L.S. 458.34 Regolamenti dwar Mediċini (Awtorizzazzjoni għat-Tqegħid fis-Suq)

(1)For the purposes of these regulations - ''abuse of medicinal products'' means persistent or sporadic, intentional excessive use of medicinal products which is accompanied by harmful physical or psychological effects; Citation. Interpretation. Amended by: L.N. 231 of 2008; L.N. 252 of 2010; L.N. 373 of

1. ''advanced therapy medicinal product'' means a product as defined in Article 2 of Regulation (EC) No 1394/2007 of the European Parliament and of the Council of 13 November 2007 on advanced therapy medicinal products ''Annex I'' means Annex I of Directive 2001/83/EC as subsequently amended and as appearing in the Schedule; ''the Act'' means the Medicines Act; ''the Agency'' means the European Medicines Agency established by Regulation (EC) No 726/2004; ''the Authority'' means the Medicines Authority established under article 4 of the Act; ''the Commission'' means the Commission in accordance with Council Decision 1999/468/EC of 28 June, 1999; ''the Community'' means the European Union, previously referred to as the European Community and the European Economic Community; ''common name'' is the international non-proprietary name recommended by the World Health Organisation, or if it does not exist, the usual common name; ''co-ordination group'' means the co-ordination group set up in accordance with Article 27 of Directive 2001/83/EC as amended by Directive 2004/27/EC; ''global marketing authorisation'' means the marketing authorisations containing the initial marketing authorisation and all variations and extensions thereof, as well as any additional strengths, pharmaceutical forms, administration routes or presentations authorised through separate procedures and under a different name, granted to the marketing authorisation holder of the initial authorisation; ''homeopathic medicinal product'' means any medicinal product prepared from substances called homeopathic stocks in accordance with a homeopathic manufacturing procedure described by the European Pharmacopoeia or, in the absence thereof, by the Cap.
2. 2 [ S.L.458.34 MEDICINES (MARKETING AUTHORISATION) pharmacopoeias currently used officially in the Member States. A homeopathic medicinal product may contain a number of principles; ''Licensing Authority'' means the Licensing Authority referred to in article 3 of the Act; ''medicinal product'' shall have the same meaning as defined by the Act; ''Member State'' means a State, which is a member of the European Union, and shall also include Iceland, Norway and Liechtenstein; "Pharmacovigilance system" means a system used by the marketing authorisation holder and by Member States to fulfil the tasks and responsibilities listed in these regulations and designed to monitor the safety of authorised medicinal products and detect any change to their risk-benefit balance; "Pharmacovigilance system master file" means a detailed description of the pharmacovigilance system used by the marketing authorisation holder with respect to one or more authorised medicinal products; "post-authorisation safety study" means any study relating to an authorised medicinal product conducted with the aim of identifying, characterising or quantifying a safety hazard, confirming the safety profile of the medicinal product, or of measuring the effectiveness of risk management measures; ''reference Member State'' means the Member State which, for a given medicinal product, has produced the assessment report, which serves as the basis for the mutual recognition procedure and the decentralised procedure; ''representative of the marketing authorisation holder'' means the person commonly known as local representative, designated by the marketing authorisation holder to represent him in the Member State concerned; ''risk-benefit balance'' means an evaluation of the positive therapeutic effects of the medicinal product in relation to the risks relating to the quality, safety and efficacy of the medicinal product as regards patients’ health or public health; "risk management system" means a set of pharmacovigilance activities and interventions designed to identify, characterise, prevent or minimise risks relating to a medicinal product, including t h e a s s e s s m e n t of t h e e ff e c t iv e ne s s o f t h o s e a c t i v it i e s a n d interventions; "risk management plan" means a detailed description of the risk management system; ''risks related to use of the medicinal product'' means any risk relating to the quality, safety or efficacy of the medicinal product as regards patients’ health or public health or any risk of undesirable effects on the environment; ''strength of the medicinal product'' means the content of the MEDICINES (MARKETING AUTHORISATION) [ S.L.458.34 3 active substances expressed quantitatively per dosage unit, per unit of volume or weight according to the dosage form; ''the Superintendent'' means the Superintendent of Public Health.

(2)The provisions of these regulations shall not apply to: (

1. a)any medicinal product prepared in a pharmacy in accordance with a medical prescription for an individual patient (commonly known as the magistral formula); (
2. b)any medicinal product which is prepared in a pharmacy in accordance with the prescriptions of a pharmacopoeia and is intended to be supplied directly to the patients served by the pharmacy in question, (commonly known as the officinal formula); (
3. c)medicinal products intended for research and development trials but without prejudice to the provisions of the Clinical Trials Regulations or of Directive 2001/20/EC of the European Parliament and of the Council of the 4th April 2001 on the approximation of the laws, regulations and administrative provisions of the Member States relating to the implementation of good clinical practice in the conduct of clinical trials on medicinal products for human use; (
4. d)S.L. 458.43 intermediate products intended for further processing by an authorised manufacturer; (
5. e)any radionuclides in the form of sealed sources; (
6. f)whole blood, plasma or blood cells of human origin, except for plasma which is prepared by a method involving an industrial process; (
7. g)medicinal products supplied in response to a bona fide unsolicited order, formulated in accordance with the specifications of an authorised health-care professional and for use by an individual patient under his direct personal responsibility; (
8. h)any advanced therapy medicinal product, as defined in Regulation (EC) No 1394/2007, which is prepared on a non-routine basis according to specific quality standards, and used in Malta in a hospital under the exclusive professional responsibility of a medical practitioner, in order to comply with an individual medical prescription for a custom-made product for an individual patient. The manufacturing of these products shall be authorised by the Licensing Authority in Malta. 2A.

(1)The Licensing Authority shall establish, notify to the Commission and publish on its website a list of medicinal products to which it has applied or intends to apply the derogations as set out in Directive (EU) 2022/642 of the European Parliament and of the Council of 12 April 2022; List of medicinal products to be published. Added by: L.N. 234 of 2022. 4 [ S.L.458.34 MEDICINES (MARKETING AUTHORISATION)

(2)The Licensing Authority shall ensure that the list referred to in sub-regulation

(1)is updated and managed in an independent manner, at least on a six-monthly basis. Applicability. 3.

(1)The provisions of these regulations shall apply to medicinal products for human use intended to be placed on the market in Malta and either prepared industrially or manufactured by a method involving an industrial process.

(2)In cases of doubt, where, taking into account all its characteristics, a product may fall within the definition of a ''medicinal product'' and within the definition of a product covered by other community legislation, the provisions of these regulations shall apply. Authorisation for placing on the market. Amended by: L.N. 231 of 2008; L.N. 373 of 2012. 4.

(1)(

1. a)Subject to the following provisions of this regulation, no medicinal product may be placed on the market in Malta unless there is in respect of that product a valid marketing authorisation issued by the Licensing Authority in accordance with these regulations or in accordance with procedures laid down in Regulation (EC) No 726/2004 of the European Parliament and of the Council of 31 March 2004 laying down Community procedures for the authorisation and supervision of medicinal products for human and veterinary use and establishing a European Medicines Agency), read in conjunction with Regulation (EC) No 1901/2006 of the European Parliament and of the Council of 12 December 2006 on medicinal products for paediatric u se , a n d R e g u l a t i o n ( E C ) N o . 1 3 9 4 / 2 0 0 7 o f t h e European Parliament and of the Council of the 13th N o v e m b e r 2 0 0 7 o n a d v a n c e d t h e r a p y m e d i ci n a l products and such placing on the market is in accordance with the terms and conditions of such marketing authorisation. (
2. b)When a medicinal product has been granted an initial marketing authorisation in accordance with the preceding paragraph, any additional strengths, pharmaceutical forms, administration routes, presentations, as well as any variations and extensions shall only be granted an authorisation in accordance with the preceding paragraph or be included in the initial marketing authorisation. All these marketing authorisations shall be considered as belonging to the same global marketing authorisation, in particular for the purpose of the application of regulation 7

(1). (

1. c)The provisions of paragraphs (
2. a)and (
3. b)shall also apply to radionuclide generators, kits, radionuclide precursor radiopharmaceuticals and industrially prepared radiopharmaceuticals. (
4. d)A marketing authorisation shall not be required in the case of a radiopharmaceutical prepared at the time of its use by a person or by an establishment duly authorised to use such medicinal products in an [ S.L.458.34 MEDICINES (MARKETING AUTHORISATION) approved health care establishment exclusively from authorised radionuclide generators, kits or radionuclide precursors in accordance with the manufacturer’s instructions. (
5. e)The Licensing Authority may, in exceptional cases, subject to any condition it deems fit, allow the use of a medicinal product which does not have a marketing authorisation. (
6. f)The Licensing Authority may temporarily authorise the distribution of an unauthorised medicinal product in response to the suspected or confirmed spread of pathogenic agents, toxins, chemical agents or nuclear radiation any of which could cause harm. (
7. g)The marketing authorisation holder shall be responsible for marketing the medicinal product and the designation of a representative shall not relieve the marketing authorisation holder of his legal responsibility. The holder of a marketing authorisation for a medicinal product and the distributors of the said medicinal product actually placed on the market in Malta shall, within the limits of their responsibilities, ensure appropriate and continued supplies of that medicinal product to pharmacies and persons authorised to supply medicinal products so that the needs of patients in Malta are covered.

(2)(

1. a)In the absence of a marketing authorisation or of a pending application for a medicinal product which is authorised in another Member State in accordance with Directive 2001/83/EC of the European Parliament and of the Council of 6 November 2001 on the community code relating to medicinal products for human use, and any amendments thereto, the Licensing Authority may for justified public health reasons authorise the placing of the said medicinal product on the market in Malta. (
2. b)The medicinal product referred to in paragraph (
3. a)has to comply in particular with the requirements of the provisions regarding the classification of medicinal products, laid down in the Act, and any regulations made thereunder, and the following regulations: (
4. i)the Medicinal Regulations; Products (
5. ii)the Medicinal Products Packaging) Regulations; (Advertising) (Labelling and S.L 458.32 S.L. 458.33 (iii) the Pharmacovigilance Regulations; and S.L. 458.35 (
6. iv)S.L. 458.37 the Wholesale Distribution Products Regulations. of Medicinal The Authority may decide that regulation 10

(1)and

(2)of the Medicinal Products (Labelling and Packaging) Regulations and Article 63

(1)and

(2)of Directive 2001/ 83/EC shall not apply to medicinal products authorised S.L. 458.33 5 6 [ S.L.458.34 MEDICINES (MARKETING AUTHORISATION) under paragraph (a). (

1. c)Any authorisation issued under this regulation shall for the purposes of articles 99 to 104 of the Act be deemed to be a marketing authorisation. (
2. d)Before granting such an authorisation the Licensing Authority shall: (
3. i)(
4. e)notify the marketing authorisation holder in the Member State in which the medicinal product concerned is authorised, of its intention to grant an authorisation under subregulation

(2), and (

1. ii)request the competent authority in that Member State to furnish a copy of the assessment report, and of the marketing authorisation in force. (
2. i)The medicinal product to be placed on the market in Malta shall be that authorised by the Member State referred to in paragraph (a). (
3. ii)An authorisation under this subregulation cannot be used as the basis for a licence in terms of the Parallel Importation of Medicinal Products Regulations. (iii) An authorisation under this subregulation cannot be used as a reference for an application submitted in accordance with regulation 7. S.L. 458.40 (
4. f)The holder of the authorisation in Malta granted in accordance with this subregulation, shall ensure that: (
5. i)the medicinal product is in accordance with the marketing authorisation issued by the Member State referred to above, and includes any variations in particular those affecting the summary of product characteristics, labelling and package leaflet of the medicinal product as approved in the said Member State, and submits the updated documentation to the Medicines Authority; (
6. ii)he implements without any delay actions relating to issues concerning the medicinal product which have resulted in a product or batch recall as may apply to the medicinal product authorised in the Member State referred to above. (
7. g)In the case of a medicinal product, where the wholesale distributor is not the authorisation holder for the medicinal product in Malta, the distributor shall, in respect of the product he is distributing in Malta, furnish to the Medicines Authority an authenticated copy of the said authorisation together with a letter of access issued by the authorisation holder granting the wholesale distributor the use of such an authorisation. MEDICINES (MARKETING AUTHORISATION) [ S.L.458.34 4A.

