Changes from report parliamentary committee draft to plenary report

AddedRecital 145: (145) In order to ensure uniform conditions for the implementation of this Directive, implementing powers should be conferred on the Commission. Those powers should be exercised in accordance with Regulation (EU) No 182/2011 of the European Parliament and of the Council66 .

Recital 149: (149) In order to supplement or amend certain non-essential elements of this Directive, the power to adopt acts in accordance with Article 290 TFEU should be delegated to the Commission in respect of specifying the procedure for examination of application of active substance master file certificate, the publication of such certificates, the procedure for changes to the active substance master file and its certificate, access to the active substance master file and its assessment report; specifying additional master files to provide information on a constituent of a medicinal product, the procedure for examination of application of a quality master file certificate or a platform technology master file certificate, the publication of such certificates, the procedure for changes to the master file and its certificate, and access to the master file and its assessment report; determining the situations in which post-authorisation efficacy studies may be required; specifying the categories of medicinal products to which a marketing authorisation subject to specific obligations could be granted and specifying the procedures and requirements for granting such a marketing authorisation and for its renewal; specifying exemptions to variation and the categories in which variations should be classified and establishing procedures for the examination of applications for variations to the terms of marketing authorisations as well as specifying conditions and procedures for cooperation with…

Change 14

RemovedSee amendment to new Article 26a.

AddedArticle 1 – paragraph 2: 2. This Directive shall apply to medicinal products for human use intended to be placed on the market in Member States.

RemovedArticle 2 – paragraph 1 a (new): 1a. For the purpose of this Article, ‘non-routine basis’ means an advanced therapy medicinal product prepared under hospital exemption on an incidental and exceptional basis to meet the special needs of an individual patient, where there is neither a centrally authorised medicinal product available,nor an ongoing relevant clinical trial or compassionate use programme for the same indication with an advanced therapy medicinal product for which the patient is eligible in the Union. The following measures shall be an indication that an activity occurs on a routine basis: / (a) the manufacturing of a product using standardised or repetitive processes; or / (b) the use of processes that involve planning in advance, beyond what is needed to address the immediate clinical needs of individual patients.

AddedArticle 1 – paragraph 4 – subparagraph 1 a (new): In cases where, taking into account all its characteristics, questions arise as to the regulatory status of a substance or a product, the competent authority or, in the case of a centralised marketing authorisation the Agency shall consult other relevant advisory and regulatory bodies with a view to reaching a decision on the regulatory status f the substance or a product concerned. In any decision on such question, the competent authority or the Agency shall make publicly available the views of other authorities or bodies consulted.

RemovedArticle 2 – paragraph 2 – subparagraph 1: The manufacturing of an advanced therapy medicinal product prepared under hospital exemption shall require an approval by the competent authority of the Member State (‘hospital exemption approval’). Member States shall notify any such approval, as well as subsequent changes, to the Agency which shall publish such approval in the repository referred to in paragraph 6. The hospital exemption approval shall be valid for a period of 12 months.

AddedArticle 1 – paragraph 5 – point b: (b) medicinal product prepared in a pharmacy in accordance with a pharmacopoeia and intended to be supplied directly to the patients served by the pharmacy in question or to another pharmacy which intends to supply the medicinal product directly to the patient (‘officinal formula’);

RemovedArticle 2 – paragraph 2 – subparagraph 2: The application for a hospital exemption approval shall be submitted to the competent authority of the Member State where the hospital is located. The application shall include evidence on quality, safety and efficacy of the advanced therapy medicinal products prepared under hospital exemption. Before a hospital exemption approval is granted, the competent authority of the Member State shall confirm that no advanced therapy medicinal product is authorised within the Union for the same therapeutic indication, and that the manufacturing of such medicinal product complies with the requirements for preparation on a non-routine basis as set out in paragraph 1.

AddedArticle 1 – paragraph 5 – point c a (new): (ca) medicinal product prepared in advance, in duly justified cases, by the pharmaceutical department of a hospital (‘hospital formula’), supplied on medical prescription to one or several patients by the hospital’s pharmaceutical department.

