the first implementing act containing the common specifications. This round should include common specifications relative to Kidd and Duffy blood grouping, Chagas and syphilis, and cytomegalovirus/Epstein-Barr virus devices, for which the drafting process is at an advanced phase.

New common specifications should be targeted to class D devices and will be developed by the IVD sub-group of the MDCG. Already existing CS under the old Directive should be transposed without major modifications.

A new implementing act on the MDR/IVDR standardisation request should be adopted by the Commission and accepted by relevant bodies (CEN/Cenelec). The Commission should also adopt the implementing acts on the publication in the Official Journal of references of harmonised European standards in support of the IVDR requirements.

Set B of actions include also the drafting and endorsement of a guidance on notified body designation codes, as well as of guidance on batch testing for notified bodies. New guidance may be also developed on significant changes and on appropriate surveillance, as referred to in Article 110(3) of IVDR. The MDCG should also complete the issuing of a new guidance on clinical evidence for IVDs, which is part of the documents needed to support the evaluation of the devices’ performances and the work of expert panels.

To this instance, the plan also indicates the need for a clarification on what constitutes a “type of device” and on the process to be followed by notified bodies in context of views of the expert panel. A template for summary of safety and performance should be also released, together with a template for the application/notification of performance studies. The issuing of an IVDR-specific guidance on harmonised administrative practices and alternative technical solutions until Eudamed is fully functional is also planned.

The joint plan also includes sections on actions required in the field of companion diagnostics, legacy devices and in-house devices.


A new joint work plan to 2023 for EMA and EUnetHTA 21

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by Giuliana Miglierini

The new Regulation (EU) 2021/228 on Health Technology Assessment (HTA) will assume full validity in January 2025, at the end of the 3-year transition period. To this instance, it is time to define the actions needed to establish the new framework for HTA in the field of medicinal products.

A central point of the new approach is represented by joint scientific consultations (JSCs) to be carried out in coordination between the European Medicines Agency (EMA) and the bodies entitled of HTA at the level of single member states.

After the termination of the European Network for Health Technology Assessment (EUnetHTA) initiative, in 2021, the new consortium EUnetHTA 21 has been created grouping thirteen HTA agencies from The Netherlands, Spain, Italy, Austria, Germany, France, Portugal, Belgium, Ireland, Hungary and Norway. EUnetHTA 21 signed a contract service in 2021 with the Health and Digital Executive Agency (HaDEA) for the provision of joint health technology assessment up to September 2023.

On this basis, EMA and EUnetHTA 21 have now published a joint work plan of the activities to be put in place until 2023; the initiative represents the continuation of the EUnetHTA Joint Actions, started in 2010 and concluded in May 2021.

The document identifies the priority areas of future collaboration between regulators and HTA bodies at European level, with the final goal to “improve efficiency and quality of processes, whilst respecting the respective remits of different decision makers, and ensure mutual understanding and dialogue on evidence needs”.

The transition to the new legislative framework shall be based on a flexible approach to the different tasks; the work plan includes both methodological and operative actions, and it will be monitored in close cooperation with the EU Commission. Progresses will be discussed during the four bilateral meetings planned until September 2023.

Under the new framework, high priority HTA activities related to the service contract will be delivered by EUnetHTA 21. Other voluntary activities can be actioned through individual HTA bodies from a European (EU/EEA) member state that expressed their interest to participate. Should this be the case, the work plan clarifies that the position is that of the individual HTA body, not of EUnetHTA 21. A public consultation on deliverables part of the EUnetHTA’s mandate is also planned.

Actions in support of JSCs

Joint scientific consultations are the core of the new approach to HTA, aimed to generate a robust evidence relative to the entire life cycle of medicinal products, including the post-licensing and launch.

The work plan establishes a new European process of “parallel joint scientific consultation” involving both HTA bodies and EMA, that will take the place of the current procedures of parallel scientific advice, parallel consultation and early dialogue. This action shall make available a single assessment process, reflecting both regulatory and HTA’s needs.

Interested parties can apply to access the EMA/EUnetHTA parallel JSC procedure; a joint guidance on how to apply and the dates of EMA’s Scientific Advice Working Party (SAWP) meetings are available at the dedicated page of the Agency’s website, together with the template of the parallel consultation briefing document and submission deadlines. The joint guideline also provides details for applicants on how to respond to a EUnetHTA 21 open call for joint scientific consultation.

Exchange of information

The setting up of the JSC procedure includes the optimisation of the use of registries to facilitate post-licensing evidence generation (PLEG) and/or launch evidence to support decision making. To this instance, and depending on the specific products selected during the JSC, advice may be provided on requirements for data collection and analysis of disease registries in the context of development plans, or for qualification of registries in disease areas of particular mutual interest (including advanced therapies, ATMPs).

This exchange of information between EMA and EUnetHTA 21 may lead to discussions in order to monitor progress in the identification of PLEG. Under this action, a voluntary pilot might be activated to explore the feasibility of earlier engagement with an HTA agency during regulatory assessment, including evidence sharing and managing of uncertainties. A main outcome of this area of cooperation shall see the initial drafting of the rules for the exchange of information on the preparation and update of joint clinical assessment of medicinal products.

Capturing patient relevant data and information

The ability to generate patient relevant data and information is key to support the process of decision making. The joint work plan aims to develop new methodologies to improve reliance of patient relevant data. To this instance, the cooperation with EUnetHTA is expected to contribute to EMA’s initiative to establish an EU network of experts on Patient Reported Outcomes (PROs). The work plan also includes voluntary actions focused on the discussion and exchange of relevant data in bilateral meetings, in parallel with the development of the respective guidelines, and a workshop on patient experience data planned in June 2022.

The work plan shall also favour a better engagement of patients and healthcare professionals in areas of mutual interest. To this regard, EMA and EUnetHTA 21 will share their best practices as for compensation for expert participation and how to incorporate the input received in regulatory and HTA deliverables.

