JUDGMENT OF THE COURT (Fourth Chamber)

11 April 2013 ( *1 )

‛Reference for a preliminary ruling — Regulation (EC) No 726/2004 — Medicinal products for human use — Procedure for authorisation — Requirement for authorisation — Concept of medicinal products ‘developed’ by means of certain biotechnological processes, as referred to in point 1 of the Annex to that regulation — Repackaging process — Injectable solution distributed in single-use vials containing a larger quantity of the therapeutic solution than that actually used for the purposes of medical treatment — Part of the content of such vials drawn off, on prescription by a doctor, into syringes pre-filled with the prescribed dose, without any modification of the medicinal product’

In Case C-535/11,

REQUEST for a preliminary ruling under Article 267 TFEU from the Landgericht Hamburg (Germany), made by decision of 12 October 2011, received at the Court on 20 October 2011, in the proceedings

Novartis Pharma GmbH

v

Apozyt GmbH,

THE COURT (Fourth Chamber),

composed of L. Bay Larsen, acting as President of the Fourth Chamber, J.-C. Bonichot, C. Toader (Rapporteur), A. Prechal and E. Jarašiūnas, Judges,

Advocate General: E. Sharpston,

Registrar: A. Impellizzeri, Administrator,

having regard to the written procedure and further to the hearing on 26 September 2012,

after considering the observations submitted on behalf of:

—

Novartis Pharma GmbH, by L. Kröner, C. Schoonderbeek and I. Millarg, Rechtsanwälte,

—

Apozyt GmbH, by W. Prinz, Rechtsanwalt, and by C. Künzer,

—

the German Government, by T. Henze and A. Wiedmann, acting as Agents,

—

the Czech Government, by M. Smolek and D. Hadroušek, acting as Agents,

—

Ireland, by E. Creedon, acting as Agent, and by S. Woulfe, Barrister-at-Law,

—

the Greek Government, by I. Bakopoulos and O. Souropani, acting as Agents,

—

the Portuguese Republic, by L. Inez Fernandes and A. Antunes, acting as Agents,

—

the European Commission, by M. Šimerdová and B.-R. Killmann, acting as Agents,

after hearing the Opinion of the Advocate General at the sitting on 31 January 2013,

gives the following

Judgment

1This request for a preliminary ruling concerns the interpretation of Article 3(1) of 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 ( OJ 2004 L 136, p. 1 ).

2The request has been made in proceedings between Novartis Pharma GmbH (‘Novartis’) and Apozyt GmbH (‘Apozyt’) concerning whether Apozyt may produce, distribute and promote ready-to-use syringes that are intended for the treatment of eye disease and contain doses of the medicinal products Lucentis and Avastin.

Legal context

European Union legislation

‘(7)

Experience gained since the adoption of Council Directive 87/22/EEC of 22 December 1986 on the approximation of national measures relating to the placing on the market of high-technology medicinal products, particularly those derived from biotechnology [ OJ 1987 L 15, p. 38 ] has shown that it is necessary to create a centralised authorisation procedure that is compulsory for high-technology medicinal products, particularly those resulting from biotechnical processes, in order to maintain the high level of scientific evaluation of these medicinal products in the European Union and thus to preserve the confidence of patients and the medical professions in the evaluation. …

(13)

In the interest of public health, authorisation decisions under the centralised procedure should be taken on the basis of the objective scientific criteria of quality, safety and efficacy of the medicinal product concerned, to the exclusion of economic and other considerations. …’

4Under Article 3(1) of Regulation No 726/2004 ‘no medicinal product appearing in the Annex may be placed on the market within the Community unless a marketing authorisation has been granted by the Community in accordance with the provisions of this Regulation’.

5Article 3(2) of the regulation adds:

‘Any medicinal product not appearing in the Annex may be granted a marketing authorisation by the Community in accordance with the provisions of this Regulation, if:

(a)

the medicinal product contains a new active substance which, on the date of entry into force of this Regulation, was not authorised in the Community; or

(b)

the applicant shows that the medicinal product constitutes a significant therapeutic, scientific or technical innovation or that the granting of authorisation in accordance with this Regulation is in the interests of patients or animal health at Community level.