(1)By way of derogation from regulation 4

(2), until the 31st December 2024, in the absence of a marketing authorisation or of a pending application for a marketing authorisation, the Licensing Authority may authorise for justified public health reasons the placing on the market of a medicinal product authorised in parts of the United Kingdom other than Northern Ireland: 7 Derogation for products from the United Kingdom. Added by: L.N. 234 of 2022. Provided that the Licensing Authority may also maintain in force or, until the 31st December 2024, extend marketing authorisations that were granted pursuant to this sub-regulation before the 20th April 2022 which authorise the placing on the market of a medicinal product authorised in parts of the United Kingdom other than Northern Ireland: Provided further that authorisations that are granted, extended or maintained in force pursuant to the provisions of this subregulation shall not be valid after the 31st December 2026.

(2)By way of derogation from regulation 5

(1)(b), the Licensing Authority may grant marketing authorisations as referred to in regulation 4

(2), to marketing authorisation holders established in parts of the United Kingdom other than Northern Ireland.

(3)Where the Licensing Authority grants or extends a marketing authorisation as referred to in sub-regulation

(1), it shall ensure compliance with the requirements of this regulation.

(4)Before granting a marketing authorisation pursuant to subregulation

(1), the Licensing Authority: (

1. a)shall notify the marketing authorisation holder in parts of the United Kingdom other than Northern Ireland of the proposal to grant a marketing authorisation or to extend a marketing authorisation under this regulation in respect of the medicinal product concerned; (
2. b)may request the competent authority in the United Kingdom to submit the relevant information regarding the marketing authorisation of the medicinal product concerned. 5.

(1)A marketing authorisation may only be granted or renewed if the general conditions applicable to authorisations and the conditions set out under Directive 2001/83/EC on the Community code relating to medicinal products for human use and subsequent amendments thereto, are fulfilled as follows: (

1. a)an application for marketing authorisation shall be made to the Licensing Authority which shall refer such application to the Authority for processing; (
2. b)a marketing authorisation may only be granted to an applicant established in the Community: Provided that by way of derogation from the above, marketing authorisations may be granted until the 31st Grant or renewal of marketing authorisation. Substituted by: L.N. 373 of 2012. Amended by: L.N. 234 of 2022. 8 [ S.L.458.34 MEDICINES (MARKETING AUTHORISATION) December 2024, by the Licensing Authority in accordance with the mutual recognition or the decentralised procedure laid down under regulation 22 to marketing authorisation holders established in parts of the United Kingdom other than Northern Ireland: Provided further that until the 31st December 2024 the Licensing Authority may extend marketing authorisations already granted prior to the 20th April 2022 to marketing authorisation holders established in parts of the United Kingdom other than Northern Ireland: Provided further that marketing authorisations granted or extended by the Licensing Authority in accordance with the preceding two provisos shall cease to be valid at the latest on the 31st December 2026. (
3. c)the application shall be accompanied by the following documents and particulars to be submitted in accordance with Annex I: (
4. i)the name or corporate name and permanent address of the applicant and, where applicable, of the manufacturer; (
5. ii)the name of the medicinal product; (iii) qualitative and quantitative particulars of all the constituents of the medicinal product, including the reference to its international non-proprietary name (INN) recommended by the World Health Organisation, where an INN for the medicinal product exists, or a reference to the relevant chemical name; (
6. iv)evaluation of the potential environmental risks posed by the medicinal product. This impact shall be assessed and, on a case-by-case basis, specific arrangements to limit it shall be envisaged; (
7. v)a description of the manufacturing method; (
8. vi)therapeutic indications, contra-indications and adverse reactions; (vii) posology, pharmaceutical form, method and route of administration and expected shelf life; (viii) reasons for any precautionary and safety measures to be taken for the storage of the medicinal product, its administration to patients and for the disposal of waste products, together with an indication of potential risks presented by the medicinal product for the environment; (
9. ix)description of the control methods employed by the manufacturer; MEDICINES (MARKETING AUTHORISATION) (
10. x)(
11. xi)[ S.L.458.34 a written confirmation that the manufacturer of the medicinal product has verified compliance of the manufacturer of the active substance with principles and guidelines of good manufacturing practice by conducting audits, in accordance with regulation 5 of the Good Manufacturing Practice in respect of Medicinal Products, Active Substances and Investigational Medicinal Products for Human Use Regulations. The written confirmation shall contain a reference to the date of the audit and a declaration that the outcome of the audit confirms that the manufacturing complies with the principles and guidelines of good manufacturing practice; results of pharmaceutical (physico-chemical, biological or microbiological) tests, pre-clinical (toxicological and pharmacological) tests, clinical trials; S.L. 458.42 (xii) a summary of the applicant’s pharmacovigilance system which shall include the following elements: - proof that the applicant has at his disposal a qualified person responsible for pharmacovigilance, - the Member States in which the qualified person resides and carries out his tasks, - the contact details of the qualified person, - a statement signed by the applicant to the effect that the applicant has the necessary means to fulfil the tasks and responsibilities listed in Title IX of Directive 2001/83/EC as amended, - a reference to the location where the pharmacovigilance system master file for the medicinal product is kept; (xiii) the risk management plan describing the risk management system which the applicant will introduce for the medicinal product concerned, together with a summary thereof of the risk management system which the applicant will introduce; (xiv) a statement to the effect that clinical trials carried out outside the European Union meet the ethical requirements of the Clinical Trials Regulations and of Directive 2001/20/EC of the European Parliament and of the Council of the 4th April, 2001 on the approximation of the laws, regulations and administrative provisions of the Member States relating to the implementation of good clinical practice in the conduct of clinical trials on medicinal products on human use; S.L. 458.43 9 10 [ S.L.458.34 MEDICINES (MARKETING AUTHORISATION) (
12. xv)S.L. 458.33 a summary, in accordance with regulation 8, of the product characteristics, a mock-up of the outer packaging, containing the details provided for in the Medicinal Products (Labelling and Packaging) Regulations, and of the immediate packaging of the medicinal product, containing the details provided for in those regulations, together with a package leaflet in accordance with those same regulations; (xvi) a document showing that the manufacturer is authorised in his own country to produce medicinal products; (xvii) copies of the following: - any authorisation, obtained in another Member State or in a third country, to place the medicinal product on the market, a summary of the safety data including the data contained in the periodic safety update reports, where available, and suspected adverse reactions reports, together with a list of those Member States in which an application for authorisation submitted in accordance with the provisions of Directive 2001/83/EC, as amended, is under examination, - S.L. 458.33 the summary of the product characteristics proposed by the applicant in accordance with regulation 8 or approved by the competent authorities of the Member State in accordance with regulation 16 and the package leaflet proposed in accordance with the Medicinal Products (Labelling and Packaging) Regulations, or as approved by the competent authorities of the Member State in accordance with the Medicinal Products (Labelling and Packaging) Regulations, - details of any decision to refuse authorisation, whether in the Community or in a third country, and the reasons for such a decision; (xviii) a copy of any designation of the medicinal product as an orphan medicinal product under Regulation (EC) No 141/2000 of the European Parliament and of the Council of 16 December 1999 on orphan medicinal products, accompanied by a copy of the relevant Agency opinion.

(2)The documents and information concerning the results of the pharmaceutical and pre-clinical tests and the clinical trials referred to in sub-regulation

(1)(c)(x) shall be accompanied by detailed summaries in accordance with regulation 9. MEDICINES (MARKETING AUTHORISATION) [ S.L.458.34 11

(3)The risk management system referred to in sub-regulation

(1)(c)(xii) shall be proportionate to the identified risks and the potential risks of the medicinal product, and the need for postauthorisation safety data.

(4)The information in sub-regulation

(1)shall be updated where and when appropriate. 5A. The derogations set out in regulations 4A and 5

(1)(b), regulations 4 and 22 of the Pharmacovigilance Regulations, and regulations 11A, 11B, 11C and 11D of the Manufacture and Importation of Medicinal Products for Human Use Regulations shall not affect the obligations of the marketing authorisation holder to ensure the quality, safety and efficacy of the medicinal product placed on the market as laid down in these regulations. Obligations of the authorisation holder. S.L. 458.35. S.L. 458.36. Added by: L.N. 234 of 2022. 6. In the case of an application for a marketing authorisation for a radionuclide generator, in addition to the requirements set out in regulations 5 and 7

(1), the application shall also contain: Application for radionuclide generator. (

1. a)a general description of the system together with a detailed description of the components of the system which may affect the composition or quality of the daughter nucleid preparation; and (
2. b)qualitative and quantitative particulars of the eluate or the sublimate. 7.

(1)(

1. a)(
2. i)By way of derogation from regulation 5

(1)(c)(x), and without prejudice to the law relating to the protection of industrial and commercial property, the applicant shall not be required to provide the results of pre-clinical tests and of clinical trials if he can demonstrate that the medicinal product is a generic of a reference medicinal product which is or has been authorised under regulation 4

(1)for not less than eight years in a Member State or in the C o m m u n i t y. A g e n e r i c m e d i c i n a l p r o d u c t authorised pursuant to this provision shall not be placed on the market until ten years have elapsed from the initial authorisation of the reference product: Provided that the said ten-year period shall be extended to a maximum of eleven years if, during the first eight years of those ten years, the marketing authorisation holder obtains an authorisation for one or more therapeutic indications which, during the scientific evaluation prior to their authorisation, are held to bring a significant clinical benefit in comparison with existing therapies. (ii) Subregulation

(1)(a)(i) shall also apply if the reference medicinal product was not authorised in Malta. In this case, the applicant shall indicate in the application form the name of the Details to be provided. Amended by: L.N. 231 of 2008. 12 [ S.L.458.34 MEDICINES (MARKETING AUTHORISATION) Member State in which the reference medicinal product is or has been authorised. At the request of the Licensing Authority, the competent authority of the other Member State shall transmit within a period of one month, a confirmation that the reference medicinal product is or has been authorised, together with the full composition of the reference product and if necessary other relevant documentation: Provided that the Licensing Authority shall within one month provide any information requested by the competent authority of another Member State in respect of a reference medicinal product authorised in Malta: Provided further that for the purposes of this regulation: ''reference medicinal product'' means a medicinal product authorised under regulation 4

(1), in accordance with the provisions of regulation 5 or authorised under Article 8 of Directive 2001/83/EC as amended; ''generic medicinal product'' means a medicinal product which has the same qualitative and quantitative composition in active substances and the same pharmaceutical form as the reference medicinal product, and whose bioequivalence with the reference medicinal product has been demonstrated by appropriate bioavailability studies. The different salts, esters, ethers, isomers, mixtures of isomers, complexes or derivatives of an active substance shall be considered to be the same active substance, unless they differ significantly in properties with regard to safety and, or efficacy. In such cases, additional information providing proof of the safety and, or efficacy of the various salts, esters or derivatives of an authorised active substance must be supplied by the applicant. The various immediate-release oral pharmaceutical forms shall be considered to be one and the same pharmaceutical form. Bioavailability studies need not be required of the applicant if he can demonstrate that the generic medicinal product meets the relevant criteria as defined in the appropriate detailed guidelines. (

1. b)In cases where the medicinal product does not fall within the definition of a generic medicinal product as provided above or where the bioequivalence cannot be demonstrated through bioavailability studies or in case of changes in any active substance, therapeutic indications, strength, pharmaceutical form or route of administration, vis-à-vis the reference medicinal product, the results of the appropriate pre-clinical tests or clinical trials shall be provided. MEDICINES (MARKETING AUTHORISATION) [ S.L.458.34 (
2. c)Where a biological medicinal product which is similar to a reference biological product does not meet the conditions in the definition of generic medicinal products, owing to, in particular, differences relating to raw materials or differences in manufacturing processes of the biological medicinal product and the reference biological medicinal product, the results of appropriate pre-clinical tests or clinical trials relating to these conditions must be provided. The type and quantity of supplementary data to be provided must comply with the relevant criteria stated in Annex I and the related detailed guidelines. The results of other tests and trials from the reference medicinal product’s dossier shall not be provided. (
3. d)In addition to the provisions laid down in paragraph (a), where an application is made for a new indication for a well-established substance, a non-cumulative period of one year of data exclusivity shall be granted, provided that significant pre-clinical or clinical studies were carried out in relation to the new indication. (
4. e)Conducting the necessary studies and trials with a view to the application of paragraphs (a), (b), and (
5. c)and the consequential practical requirements shall not be regarded as contrary to patent rights or to supplementary protection certificates for medicinal products. (
6. f)The periods of protection provided for in paragraphs (a), (b), (
7. c)and (
8. d)shall not apply to reference medicinal products for which an application for authorisation has been submitted before the date of coming into force of these regulations.