Preparedness for future challenges

The need to better understand challenges arising from the development of innovative treatments will benefit the sharing of horizon scanning activities between EMA and EUnetHTA 21. This may include, on a voluntary basis, joint discussions on data requirements and preparative measures relative to high-impact innovative medicines for patients with high unmet needs. Other voluntary activities by individual HTA bodies may focus on the optimisation of regulatory assessment reports in order to facilitate the uptake of their outcomes as part of the HTA process. Sharing of experience and guidance on the optimisation of information on subpopulations (e.g. labelling and EPARs) may also be considered, as well as the improvement of Orphan Medicines Assessment Reports (OMARs). Under the methodological perspective needed to make real-world evidence more available, a main goal of the plan shall achieve HTA representation in the advisory board of Darwin EU, the Data Analysis and Real World Interrogation Network established and coordinated by EMA to provide timely and reliable evidence on the use, safety and effectiveness of medicines for human use from real-world healthcare databases across the EU.

Other voluntary activities in this area may include multi-stakeholder discussions aimed to optimise the design, quality and utilisation of disease registries and the training on new guidance on registry-based studies. Joint methodological work may be also carried out to identify key concepts supporting the acceptance of extrapolation and/or evidence transfer, and to share best practices and experiences in the field of the integrated assessment of companion diagnostics, or other diagnostics for targeting therapeutics not directly related to the use of specific medicines.


The new Annex 21 to GMPs

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by Giuliana Miglierini

The new Annex 21 to GMPs (C(2022) 843 final) that EIPG gave a significant contribution in reviewing the original draft and thoroughly presented it within a webinar to its members on August 2020, was published by the European Commission on 16 February 2022; the document provides a guideline on the import of medicinal products from extra-EU countries. The new annex will entry into force six months after its publication, on 21 August 2022. Its contents should be read in parallel with the EU Guide to Good Manufacturing Practice for Medicinal Products and its other annexes, those requirements continue to apply as appropriate.

Annex 21 details the GMP requirements referred to human, investigational and/or veterinary medicinal products imported in the European Union and European Economic Area (EEA) by holders of a Manufacturing Import Authorisation (MIA). The new Annex does not apply to medicinal products entering the EU/EEA for export only, as they do not undergo any process or release aimed to place them on the internal market. Fiscal transactions are also not considered as a part of the new annex.

The main principles

According to Annex 21, once a batch of a medicinal product has been physically imported in a EU/EEA country, including clearance by the custom authority of the entrance territory, it is subject to the Qualified Person (QP) certification or confirmation. Manufacturing operations in accordance with the marketing authorisation or clinical trial authorisation can be run on imported bulk and intermediate products prior to the QP certification/confirmation. To this regard, all importation responsibilities for both medicinal products and bulks/intermediates must be carried out at specific sites authorised under a MIA. These include the site of physical importation and the site of QP certification (for imported medicinal products) or QP confirmation (for bulk or intermediate products undergoing further processing).

Marketing authorisation holders (MAHs) for imported products authorised in the EU remain in any case the sole responsible for placing the products in the European/EEA market. Annex 21 requires sites responsible for QP certification to verify an ongoing stability program is in place at the third country site where manufacturing is performed. This last one has to transmit to the QP all the information needed to verify the ongoing product quality, and relevant documentation (i.e. protocols, results and reports) should be available for inspection at the site responsible for QP certification. QP’s responsibilities also extend to the verification that reference and retention samples are available in accordance to Annex 19 of the GMPs, and that safety features are placed on the packaging, if required.

Importation sites should be adequately organised and equipped to ensure the proper performance of activities on imported products. More specifically, a segregated quarantine area should be available to store the incoming products until the occurrence of release for further processing or QP certification/confirmation.

European GMP rules or equivalent standards shall be followed for the manufacturing of medicinal products in third countries due to be imported in the EU. The manufacturing process has to comply to the one described in the Marketing Authorisation (MA), the clinical trial authorization (CTA) and the relevant quality agreement in place between the MAH and the manufacturer. The respect of EU GMP rules or equivalent standards should be documented through regular monitoring and periodic on-site audits of the third country manufacturing sites, to be implemented by the site responsible for QP certification or by a third party on its behalf.

The QP of the importation site is also responsible for the verification of testing requirements, in order to confirm the compliance of the imported products to the authorised specifications detailed in the MA. The verification of testing requirements can be avoided only in the case a Mutual Recognition Agreement (MRA) or an Agreement on conformity assessment and acceptance of industrial products (ACAA) is in place between the European Union and the third country where the production of the medicinal product is located.

All agreements between the different entities involved in the manufacturing and importation process, including the MAH and/or sponsor, should be in the written form, as indicated by Chapter 7 of the EU GMP Guide.

The Pharmaceutical Quality System of the importing site

According to the European legislation (Chapter 1 of the EU GMP Guide), all activities performed in the EU with reference to the manufacturing and distribution of pharmaceutical products should fall under to umbrella of the company’s Pharmaceutical Quality System (PQS). This is also true for sites involved with importation activities, those PQS should reflect the scope of the activities carried out. A specific procedure should be established to manage complaints, quality defects and product recalls.

More in detail, the new Annex 21 establishes that sites responsible for QP certification of imported products (including the case of further processing before export with the exception of investigational medicinal products) have to run periodic Product Quality Reviews (PQR). In this case too, the respective responsibilities of the parties involved in compiling the Reviews should be specified by written agreements. Should the sampling of the imported product be conducted in a third country (in accordance with Annex 16 of the GMPs), the the PQR should also include an assessment of the basis for continued reliance on the sampling practice. A review of deviations encountered during transportation up to the point of batch certification should be also available, and a comparison should be run to assess the correspondence of analytical results from importation testing with those listed by the Certificate of Analysis generated by the third country manufacturer.

Full documentation available at MIA sites

The QP’s certification/confirmation step for an imported batch has to be paralleled by the availability of the full batch documentation at the corresponding MIA holder’s site; in case of need, this site may also have access to documents supporting batch certification, according to Annex 16. Other MIA holders involved in the process may access batch documentation for their respective needs and responsibilities, as detailed in the written agreements. A risk assessment is needed to justify the frequency for the review of the full batch documentation at the site responsible for QP certification/confirmation; the so established periodicity should be included in the PQS.

Annex 21 also lists the type of documents that should be available at the importation sites, including the details of transportation and receipt of the product, and relevant ordering and delivery documentation. This last one should specify the site of origin of the product, the one of physical importation and shipping details (including transportation route, temperature monitoring records, and customs documentation). Appropriate documentation should be also available to confirm reconciliation of the quantities of batches which underwent subdivision and were imported separately.