…’

6Point 1 of the Annex to Regulation No 726/2004, which concerns ‘Medicinal products to be authorised by the Community’, reads as follows:

‘Medicinal products developed by means of one of the following biotechnological processes:

—

recombinant DNA technology,

—

controlled expression of genes coding for biologically active proteins in prokaryotes and eukaryotes including transformed mammalian cells,

—

hybridoma and monoclonal antibody methods.’

7As regards the content of an application for a marketing authorisation, Article 6(1) of Regulation No 726/2004 refers to the information in, inter alia, Article 8(3) of 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 ( OJ 2001 L 311, p. 67 ), as amended by Directive 2010/84/EU of the European Parliament and of the Council of 15 December 2010 ( OJ 2010 L 348, p. 74 ) (‘Directive 2001/83’).

8In that regard, it is apparent from Article 8(3) of Directive 2001/83 that the particulars and documents which must accompany an application for a marketing authorisation include, inter alia, the name of the medicinal product, the qualitative and quantitative particulars of all the constituents of that product, a description of the manufacturing method, posology, pharmaceutical form, method and route of administration and expected shelf life.

9Under Article 16 of Regulation No 726/2004, the holder of a marketing authorisation is obliged to supply forthwith to the European Agency Medicines Agency (EMA), to the European Commission and to the Member States any new information which might entail the variation of the particulars or documents referred to in Article 8(3) of Directive 2001/83. If that holder proposes to make any variation of those particulars and documents, he is to submit the relevant application to the EMA.

10Article 19(1) of Regulation No 726/2004 provides that the supervisory authorities are for their part to be responsible for verifying on behalf of the European Union that the holder of the marketing authorisation for a medicinal product for human use satisfies the requirements laid down in, inter alia, Title IV of Directive 2001/83, which contains Articles 40 to 53.

11In that regard, Article 40 of Directive 2001/83 provides:

‘1. Member States shall take all appropriate measures to ensure that the manufacture of the medicinal products within their territory is subject to the holding of an authorisation. …

2. The authorisation referred to in paragraph 1 shall be required for both total and partial manufacture, and for the various processes of dividing up, packaging or presentation.

However, such authorisation shall not be required for preparation, dividing up, changes in packaging or presentation where these processes are carried out, solely for retail supply, by pharmacists in dispensing pharmacies or by persons legally authorised in the Member States to carry out such processes.

...’

12Article 2(1) of Directive 2001/83 provides:

‘This Directive shall apply to medicinal products for human use intended to be placed on the market in Member States and either prepared industrially or manufactured by a method involving an industrial process.’

13Article 3 of that directive provides:

‘This Directive shall not apply to:

(1)

Any medicinal product prepared in a pharmacy in accordance with a medical prescription for an individual patient (commonly known as the magistral formula).

(2)

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).

...’

14Article 5(1) of the directive provides:

‘A Member State may, in accordance with legislation in force and to fulfil special needs, exclude from the provisions of this Directive 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.’

15Article 6(1) of Directive 2001/83 reads as follows:

‘No medicinal product may be placed on the market of a Member State unless a marketing authorisation has been issued by the competent authorities of that Member State in accordance with this Directive or an authorisation has been granted in accordance with Regulation … No 726/2004 …

When a medicinal product has been granted an initial marketing authorisation in accordance with the first subparagraph, any additional strengths, pharmaceutical forms, administration routes, presentations, as well as any variations and extensions shall also be granted an authorisation in accordance with the first subparagraph or be included in the initial marketing authorisation …’

German law

16Paragraph 4 of the Law on the marketing of medicinal products (Gesetz über den Verkehr mit Arzneimitteln) provides:

‘1. Finished medicinal products are medicinal products which are produced and marketed in particular packaging for sale to the consumer, or other medicinal products intended for consumers, in the preparation of which an industrial process is applied in another way or which, apart from in pharmacies, are produced industrially. Finished medicinal products are not intermediates intended for further processing by a manufacturer.

...

14. Production shall include making, preparing, processing or working, transferring to other containers – including bottling –, packaging, marking and selling …’

17Paragraph 21 of the Law on the marketing of medicinal products, which concerns the requirement for authorisation, provides:

‘1. Finished medicinal products … may be marketed, under this Law, only if they have been approved by the competent Federal authorities or if the Commission of the European Communities or the Council of the European Union has granted a marketing authorisation in accordance with Article 3(1) or (2) of Regulation No 726/2004 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 use and amending Regulation (EEC) No 1768/92, Directive 2001/20/EC, Directive 2001/83/EC and Regulation (EC) No 726/2004 ( OJ 2006 L 378, p. 1 ) ...