RemovedArticle 2 – paragraph 4: 4. Member States shall ensure that data on the use, quality, safety and the efficacy of advanced therapy medicinal products prepared under hospital exemption, as well as any relevant data from patient follow-up, is collected and reported by the hospital exemption approval holder to the competent authority of the Member State at least annually. The competent authority of the Member State shall review such data and shall verify the compliance of advanced therapy medicinal products prepared under hospital exemption with the requirements referred to in paragraph 3.

AddedArticle 1 – paragraph 6: 6. Medicinal products referred to in paragraph 5, points (a) and (b), may be prepared in duly justified cases in advance by a pharmacy serving a hospital, on the basis of the estimated medical prescriptions within that hospital for the following seven days, or when duly justified based on the stability of the medicinal product within a different time limit.

RemovedArticle 2 – paragraph 5: 5. If a hospital exemption approval is revoked due to quality, safety or efficacy concerns the competent authority of the Member States that approved the hospital exemption shall inform the Agency and the competent authorities of the other Member States.

AddedArticle 1 – paragraph 7: 7. Member States shall take the necessary measures to develop the production and use of medicinal products derived from substances of human origin coming from voluntary unpaid donations in accordance with Regulation (EU) 2024/... [SoHO Regulation].

RemovedArticle 2 – paragraph 6: 6. The competent authority of the Member State shall transmit the data related to the use, quality, safety and efficacy of an advanced therapy medicinal product prepared under the hospital exemption approval to the Agency annually. The Agency shall, in collaboration with the competent authorities of Member States and the Commission, set up and maintain a publicly accessible repository of that data, as well as of information on the authorisation, suspension or withdrawal of hospital exemption approvals, which shall be updated regularly.

AddedArticle 1 – paragraph 10 – point a: deleted

AddedArticle 2 – paragraph 1: 1. By way of derogation from Article 1(1), only this Article shall apply to advanced therapy medicinal products prepared a non-routine basis in accordance with the requirements set in paragraph 3 and used within the same Member State in a hospital under the exclusive professional responsibility of a medical practitioner and, where relevant, a hospital pharmacist. To satisfy the criteria of 'non-routine basis', the exemption shall be made only in order to comply with an individual medical prescription for a custom-made product to meet the special need of an individual patient (‘advanced therapy medicinal products prepared under hospital exemption’).

AddedArticle 2 – paragraph 2 – subparagraph 2: The application for a hospital exemption approval shall be submitted to the competent authority of the Member State where the hospital is located. The application shall include evidence on quality, safety and expected efficacy of the advanced therapy medicinal products prepared under hospital exemption.

AddedArticle 2 – paragraph 3: 3. Member States shall ensure that advanced therapy medicinal products prepared under hospital exemption comply with the good pharmacy preparation practices that are adapted to hospital processes while still equivalent to the good manufacturing practices and traceability for advanced therapy medicinal products referred to in Articles 5 and 15 of Regulation (EC) No 1394/2007 of the European Parliament and of the Council69 respectively, and with pharmacovigilance requirements equivalent to those provided for at Union level pursuant to [revised Regulation (EC) No 726/2004]. This shall include site inspections as well as traceability and pharmacovigilance plans and the evaluation of the preclinical and clinical data generated by the applicant.

AddedArticle 2 – paragraph 4: 4. Member States shall ensure that data on the use, safety and the efficacy of advanced therapy medicinal products prepared under hospital exemption, as well as any relevant data from patient follow-up for a sufficient period of time after the administration of the advanced therapy medicinal product, is collected and reported by the hospital exemption approval holder to the competent authority of the Member State at least annually. The data shall be collected and reported in a structured and standardised way that enables robust, reliable and comparable results and conclusions. The competent authority of the Member State shall review such data and shall verify the compliance of advanced therapy medicinal products prepared under hospital exemption with the requirements referred to in paragraph 3. Competent authorities shall ensure that scientific and regulatory advice is provided to non-profit and academic institutions in order to ensure appropriate reporting mechanisms.