Requirements set forth in Chapter 4 of the GMPs apply to the retention of the documentation; the availability at the third country manufacturing site of an adequate record retention policy equivalent to EU requirements shall be assessed by the site responsible for QP certification. Should it be appropriate, translations of original documents and certificates should be provided to improve understanding.


Revision of the CDMh’s Q&As document on nitrosamine impurities

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by Giuliana Miglierini

The review process of medicinal products started in 2018 to assess the presence of nitrosamine impurities is still ongoing. The Coordination Group for Mutual Recognition and Decentralised Procedure (CMDh) last updated in December2021 its Questions & Answers document (Q&A) proving guidance on how to approach the revision procedure.

The US’s Food and Drug Administration (FDA) also updated its guidance on how to minimise the risks related to nitrosamine through formulation design changes. We summarise the latest news of the topic of nitrosamine impurities.

The CMDh’s update of the Q&A document

The CMDh Questions & Answers document (CMDh/400/2019, Rev.5) specifically refers to the implementation of the outcome of Art. 31 referral on angiotensin-II-receptor antagonists (sartans) containing a tetrazole group. According to the indications released in November 2020 by EMA’s human medicines committee (CHMP), these outcomes should now be aligned with those issued for other classes of medicines. This provision impacted on the allowed limits for nitrosamines, which are now applied to the finished products instead than to the active ingredient. The limits are determined on the basis of internationally agreed standards (ICH M7(R1)).

Companies are called to implement an appropriate control strategy to prevent or limit the presence of nitrosamine impurities as much as possible and to improve their manufacturing processes where necessary. A risk assessment should be run to evaluate the possible presence of N-nitrosamines in medicinal products, and tests carried out if appropriate.

Four different conditions (A-D) are set for the marketing authorisation (MA) of tetrazole sartans, with specific dates to be met for their fulfilment by marketing authorisation holders (MAHs). Revision 5 of the Q&As document specifically addresses conditions B and D.

Condition B asks the MAH to submit a step 2 response in the general “call for review”. To lift the condition on the risk assessment for the finished product, and provided no nitrosamine was detected in step 2 or levels are below 10% of acceptable intake (AI), submission of the step 2 response must now be followed by the submission of the outcome of the risk assessment. To this instance, the relevant template “Step 2 – No nitrosamine detected response template” should be used to fill a type IA C.I.11.a variation.

A further amendment to Condition B refers to nitrosamines being detected in step 2 above 10% AI. In this case, a variation application should be submitted as appropriate to support changes to the manufacturing process and the possible introduction of a limit in the specification of the finished product.

Condition D now specifies that it applies only to N-nitrosodimethylamine (NDMA) and N nitrosodiethylamine (NDEA) impurities. Thus, to lift the condition on the change of the finished product specification, and if the MAH wants to apply for omission from the specification, supporting data and risk assessments should be submitted via a type IB C.I.11.z variation referring only to these two impurities. Should any other nitrosamine impurity be potentially present, data should be submitted under separate variation (also grouping them together). Conditions A and C remain unchanged. The former refers to the three different possibilities for lifting the condition on the risk assessment for the active substance and with specific reference to the manufacturing process used to prepare it, the second to lifting the condition on the control strategy.

The guidance from the FDA

The US regulatory agency Food and Drug Administration (FDA) released in February 2021 the first revision of the “Guidance for Industry Control of Nitrosamine Impurities in Human Drugs”, establishing a three-step process to demonstrate the fulfilment of requirements.

The guideline widely discusses the structure of nitrosamine impurities and the possible root causes for their presence in medicinal products. While not binding for manufacturers, recommendations contained in the document should be applied in order to evaluate the risk level for the contamination of both active ingredients and finished products. This exercise should be run on the basis of a prioritisation taking into consideration the maximum daily dose, the duration of treatment, the therapeutic indication, and the number of patients treated.

The FDA provides also the acceptable intake limits for a set of different nitrosamine impurities (NDMA, NDEA, NMBA, NMPA, NIPEA, and NDIPA); the approach outlined in ICH M7(R1) should be used to determine the risk associated with other types of nitrosamines.

Manufacturers do not need to submit the results of the risk assessment to the FDA, the relevant documentation has to be made available just upon specific request.

The second step refers to products showing a risk for the presence of nitrosamine impurities. In this case, highly sensitive confirmatory testing is needed to confirm the presence of the impurities.

The implementation of all changes to the manufacturing process for the API or final product have then to be submitted to the FDA in the form of drug master file amendments and changes to approved applications.

The Agency also provides specific guidance for API manufacturers to optimise the route of manufacturing in order to prevent the possible formation of nitrosamine impurities. API manufacturers should participate to the risk assessment run by the MAH; this last exercise should include the evaluation of any pathway (including degradation) that may introduce nitrosamines during drug product manufacture or storage.

Additional points to be considered

A Communication issued in November 2021 by the FDA specifies the terms for the recommended completion dates of the above mentioned three steps and adds some additional points to be considered in the evaluations. MAHs should have already completed by 31st March 2021 all risk assessments, while there is time up to 1st October 2023 for confirmatory testing and reporting changes. According to the FDA, the time left is enough to include in the development of the mitigation strategies also new considerations on how formulation design may prove useful to control nitrosamine levels in drug products.

More in particular, manufacturers are asked to evaluate the presence of nitrosamine drug substance-related impurities (NDSRIs), that may be produced if nitrite impurities are present in excipients (at parts-per-million amounts) or may be generated during manufacturing or shelf-life storage. Should NDSRIs be present, FDA recommends the mitigation strategy should include a supplier qualification program that takes into account potential nitrite impurities across excipient suppliers and excipient lots.

Formulation design is another possible approach to solve the issue. This may use, for example, common antioxidants – such as ascorbic acid (vitamin C) or alpha-tocopherol (vitamin E) – that according to the scientific literature inhibit the formation of nitrosamines in vivo. The kinetic of the reaction leading to the formation of nitrosamine impurities may be also addressed by using a neutral or basic pH for formulation, to avoid acidic conditions which favours the side reaction.

Formulation changes may be submitted to the FDA through supplements or amendments to the applications, also following a preliminary meeting with the Agency to better discuss the approach to be used. Should this be the case, applicants or manufacturers are asked to prepare a comprehensive meeting package with the appropriate regulatory and scientific data on the selected approach to be submitted to the FDA in advance of the meeting.