2. Authorisation is not required for medicinal products

...

1(b)

other than the medicinal products listed in point 1, or for medicinal products authorised outside the scope of this Law for pharmacies in possession of a prescription for a patient.

...

(c)

put into a container without being modified ...’

The dispute in the main proceedings and the question referred for a preliminary ruling

18Novartis is the holder of a marketing authorisation for Lucentis. The marketing authorisation was granted by the Commission by decision of 22 January 2007 (C(2007) 237)), adopted under Article 3(1) of Regulation No 726/2004.

19One of the therapeutic indications specifically mentioned in the marketing authorisation for Lucentis is treatment of wet age-related macular degeneration (‘AMD’). The wet form of AMD involves the pathological growth of blood-vessels in the retina together with fluid and blood secretions which damage the tissue of the retina. The disease results in serious visual impairment.

20Lucentis is distributed in perforable vials containing 0.23 ml which are sold for around EUR 1 200 per unit, each vial being supplied with a syringe authorised for that use, a filter cannula and an injection cannula. According to the instructions for health professionals, the product concerned should be drawn up from the vial using the 1 ml syringe and filter cannula supplied with the vial. The filter cannula placed on the syringe must then be replaced by an injection cannula and the contents of the syringe must be discarded until the syringe contains only the recommended dose of 0.05 ml of the product. An injection into the eye may then be given. The content of the vial is intended for the administration of a single dose, even though ultimately only 0.05 ml out of 0.23 ml of the medicinal liquid is used.

21Roche Pharma AG, which is not a party to the main proceedings, is the holder of a marketing authorisation for Avastin. That marketing authorisation was granted by the Commission by a decision of 12 January 2005 (C(2005) 97)), which was adopted under Article 3(1) of Regulation No 726/2004.

22The marketing authorisation for Avastin covers, in essence, therapeutic indications connected to the treatment of metastatic cancers of the colon, breast and kidney. In Germany, Avastin is used, on a doctor’s prescription, in the treatment of AMD, since it was already used for that purpose before Lucentis was authorised and since at that time there were no medicinal products specifically for the treatment of AMD. As in other Member States, Avastin continues to be used in ophthalmology because it costs substantially less than Lucentis. The referring court states that in Germany that use, which relates to the therapeutic freedom of medical practitioners, is lawful provided that the patient gives his consent. Avastin is sold in 4 ml or 16 ml vials. However, the concentrate contained in the vials must not be used in undiluted form but must be diluted with saline solution and administered by infusion.

23Apozyt prepares, using the content of the medicinal products Lucentis and Avastin, syringes which contain only the dose necessary for an injection on the basis of the dose prescribed by a doctor. The pre-prepared syringes are filled in a sterile environment in a production unit with an isolation chamber. The pre-filled syringes are dispatched and delivered to the pharmacy which has ordered them. According to Apozyt, pharmacies place orders only when patients produce prescriptions to this effect. The decanting into the syringes carried out in that way allows the content of the vials of Lucentis and Avastin to be used for a number of injections, so that the final price of an injection is considerably lower than the price that would be paid for an injection using solely the medicinal products as they are marketed.

24Novartis brought proceedings before the referring court seeking an order that Apozyt cease commercial activities of this kind, which, according to Novartis, amount to acts of unfair competition. In support of its action, Novartis asserts that the activity of filling ready-to-use syringes with doses of the unmodified medicinal product also requires a marketing authorisation, in particular because – as referred to in the first and third indents of point 1 of the Annex to Regulation No 726/2004 – the active substances in Lucentis and Avastin have been developed by means of recombinant DNA technology and are also obtained using hybridoma and monoclonal antibody methods.

25Moreover, in Novartis’ submission, the fact that the single-use vials contain a higher dose than necessary in therapeutic terms is accounted for by production procedures. The surplus content is also intended to ensure the safe application of Lucentis. Novartis maintains that there is a danger of infiltration of bacteria when the original product is transferred from one container to another, as well as a problem relating to the conservation of the product in ready-to-use syringes such as those produced by the defendant in the main proceedings.

