medicinal products Archives - European Industrial Pharmacists Group (EIPG)

Patient involvement in the development, regulation and safe use of medicines


by Giuliana Miglierini The Council for International Organizations of Medical Sciences (CIOMS) has published the CIOMS report on “Patient involvement in the development, regulation and safe use of medicines”. The report marks an important step forward towards a harmonised approach to Read more

Webinar: Implementation of Contamination Control Strategy Using the ECA template


The next EIPG webinar will be held in conjunction with PIER and University College Cork on Friday 21st of October 2022 (16.00 CEST), on the implementation of Contamination Control Strategy (CCS) using the ECA* template. This is the second Read more

Real-world evidence for regulatory decision-making


by Giuliana Miglierini Digitalisation is rapidly advancing also in the regulatory field, as a tool to improve the efficiency and accuracy of processes used for the generation and use of data to inform the regulatory decision-making. To this instance, real-world Read more

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.


Revision of the PIC/S GMP Guide: Annex 13 and Annex 16

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by Giuliana Miglierini

The entry into force of EU Regulation 536/2014 “Clinical trials”, at the end of January, resulted in the parallel updating of some international guidelines. In particular, a new version of the GMP Guide PE016 was published by PIC/S (Pharmaceutical Inspection Co-operation Scheme) on 1st February 2022. The revision included Annex 13 on the manufacturing of Investigational Medicinal Products (IMPs), and the new Annex 16 on the certification and batch release to be performed by Authorised Persons (AP) (click here to access all PIC/S guidance related to GMP). The revision of PIC/s guidelines is aimed to reflect the last changes occurred in the corresponding EMA documents, so to maintain the alignment between the two regulatory references (as established by the cooperation agreement between EMA and PIC/S). PIC/S has invited all non- EEA Participating Authorities and applicants to transpose the new Annexes 13 and 16 into their own GMP Guides.

The new Annex 16

Annex 16 represents a completely new addition to the PIC/S GMP guide; the EU Annex 16 (part of the EU GMP Guide) was initially considered to be too EU-specific and difficult to transpose for PIC/S purposes. Following a consultation in 2017, PIC/S Participating Authorities agreed to make an attempt to transpose EU Annex 16, as the adaptation may support a better harmonisation of GMP standards at the international level.

Annex 16 refers to both human and veterinary medicinal products which are subject to the PIC/S Participating Authority or are made for export. Furthermore, the Annex applies to investigational medicinal products for human use, “subject to any difference in the legal provisions and more specific guidance published by PIC/S Participating Authorities under national law”. With reference to imported medicinal products, each PIC/S Participating Authority may independently and voluntary decide whether to adopt the guidance as a legally-binding standard.

Certain types of medicinal products (e.g. blood and immunological products) are not addressed by the Annex, as they are regulated by national laws and fall under the competences of National authorities; to this instance, Annex 16 applies to the certification process performed by the AP and to the subsequent release of the batches.

The marketing authorisation holder (MAH) remains the sole responsible for the safety, quality and efficacy of the marketed products. Authorised Persons are required to check each single batch to verify compliance to national and GMP requirements, as well as to those detailed within the marketing authorisation (MA). After certification by the AP, batches of finished products can be transferred to saleable stock and/or export. Specific and documented agreements are needed should this require transfer to a site different from the certification’s one. Authorised Persons should be clearly identifiable, with reference to any quality defect leading to investigation or batch recall. APs certifying the release of the finished product are responsible for verifying the conditions of storage and transport for the batch and the sample, if sent separately, and of all testing required upon importation (including sampling, where needed).

A formal Quality Risk Management (QRM) process is required when sampling is performed at a manufacturing site located in another jurisdiction; Annex 16 provides detailed guidance on the elements to be considered in this exercise. Documentation of the continuous training received by the AP in charge of certification and batch release should be always available, with specific reference to the product type, production processes, technical advances and changes to GMP.

Annex 16 provides detailed guidance on how to conduct the process of certification of each batch of finished product, independently of the number of sites involved. With reference to specific manufacturing or control steps performed at different sites, their respective AP has to provide confirmation of the performed activities, sharing responsibilities with the AP in charge of the final batch release.

The certification process should take into consideration the entire supply chain of both the active substance and the finished product, including manufacturing sites of the starting and packaging materials. The AP responsible for certification should be able to access results of the audits performed at the sites involved, in order to check the consistency of all activities with those described in the MA and within GMPs. Audits run by third parties should reflect requirements set forth in Chapter 7 of the PIC/S GMP Guide.

In particular, suppliers of active substances should comply with GMP and GDP requirements relating to the supply of the active ingredient used to the finished product manufacturing. Excipients should also fulfil GMP requirements, and be possibly manufactured and supplied in accordance with the PI 045-1 guideline. Specific guidance may also apply for other types of products, i.e. biological active substances and medicinal products for human use or radiopharmaceuticals. Annex 16 provides templates for the confirmation letters to be used for the partial manufacturing of a medicinal product and for the content of Batch Certificates.

The revision of Annex 13

Annex 13 has been revised in order to reflect the contents of the new EU Regulation n. 536/2014 on clinical trials, which will replace EU Annex 13. PIC/S Annex 13 discusses the manufacturing of Investigational Medicinal Products (IMP), apart from the reconstitution phase, which is not considered to be part of the process. Provisions set forth by Annex 13 should be taken into consideration with reference to the re-labelling or re-packaging of IMPs and to the preparation of radiopharmaceuticals used as diagnostic investigational medicinal products, occurring in hospitals, health centres or clinics and performed by pharmacists or other persons legally authorised in the country concerned.

All activities should refer to an appropriate Pharmaceutical Quality System to be in place, according to requirements set forth in Chapter 1 of Part 1 of the PIC/S GMP Guide.

 The characteristics of IMPs may intrinsically evolve along the development process, as new data become available that may require changes to, for example, the formulation or the dosage form. This has to be reflected into the respective product specifications and manufacturing instructions, that should also evolve in parallel and be fully traceable and documented. Annex 13 indicates that all deviations should be registered and investigated, and preventive and corrective actions put in place. The new Annex provides detailed guidance on the different items to be considered within the product specification file, as well as for the proper management of personnel, premises and equipment.

All the documentation generated during the clinical development phases should fulfil requirements specified by the PIC/S GMP Guide, Part I, Chapter 4. To this instance, relevant documentation includes specifications and instructions, orders, manufacturing formulae and processing instructions, packaging instructions and batch records. Detailed guidance is provided also for production, including packaging materials and manufacturing operations, the modification of comparator products, blinding operations, and the packaging and labelling of the IMP. Annex 13 also offers guidance on how to perform quality control and batch release, and how to address outsourced operations, complaints and recalls and or the destruction of batches of IMP products.


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.