EMA’s Q&A on the integration of EudraGMDP and OMS

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by Giuliana Miglierini

A new step in the integration at the central level of data needed to manage regulatory procedures is going to be activated on 28 January 2022: starting from this date, member states’ national competent authorities (NCAs) shall use the data available in EMA’s Organisation Management System (OMS) to issue all type of certificates regulated under the EudraGMDP database, for human, veterinary and experimental medicines, as well as active substances (API).

A Questions & Answers guideline on the integration of EUdraGMDP and OMS has been released by EMA; the document reflects the points of discussion which arose in the course of a webinar organised by EMA to better inform about the new modalities for the release of the certificates and other services provided through the OMS system, and how to face the change request process.

The new procedures to uniquely identify the interested parties

As discussed few weeks ago on this blog, the use of the OMS dictionary became mandatory for all centrally authorised products (CAPs) since 1st November 2021. The integration of OMS with EudraGMDP database is a specific requirement arising from the new Veterinary Medicinal Products Regulation ((EU) 2019/6), which will become fully applicable on 28 January 2022.

The new procedures refer to different types of certificates, including the Manufacturing and Importation Authorisations (MIA), the Wholesale Distributor Authorisations (WDA), GMP and GDP certificates and API Registration certificates. GDP certificates will maintain their current validity, with re-inspections to occur after 5 years at the latest. Any new GMP certificate/authorisation for Clinical trials issued after 28 January 2022 will be also impacted. CEP certificates of suitability issued by the EDQM fall out of the scope of EudraGMDP, and are thus not impacted.

Should there be two different organisations with the same legal address, each of them will have a distinct ORG ID in the system; a single organisation with two different locations will have two LOC IDs. Multiples ORG IDs will be generated for marketing authorisation holders (MAHs) located in one country and having subsidiaries in other countries, as the identification is specific to the single subsidiary/location. A particular case may be represented by India, where some plots are recognised as one address by National postal services. In that case, just one LOC ID will be available; on the contrary, should the plot be not recognised as a single address, different LOC IDs will be generated.

In case of a single warehouse for human and veterinary medicines for a single company with a single address, the OMS will only have 1 contact; in these instances, NCAs will select if the certificate applies to human or veterinary medicinal products.

In the case of transfer of the location under another organisation, the OMS system is provided with the technical functionality to move the location from an organisation to another. Nevertheless, advices EMA, the activation of this procedure requires a careful verification and validation of the supporting documentation in order to avoid breaking the business rules of both EudraGMDP and OMS.

Changes requests and Super users

Since the end of January, NCAs shall extract from the OMS database all data relative to the specific organisation (i.e. name and location address details, including the legally registered address).

It is thus of paramount importance that all interested parties which appear on documents recorded in EudraGMDP – i.e. pharmaceutical companies, contract manufacturing organisations (CMOs), importers and distributors, both EU and non-EU – shall verify the correctness of their data registered in the database prior to the submission of any new or updated application for manufacturing or wholesale distribution authorisation with national competent authorities.

Should the submission of a change request be needed, anyone among the interested parties may provide to file it with EMA. Change requests can be submitted starting from 28 January 2022; the requests have to be validated by EMA against the reference sources (e.g. Trade registry and Postal services) before the OMS Data stewards can proceed to change the data in the system.

The availability of the correct information is particularly important in the case of CMOs located in extra-EEA countries, and which may request inspections or need to update their GMP certificates. EMA’s advices companies to promptly liaise with their partners to manage in due time any change request needed to correct data recorded in the OMS.

The “Organisation Super users” can verify all of the users affiliated to their respective organization through the EMA’s Account management portal; they can also change the user roles and users affiliated at any point in time. EMA suggests companies to have at least two Super users, in order to guarantee one of them is always available and active. A single Super user can be affiliated with different organisations.

Other answers provided by the guideline

The Q&As guideline published by EMA consists of 87 questions and their corresponding answers. Question n°2 addresses the issue of the legal basis of GDP certificates for Veterinary medicines: as the new Regulation and its associated secondary legislative acts still do not include such a legal basis, EMA will update the GDP module of EudraGMDP after January 2022 in order to provide consistency in the approach. It shall thus be possible for NCAs to voluntary use the database to record GDP certificates for companies distributing veterinary medicines. The guideline also indicates that national competent authorities are prepared to the handle the new framework and can plan in advance activities needed in the near time to issue WDA and API Registration certificates for veterinary Organisation.

Even if the use of OMS is yet mandatory for CAPs only, the Q&As guideline indicates that NCAs need to ensure that the relevant organisations are available in OMS before submitting information into the system, both for CAPs and non-CAPs. The suggestion is thus to ensure that the OMS data is present and correct for all organisations/sites, even if its use in electronic application forms (eAF) is not mandatory for the time being.

Details of manufacturing sites such as buildings or plots are not registered in OMS, but they have to be included in the GMP certificate; this extra information will be inserted in the ‘Restrictions’ section of the certificate. There is no change to the procedures for the issuing of GMP certificates.

When a change to an organisation occur in the OMS, the dictionary part of EudraGMDP gets refreshed, but no change is reflected in the documents already issued unless there is a specific action on them. The synchronisation between the two databases occurs on the following business day after the change was registered.

In case of transfer of the company to a new location, the change has to be registered in the OMS before new certificates can be issued; according to the guideline, this should not represent a problem while the current certificate are still valid.

During the webinar some doubts have been expressed as for the possible confusion arising from the guidance document “Manufacturer organisations in the OMS dictionary” (EMA/465039/2018), which divides OMS data responsibility for manufacturers and MAHs/Applicants. This document shall be reviewed by the Agency, says EMA’s guideline.


EMA’s OMS has turned mandatory for centrally authorised products

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by Giuliana Miglierini

Since November 1st, 2021, the use of the Organisation Management Service (OMS) became mandatory for all Centrally Authorised Products (CAPs). The European Medicines Agency (EMA) has published a Questions & Answers document to better explain the new procedures, that will impact the source of data to be used to exactly identify the organisations filing CAP procedures with EMA.