26Apozyt contends that a marketing authorisation is not required for the procedures it carries out, since the process of producing the medicinal product has already been completed at the time when it re-packages it, then distributes it in the form of ready-to-use syringes containing lower doses than those contained in the original medicinal products that are the subject of a marketing authorisation. Thus, the preparation of ready-to-use syringes, such as those at issue in the main proceedings, cannot be regarded as the ‘development’ of a medicinal product by means of one of the processes listed in the Annex to Regulation No 726/2004. Furthermore, Apozyt submits that the preparation of ready-to-use syringes under sterile conditions, such as those which obtain in its filling units, is a guarantee of a higher degree of safety, given that doctors who themselves transfer the product to another container prior to an injection are not operating under sterile conditions. The syringes used are the same as those supplied by the original manufacturer, so that issue cannot be taken with Apozyt for altering the process for administering the medicinal products in question.

27The Landgericht Hamburg explains that under Articles 3 and 4 of the Law against unfair competition (Gesetz gegen den unlauteren Wettbewerb), any person who, by reason of his conduct, infringes a requirement for approval or authorisation acts unfairly. Furthermore, such conduct may be challenged by any competitor who may require the conduct to be prohibited. Thus, if Apozyt’s business of packaging ready-to-use syringes was covered by the requirement for authorisation laid down in Article 3 of Regulation No 726/2004, that business would be unfair within the meaning of Articles 3 and 4 of that law. In that connection, the Landgericht Hamburg refers to the fact that the Hanseatisches Oberlandesgericht Hamburg (Hamburg Higher Regional Court) has held, in a previous judgment, that the term ‘developed’, which is used in the introductory words of point 1 of the Annex to Regulation No 726/2004, also covers the filling of syringes and that consequently a marketing authorisation was also required for that activity. The referring court tends to concur with view but points out that the issue has considerable significance for the pharmaceutical sector, particularly since such filling of syringes, in a sterile environment, on the basis of the recommended dose, could allow substantial savings to be made.

‘Does the term “developed” in the introductory words of point 1 of the Annex to [Regulation No 726/2004] extend to processes in which portions only of a medicinal product which has been developed and produced on a ready-to-use basis in accordance with the above procedures are drawn off into another container, after being prescribed and ordered at the time concerned by a doctor, if as a result of the process the composition of the medicinal product is not modified, and therefore in particular to the production of pre-filled syringes which have been filled with a medicinal product which is authorised under the Regulation?’

The application for the reopening of the oral procedure

29By letter of 25 February 2013, Apozyt requested that the Court order the reopening of the oral procedure pursuant to Article 83 of the Rules of Procedure, on the ground that the Opinion of the Advocate General was based on inaccurate factual and legal considerations, particularly in relation to, on the one hand, the conclusion that Apozyt’s activities amounted to the placing on the market of a new medicinal product and, on the other, the conditions for Article 5(1) of Directive 2001/83 to apply.

32In the present case, since the Court considers that it has sufficient information to give a ruling and since the case does not have to be decided on the basis of arguments which have not been debated between the parties, there is no need to grant the request that the oral procedure be reopened.

The question referred for a preliminary ruling

33By its question, the referring court asks, in essence, whether activities such as those at issue in the main proceedings require a marketing authorisation under Article 3(1) of Regulation No 726/2004 and, if not, whether those activities remain subject to Directive 2001/83.

34Novartis and the Czech and Greek Governments submit that activities such as those at issue in the main proceedings amount to repackaging and are not covered by the marketing authorisation granted for the original medicinal products, with the result that those activities are unlawful. Novartis thus considers that, if Apozyt is to repackage the medicinal products in question in a pre-filled syringe, it should submit an application for a marketing authorisation to that effect to the EMA.

35Apozyt, the German Government, Ireland and the Portuguese Government defend the contrary position, submitting that such activities do not require the grant of a marketing authorisation additional to those already granted.