(2)By way of derogation from regulation 5

(1)(c)(x), and without prejudice to the law relating to the protection of industrial and commercial property, the applicant shall not be required to provide the results of pre-clinical tests or clinical trials if he can demonstrate that the active substances of the medicinal product have been in well-established medicinal use within the Community for at least ten years, with recognised efficacy and an acceptable level of safety in terms of the conditions set out in Annex I. In that event, the test and trial results shall be replaced by appropriate scientific literature.

(3)In the case of medicinal products containing active substances used in the composition of authorised medicinal products but not hitherto used in combination for therapeutic purposes, the results of new pre-clinical tests or new clinical trials relating to that combination shall be provided in accordance with regulation 5

(1)(c)(x), but it shall not be necessary to provide scientific references relating to each individual active substance.

(4)Following the granting of a marketing authorisation, the authorisation holder may allow use to be made of the pharmaceutical, pre-clinical and clinical documentation contained 13 14 [ S.L.458.34 MEDICINES (MARKETING AUTHORISATION) in the file on the medicinal product, with a view to examining subsequent applications relating to other medicinal products possessing the same qualitative and quantitative composition in terms of active substances and the same pharmaceutical form. Summary of product characteristics. Amended by: L.N. 373 of 2012. 8.

(1)The summary of the product characteristics shall contain, in the order indicated below, the following information: (

1. a)name of the medicinal product followed by the strength and the pharmaceutical form; (
2. b)qualitative and quantitative composition in terms of the active substances and constituents of the excipient, knowledge of which is essential for proper administration of the medicinal product. The usual common name or chemical description shall be used; (
3. c)pharmaceutical form; (
4. d)clinical particulars: (
5. i)therapeutic indications, (
6. ii)posology and method of administration for adults and, where necessary for children, (iii) contra-indications, (
7. iv)special warnings and precautions for use and, in the case of immunological medicinal products, any special precautions to be taken by persons handling such products and administering them to patients, together with any precautions to be taken by the patient, (
8. v)interaction with other medicinal products and other forms of interactions, (
9. vi)use during pregnancy and lactation, (vii) effects on ability to drive and to use machines, (viii) undesirable effects, (
10. ix)overdose (symptoms, emergency procedures, antidotes); (
11. e)pharmacological properties: (
12. i)pharmacodynamic properties, (
13. ii)pharmacokinetic properties, (iii) preclinical safety data; (
14. f)pharmaceutical particulars: (
15. i)list of excipients, (
16. ii)major incompatibilities, (iii) shelf life, when necessary after reconstitution of the medicinal product or when the immediate packaging is opened for the first time, (
17. iv)special precautions for storage, (
18. v)nature and contents of container, (
19. vi)special precautions for disposal of a used medicinal product or waste materials derived MEDICINES (MARKETING AUTHORISATION) [ S.L.458.34 15 from such medicinal product, if appropriate; (
20. g)marketing authorisation holder; (
21. h)marketing authorisation numbers; (
22. i)date of the first authorisation or renewal of the authorisation; (
23. j)date of revision of the text; (
24. k)for radiopharmaceuticals: (
25. i)full details of internal radiation dosimetry; (
26. ii)additional detailed instructions for extemporaneous preparation and quality control of such preparation and, where appropriate, maximum storage time during which any intermediate preparation such as an eluate or the ready-touse pharmaceutical will conform with its specifications.

(2)For the authorisations referred to under regulation 7, those parts of the summary of product characteristics of the reference medicinal product referring to indications or dosage forms which were still covered by patent law at the time when a generic medicine was marketed need not be included.

(3)For medicinal products included in the list referred to in Article 23 of Regulation (EC) No 726/2004, the summary of product characteristics shall include the statement: "This medicinal product is subject to additional monitoring". This statement shall be preceded by the black symbol referred to in Article 23 of Regulation (EC) No 726/2004 and followed by an appropriate standardised explanatory sentence. For all medicinal products, a standard text shall be included expressly asking healthcare professionals to report any suspected adverse reaction in accordance with the national spontaneous reporting system. Different ways of reporting, including electronic reporting, shall be available in compliance with the second subparagraph of Article 107a

(1)of Directive 2001/83/EC as amended. 9.

(1)The applicant shall ensure that, before the detailed summaries referred to in the regulation 5

(3)are submitted to the Licensing Authority, they have been drawn up and signed by experts with the necessary technical or professional qualifications, which shall be set out in a brief curriculum vitae. Experts to formulate and sign documents.

(2)Persons having the technical and professional qualifications referred to in the preceding subregulation shall justify any use made of scientific literature under regulation 7

(2)in accordance with the conditions set out in Annex I.

(3)The detailed summaries shall form part of the file which the applicant submits to the Licensing Authority. 10.

(1)The Authority shall ensure that homeopathic medicinal products manufactured and placed on the market within the Community are registered or authorised in accordance with this regulation and regulation 11. In case of registrations, regulation Specific provisions applicable to homeopathic medicinal products. 16 [ S.L.458.34 MEDICINES (MARKETING AUTHORISATION) 22

(1)(

1. a)to (
2. f)shall apply.

(2)The Authority shall establish a special simplified registration procedure for the homeopathic medicinal products referred to in subregulation

(3).

(3)Only homeopathic medicinal products which satisfy all of the following conditions may be subject to a special, simplified registration procedure: (

1. a)they are administered orally or externally; (
2. b)no specific therapeutic indication appears on the labelling of the medicinal product or in any information relating thereto; (
3. c)there is a sufficient degree of dilution to guarantee the safety of the medicinal product; in particular, the medicinal product may not contain either more then one part per 10 000 of the mother tincture or more than 1/100th of the smallest dose used in allopathy with regard to active substances whose presence in an allopathic medicinal product results in the obligation to submit a doctor’s prescription. The classification for the dispensing of the medicinal product, shall be determined by the Authority at the time of registration. The criteria and rules of procedure provided for in regulations 12, 17, 18, 19, 20 and 21, and Articles 4

(4), 112, 116 and 125 of Directive 2001/83/EC, as amended, shall apply by analogy to the special, simplified re gistration procedure for homeopathic medicinal products with the exception of the proof of therapeutic efficacy.

(4)An application for special, simplified registration may cover a series of medicinal products derived from the same homeopathic stock or stocks. The following documents shall be included with the application in order to demonstrate, in particular, the pharmaceutical quality and the batch-to-batch homogeneity of the products concerned: (

1. a)scientific name or other name given in a pharmacopoeia of the homeopathic stock or stocks, together with a statement of the various routes of administration, pharmaceutical forms and degree of dilution to be registered; (
2. b)dossier describing how any homeopathic stock or stocks is obtained and controlled, and justifying its homeopathic use, on the basis of an adequate bibliography; (
3. c)manufacturing and control file for each pharmaceutical form and a description of the method of dilution and potentization; (
4. d)manufacturing authorisation for the medicinal product concerned; (
5. e)copies of any registrations or authorisations obtained for the same medicinal product in other Member MEDICINES (MARKETING AUTHORISATION) [ S.L.458.34 17 States; (
6. f)one or more mock-ups of the outer packaging and the immediate packaging of the medicinal products to be registered; (
7. g)data concerning the stability of the medicinal product. 11. Homeopathic medicinal products, other than those referred to in regulation 10

(3), shall be authorised and labelled in accordance with regulations 5, 7 and

1. Saving.
2. It shall be the duty of the Authority to ensure that the procedure for granting a marketing authorisation for medicinal products is completed within a maximum of two hundred and ten days after the submission of a valid application: Processing of application. Provided that applications for marketing authorisations in two or more Member States in respect of the same medicinal product shall be submitted in accordance with the mutual recognition and decentralised procedures.
3. Where the Authority notes that another marketing authorisation application for the same medicinal product is being examined in another Member State, the Authority shall decline to assess the application and shall advise the applicant that the mutual recognition and decentralised procedures apply. Application already under examination in a Member State.
4. Where the Authority is informed in accordance with regulation 5

(1)(c)(xiii) that another Member State has authorised a medicinal product, which is the subject of a marketing authorisation application in Malta, it shall reject the application unless it was submitted in compliance with the mutual recognition or decentralised procedures. Duties of the Authority on receiving the report. 15.

(1)In order to examine the application submitted in accordance with regulations 5 and 7, the Authority - Examination of application. (

1. a)shall verify whether the particulars submitted by the applicant are in terms of the provisions of these regulations and examine whether the conditions for issuing a marketing authorisation are complied with; (
2. b)may submit the medicinal product, its starting materials and, if need be, its intermediate products or other constituent materials, for testing by an Official Medicines Control Laboratory or by a laboratory designated for that purpose by the Authority in order to ensure that the control methods employed by the manufacturer and described in the particulars accompanying the application in accordance with regulation 5

(1)(c)(

1. ix)are satisfactory; (
2. c)may, where appropriate, require the applicant to supplement the particulars accompanying the application in respect of the items listed under regulations 5

(1)(c) and 7, in which case, the two hundred and ten days referred to under regulation 12 shall be suspended until such time as the supplementary information required has been 18 [ S.L.458.34 MEDICINES (MARKETING AUTHORISATION) provided. Likewise, these time limits shall be suspended when the applicant is given the opportunity of providing an oral or written explanation.