The progression in the implementation of the new provisions

The use of the OMS system is now compulsory for all organisations filing CAP submissions, with the final goal to improve the interoperability of data and the overall efficiency of the regulatory process. Should applicants lack to use OMS data, the relevant applications will be filtered out of the EMA’a validation procedure and sent back to the applicant for remedial action.

The OMS data management service was launched in 2015, and applied to electronic application forms (eAFs) since 2017, and then to many other types of procedures. The availability of OMS data may prove critical to allow the smooth implementation, in early 2022, of the new Clinical Trial Information System (CTIS) and of the Clinical Trial application procedure; during the next year, EMA plans to integrate the OMS also with the Union Product Database (UPD), Variation applications (via DADI project) and Manufacturing/Importers Authorisations (MIAs), Good Manufacturing Practice (GMP) inspections and Wholesale distribution authorisations (via EudraGMDP).

Validated OMS data also need to be used with reference to the “applicant” and “contact person affiliated organisation” sections of pre-submission applications. With the new eAF release (eAF V.1.25.0.0) for Medical Devices, the compulsory use of OMS data will also refer to the “Device Manufacturer”, “Notified Body” and “Companion diagnostic” sections.

Remediation in case of lack to use OMS data includes the insertion of all relevant information in the OMS database before updating and re-submitting the application form. Should applicants not provide sufficient responses, the application may be completely or partially invalidated.

Discussions are undergoing to further extend the use of OMS data also to National Procedures (NP); according to EMA, this may be turn inevitable in the next couple of years, as current eAF forms will be progressively replaced by web-based application forms (through the DADI project), being the latter the same for centrally and nationally authorised products by design.

Any question on the use of the OMS can be sent to EMA’s e-mail addresses specified in the Q&As document.

What is new for applicants

The use of OMS master data (the so-called “OMS Dictionary”) is now mandatory for both Human and Veterinary centralised procedures, namely those making use of eAFs (initial marketing authorization applications, variations applications, and renewals) and well as other procedures (see the Q&A document for more detail). The name and contact details of the contact person are not OMS data, and do not need to be registered with the system; historical organisational data do not have to be registered as well.

To manage a CAP procedure, applicants now need to first register their organisation data with the OMS, or request the update of data already registered by submitting a “Change Request” before filing of the regulatory application.

All requests will be assessed by EMA OMS Data stewards, that will also update data in the systems if the requirements are met. This validation step is fundamental to avoid duplication of data, as all information is checked against the same reference sources (i.e. national business registry, DUNS and/or GMP/MIA certificates) and standardised according to the OMS rules agreed with the Network. The Service Level Agreement provide for EMA to process 75% of OMS requests within five working days and 90% within ten working days. Changes will become visible in the eAF the day after they had been processed, and only upon active refresh of the relevant lists.

The business process which makes use of OMS data is usually responsible to submit such a request, but it can arise also form other parties. More specifically, EMA advises the user who needs to use the data should take the lead in updating it. This may prove relevant, for example, to ensure all manufacturer organisations are included in the OMS Dictionary as needed.

EMA warns applicants to consider the turnaround time for processing the OMS change request when planning to submit applications: even if the application forms will not immediately change and everything may appear as usual, the background process has been now modified and may need additional activities to validate the change requests.

Changes in the eAF templates are planned to remove the free text fields for CAP applications, but until the new models will be available, the free text field for “organisations” should not be used. Planned availability and entry into force of the new versions are December 2021 for Human procedures (v1.26.0.0) and January 28th, 2022 for Veterinary procedures (in line with the veterinary regulation).

How to access the OMS

EMA’s data management system refers to four different domains of data, including the substance, the product, the organisation and referential (SPOR) master data in pharmaceutical regulatory processes.

The SPOR portal provides access to the respective four specific areas of service (e.g. SMS for substances, PMS for products, OMS for organisations and RMS for referential). SPOR is the mechanism used by EMA to implement the ISO IDMP standards, as required by articles 25 and 26 of the Commission Implementing Regulation (EU) No. 520/2012. Organisation master data, even if not covered by ISO IDMP, have been considered by EMA, National Competent Authorities and Industry in Europe to be essential in order to make the master data operating model work.

Applicants need to create an EMA account with SPOR user roles to conduct additional tasks, such as requesting changes to data, translating data or managing user preferences. Already granted credentials to access other active accounts for any EMA-hosted website or online application can also be used. OMS data can now no longer be captured in other EMA databases.

OMS master data include the organisation name and address, labelled by mean of unique identities (ID) (i.e. ‘Organisation_ID’ and ‘Location_ID’). Different categories of organisations are possible (i.e. ‘Industry’, ‘Regulatory Authority’ or ‘Educational Institution’), and of different size (i.e. ‘Micro’, ‘Small’, or ‘Medium’). The role played by a certain organisation is context-specific and cannot be defined within the OMS.


A new role for EMA and a pilot project for the repurposing of medicines

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by Giuliana Miglierini

A draft agreement was reached at the end of October between the Council of the European Union and the European Parliament to reinforce the mandate of the European Medicines Agency (EMA) with reference to crisis preparedness and management for medicinal products and medical devices. “EU-level preparation and coordination are two essential ingredients to fight future health crises. Thanks to this deal we are adding an essential new building block to upgrade the EU’s health architecture. It will allow the EU’s Medicines Agency to make sure we have the medicines needed to deal with public health emergencies”, said Janez Poklukar, the Slovenian minister for health.

The revision of EMA mandate is part of the broader activities announced by the EU Commission in November 2020 to achieve the European Health Union; these also include the reinforcement of the European Centre for Disease Prevention and Control and a draft law on cross-border health threats. The establishment of the new Health Emergency Preparedness and Response Authority (HERA), announced in September 2021, is also part of the package. The draft agreement shall now be endorsed both by the Council and the Parliament before entering into force.

Three new key targets for EMA

The draft agreement reached by the Council and Parliament negotiators focuses on three main areas. The first one refers to the definition of a major event and how to recognise it: these shall be events likely to pose a serious risk to public health in relation to medicinal products, as acknowledged by a positive opinion from the Medicines Shortages Steering Group, and which may trigger specific actions such as the adoption of a list of critical medicinal products to fight the health threat.

Solid funding from the Union budget shall be also provided to EMA in order to support the work of the new steering groups, task force, working parties and expert panels. The availability of provisions for adequate data protection is important to guarantee the full compliance to the GDPR regulation and other EU data protection rules, and the safe transfer of personal data relevant to EMA’s activities (e.g. data from clinical trials).