36The Commission contends that the question raised may be of no relevance for the resolution of the dispute in the main proceedings, since, in its view, the word ‘hergestellt’ (developed) in the introductory words of the German-language version of point 1 of the Annex to Regulation No 726/2004 cannot be construed as a means of determining whether the obligation to hold a marketing authorisation also applies to activities whereby portions of a medicinal product which has been developed and produced in accordance with authorised procedures are, on a doctor’s prescription, subsequently transferred into another container. It also maintains that, in order to decide on the case before it, the referring court must in reality ascertain whether activities such as those at issue in the main proceedings, whereby ready-to-use syringes are filled with a medicinal product which is already authorised and is contained in perforable vials, must be regarded as processes involving dividing up or changes in packaging or presentation within the meaning of Article 40(2) of Directive 2001/83. If that is the case, Apozyt will not need a marketing authorisation to carry out such processes. If, however, such processes cannot be regarded as falling within Article 40 of that directive, that would be a strong indication that a marketing authorisation is necessary to carry them out.

37In that regard, the Court observes that Article 3(1) of Regulation No 726/2004 establishes an obligation to submit an application for a marketing authorisation in the framework of the centralised procedure in which the EMA has mandatory competence so far as the granting of those authorisations is concerned. That obligation relates to the high-technology medicinal products included in the Annex to the regulation, in particular medicinal products developed by means of one of the three biotechnological processes listed in point 1 of the Annex.

38It follows from Article 3 of Regulation No 726/2004 in conjunction with Articles 2 and 6 of Directive 2001/83 that industrially produced medicinal products for human use intended to be placed on the market in Member States, other than those included in the Annex to Regulation No 726/2004, must as a rule have a marketing authorisation granted by the authorities of those Member States under that directive. There is an option – in the present case on the terms set out in Article 3(2) of Regulation No 726/2004 – whereby medicinal products not included in the Annex thereto may none the less be granted a marketing authorisation under the centralised procedure, thereby avoiding the need to submit multiple applications for marketing authorisations under the authorisation procedure established by Directive 2001/83.

39Accordingly, in adopting Article 3 of Regulation No 726/2004, the European Union legislature established a test for determining whether a given medicinal product must, in order to be placed on the market in the European Union, be authorised under the centralised authorisation procedure established by that regulation or under the national procedures implementing Directive 2001/83.

45The German Government points out that it has made use of the derogation provided for in Article 5(1) of Directive 2001/83 by excluding from the scope of that directive, in order to fulfill special needs, 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. According to the German Government, an activity such as that at issue in the main proceedings falls within the scope of that derogation and therefore requires neither a specific authorisation nor, a fortiori, a marketing authorisation.

49Concerning the last point, it should, however, be recalled that a prescribing doctor is required, from the point of view of professional conduct, not to prescribe a given medicinal product if it is not appropriate for the therapeutic treatment of his patient, including from the point of view of how it is administered (see Case C-62/09 Association of the British Pharmaceutical Industry [2010] ECR I-3603 , paragraph 40).

50Such considerations do not, however, settle the question as to whether the activity of a company such as Apozyt, at least so far as Lucentis is concerned, requires a specific authorisation under the European Union rules.

51With regard to the requirements applying to an activity such as that carried out by Apozyt, the referring court mentions Article 40 of Directive 2001/83. In that regard, it is indeed the case that, under the first subparagraph of Article 40(2) of the directive, authorisation, as referred to in that provision, is required for that activity in so far as it concerns the repackaging of medicinal products which have a marketing authorisation.

54In view of all the foregoing considerations, the answer to the question referred is that activities such as those at issue in the main proceedings, provided that they do not result in a modification of the medicinal product concerned and are carried out solely on the basis of individual prescriptions calling for processes of such a kind – a matter which falls to be determined by the referring court –, do not require a marketing authorisation under Article 3(1) of Regulation No 726/2004 but remain, in any event, subject to Directive 2001/83.

Costs

55Since these proceedings are, for the parties to the main proceedings, a step in the action pending before the national court, the decision on costs is a matter for that court. Costs incurred in submitting observations to the Court, other than the costs of those parties, are not recoverable.

On those grounds, the Court (Fourth Chamber) hereby rules:

Activities such as those at issue in the main proceedings, provided that they do not result in a modification of the medicinal product concerned and are carried out solely on the basis of individual prescriptions calling for processes of such a kind – a matter which falls to be determined by the referring court –, do not require a marketing authorisation under Article 3(1) of 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, but remain, in any event, subject to 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, as amended by Directive 2010/84/EU of the European Parliament and of the Council of 15 December 2010.

[Signatures]

( *1 ) Language of the case: German.