(2)The Authority: (a) shall verify that manufacturers and importers of medicinal products coming from third countries are able to carry out manufacture in compliance with the particulars supplied pursuant to regulation 5

(1)(c)(v) and, or to carry out controls according to the methods described in the particulars accompanying the application in accordance with regulation 5

(1)(c)(ix); (

1. b)may allow manufacturers and importers of medicinal products coming from third countries, in justifiable cases, to have certain stages of manufacture and, or certain of the controls referred to in paragraph (
2. a)carried out by third parties; in such cases, the verifications by the Authority shall also be made in the establishment designated. Information to holder. Amended by: L.N. 373 of 2012. 16. (
3. a)When the marketing authorisation is issued it shall be subject to the conditions as specified in the Marketing Authorisation, the Act and any regulations made t h e r e u nd e r as w e l l as t o a ny co nd i ti o ns t ha t t he Licensing Authority may deem necessary, and the holder shall be informed by the Authority of the summary of the product characteristics as approved by it. (
4. b)The Authority shall: (
5. i)take all necessary measures to ensure that the information given in the summary is in conformity with that accepted when the marketing authorisation is issued or subsequently; (
6. ii)make publicly available without delay the marketing authorisation together with the summary of the product characteristics for each medicinal product which it has authorised; Cap. 458. (iii) shall, without delay, make publicly available the marketing authorisation together with the package leaflet, the summary of the product characteristics and any conditions established in accordance with article 23 of the Medicines Act and paragraph (
7. c)and regulation 17(
8. a)and (b), and together with any deadlines for the fulfilment of those conditions for each medicinal product which they have authorised;; (
9. iv)shall draw up an assessment report and make comments on the file as regards the results of the pharmaceutical and pre-clinical tests, the clinical trials, the risk management system and the pharmacovigilance system of the medicinal MEDICINES (MARKETING AUTHORISATION) [ S.L.458.34 19 product concerned. The assessment report shall be updated whenever new information becomes available which is important for the evaluation of the quality, safety or efficacy of the medicinal product concerned. The Authority shall make the assessment report publicly accessible without delay, together with the reasons for their opinion, after deletion of any information of a commercially confidential nature. The justification shall be provided separately for each indication applied for. The public assessment report shall include a summary written in a manner that is understandable to the public. The summary shall contain, in particular, a section relating to the conditions of use of the medicinal product. (
10. c)In addition to the provisions laid down in regulation 15, a marketing authorisation for a medicinal product may be granted subject to one or more of the following conditions: (
11. i)to take certain measures for ensuring the safe use of the medicinal product to be included in the risk management system; (
12. ii)to conduct post-authorisation safety studies; (iii) to comply with obligations on the recording or reporting of suspected adverse reactions which are stricter than those referred to in Title IX of Directive 2001/83/EC as amended; (
13. iv)any other conditions or restrictions with regard to the safe and effective use of the medicinal product; (
14. v)the existence of an adequate pharmacovigilance system; (
15. vi)to conduct post-authorisation efficacy studies where concerns relating to some aspects of the efficacy of the medicinal product are identified and can be resolved only after the medicinal product has been marketed. Such an obligation to conduct such studies shall be based on the delegated acts adopted pursuant to Regulation 17 of these regulations, while taking into account the scientific guidance referred to in Article 108a of Directive 2001/83/EC as amended. The marketing authorisation shall lay down deadlines for the fulfilment of these conditions where necessary. 17. (
16. a)In exceptional circumstances and following consultation with the applicant, the marketing authorisation may be granted subject to certain conditions, in particular relating to the safety of the Exceptional circumstances. Substituted by: L.N. 373 of 2012. 20 [ S.L.458.34 MEDICINES (MARKETING AUTHORISATION) medicinal product, notification to the Authority of any incident relating to its use, and action to be taken. The marketing authorisation may be granted only when the applicant can show that he is unable to provide comprehensive data on the efficacy and safety of the medicinal product under normal conditions of use, for objective, verifiable reasons and it should be based on one of the grounds set out in Schedule I. Continuation of the marketing authorisation shall be linked to the annual reassessment of these conditions. (
17. b)After the granting of a marketing authorisation, the Licensing Authority may impose an obligation on the marketing authorisation holder: (
18. i)to conduct a post-authorisation safety study if there are concerns about the risks of an authorised medicinal product. If the same concerns apply to more than one medicinal product, the Authority shall, following consultation with the Pharmacovigilance Risk Assessment Committee, encourage the marketing authorisation holders concerned to conduct a joint post-authorisation safety study; (
19. ii)to conduct a post-authorisation efficacy study when the understanding of the disease or the clinical methodology indicate that previous efficacy evaluations might have to be revised significantly. The obligation to conduct the postauthorisation efficacy study shall be based on the guidelines or Regulations published by the Commission pursuant to Article 22b of Directive 2001/83/EC as amended, while taking into account the scientific guidance referred to in Article 108a of Directive 2001/83/EC as amended. The imposition of such an obligation shall be duly justified, notified in writing, and shall include the objectives and timeframe for submission and conduct of the study. The Authority shall provide the marketing authorisation holder with an opportunity to present written observations in response to the imposition of the obligation within a time limit which it shall specify, if the marketing authorisation holder so requests within thirty days of receipt of the written notification of the obligation. On the basis of the written observations submitted by the marketing authorisation holder, the Licensing Authority shall withdraw or confirm the obligation. Where the Licensing Authority confirms the obligation, the marketing authorisation shall be varied to include the obligation as a condition of the MEDICINES (MARKETING AUTHORISATION) [ S.L.458.34 21 marketing authorisation and the risk management system shall be updated accordingly. (
20. c)The marketing authorisation holder shall incorporate any conditions referred to in paragraphs (
21. a)and (
22. b)and in regulation 16(b), in his risk management system. (
23. d)The Member States shall inform the Agency of the marketing authorisations that they have granted subject to conditions pursuant to paragraphs (
24. a)or (
25. b)or in regulation 16(c). 18.

(1)After a marketing authorisation has been granted, the marketing authorisation holder shall, in respect of the methods of manufacture and control provided for in regulation 5

(1)(c)(v) and (ix), take account of scientific and technical progress and introduce any changes that may be required to enable the medicinal product to be manufactured and checked by means of generally accepted scientific methods. Those changes shall be subject to the approval of the Licensing Authority.

(2)The marketing authorisation holder shall forthwith provide the national competent authority with any new information which might entail the amendment of the particulars or documents referred to in regulation 5

(1)(c), regulation 7

(1),

(2)and

(3), and regulation 8 , or Article 32

(5), or Annex I of Directive 2001/83/EC as amended. In particular, the marketing authorisation holder shall forthwith inform the national competent authority of any prohibition or restriction imposed by the competent authorities of any country in which the medicinal product is marketed and of any other new information which might influence the evaluation of the benefits and risks of the medicinal product concerned. The information shall include both positive and negative results of clinical trials or other studies in all indications and populations, whether or not included in the marketing authorisation, as well as data on the use of the medicinal product where such use is outside the terms of the marketing authorisation.

(3)The marketing authorisation holder shall ensure that the product information is kept up to date with the current scientific knowledge, including the conclusions of the assessment and recommendations made public by means of the European medicines web-portal established in accordance with Article 26 of Regulation (EC) No 726/2004.

(4)In order to be able to continuously assess the risk-benefit balance, the national competent authority may at any time ask the marketing authorisation holder to forward data demonstrating that the risk-benefit balance remains favourable. The marketing authorisation holder shall answer fully and promptly any such request. The national competent authority may at any time ask the marketing authorisation holder to submit a copy of the Duties of authorisation holder. Substituted by: L.N. 373 of 2012. Amended by: L.N. 349 of 2013. 22 [ S.L.458.34 MEDICINES (MARKETING AUTHORISATION) pharmacovigilance system master file. The marketing authorisation holder shall submit the copy at the latest seven days after receipt of the request.

(5)After a marketing authorisation has been granted, the holder of the authorisation shall inform the Authority of the date of actual marketing of the medicinal product for human use in Malta, taking into account the various presentations authorised. If the product ceases to be placed on the Maltese market, either temporarily or permanently, the marketing authorisation holder shall notify the Medicines Authority. Such notification shall, other than in exceptional circumstances, be made no less than two months before the interruption in the placing on the market of the product. The marketing authorisation holder shall inform the Medicines Authority of the reasons for such action in accordance with regulation 23

(7).

(6)Upon request by the Authority, particularly in the context of pharmacovigilance, the marketing authorisation holder shall provide it with all data relating to the volume of sales of the medicinal product, and any data in his possession relating to the volume of prescriptions. Validity of marketing authorisation. Substituted by: L.N. 373 of 2012. 19.

(1)Without prejudice to sub-regulations

(5)and

(6), a marketing authorisation shall be valid for five years.

(2)The marketing authorisation may be renewed after five years on the basis of a re-evaluation of the risk-benefit balance by the Authority.

(3)To this end, the marketing authorisation holder shall provide the Authority with a consolidated version of the file in respect of quality, safety and efficacy, including the evaluation of data contained in suspected adverse reactions reports and periodic safety update reports submitted in accordance with Title IX of Directive 2001/83/EC as amended, and information on all variations introduced since the marketing authorisation was granted, at least nine months before the marketing authorisation ceases to be valid in accordance with sub-regulation

(1).

(4)Once renewed, the marketing authorisation shall be valid for an unlimited period, unless the national competent Authority decides, on justified grounds relating to pharmacovigilance, including exposure of an insufficient number of patients to the medicinal product concerned, to proceed with one additional fiveyear renewal in accordance with sub-regulation

(2).

(5)Any authorisation granted by the Authority which within three years of its granting is not followed by the actual placing on the market of the authorised product in Malta shall cease to be valid.

(6)When an authorised product previously placed on the market in Malta is no longer actually present on the market for a period of three consecutive years, the authorisation for that product shall cease to be valid.

(7)The Authority may, in exceptional circumstances and on public health grounds, grant exemptions from sub-regulations

(4)and

(5)provided that such exemptions are duly justified. MEDICINES (MARKETING AUTHORISATION) [ S.L.458.34 23 20. An authorisation or licence for placing a medicinal product on the market shall not affect the civil and criminal liability of the manufacturer and, where applicable, of the marketing authorisation holder who has placed such medicinal product on the market in any European Union or European Economic Area state. Such manufacturer or marketing authorisation holder shall in particular remain liable for any deficiencies in quality, safety and efficacy of such medicinal products. Civil and criminal liability. 21.

(1)The marketing authorisation of a medicinal product shall be refused if, after verification of the particulars and documents listed in regulations 5 and 7 it is clear that: Refusal of marketing authorisation. (

1. a)the risk-benefit balance is not considered to be favourable, or (
2. b)the therapeutic efficacy of the medicinal product is insufficiently substantiated by the applicant, or (
3. c)the qualitative and quantitative composition of the medicinal product is not as declared.

(2)Authorisation shall likewise be refused if any particulars or documents submitted in support of the application do not comply with the provisions of regulations 5 and 7.

(3)The applicant or the holder of a marketing authorisation shall be responsible for the accuracy of the documents and the data submitted. 22. (

1. a)With a view to the granting of a marketing authorisation for a medicinal product in more than one Member State, including Malta, an applicant shall submit an application to the Authority, based on a dossier identical to that submitted in the other Member States. The dossier shall contain the information and documents referred to in regulations 5, 7 and 8. The documents submitted shall include a list of Member States concerned by the application. The applicant shall request one Member State to act as ''reference Member State'' and to prepare an assessment report on the medicinal product in accordance with paragraphs (
2. b)and (c). (
3. b)Where the medicinal product has already received a marketing authorisation at the time of application, if Malta is a concerned Member State, the Authority shall recognise the marketing authorisation granted by the reference Member State. To this end, the marketing authorisation holder shall request the reference Member State either to prepare an assessment report on the medicinal product or, if necessary, to update any existing assessment report. If Malta is the reference Member State, the Authority shall prepare or update the assessment report within ninety days of receipt of a valid application. The assessment report together with the approved summary of product characteristics, labelling and package leaflet shall be sent to the Mutual recognition and decentralised procedure. 24 [ S.L.458.34 MEDICINES (MARKETING AUTHORISATION) concerned Member States and to the applicant. (
4. c)In cases where the medicinal product has not received a marketing authorisation at the time of application, the applicant shall request the reference Member State to prepare a draft assessment report, a draft summary of product characteristics and a draft of the labelling and package leaflet. If Malta is the Reference Member State, the Authority shall prepare these draft documents within one hundred and twenty days after receipt of a valid application and shall send them to the concerned Member States and to the applicant. (
5. d)If Malta is a concerned Member State, within ninety days of receipt of the documents referred to in paragraphs (
6. b)and (c), the Authority shall approve the assessment report, the summary of product characteristics and the labelling and package leaflet and shall inform the reference Member State accordingly. If Malta is the reference Member State, the Authority shall record the agreement of all parties, close the procedure and inform the applicant accordingly. (
7. e)The Authority shall adopt a decision in conformity with the approved assessment report, the summary of product characteristics and the labelling and package leaflet as approved, within thirty days after acknowledgement of the agreement. (
8. f)If, within the period laid down in paragraph (d), the Authority cannot approve the assessment report, the summary of product characteristics, the labelling and the package leaflet on the grounds of potential serious risk to public health, it shall give a detailed exposition of the reasons for its position to the reference Member State, to the other Member States concerned and to the applicant. The points of disagreement shall be forthwith referred to the co-ordination group. Within such co-ordination group, the Authority shall use its best endeavours to reach agreement on the action to be taken and it shall allow the applicant the opportunity to make his point of view known orally or in writing. If, within sixty days of the communication of the points of disagreement, all Member States reach an agreement, if Malta is the Reference Member State, the Authority shall record the agreement, close the procedure and inform the applicant accordingly and paragraph (
9. e)shall apply: Provided that if Member States fail to reach an agreement within the co-ordination group, within such sixty-day period, and if the Authority has approved the assessment report, the draft summary of product characteristics and the labelling and package leaflet of the reference Member State, the Authority may, at the request of the applicant, authorise the medicinal MEDICINES (MARKETING AUTHORISATION) [ S.L.458.34 25 product without waiting for the outcome of the procedure laid down in Article 32 of Directive 2001/ 83/EC as amended by Directive 2004/27/EC. In that event, the authorisation granted shall be without prejudice to the outcome of that procedure. 23.