EMA shall play an improved role in the monitoring and management of shortages of medicines and medical devices, a critical activity for the availability of the products needed during public health emergencies. Other points of the agreement include the timely development of high-quality, safe and efficacious medicinal products, and the creation of a new EMA’s structure specific for expert panels in charge of the assessment of high-risk medical devices and of essential advice on crisis preparedness and management.

How to tackle shortages of medicines

According to the EU Parliament, two “shortages steering groups” (for medicines and medical devices, respectively) shall be created by EMA; if needed, these groups may also include expert advice from relevant stakeholders (e.g. patients and medical professionals, marketing authorization holders, wholesale distributors, etc.).

Parliament negotiators highlighted the importance to achieve a high transparency of the process, including avoidance of interests related to industry sectors for members of the two groups; summaries of the proceedings and recommendations shall be also made publicly available.

A European Shortages Monitoring Platform shall be created by EMA to facilitate the collection of information on shortages, supply and demand of medicinal products; a public webpage with information on shortages of critical medicines and medical devices shall be also made available.

As already occurred during the Covid pandemic, future public health emergencies may boost the development of new medicines and medical devices. Sponsors of clinical trials conducted during health emergencies will be required to make the study protocol publicly available in the EU clinical trials register at the start of the trial, as well as a summary of the results. Following the granting of the marketing authorisation, EMA will also publish product information with details of the conditions of use and clinical data received (e.g. anonymised personal data and no commercially confidential information).

With this agreement, Parliament makes both the Agency and all actors in the supply chain more transparent, involving them more in the process and fostering synergies between EU agencies. Moreover, we pave the way to promoting clinical trials for the development of vaccines and treatments, boosting transparency on those issues. In short, more transparency, more participation, more coordination, more effective monitoring and more prevention”, said Rapporteur Nicolás González Casares (S&D, ES).

EMA’s pilot project for the repurposing of medicines

The repurposing of already approved and marketed medicines is another key action put in place to ensure improved response capacity in case of future health emergencies.

A new pilot project to support the repurposing of off-patent medicines has been launched by EMA and the Heads of Medicines Agencies (HMA), with special focus on not-for-profit organisations and the academia as the main actors to carry out research activities needed to support the regulatory submission for the new indication. The initiative follows the outcomes reached by the European Commission’s Expert Group on Safe and Timely Access to Medicines for Patients (STAMP).

Interested sponsors may access EMA’s specific scientific advice upon submission of the drug repurposing submission form to the e-mail address [email protected] by 28 February 2022. More information is available in a Question-and-Answer document. The pilot will last until scientific advice for the selected repurposing candidate projects; filing of an application by a pharmaceutical company for the new indication is another target. Final results of the project will be published by EMA.

Comments from the industry

The European Federation of Pharmaceutical Industry Associations (EFPIA) welcomed the proposed framework for the repurposing of authorised medicines. “This pilot launch comes at a timely moment to test whether a streamlined and more transparent regulatory pathway for repurposing of off-patent established products increases the chances of including existing scientific evidence into regulatory assessment. One of the goals of the pilot is to raise awareness regarding the standards required for regulatory-ready evidence on the road to further increase availability of authorised therapeutic use”, said the chair of EFPIA’s Regulatory Strategy Committee Alan Morrison.

Innovation on existing, well-known molecules through repurposing can deliver huge benefits for patients, according to Medicines for Europe. The Association of the generic and biosimilar industry supports the pilot project as a way to generate robust data packages and to translate research into access for patients. A sustainable innovation ecosystem for off-patent medicine is the expected final outcome, possibly including also reformulation of existing medicines, new strengths or adaptation for specific patient groups (i.e. paediatric populations). “These investments must also be recognised in pricing and reimbursement policies to make access a reality for all patients”, writes Medicines for Europe.


Consultation open on the ICH Q13 guideline on continuous manufacturing

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by Giuliana Miglierini

The new ICH Q13 guideline on the continuous manufacturing of drug substances and drug products aims to harmonise at the international level this rapidly growing sector of pharmaceutical production, providing manufacturers with a flexible approach for the implementation of innovative technologies and ensuring compliance to Current Good Manufacturing Practices (CGMP) specific to continuous manufacturing.

The draft guideline was released in July 2021 and is currently subject to the public consultation phase, which will remain open for comments until 20 December 2021. Comments should be forwarded by e-mail to EMA at the address [email protected] The process to develop the new guideline started in November 2018 with the publication of the final Concept paper on continuous manufacturing.

The new ICH Q13 guideline is expected to support the adoption of continuous manufacturing systems by the pharmaceutical industry, thus providing innovation of manufacturing methods and availability of more robust and efficient processes, in order to increase options available in case of public health needs and to implement new approaches to Quality Assurance. The new provisions shall also contribute to the reduction of risks for operators, and to resource consumption and waste generation.

The key principles

The guideline on continuous manufacturing builds upon the existing ICH Quality guidelines to specifically address the production of drug substances and drug products for chemical entities and therapeutic proteins, and the conversion of batch manufacturing to continuous manufacturing modalities for existing products. It may also apply to other biological/biotechnological entities. The discussion takes into consideration both scientific and regulatory elements, with respect to the entire lifecycle management of the continuous manufacturing process.

This manufacturing technique is characterised by the continuous feeding of input materials into the productive flow, the transformation of in-process materials within, and the concomitant removal of output materials from the flow. A special attention is paid by the guideline to continuous manufacturing systems in which two or more unit operations are directly connected.

More in particular, Part I of the document addresses general aspects of continuous manufacturing not specific to the technology, dosage form or molecule type under consideration. Many illustrative examples are provided in Part II (Annexes) to support the implementation of the provisions to different operative setups.

Among available modes to run continuous manufacturing, the guideline discusses the combination of traditional approaches inclusive of units operating in a batch mode and integrated continuous manufacturing unit operations, the situation in which all unit operations are integrated and operate in a continuous mode, and the possibility the drug substance and drug product unit operations are integrated across the boundary between drug substance and drug product to form a single continuous manufacturing process.