AddedArticle 2 – paragraph 6: 6. The competent authority of the Member State shall transmit the data related to the use, safety and efficacy of an advanced therapy medicinal product prepared under the hospital exemption approval to the Agency annually. The Agency shall, in collaboration with the competent authorities of Member States and the Commission, set up and maintain via regular updates a repository of that data as well as of information on the authorisation, suspension or withdrawal of hospital exemption approvals, which shall be updated regularly. The repository shall be publicly available except for personal data and commercially confidentail information.

AddedArticle 2 – paragraph 7 – subparagraph 1 – point a: deleted

AddedArticle 2 – paragraph 7 – subparagraph 1 – point c a (new): (ca) the modalities of guidance for academic and other not-for-profit entities through the requirements of the hospital exemption clause.

Article 2 – paragraph 7 – subparagraph 1 – point d: deleted

Change 15

RemovedSee amendment to Article 2 – paragraph 1 a (new).

AddedArticle 2 – paragraph 7 – subparagraph 2 a (new): By ... [24 months from the date of entry into force of this Directive], the Commission shall adopt delegated acts in accordance with Article 215 to supplement this Directive by establishing: / (a) details of the application for the approval of hospital exemption referred to in paragraph 1, second subparagraph, including the evidence on quality, safety and efficacy of the advance therapy medicinal products prepared under hospital exemption for the approval and the subsequent changes; / (b) the modalities for harmonised implementation of the preparation and use of advanced therapy medicinal products under hospital exemption on a non-routine basis.

Article 2 – paragraph 8: 8. The Agency shall provide to the Commission a report on the experience acquired with the hospital exemption approvals on the basis of contributions from Member States and the data referred to in paragraph 4. The report shall be made publicly available. The first report shall be provided three years after [OP please insert the date =18 months after the date of entering into force of this Directive] and then every five years thereafter.

Change 16

RemovedArticle 4 – paragraph 1 – point 2 – point d: (d) chemical, e.g. elements, including radioactive isotopes thereof (radionuclides), naturally occurring chemical materials and chemical products obtained by chemical change or synthesis;

AddedArticle 2 – paragraph 8 a (new): 8a. By way of derogation from paragraph 1, Member States may authorise the cross-border exchange of advanced therapy medicinal products prepared under hospital exemption in justified cases of medical need and in the absence of other solutions for the individual patient. A second medical practitioner and a hospital pharmacist in the receiving Member State shall be designated for the exclusive professional responsibility of the use and collection of follow-up data for the advanced therapy medicinal product. Information about the cross-border exchange shall be submitted to the competent authorities of both Member States, and shall be shared in the public repository referred to in paragraph 6 by the competent authority of the Member State of origin of the advanced therapy medicinal product.

RemovedArticle 4 – paragraph 1 – point 4: (4) ‘starting material’ means any material, including radioactive materials, from which an active substance is manufactured or extracted;

AddedArticle 3 – paragraph 1 – subparagraph 1: A Member State may, in order to fulfil special needs, exclude from the scope of this Directive medicinal products supplied in response to a bona fide unsolicited order, prepared in accordance with the specifications of an authorised healthcare professional and for use by an individual patient under their direct personal responsibility, or prepared in accordance with the specifications of a competent authority. However, in such case Member States shall encourage and establish channels for healthcare professionals and patients to report data on the safety of the use of such products to the competent authority of the Member State in accordance with Article 97.

RemovedArticle 4 – paragraph 1 – point 18: (18) ‘radiopharmaceutical’ means any medicinal product that, when ready for use, contains a radioactive component and that is intended to treat or diagnose a disease, including radionuclide radiopharmaceuticals and complex radiopharmaceuticals, not including radionuclides used only for radiolabelling purposes, medical devices and in-vitro diagnostic devices;

AddedArticle 4 – paragraph 1 – point 11: (11) ‘non-clinical’ means a study or a test conducted in vitro, ex vivo, in silico, or in chemico, or a non-human in vivo test related to the investigation of the safety and efficacy of a medicinal product. Such test may include simple and complex human cell-based assays, microphysiological systems including organ-on-chip, computer modelling and other in silico methods, other non-human or human biology-based test methods, including aquatic egg models as well as invertebrate species, and animal-based tests;