(1)If two or more applications submitted in accordance w i t h r e g u l a t i o n s 5 , 7 a n d 8 h a v e b e e n m ad e f o r m a r k e t i n g authorisation for a particular medicinal product, and if Member States have adopted divergent decisions concerning the authorisation of the medicinal product or its suspension or revocation, the Authority, the Commission or the applicant or the mark eting auth orisati on h older may ref er th e mat ter t o th e Committee for Medicinal Products for Human Use, hereinafter referred to as the Committee, for the application of the procedure laid down in Articles 32, 33 and 34 of Directive 2001/83 as amended by Directive 2004/27. Referral to Committee for Medicinal Products for Human Use. Amended by: L.N. 373 of 2012; L.N. 349 of 2013.

(2)In order to promote harmonisation of authorisations for medicinal products authorised in the Community, the Authority shall, each year, forward to the coordination group a list of medicinal products for which a harmonised summary of product characteristics should be drawn up.

(3)The Authority or the Commission, in agreement with the Agency and taking into account the views of interested parties, may refer these products to the Committee in accordance with subregulation

(1).

(4)The Member States, the Commission, the applicant or the marketing authorisation holder shall, in specific cases where the interests of the European Union are involved, refer the matter to the Committee for application of the procedure laid down in Articles 32, 33 and 34 of Directive 2001/83/EC as amended before any decision is reached on an application for a marketing authorisation or on the suspension or revocation of a marketing authorisation, or on any other variation of the marketing authorisation which appears necessary. Where the referral results from the evaluation of data relating to pharmacovigilance of an authorised medicinal product, the matter shal l be referred to t he P harmacovigilance Risk Assessment Committee and Article 107j

(2)of Directive 2001/83/ EC may be applied. The Pharmacovigilance Risk Assessment C o m m i t t e e s h a l l i ss u e a r e c o m m e n d a t i o n a c c o r d i n g t o t h e procedure laid down in Article 32 of Directive 2001/83/EC as amended. The final recommendation shall be forwarded to the Committee for Medicinal Products for Human Use or to the coordination group, as appropriate, and the procedure laid down in regulation 65 of the Pharmacovigilance Regulations shall apply. However, where one of the criteria listed in regulation 57

(1)(a)(i) of the Pharmacovigilance Regulations is met, the procedure laid down in regulation 57 thereof applies.

(5)The Authority or the Commission shall clearly identify the question which is referred to the Committee for consideration and shall inform the applicant or the marketing authorisation holder. S.L. 458.35 S.L. 458.35 26 [ S.L.458.34 MEDICINES (MARKETING AUTHORISATION)

(6)The Authority and the applicant or the marketing authorisation holder shall supply the Committee with all available information relating to the matter in question.

(7)(

1. a)Where the referral to the Committee concerns a range of medicinal products or a therapeutic class, the Agency may limit the procedure to certain specific parts of the authorisation. In that event, regulation 24 shall apply to those medicinal products only if they were covered by the authorisation procedures referred to in regulations 22 and 23. (
2. b)Where the scope of the procedure initiated under regulations 22 and 23 concerns a range of medicinal products or a therapeutic class, medicinal products authorised in accordance with Regulation (EC) No 726/2004 which belong to that range or class shall also be included in the procedure.

(8)Without prejudice to sub-regulation

(4), the Licensing Authority may, where urgent action is necessary to protect public health at any stage of the procedure, suspend the marketing authorisation and prohibit the use of the medicinal product concerned in Malta until a definitive decision is adopted. It shall inform the Commission, the Agency and the other Member States, no later than the following working day, of the reasons for its action.

(9)Where the scope of the procedure initiated in accordance with sub-regulation

(7)includes medicinal products authorised in accordance with Regulation (EC) No 726/2004, the Commission may, where urgent action is necessary to protect public health, at any stage of the procedure, suspend the marketing authorisations and prohibit the use of the medicinal products concerned until a definitive decision is adopted. The Commission shall inform the Agency and the Licensing Authority no later than the following working day of the reasons for its action. Application for variation. Amended by: L.N. 373 of

2. A marketing authorisation holder may apply to vary the marketing authorisation, which has been granted in accordance with regulations 22 and 23, and such application shall be submitted to the Authority and to all other Member States which have previously authorised the medicinal product concerned. This regulation shall apply by analogy to medicinal products authorised by the Authority following an opinion of the Committee given in accordance with Article 4 of Directive 87/22/ EEC before 1 January,
3. Applications to be considered in accordance with regulation (EC) No 726/
5. Applications for marketing authorisations which have been referred to the Committee for Proprietary Medicinal Products before the 1 January, 1995 in accordance with Article 2 of Directive 87/22/EEC and in respect of which the Committee concerned has not given an opinion by 1 January, 1995, shall be considered in accordance with Regulation (EC) No 726/
6. Regulation 22

(1)(f) second paragraph, regulation 23 and Articles 32 to 34 of Directive 2001/83/EC and its subsequent [ S.L.458.34 MEDICINES (MARKETING AUTHORISATION) 27 amendments, shall not apply to homeopathic medicinal products referred to in regulation 10

(1),

(2)and

(3). 26.

(1)When a marketing authorisation is granted, the Authority shall specify the classification of the medicinal product into: Classification of medicinal products. (

1. a)a medicinal product subject to medical prescription, (
2. b)a medicinal prescription. apply. product not subject to medical To this end, the criteria laid down in regulation 27

(1)shall

(2)The Authority may fix sub-categories for medicinal products which are available on medical prescription only. In that case, they shall refer to the following classification: (

1. a)medicinal products on medical prescription for renewable or non-renewable delivery; (
2. b)medicinal products prescription; subject to special medical (
3. c)medicinal products on ''restricted'' medical prescription, reserved for use in certain specialised areas: Provided that where the Authority does not designate medicinal products into sub-categories, it shall nevertheless take into account the criteria referred to in regulation 27

(2)and

(3)in determining whether any medicinal product shall be classified as a prescription-only medicine. 27.

(1)Medicinal products shall be subject to medical prescription where they (

1. a)are likely to present a danger either directly or indirectly, even when used correctly, if utilized without medical supervision, or (
2. b)are frequently and to a very wide extent used incorrectly, and as a result are likely to present a direct or indirect danger to human health, or (
3. c)contain substances or preparations thereof, the activity and any adverse reactions of which require further investigation, or (
4. d)are normally prescribed by a doctor to be administered parenterally.

(2)For the sub-category of medicinal products subject to special medical prescription, the Authority shall take account of the following factors: (

1. a)the medicinal product contains, in a non-exempt quantity, a substance classified as a narcotic or a psychotropic substance within the meaning of the international conventions in force, such as the United Nations Conventions of 1961 and 1971, or Medicinal products subject to medical prescription. 28 [ S.L.458.34 MEDICINES (MARKETING AUTHORISATION) (
2. b)the medicinal product is likely, if incorrectly used, to present a substantial risk of medicinal abuse, to lead to addiction or be misused for illegal purposes, or (
3. c)the medicinal product contains a substance which, by reason of its novelty or properties, could be considered as belonging to the group envisaged in paragraph (b), as a precautionary measure.

(3)For the sub-category of medicinal products subject to restricted prescription, the Authority shall take account of the following factors: (

1. a)the medicinal product, because of its pharmaceutical characteristics or novelty or in the interests of public health, is reserved for treatments which can only be followed in a hospital environment; (
2. b)the medicinal product is used in the treatment of conditions which must be diagnosed in a hospital environment or in institutions with adequate diagnostic facilities, although administration and follow-up may be carried out elsewhere, or (
3. c)the medicinal product is intended for out-patients but its use may produce very serious adverse reactions requiring a prescription drawn up as required by a specialist and special supervision throughout the treatment.

(4)The Authority may waive application of subregulations

(1),

(2)and

(3)having regard to: (

1. a)the maximum single dose, the maximum daily dose, the strength, the pharmaceutical form, certain types of packaging; and, or (
2. b)other circumstances of use which it has specified. Medicinal products not subject to a prescription. 28. Medicinal products not subject to prescription shall be those which do not meet the criteria listed in regulation 27. List of medicinal products. 29. The Authority shall draw up a list of the medicinal products subject to medical prescription, specifying, if necessary, the category of classification, and it shall update this list annually. Amendment of classification. 30.

(1)When new facts are brought to its attention, the Authority shall examine and, as appropriate, amend the classification of a medicinal product by applying the criteria listed in regulation 27.

(2)Where a change of classification of a medicinal product has been authorised on the basis of significant pre-clinical tests or clinical trials, the Authority shall not refer to the results of those tests or trials when examining an application by another applicant or holder of marketing authorisation for a change of classification of the same substance for one year after the initial change was authorised. MEDICINES (MARKETING AUTHORISATION) [ S.L.458.34 31.

(1)The Medicines Authority shall take all the appropriate measures to ensure that decisions authorising marketing, refusing or revoking a marketing authorization, cancelling a decision refusing or revoking a marketing authorization, prohibiting supply, or withdrawing a product from the market, together with the reasons on which such decisions are based, are brought to the attention of the Agency forthwith. Informing the Agency of the actions taken. Added by: L.N. 349 of 2013. Amended by: L.N. 61 of 2024.

(2)The marketing authorisation holder shall be obliged to notify the Medicines Authority forthwith of any action taken by the holder to suspend the marketing of a medicinal product, to withdraw a medicinal product from the market, to request the withdrawal of a marketing authorisation or not to apply for the renewal of a marketing authorisation, together with the reasons for such action. The marketing authorisation holder shall in particular declare if such action is based on any of the grounds set out in article 28

(1)of the Medicines Act. Cap. 458

(3)The marketing authorisation holder shall also make the notification pursuant to sub-regulation

(2)in cases where the action is taken in a third country and where such action is based on any of the grounds set out in article 28

(1)of the Medicines Act. Cap. 458.

(4)The marketing authorisation holder shall furthermore notify the Agency where the action referred to in sub-regulation

(2)is based on any of the grounds referred to in article 28 of the Medicines Act. Cap. 458.

(5)The Medicines Authority shall ensure that appropriate information about action taken pursuant to sub-regulations

(1)and

(2)which may affect the protection of public health in third countries is forthwith brought to the attention of the World Health Organization, with a copy to the Agency.