Part I: How to approach continuous manufacturing

The main part of the guideline is composed of six different sections aimed to provide a general vision of possible issues found in continuous manufacturing, under complementary points of view. The Introduction describes the guiding principles that inspired the document, including scientific and regulatory considerations to be taken in mind for the development of a new continuous manufacturing system.

Section 2 focuses on key concepts, among which is batch definition: according to the guideline, the ICH Q7 definition of a batch is applicable to all modes of continuous manufacturing, for both drug substances and drug products. Different options are available to define the size of a batch produced by continuous manufacturing, i.e., in terms of quantity of output material, quantity of input material, and run time at a defined mass flow rate. Other approaches to batch definition can be also considered upon justification, on the basis of the characteristics of the single process. For example, a batch size range can be established by defining a minimum and maximum run time.

Control strategy, changes in production output and continuous process verification are the key scientific principles addressed in Section 3, being the last item a possible, alternative approach for validating continuous manufacturing processes.

Principles described in ICH Q8-Q11 have always to be taken into consideration while developing the control strategy, using a holistic approach to properly consider aspects specific to continuous manufacturing.

The guideline takes into consideration all items which are part of the control strategy, starting from the state of control, according to ICH Q10, to provide assurance of continued process performance and product quality. Mechanisms should be in place to evaluate the consistency of the operations and to identify parameters outside the historical operating ranges, or signs of drifts/trends indicative the process could be at risk of falling outside the specified operating range. Knowledge of process dynamics is also important to maintain the state of control in continuous manufacturing. To this instance, a useful parameter may be represented by the characterisation of the residence time distribution (RTD). Furthermore, process dynamics should be assessed over the planned operating ranges and anticipated input material variability using scientifically justified approaches.

The guideline provides detailed examples of material attributes that can impact various aspects of continuous manufacturing operation and performance, with specific reference to a solid dosage form process, a chemically synthesised drug substance process, and a therapeutic protein process. Not less important is the design of equipment and the integration to form the continuous manufacturing system. Examples are provided as for the design and configuration of equipment, connections between equipment and locations of material diversion and sampling points.

Process analytical technologies (PAT) developed according to ICH Q8 are suited to implement real-time automated control strategies aimed to promptly detect transient disturbances that may occur during the continuous process. In-line UV flow cells, in-line near-infrared spectroscopy and in-line particle size analysis are possible examples. PAT’s measurements also support traceability of all materials that enter the process and diversion of the potential non-conforming ones.

The different definitions of batches in continuous manufacturing impact also on change management activities. The optimisation of the process may require changes of different parameters; examples discussed by the guideline include changes in run time with no change to mass flow rates and equipment, increase mass flow rates with no change to overall run time and equipment, increase output through duplication of equipment (i.e., scale-out), and scale up by increasing equipment size/capacity.

The above-mentioned critical aspects are also considered in Section 4 as part of the regulatory expectations the development of a continuous manufacturing process should fulfil. A sequential narrative description of the manufacturing process should be included in the Common Technical Document (CTD) and supported by suitable pharmaceutical development data. The description of the continuous manufacturing operational strategy should include operating conditions, in-process controls or tests, criteria that should be met for product collection during routine manufacturing, and the strategy for material collection and, when applicable, diversion. Other information also includes a description of how the material is transported from different pieces of equipment, a flow diagram outlining the direction of material movement through each process step, details about the locations where materials enter and leave the process, the locations of unit operations and surge lines or tanks, and a clear indication of the continuous and batch process steps. Critical points at which process monitoring and controls (e.g., PAT measurement, feedforward, or feedback control), intermediate tests, or final product controls are conducted should be also provided, together with a detailed description of any aspects of equipment design or configuration and system integration identified during development as critical with respect to process control or product quality. Sections 5 and 6 provide, respectively, a Glossary of terms used in continuous manufacturing and a list of useful references.

Part II: Five Annexes to illustrate different fields of continuous manufacturing application

Each of the five Annexes that form Part II of the ICHQ13 guideline addresses issues specific to the application of continuous manufacturing to the target domains typical of the pharmaceutical manufacturing process.

Annex I refers to drug substances for chemical entities. It provides an example of a process containing both continuous and batch operations, where the segment run under continuous conditions consists of a series of unit operations for reactions, liquid phase extraction, carbon filtration, continuous crystallisation, and filtration. A second intermediate synthesised in batch mode enters the continuous flow to participate to the second step in the synthesis of the final drug substance.

Annex II describes a possible implementation of continuous manufacturing for the production of a solid dose drug product.

Here too, a flow diagram exemplifies the different steps of the process, including the blending of different materials followed by direct compression of the tablets and a final step of batch-mode film coating. The guideline also addresses the use of PAT technologies to monitor blend uniformity and trigger tablet diversion. The batch size range is defined on the basis of a predefined mass flow rate.

The manufacturing of therapeutic protein drug substances (e.g., monoclonal antibodies) is discussed in Annex III. This type of process may be used to produce intermediates for the manufacturing of conjugated biological products, and it could be integrated partially or in full of the continuous manufacturing system. The process described in the guideline includes a perfusion cell culture bioreactor with continuous downstream chromatography and other purification steps to continuously capture and purify the target protein. As regard to viral safety and clearance, the guideline specifies that the general recommendations of ICH Q5A remain applicable also for continuous manufacturing; alternative approaches need to be justified.

Many continuous processes integrate in the same flow the manufacturing of both the drug

substance and drug product. This type of circumstance is approached in Annex IV with reference to the production of a small molecule tablet dosage form. The two parts of the overall process may differ under many aspects, e.g., the prevalence for liquid or solid input material addition, different run times, different frequency of in-process measurements. This impacts on the choice of the equipment and the design of locations of in-process measurements and material diversion.

Annex V discusses some possible examples for the management of transient disturbances that may occur during continuous manufacturing, potentially affecting the final quality of the product. Three different approaches are provided, based on the frequent/infrequent occurrence of the disturbance and on its amplitude and duration with respect to predefined acceptance criteria.


The new guideline on combination products between medicines and medical devices

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by Giuliana Miglierini

The new “Guideline on quality documentation for medicinal products when used with a medical device” (EMA/CHMP/QWP/BWP/259165/2019), adopted by the European Medicines Agency in July 2021, will come into force starting 1st January 2022.