RemovedArticle 4 – paragraph 1 – point 18 a (new): (18a) 'radionuclide radiopharmaceuticals' means a radiopharmaceutical where the radionuclide or its salt is the active substance;

AddedArticle 4 – paragraph 1 – point 22: (22) ‘antimicrobial’ means any medicinal product with a direct action on micro-organisms used for treatment or prevention of infections or infectious diseases, including antibiotics, antivirals, antifungals and antiprotozoals;

RemovedArticle 4 – paragraph 1 – point 18 b (new): (18b) 'complex radiopharmaceutical' means a radiopharmaceutical where the radionuclide is bound to or within a carrier molecule to achieve the targeted accumulation, including ready-to-use dosage forms and kits for radiopharmaceutical preparation;

AddedArticle 4 – paragraph 1 – point 26: (26) ‘combination of a medicinal product with a product other than a medical device’ means a combination of a medicinal product with a product other than a medical device (as defined by Regulation (EU) 2017/745 and Regulation (EU) 2017/746 of the European Parliament and of the Council1a) and where the two are intended for use in the given combination in accordance with the summary of product characteristics; / 1a Regulation (EU) 2017/746 of the European Parliament and of the Council of 5 April 2017 on in vitro diagnostic medical devices and repealing Directive 98/79/EC and Commission Decision 2010/227/EU (OJ L 117 5.5.2017, p. 176).

RemovedArticle 4 – paragraph 1 – point 19: (19) ‘radionuclide generator’ means any system incorporating a fixed parent radionuclide from which a daughter radionuclide is produced, where the daughter radionuclide is used either as a medicinal product or as a radionuclide for radiolabelling purposes;

AddedArticle 4 – paragraph 1 – point 29 – introductory part: (29) “gene therapy medicinal product” means a type 1 or type 2 medicinal product; / (deleted) / (deleted)

Change 17

ChangedArticle 4 – paragraph 1 – point 20:29 (20)a ‘kit(new): for(29a) radiopharmaceutical“type preparation’1 gene therapy medicinal product” means a pre-formulated medicinal product containingthat allcontains ingredientsor requiredconsists toof directlya preparesubstance or a radiopharmaceutical,combination withof substances that edit the exceptionhost genome in a sequence-specific manner or that contain or consists of thecells radionuclide;subjected to such modification;

Change 18

RemovedArticle 4 – paragraph 1 – point 21: deleted

AddedArticle 4 – paragraph 1 – point 29 b (new): (29b) “type 2 gene therapy medicinal product” means a medicinal product, except a vaccine against infectious disease that contains or consists of a recombinant or synthetic nucleic acid used in or administered to human beings with a view to regulating, replacing or adding a genetic sequence that mediates its effect by transcription or translation of the transferred genetic materials or that contain or consists of cells subjected to these modifications;

RemovedArticle 4 – paragraph 1 – point 26: (26) ‘combination of a medicinal product with a product other than a medical device’ means a combination of a medicinal product with a product other than a medical device (as defined by Regulations (EU) 2017/745 and (EU) 2017/746) and where the two are intended for use in the given combination in accordance with the summary of product characteristics;

AddedArticle 4 – paragraph 1 – point 30 a (new): (30a) ‘platform technology’ means a technology or collection of technologies that is comprehensive, well-characterised, reproducible and used to support the development, manufacturing process, quality control, or testing of medicinal products or their components that rely on prior knowledge and are established under the same underlying scientific principles

RemovedArticle 4 – paragraph 1 – point 28: (28) 'vaccine’ means any medicinal product that is intended to elicit an immune response for prevention, including post exposure prophylaxis, of diseases caused by an infectious agent;