(6)The marketing authorisation holder shall notify the Medicines Authority before the commencement of any recall of medicinal product from the local market, and to submit all pertinent and required information. 29 30 [ S.L.458.34 MEDICINES (MARKETING AUTHORISATION) MEDICINES (MARKETING AUTHORISATION) SCHEDULE [ S.L.458.34 31 Added by: L.N. 252 of 2010. ANALYTICAL, PHARMACOTOXICOLOGICAL AND CLINICAL STANDARDS AND PROTOCOLS IN RESPECT OF THE TESTING OF MEDICINAL PRODUCTS TABLE OF CONTENTS Introduction and general principles Part I: Standardised marketing authorisation dossier requirements 1. Module 1: Administrative information 1.1. Table of contents 1.2. Application form 1.3. Summary of product characteristics, labelling and package leaflet 1.3.1. Summary of product characteristics 1.3.2. Labelling and package leaflet 1.3.3. Mock-ups and specimens 1.3.4. Summaries of product characteristics already approved in the Member States 1.4. Information about the experts 1.5. Specific requirements for different types of applications 1.6. Environmental risk assessment 2. Module 2: Summaries 2.1. Overall table of contents 2.2. Introduction 2.3. Quality overall summary 2.4. Non-clinical overview 2.5. Clinical overview 2.6. Non-clinical summary 2.7. Clinical Summary 3. Module 3: Chemical, pharmaceutical and biological information for medicinal products containing chemical and/or biological active substances 3.1. Format and presentation 3.2. Content: basic principles and requirements 3.2.1. Active substance(

1. s)3.2.1.1. General information and information related to the starting and raw materials 3.2.1.2. Manufacturing process of the active substance(
2. s)3.2.1.3. Characterisation of the active substance(
3. s)3.2.1.4. Control of active substance(
4. s)32 [ S.L.458.34 MEDICINES (MARKETING AUTHORISATION) 3.2.1.5. Reference standards or materials 3.2.1.6. Container and closure system of the active substance 3.2.1.7. Stability of the active substance(
5. s)3.2.2. Finished medicinal product 3.2.2.1. Description and composition of the finished medicinal product 3.2.2.2. Pharmaceutical development 3.2.2.3. Manufacturing process of the finished medicinal product 3.2.2.4. Control of excipients 3.2.2.5. Control of the finished medicinal product 3.2.2.6. Reference standards or materials 3.2.2.7. Container and closure of the finished medicinal product 3.2.2.8. Stability of the finished medicinal product 4. Module 4: Non-clinical reports 4.1. Format and Presentation 4.2. Content: basic principles and requirements 4.2.1. Pharmacology 4.2.2. Pharmaco-kinetics 4.2.3. Toxicology 5. Module 5: Clinical study reports 5.1. Format and Presentation 5.2. Content: basic principles and requirements 5.2.1. Reports of bio-pharmaceutics studies 5.2.2. Reports of studies pertinent to pharmaco-kinetics using human biomaterials 5.2.3. Reports of human pharmaco-kinetic studies 5.2.4. Reports of human pharmaco-dynamic studies 5.2.5. Reports of efficacy and safety studies 5.2.5.1. Study Reports of Controlled Clinical Studies Pertinent to the Claimed Indication 5.2.5.2. Study reports of uncontrolled clinical studies reports of analyses of data from more than one study and other clinical study reports 5.2.6. Reports of post-marketing experience 5.2.7. Case reports forms and individual patient listings Part II: Specific marketing authorisation dossiers and requirements 1. Well-established medicinal use 2. Essentially similar medicinal products 3. Additional data required in specific situations 4. Similar biological medicinal products MEDICINES (MARKETING AUTHORISATION) [ S.L.458.34 5. Fixed combination medicinal products 6. Documentation for applications in exceptional circumstances 7. Mixed marketing authorisation applications 33 Part III: Particular medicinal products 1. Biological medicinal products 1.1. Plasma-derived medicinal product 1.2. Vaccines 2. Radio-pharmaceuticals and precursors 2.1. Radio-pharmaceuticals 2.2. Radio-pharmaceutical precursors for radio-labelling purposes 3. Homeopathic medicinal products 4. Herbal medicinal products 5. Orphan Medicinal Products Part IV: Advanced therapy medicinal products 1. Introduction 2. Definitions 2.1. Gene therapy medicinal products 2.2. Somatic cell therapy medicinal products 3. Specific requirements regarding Module 3 3.1. Specific requirements for all advanced therapy medicinal products 3.2. Specific requirements for gene therapy medicinal products 3.2.1. Introduction: finished product, active substance and starting materials 3.2.2. Specific requirements 3.3. Specific requirements for somatic cell therapy medicinal products and tissue engineered products 3.3.1. Introduction: finished product, active substance and starting materials 3.3.2. Specific requirements 3.4. Specific requirements for advanced therapy medicinal products containing devices 3.4.1. Advanced therapy medicinal products containing devices referred to in Article 7 of Regulation (EC) 1394/2007 3.4.2. Combined advanced therapy medicinal products as defined in Article 2

(1)(d) of Regulation (EC) 1394/2007

1. Specific requirements regarding Module 4 4.
2. Specific requirements for all advanced therapy medicinal products 4.
3. Specific requirements for gene therapy medicinal products 4.2.
4. Pharmacology 4.2.
5. Pharmacokinetics 4.2.
6. Toxicology 34 [ S.L.458.34 MEDICINES (MARKETING AUTHORISATION) 4.
7. Specific requirements for somatic cell therapy medicinal products and tissue engineered products 4.3.
8. Pharmacology 4.3.
9. Pharmacokinetics 4.3.
10. Toxicology
11. Specific requirements regarding Module 5 5.
12. Specific requirements for all advanced therapy medicinal products 5.
13. Specific requirements for gene therapy medicinal products 5.2.
14. Human pharmacokinetic studies 5.2.
15. Human pharmacodynamic studies 5.2.
16. Safety studies 5.
17. Specific requirements for somatic cell therapy medicinal products 5.
18. Specific requirements for tissue engineered products 5.4.
19. Pharmacokinetic studies 5.4.
20. Pharmacodynamic studies 5.4.
21. Safety studies Introduction and general principles

(1)The particulars and documents accompanying an application for marketing authorisation pursuant to Articles 8 and 10

(1)shall be presented in accordance with the requirements set out in this Schedule and shall follow the guidance published by the Commission in The rules governing medicinal products in the European Community,Volume 2 B, Notice to applicants, Medicinal products for human use, Presentation and content of the dossier, Common Technical Document (CTD).

(2)The particulars and documents shall be presented as five modules: Module 1 provides European Community specific administrative data; Module 2 provides quality, non-clinical and clinical summaries, Module 3 provides chemical, pharmaceutical and biological information, Module 4 provides non-clinical reports and Module 5 provides clinical study reports. This presentation implements a common format for all ICH regions (European Community, United States of America, Japan). These five Modules shall be presented in strict accordance with the format, content and numbering system delineated in details in Volume 2 B of the Notice to Applicants referred to above.

(3)The European Community-CTD-presentation is applicable for all types of marketing authorisation applications irrespective of the procedure to be applied (i.e. centralised, mutual recognition or national) and of whether they are based on a full or abridged application. It is also applicable for all types of products including new chemical entities (NCE), radio-pharmaceuticals, plasma derivatives, vaccines, herbal medicinal products, etc.

(4)In assembling the dossier for application for marketing authorisation, applicants shall also take into account the scientific guidelines relating to the quality, safety and efficacy of medicinal products for human use as adopted by the Committee for Proprietary Medicinal Products (CPMP) and published by the European Medicine Evaluation Agency (EMEA) and the other pharmaceutical Community guidelines published by the Commission in the different volumes of the MEDICINES (MARKETING AUTHORISATION) [ S.L.458.34 35 rules governing medicinal products in the European Community.

(5)With respect to the quality part (chemical, pharmaceutical and biological) of the dossier, all monographs including general monographs and general chapters of the European Pharmacopoeia are applicable.

(6)The manufacturing process shall comply with the requirements of Commission Directive 91/356/EEC laying down the principles and guidelines of Good Manufacturing Practice (GMP) for medicinal products for human use and with the principles and guidelines on GMP, published by the Commission in the rules governing medicinal products in the European Community, Volume 4.

(7)All information, which is relevant to the evaluation of the medicinal product concerned, shall be included in the application, whether favourable or unfavourable to the product. In particular, all relevant details shall be given of any incomplete or abandoned pharmaco-toxicological or clinical test or trial relating to the medicinal product and/or completed trials concerning therapeutic indications not covered by the application.

(8)All clinical trials, conducted within the European Community, must comply with the requirements of Directive 2001/20/EC of the European Parliament and of the Council on the approximation of the laws, regulations and administrative provisions of the Member States relating to the implementation of good clinical practice in the conduct of clinical trials on medicinal products for human use. To be taken into account during the assessment of an application, clinical trials, conducted outside the European Community, which relate to medicinal products intended to be used in the European Community, shall be designed, implemented and reported on what good clinical practice and ethical principles are concerned, on the basis of principles, which are equivalent to the provisions of Directive 2001/20/EC. They shall be carried out in accordance with the ethical principles that are reflected, for example, in the Declaration of Helsinki.

(9)Non-clinical (pharmaco-toxicological) studies shall be carried out in conformity with the provisions related to Good Laboratory Practice laid down in Council Directives 87/18/EEC on the harmonisation of regulations and administrative provisions relating to the application of the principles of good laboratory practice and the verification of their application for tests in chemical substances and 88/320/EEC on the inspection and verification of good laboratory practice (GLP).

(10)Member States shall also ensure that all tests on animals are conducted in accordance with Council Directive 86/609/EEC of 24 November 1986 on the approximation of laws, regulation and administrative provisions of the Member States regarding the protection of animals for experimental and other scientific purposes.

(11)In order to monitor the benefit/risk assessment, any new information not in the original application and all pharmaco-vigilance information shall be submitted to the competent authority. After marketing authorisation has been granted, any change to the data in the dossier shall be submitted to the competent authorities in accordance with the requirements of Commission Regulations (EC) No 1084/2003 and (EC) No 1085/2003 of the Commission or, if relevant, in accordance with national provisions, as well as the requirements in Volume 9 of Commission publication The rules governing medicinal products in the European Community. This Schedule is divided in four different parts: - Part I describes the application format, the summary of product characteristics, the labelling, the leaflet and presentation requirements [ S.L.458.34 36 MEDICINES (MARKETING AUTHORISATION) for standard applications (Modules 1 to 5). - Part II provides derogation for ‘Specific applications’, i.e. wellestablished medicinal use, essentially similar products, fixed combinations, similar biological products, exceptional circumstances and mixed applications (part bibliographic and part own studies). - Part III deals with ‘Particular application requirements’ for biological medicinal products (Plasma Master File; Vaccine Antigen Master File), radio-pharmaceuticals, homeopathic medicinal products, herbal medicinal products and orphan medicinal products. - Part IV deals with ‘Advanced therapy medicinal products’ and concerns specific requirements for gene therapy medicinal products (using human autologous or allogeneic system, or xenogeneic system) and cell therapy medicinal products both of human or animal origin and xenogeneic transplantation medicinal products. PART I STANDARDISED MARKETING AUTHORISATION DOSSIER REQUIREMENTS

1. MODULE 1: ADMINISTRATIVE INFORMATION 1.
2. Table of contents A comprehensive table of contents of Modules 1 to 5 of the dossier submitted for marketing authorisation application shall be presented. 1.
3. Application form The medicinal product, which is the subject of the application, shall be identified by name and name of the active substance(s), together with the pharmaceutical form, the route of administration, the strength and the final presentation, including packaging. The name and address of the applicant shall be given, together with the name and address of the manufacturers and the sites involved in the different stages of the manufacture (including the manufacturer of the finished product and the manufacturer(s) of the active substance(s)), and where relevant the name and address of the importer. The applicant shall identify the type of application and indicate what samples, if any, are also provided. Annexed to the administrative data shall be copies of the manufacturing authorisation as defined in Article 40, together with a list of countries in which authorisation has been granted, copies of all the summaries of product characteristics in accordance with Article 11 as approved by Member States and a list of countries in which an application has been submitted. As outlined in the application form, the applicants shall provide, inter alia, details of the medicinal product subject of the application, the legal basis of the application, the proposed marketing authorisation holder and manufacture(s), information on orphan medicinal product status, scientific advice and paediatric development program. 1.
4. Summary of product characteristics, labelling and package leaflet 1.3.
5. Summary of product characteristics The applicant shall propose a summary of the product characteristics, in accordance with Article
6. MEDICINES (MARKETING AUTHORISATION) 1.3.
7. [ S.L.458.34 37 Labelling and package leaflet A proposed labelling text for immediate and outer packaging as well as for the package leaflet shall be provided. These shall be in accordance with all mandatory items listed in Title V on the labelling of medicinal products for human use (Article 63) and on package leaflet (Article 59). 1.3.
8. Mock-ups and specimens The applicant shall provide specimen and/or mock-ups of the immediate and outer packaging, labels and package leaflets for the medicinal product concerned. 1.3.
9. States Summaries of product characteristics already approved in the Member Annexed to the administrative data of the application form shall be copies of all the summaries of product characteristics in accordance with Articles 11 and 21 as approved by Member States, where applicable and a list of countries in which an application has been submitted. 1.
10. Information about the experts In accordance with Article 12