The first draft of the guideline was presented in May 2019; according to EMA, the document aims to solve the often observed issues of inconsistent and/or incomplete data submitted to competent authorities. It also considers the amendment to Annex I of Directive 2001/83/EC introduced by Article 117 of the new Medical Devices Regulation ((EU)2017/745, MDR).

A Questions and Answers document to support in the implementation of the MDR and In Vitro Diagnostic Medical Devices Regulations ((EU) 2017/746) was also published by EMA in June 2021.

Three different combinations with medical devices

The guideline applies to the product-specific quality aspects of a medical device/device part, that may have an impact on the quality, safety and/or efficacy of the associated medicinal product, as defined by a specific risk assessment. The submitted documentation is part of the Quality part of a marketing authorisation dossier. Makers has also to prove the conformity of the device/device part to MDR’s requirements by mean of a EU Declaration of Conformity or CE certification released by the Notified Body that assessed the device.

The products covered by the new guideline include integral products made up of an integral and not reusable combination of the medical device/device part and the medicinal product (where the action of the medicinal product is principal), medical devices placed on the market co-packaged with a medicinal product, and referenced medicinal products to be used in conjunction with a specific medical device described in the product information (SmPC and/or package leaflet) and obtained separately by the user. The classification in one of the above mentioned categories of medicine/device combination impacts the information that should be submitted to competent authorities.

The guideline applies also to medicinal products intended to be used with a Class I medical devices, with electromechanical devices (including active implantable devices), electronic add-ons and digital elements of devices (if expected to impact the benefit-risk assessment of the medicinal product from a quality perspective). Combined advanced therapy products defined under Article 2(1)(d) of the ATMP Regulation fall out of the scope of Article 117, as well as veterinary products, in-vitro diagnostic devices (including companion diagnostics), system and procedure packs regulated under Article 22 of the MDR.

Examples of integral products include medicinal products with an embedded sensor performing an ancillary action, single-use prefilled syringes, pens or injectors, drug-releasing intrauterine devices or pre-assembled, non-reusable applicators for vaginal tablets, dry powder inhalers and preassembled, ready-to-use pressurised metered dose inhalers, implants containing medicinal products whose primary purpose is to release the medicinal product. For this type of products, the safety and performance of the device/device part has to reflect the relevant General Safety and Performance Requirements (GSPRs) described in Annex I of the MDR.

Examples of co-packaged or specifically referenced medical devices include spoons and syringes used for oral administration, injectors needles, refillable or reusable pens/injectors, dry powder inhalers and metered dose inhalers, nebulisers and vaporisers and single use or reusable pumps for medicinal product delivery. These two categories of products should comply with the requirements of the applicable medical device legal framework.

The approach to the overall product quality

The discussion of the quality of the device/device part on the Quality Target Product Profile (QTPP), Critical Quality Attributes (CQA) and overall control strategy of the medicinal product has to be included in the regulatory dossier.

More specifically, for integral products the EU Declaration of Conformity or the relevant EU certificate issued by a Notified Body for the device/device part has to be produced. Should this not be possible, the applicant has to provide an opinion (NBO) on the conformity of the device/device part with the relevant GSPRs, issued by a Notified Body enlisted in the NANDO website.

The information provided with the authorisation dossier shall be assessed by the competent authority to determine the overall benefit/risk ratio of the medicinal product. All information relevant to the device/device part has to be submitted using the usual eCTD format. Data on preexisting combination of the device/device part with an already approved medicinal product can be provided on a case-by-case basis and needs to be adequately justified. Early scientific and/or regulatory advice can be activated in the case of particularly innovative and emerging technologies.

The guideline provides a detailed description of the information to be submitted to competent authorities in relation to each of the different types of device/medicinal products combinations.

Reference is made to Module 1 (Product Information), Module 3.2.P (Drug Product), Module 3.2.A.2 (Adventitious Agents Safety Evaluation) and Module 3.2.R (Regional Information, Medical Device). This last section includes the Notified Body Opinion for integral medicinal products in the form of a summary technical report. Usability studies should be also available in the case supporting information is not included in the dossier, and the device/device part has not been used in the intended user population before, or where other aspects of the intended use, including changes to the clinical setting or use environment, are new or different from the intended use as confirmed by the EU certificate issued by a Notified Body or NBO.

The guideline also highlights the need the device/device part should be as advanced as possible in the development process (e.g. meets relevant GSPRs) by the time pivotal clinical trials commence. Any change to the device occurred during the trials has to be described, evaluated and justified with respect to the potential impact on the quality, safety and/or efficacy of the medicinal product. The guideline also provides information on how to manage the life cycle of the integral, co-packaged or referenced medicinal products.


Artificial intelligence in medicine regulation

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The International Coalition of Medicines Regulatory Authorities (ICMRA) sets out recommendations to help regulators to address the challenges that the use of artificial intelligence (AI) poses for global medicines regulation, in a report published on 16 August 2021.

AI includes various technologies (such as statistical models, diverse algorithms and self-modifying systems) that are increasingly being applied across all stages of a medicine’s lifecycle: from preclinical development to clinical trial data recording and analysis, to pharmacovigilance and clinical use optimisation. This range of applications brings with it regulatory challenges, including the transparency of algorithms and their meaning, as well as the risks of AI failures and the wider impact these would have on AI uptake in medicine development and patients’ health.

The report identifies key issues linked to the regulation of future therapies using AI and makes specific recommendations for regulators and stakeholders involved in medicine development to foster the uptake of AI. Some of the main findings and recommendations include:

  • Regulators may need to apply a risk-based approach to assessing and regulating AI, which could be informed through exchange and collaboration in ICMRA;
  • Sponsors, developers and pharmaceutical companies should establish strengthened governance structures to oversee algorithms and AI deployments that are closely linked to the benefit/risk of a medicinal product;
  • Regulatory guidelines for AI development, validation and use with medicinal products should be developed in areas such as data provenance, reliability, transparency and understandability, pharmacovigilance, and real-world monitoring of patient functioning.

The report is based on a horizon-scanning exercise in AI, conducted by the ICMRA Informal Network for Innovation working group and led by EMA. The goal of this network is to identify challenging topics for medicine regulators, to explore the suitability of existing regulatory frameworks and to develop recommendations to adapt regulatory systems in order to facilitate safe and timely access to innovative medicines.

The implementation of the recommendations will be discussed by ICMRA members in the coming months.

Source: EMA