AddedArticle 4 – paragraph 1 – point 30 b (new): (30b) ‘platform technology master file’ means a document, prepared by the owner of the platform technology, that contains data of a platform technology for which the underlying scientific principles, under which the platform technology is established, have reasonable scientific certainty to remain unchanged across medicinal products and to apply regardless of components added to the platform for a medicinal product;

RemovedArticle 4 – paragraph 1 – point 30 a (new): (30a) ‘platform technology’ means a technology or collection of technologies used in the manufacturing process, quality control, or testing of medicinal products or their components that rely on prior knowledge and are established under the same underlying scientific principles;

AddedArticle 4 – paragraph 1 – point 31 – point a: (a) a method involving an industrial process which includes pooling of donations, for purposes beyond processing of substances of human origin for concentrates or pathogen inactivation; or

RemovedSee amendments to new Article 26a.

AddedArticle 4 – paragraph 1 – point 33: (33) ‘environmental risk assessment’ means the evaluation of the risks to the environment, or risks to public health, posed by the release of the medicinal product in the environment from the manufacturing, use and disposal of the medicinal product and the identification of risk prevention, limitation and mitigation measures. For medicinal product with an antimicrobial mode of action, the ERA also encompasses an evaluation of the risk for antimicrobial resistance selection in the environment due to the manufacturing, use and disposal of that medicinal product;

RemovedArticle 4 – paragraph 1 – point 30 b (new): (30b) ‘platform technology master file’ means a document, prepared by the owner of the platform technology, that contains data of a platform technology for which the underlying scientific principles, under which the platform technology is established, will apply regardless of components added to the platform as part of the manufacturing process for a medicinal product;

AddedArticle 4 – paragraph 1 – point 34: (34) ‘antimicrobial resistance’ means the ability of a micro-organism to survive or to grow in the presence of a concentration of an antimicrobial agent that is usually or was previously sufficient to inhibit or kill that micro-organism;

RemovedSee amendments to new Article 26a.

AddedArticle 4 – paragraph 1 – point 62: (62) ‘homeopathic product’ means a medicinal product prepared from homeopathic stocks in accordance with a homeopathic manufacturing procedure described by the European Pharmacopoeia or, in the absence thereof, by the pharmacopoeias currently used officially in the Member States;

RemovedArticle 4 – paragraph 1 – point 33: (33) ‘environmental risk assessment’ means the evaluation of the potential risks to the environment, including risks to public health arising from risks to the environment, posed by the release of the medicinal product in the environment from the use and disposal of the medicinal product and the identification of risk prevention, limitation and mitigation measures. For medicinal product with an antimicrobial mode of action, the ERA also encompasses an evaluation of the risk for antimicrobial resistance selection in the environment due to the manufacturing, use and disposal of that medicinal product;

AddedArticle 4 – paragraph 1 – point 70: (70) ‘public service obligation’ means to ensure permanently an adequate range of medicinal products to meet the requirements of a specific geographical area and to deliver the supplies requested within a very short time over the whole of the area in question.

RemovedArticle 4 – paragraph 1 – point 53: (53) ‘micro, small and medium-sized enterprises’ means micro, small and medium-sized enterprises as defined in Article 2 of Commission Recommendation 2003/361/EC72 and, from ... [18 months after the date of entry into force of this Directive], it means micro, small and medium-sized enterprises as defined in the delegated act referred to in Article 58a(1);

AddedArticle 4 – paragraph 2: 2. The Commission is empowered to adopt delegated acts in accordance with Article 215 to amend the definitions in paragraph 1, points (2) to (6), (8), (14), (16) to (28) and (30) in the light of technical and scientific progress and taking into account definitions agreed at Union and international level without extending the scope of the definitions.

RemovedArticle 4 – paragraph 1 – point 70: (70) ‘public service obligation’ means to guarantee permanently an adequate range of medicinal products to meet the requirements of a specific geographical area and to deliver the supplies requested within a reasonable time over the whole of the area in question.

AddedArticle 6 – paragraph 2 a (new): 2a. A marketing authorisation may be granted for a medicinal product on the basis of an active substance master file, an additional quality master file or a platform technology master file where such a file exists and is referred to in the application.