(2)experts must provide detailed reports of their observations on the documents and particulars which constitute the marketing a u t h o r i sa t i o n d o s s i e r a n d i n p a r t i c u l a r o n M o d u l e s 3 , 4 a n d 5 ( c h e m i ca l , pharmaceutical and biological documentation, non-clinical documentation and clinical documentation, respectively). The experts are required to address the critical points related to the quality of the medicinal product and of the investigations carried out on animals and human beings and bring out all the data relevant for evaluation. These requirements shall be met by providing a quality overall summary, a nonclinical overview (data from studies carried out in animals) and a clinical overview that shall be located in Module 2 of the marketing authorisation application dossier. A declaration signed by the experts together with brief information on their educational background, training and occupational experience shall be presented in Module

1. The experts shall have suitable technical or professional qualifications. The professional relationship of the expert to the applicant shall be declared. 1.
2. Specific requirements for different types of applications Specific requirements for different types of applications are addressed in Part II of this Schedule. 1.
3. Environmental risk assessment Where applicable, applications for marketing authorisations shall include a risk assessment overview evaluating possible risks to the environment due to the use and/ or disposal of the medicinal product and make proposals for appropriate labelling provisions. Environmental risk connected with the release of medicinal products containing or consisting of GMOs (Genetically Modified Organisms) within the meaning of Article 2 of Directive 2001/18/EC of the European Parliament and of the Council of 12March 2001 on the deliberate release into the environment of modified organisms and repealing Council Directive 90/220/EEC

(1)shall be addressed. Information pertaining to the environmental risk shall appear as an appendix to Module 1. The information shall be presented in accordance with the provisions of Directive 2001/18/EC, taking into account any guidance documents published by the Commission in connection with the implementation of the said Directive. 38 [ S.L.458.34 MEDICINES (MARKETING AUTHORISATION) The information shall consist of: - an introduction; - a copy of any written consent or consents to the deliberate release into the environment of the GMO(

1. s)for research and development purposes according to Part B of Directive 2001/18/EC; - the information requested in Annexes II to IV of the Directive 2001/18/ EC, including detection and identification methods as well as unique code of the GMO, plus any additional information on the GMO or the product of relevance to evaluating the environmental risk; - an environment risk assessment (ERA) report prepared on basis of the information specified in Annexes III and IV of Directive 2001/18/EC and in accordance with Annex II of Directive 2001/18/EC; - taking into account the above information and the ERA, a conclusion which proposes an appropriate risk management strategy which includes, as relevant to the GMO and product in question, a post market monitoring plan and the identification of any special particulars which need to appear in the Summary of Product Characteristics, labelling and package leaflet; - appropriate measures in order to inform the public. A dated signature of the author, information on the author’s educational, training and occupational experience, and a statement of the author’s relationship with the applicant, shall be included. 2. MODULE 2: SUMMARIES This Module aims to summarise the chemical, pharmaceutical and biological data, the non-clinical data and the clinical data presented in Modules 3, 4 and 5 of the dossier for marketing authorisation, and to provide the reports/overviews described in Article 12 of this Directive. Critical points shall be addressed and analysed. Factual summaries including tabular formats shall be provided. Those reports shall provide cross-references to tabular formats or to the information contained in the main documentation presented in Module 3 (chemical, pharmaceutical and biological documentation), Module 4 (non-clinical documentation) and Module 5 (clinical documentation). Information contained in Module 2 shall be presented in accordance with the format, content and numbering system delineated in the Volume 2 of the Notice to Applicants. The overviews and summaries shall comply with the basic principles and requirements as laid down herewith: 2.1. Overall table of contents Module 2 shall contain a table of contents for the scientific documentation submitted in Modules 2 to 5. 2.2. Introduction Information on the pharmacological class, mode of action and proposed clinical use of the medicinal product for which a marketing authorisation is requested shall be supplied. 2.3. Quality overall summary A review of the information related to the chemical, pharmaceutical and biological data shall be provided in a quality overall summary. MEDICINES (MARKETING AUTHORISATION) [ S.L.458.34 39 Key critical parameters and issues related to quality aspects shall be emphasised as well as justification in cases where the relevant guidelines are not followed. This document shall follow the scope and outline of the corresponding detailed data presented in Module 3. 2.4. Non-clinical overview An integrated and critical assessment of the non-clinical evaluation of the medicinal product in animals/in vitro shall be required. Discussion and justification of the testing strategy and of deviation from the relevant guidelines shall be included. Except for biological medicinal products, an assessment of the impurities and degradation products shall be included along with their potential pharmacological and toxicological effects. The implications of any differences in the chirality, chemical form, and impurity profile between the compound used in the non-clinical studies and the product to be marketed shall be discussed. For biological medicinal products, comparability of material used in non-clinical studies, clinical studies, and the medicinal product for marketing shall be assessed. Any novel excipient shall be the subject of a specific safety assessment. The characteristics of the medicinal product, as demonstrated by the non-clinical studies shall be defined and the implications of the findings for the safety of the medicinal product for the intended clinical use in humans shall be discussed. 2.5. Clinical overview The clinical overview is intended to provide a critical analysis of the clinical data included in the clinical summary and Module 5. The approach to the clinical development of the medicinal product, including critical study design, decisions related to and performance of the studies shall be provided. A brief overview of the clinical findings, including important limitations as well as an evaluation of benefits and risks based on the conclusions of the clinical studies shall be provided. An interpretation of the way the efficacy and safety findings support the proposed dose and target indications and an evaluation of how the summary of product characteristics and other approaches will optimise the benefits and manage the risks is required. Efficacy or safety issues encountered in development and unresolved issues shall be explained. 2.6. Non-clinical summary The results of pharmacology, pharmaco-kinetics and toxicology studies carried out in animals/in vitro shall be provided as factual written and tabulated summaries which shall be presented in the following order: - Introduction - Pharmacology Written Summary - Pharmacology Tabulated Summary - Pharmaco-kineticsWritten Summary - Pharmaco-kinetics Tabulated Summary - Toxicology Written Summary 2.7. Toxicology Tabulated Summary. Clinical Summary 40 [ S.L.458.34 MEDICINES (MARKETING AUTHORISATION) A detailed, factual summary of the clinical information on the medicinal product included in Module 5 shall be provided. This shall include the results of all biopharmaceutics studies, of clinical pharmacology studies, and of clinical efficacy and safety studies. A synopsis of the individual studies is required. Summarised clinical information shall be presented in the following order: - Summary of Bio-pharmaceutics and Associated Analytical Methods - Summary of Clinical Pharmacology Studies - Summary of Clinical Efficacy - Summary of Clinical Safety - Synopses of Individual Studies 3. MODULE 3: CHEMICAL, PHARMACEUTICAL AND BIOLOGICAL INFORMATION FOR MEDICINAL PRODUCTS CONTAINING CHEMICAL AND/OR BIOLOGICAL ACTIVE SUBSTANCES 3.1. Format and presentation The general outline of Module 3 is as follows: - Table of contents - Body of data - Active substance General Information Nomenclature Structure General Properties Manufacture Manufacturer(
2. s)Description of Manufacturing Process and Process Controls Control of Materials Controls of Critical Steps and Intermediates Process Validation and/or Evaluation Manufacturing Process Development Characterisation Elucidation of Structure and other Characteristics Impurities Control of Active Substance Specification Analytical Procedures Validation of Analytical Procedures Batch Analyses Justification of Specification Reference Standards or Materials Container Closure System Stability Stability Summary and Conclusions Post-approval Stability Protocol and Stability Commitment MEDICINES (MARKETING AUTHORISATION) - - [ S.L.458.34 41 Stability Data Finished Medicinal Product Description and Composition of the Medicinal Product Pharmaceutical Development Components of the Medicinal Product Active Substance Excipients Medicinal Product Formulation Development Overages Physicochemical and Biological Properties Manufacturing Process Development Container Closure System Microbiological Attributes Compatibility Manufacture Manufacturer(
3. s)Batch Formula Description of Manufacturing Process and Process Controls Controls of Critical Steps and Intermediates Process Validation and/or Evaluation Control of Excipients Specifications Analytical Procedures Validation of Analytical Procedures Justification of Specifications Excipients of Human or Animal Origin Novel Excipients Control of Finished Medicinal Product Specification(
4. s)Analytical Procedures Validation of Analytical procedures Batch Analyses Characterisation of Impurities Justification of Specification(
5. s)Reference Standards or Materials Container Closure System Stability Stability Summary and Conclusion Post-approval Stability Protocol and Stability Commitment Stability Data Appendices Facilities and Equipment (Biological Medicinal Products only) 42 [ S.L.458.34 - 3.2. MEDICINES (MARKETING AUTHORISATION) Adventitious Agents Safety Evaluation Excipients European Community Additional Information Process Validation Scheme for the Medicinal Product Medical Device Certificate(
6. s)of Suitability Medicinal products containing or using in the manufacturing process materials of animal and/or human origin (TSE procedure) Literature References Content: basic principles and requirements

(1)The chemical, pharmaceutical and biological data that shall be provided shall include for the active substance(s) and for the finished medicinal product all of relevant information on: the development, the manufacturing process, the characterisation and properties, the quality control operations and requirements, the stability as well as a description of the composition and presentation of the finished medicinal product.

(2)Two main sets of information shall be provided, dealing with the active substance(s) and with the finished medicinal product, respectively.

(3)This Module shall in addition supply detailed information on the starting and raw m aterials used during the manufacturing operat ions of the active substance(s) and on the excipients incorporated in the formulation of the finished medicinal product.

(4)All the procedures and methods used for manufacturing and controlling the active substance and the finished medicinal product shall be described in sufficient details to enable them to be repeated in control tests, carried out at the request of the competent authority. All test procedures shall correspond to the state of scientific progress at the time and shall be validated. Results of the validation studies shall be provided. In the case of test procedures included in the European Pharmacopoeia, this description shall be replaced by the appropriate detailed reference to the monograph(s) and general chapter(s).

(5)The monographs of the European Pharmacopoeia shall be applicable to all substances, preparations and pharmaceutical forms appearing in it. In respect of other substances, each Member State may require observance of its own national pharmacopoeia. H o w e v e r, w h e r e a m a t e r i a l i n t h e E u r o p e a n P h a r m a c o p o e i a o r i n t h e pharmacopoeia of a Member State has been prepared by a method liable to leave impurities not controlled in the pharmacopoeia monograph, these impurities and their maximum tolerance limits must be declared and a suitable test procedure must be described. In cases where a specification contained in a monograph of the European Pharmacopoeia or in the national pharmacopoeia of a Member State might be insufficient to ensure the quality of the substance, the competent authorities may request more appropriate specifications from the marketing authorisation holder. The competent authorities shall inform the authorities responsible for the pharmacopoeia in question. The marketing authorisation holder shall provide the authorities of that pharmacopoeia with the details of the alleged insufficiency and the additional specifications applied. In the case of analytical procedures included in the European Pharmacopoeia, this description shall be replaced in each relevant section by the appropriate detailed MEDICINES (MARKETING AUTHORISATION) [ S.L.458.34 43 reference to the monograph(s) and general chapter(s).

(6)In case where starting and raw materials, active substance(

1. s)or excipient(
2. s)are described neither in the European Pharmacopoeia nor in the pharmacopoeia of a Member State, compliance with the monograph of a third country pharmacopoeia can be accepted. In such cases, the applicant shall submit a copy of the monograph accompanied by the validation of the analytical procedures contained in the monograph and by a translation where appropriate.

(7)Where the active substance and/or a raw and starting material or excipient(s) are the subject of a monograph of the European Pharmacopoeia, the applicant can apply for a certificate of suitability that, where granted by the European Directorate for the Quality of Medicines, shall be presented in the relevant section of this Module. Those certificates of suitability of the monograph of the European Pharmacopoeia are deemed to replace the relevant data of the corresponding sections described in this Module. The manufacturer shall give the assurance in writing to the applicant that the manufacturing process has not been modified since the granting of the certificate of suitability by the European Directorate for the Quality of Medicines.

(8)For a well-defined active substance, the active substance manufacturer or the applicant may arrange for the (

1. i)detailed description of the manufacturing process, (
2. ii)quality control during manufacture, and (iii) process validation to be supplied in a separate document directly to the competent authorities by the manufacturer of the active substance as an Active Substance Master File. In this case, the manufacturer shall, however, provide the applicant with all of the data, which may be necessary for the latter to take responsibility for the medicinal product. The manufacturer shall confirm in writing to the applicant that he shall ensure batch to batch consistency and not modify the manufacturing process or specifications without informing the applicant. Documents and particulars supporting the application for such a change shall be supplied to the competent authorities; these documents and particulars will be also supplied to the applicant when they concern the open part of the active substance master file.

(9)Specific measures concerning the prevention of the transmission of animal spongiform encephalopathies (materials from ruminant origin): at each step of the manufacturing process, the applicant must demonstrate the compliance of the materials used with the Note for Guidance on Minimising the Risk of Transmitting Animal Spongiform Encephalopathy Agents via Medicinal Products and its updates, published by the Commission in the Official Journal of the European Union. Demonstration of compliance with the said Note for Guidance can be done by submitting either, preferably a certificate of suitability to the relevant monograph of the European Pharmacopoeia that has been granted by the European Directorate for the Quality of Medicines or by the supply of scientific data to substantiate this compliance.

(10)For adventitious agents, information assessing the risk with respect to potential contamination with adventitious agents, whether they are non-viral or viral, as laid down in relevant guidelines as well as in relevant general monograph and general chapter of the European Pharmacopoeia, shall be provided.

(11)Any special apparatus and equipment, which may be used at any stage of the 44 [ S.L.458.34 MEDICINES (MARKETING AUTHORISATION) manufacturing process and control operations of the medicinal product, shall be described in adequate details.

(12)Where applicable and if needed, a CE marking which is required by Community legislation on medical devices shall be provided. Special attention shall be paid to the following selected elements. 3.2.1. 3.2.1.1. materials Active substance(

1. s)General information and information related to the starting and raw (
2. a)Information on the nomenclature of the active substance shall be provided, including recommended International Non-proprietary Name (INN), European Pharmacopoeia name if relevant, chemical name(s). The structural formula, including relative and absolute stereo-chemistry, the molecular formula, and the relative molecular mass shall be provided. For biotechnological medicinal products if appropriate, the schematic amino acid sequence and relative molecular mass shall be provided. A list shall be provided of physicochemical and other relevant properties of the active substance, including biological activity for biological medicinal products. (
3. b)For the purposes of this Schedule, starting materials shall mean all the materials from which the active substance is manufactured or extracted. For biological medicinal products, starting materials shall mean any substance of biological origin such as micro-organisms, organs and tissues of either plant or animal origin, cells or fluids (including blood or plasma) of human or animal origin, and biotechnological cell constructs (cell substrates, whether they are recombinant or not, including primary cells). A biological medicinal product is a product, the active substance of which is a biological substance. A biological substance is a substance that is produced by or extracted from a biological source and that needs for its characterisation and the determination of its quality a combination of physicochemical-biological testing, together with the production process and its control. The following shall be considered as biological medicinal products: immunological medicinal products and medicinal products derived from human blood and human plasma as defined, respectively in paragraphs

(4)and

(10)of Article 1; medicinal products falling within the scope of Part A of the Annex to Regulation (EEC) No 2309/93; advanced therapy medicinal products as defined in Part IV of this Schedule. Any other substances used for manufacturing or extracting the active substance(

1. s)but from which this active substance is not directly derived, such as reagents, culture media, foetal calf serum, additives, and buffers involved in chromatography, etc. are known as raw materials. 3.2.1.2. Manufacturing process of the active substance(
2. s)(
3. a)The description of the active substance manufacturing process represents the applicant’s commitment for the manufacture of the active substance. To adequately describe the manufacturing process and process controls, appropriate information as laid down in guidelines published by the Agency shall be provided. (
4. b)All materials needed in order to manufacture the active substance(
5. s)shall be listed, identifying where each material is used in the process. Information on the quality and control of these materials shall be provided. Information demonstrating that materials meet standards appropriate for their intended use shall be provided. MEDICINES (MARKETING AUTHORISATION) [ S.L.458.34 45 Raw materials shall be listed and their quality and controls shall also be documented. The name, address, and responsibility of each manufacturer, including contractors, and each proposed production site or facility involved in manufacturing and testing shall be provided. (
6. c)For biological medicinal products, the following additional requirements shall apply. The origin and history of starting materials shall be described and documented. Regarding the specific measures for the prevention of the Transmission of animal Spongiform Encephalopathies, the applicant must demonstrate that the active substance complies with the Note for Guidance on Minimising the Risk of Transmitting Animal Spongiform Encephalopathy Agents via Medicinal Products and its updates, published by the Commission in the Official Journal of the European Union. When cell banks are used, the cell characteristics shall be shown to have remained unchanged at the passage level used for the production and beyond. Seed materials, cell banks, pools of serum or plasma and other materials of biological origin and, whenever possible, the materials from which they are derived shall be tested for adventitious agents. If the presence of potentially pathogenic adventitious agents is inevitable, the corresponding material shall be used only when further processing ensures their elimination and/or inactivation, and this shall be validated. Whenever possible, vaccine production shall be based on a seed lot system and on established cell banks. For bacterial and viral vaccines, the characteristics of the infectious agent shall be demonstrated on the seed. In addition, for live vaccines, the stability of the attenuation characteristics shall be demonstrated on the seed; if this proof is not sufficient, the attenuation characteristics shall also be demonstrated at the production stage. For medicinal products derived from human blood or plasma, the origin and the criteria and procedures for collection, transportation and storage of the starting material shall be described and documented in accordance with provisions laid down in Part III of this Schedule. The manufacturing facilities and equipment shall be described. (
7. d)Tests and acceptance criteria carried out at every critical step, information on the quality and control of intermediates and process validation and/or evaluation studies shall be provided as appropriate. (
8. e)If the presence of potentially pathogenic adventitious agents is inevitable, the correspondent material shall be used only when further processing ensures their elimination and/or inactivation and this shall be validated in the section dealing with viral safety evaluation. (
9. f)A description and discussion of the significant changes made to the manufacturing process during development and/or manufacturing site of the active substance shall be provided. 3.2.1.3.1. Characterisation of the active substance(
10. s)Data highlighting the structure and other characteristics of the active substance(
11. s)shall be provided. Confirmation of the structure of the active substance(
12. s)based on any physicochemical and/or immunochemical and/or biological methods, as well as information on impurities shall be provided. [ S.L.458.34 46 MEDICINES (MARKETING AUTHORISATION) 3.2.1.3.2. Control of active substance(
13. s)Detailed information on the specifications used for routine control of active substance(s), justification for the choice of these specifications, methods of analysis and their validation shall be provided. The results of control carried out on individual batches manufactured during development shall be presented. 3.2.1.3.3. Reference standards or materials Reference preparations and standards shall be identified and described in detail. Where relevant, chemical and biological reference material of the European Pharmacopoeia shall be used. 3.2.1.6. Container and closure system of the active substance A description of the container and the closure system(
14. s)and their specifications shall be provided. 3.2.1.7. Stability of the active substance(
15. s)(
16. a)The types of studies conducted, protocols used, and the results of the studies shall be summarized (
17. b)Detailed results of the stability studies, including information on the analytical procedures used to generate the data and validation of these procedures shall be presented in an appropriate format (
18. c)The post authorisation stability protocol and stability commitment shall be provided 3.2.2. Finished medicinal product 3.2.2.1. Description and composition of the finished medicinal product A description of the finished medicinal product and its composition shall be provided. The information shall include the description of the pharmaceutical form and composition with all the constituents of the finished medicinal product, their amount on a per-unit basis, the function of the constituents of: - the active substance(s), - the constituent(
19. s)of the excipients, whatever their nature or the quantity used, including colouring matter, preservatives, adjuvants, stabilisers, thickeners, emulsifiers, flavouring and aromatic substances, etc., - the constituents, intended to be ingested or otherwise administered to the patient, of the outer covering of the medicinal products (hard capsules, soft capsules, rectal capsules, coated tablets, films-coated tablets, etc.), - these particulars shall be supplemented by any relevant data concerning the type of container and, where appropriate, its manner of closure, together with details of devices with which the medicinal product will be used or administered and which will be delivered with the medicinal product. The ‘usual terminology’, to be used in describing the constituents of medicinal products, shall mean, notwithstanding the application of the other provisions in Article 8

(3)(c): - in respect of substances which appear in the European Pharmacopoeia or, failing this, in the national pharmacopoeia of one of the Member States, the main title at the head of the monograph in question, with reference to the pharmacopoeia concerned, MEDICINES (MARKETING AUTHORISATION) [ S.L.458.34 47 - in respect of other substances, the international non-proprietary name (INN) recommended by the World Health Organisation, or, failing this, the exact scientific designation; substances not having an international non-proprietary name or an exact scientific designation shall be described by a statement of how and from what they were prepared, supplemented, where appropriate, by any other relevant details, - in respect of colouring matter, designation by the ‘E’ code assigned to them in Council Directive 78/25/EEC of 12 December 1977 on the approximation of the rules of the Member States concerning the colouring matters authorised for use in medicinal products and/or European Parliament and Council Directive 94/36/EC of 30 June 1994 on colours for use in foodstuffs. In order to give the ‘quantitative composition’ of the active substance(s) of the finished medicinal products, it is necessary, depending on the pharmaceutical form concerned, to specify the mass, or the number of units of biological activity, either per dosage-unit or per unit of mass or volume, of each active substance. Active substances present in the form of compounds or derivatives shall be designated quantitatively by their total mass, and if necessary or relevant, by the mass of active entity or entities of the molecule. For medicinal products containing an active substance, which is the subject of an application for marketing authorisation in any Member State for the first time, the quantitative statement of an active substance, which is a salt or hydrate shall be systematically expressed in terms of the mass of the active entity or entities in the molecule. All subsequently authorised medicinal products in the Member States shall have their quantitative composition stated in the same way for the same active substance. Units of biological activity shall be used for substances, which cannot be defined molecularly. Where an International Unit of biological activity has been defined by the World Health Organisation, this shall be used. Where no International Unit has been defined, the units of biological activity shall be expressed in such a way as to provide unambiguous information on the activity of the substances by using where applicable the European Pharmacopoeia Units. 3.2.2.2. Pharmaceutical development This chapter shall be devoted to information on the development studies conducted to establish that the dosage form, the formulation, manufacturing process, container closure system, microbiological attributes and usage instructions are appropriate for the intended use specified in the marketing authorisation application dossier. The studies described in this chapter are distinct from routine control tests conducted according to specifications. Critical parameters of the formulation and process attributes that can influence batch reproducibility, medicinal product performance and medicinal product quality shall be ide