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Market withdrawal and suspension of marketing authorisation of medicinal
product due to good manufacturing practice noncompliance in India

C-269/13 Acino AG vs. European Commission
Citeersuggestie: Hanneke Later-Nijland, ‘Market withdrawal and suspension of marketing authorisation of medicinal product due to good manufacturing practice noncompliance in India' INTRODUCTION (AND SUMMARY)
reasonable doubt as to their qualitative and quantitative composition, as declared, of the On the 10th of April 20141, the Court of Justice of medicinal products at issue. Where it proves to be the European Union (hereinafter: "CJEU") has
impossible to determine with certainty the clarified that upon establishment of breach of the existence or extent of the alleged risk, the rules of Good Manufacturing Practice ("GMP"),
precautionary principle justifies the adoption of the Commission is entitled to suspend the restrictive measures. withdrawal of the medicinal product from the With respect to the withdrawal of the product distribution network, including pharmacies - even from the distribution network, the CJEU ruled that when there is no evidence that the medicinal non-compliance with GMP may constitute such a products at stake were harmful to patients. potential risk of impairment of the qualitative composition and therefore of detriment to public To our knowledge, this is the first ruling of the health, the General Court was justified in holding CJEU pertaining to noncompliance with GMP and that the conditions for the application of the relevant provision3 of the Medicines Directive authorisation for a medicinal product and imposed withdrawal from the distribution network of the medicinal product concerned. This case is highly relevant for marketing authorisation The conditions for suspension, withdrawal or pharmaceutical ingredients or medicinal products variation of a marketing authorisation are are manufactured in a factory in India or China, as limitatively listed in the Medicines Directive2. it has recently been published that relatively more However, noncompliance with the rules of GMP is GMP noncompliance has been established in not listed as one of those conditions, whereas the those countries4. fact that the qualitative and quantitative composition of the medicinal product not being as BACKGROUND
declared, is mentioned as such a condition. The CJEU ruled that the General Court correctly Acino Pharma (hereinafter: "Acino") has obtained
applied the precautionary principle when stating a centralised authorisation for eight medicinal that the grounds laid down in the Medicines products containing clopidogrel5. The marketing Directive aim to prevent certain risks to health, authorisations applications indicated that the the fact remains that those risks need not be active substance, clopidogrel, was (among others) specific but only potential. The Commission was entitled to restrict itself to supplying solid and persuasive evidence which could give rise to 3 Article 117(1)(e) Directive 2001/83/EC (as amended). 4 See 1 C-269/13 Acino AG v. European Commission. accessed: June 16, 2014. 2 Article 116 Directive 2001/83/EC (as amended). 5 An antiplatelet agent. manufactured in a factory in Visakhapatnam, decisions entailing that (1) the marketing of consignments of medicinal products containing the active ingredient clopidogrel manufactured on In 2010, the Committee for Medicinal Products for that site was suspended, and that (2) all Human Use (hereinafter: "CHMP") requested the
consignments of medicinal products containing competent authority of Oberbayern (Germany) to the active ingredient clopidogrel manufactured by inspect the factory whether the manufacturing of that factory were to be withdrawn from the medicinal was in compliance with the principles distribution network, including pharmacies. and guidelines of Good Manufacturing Practice
(hereinafter: "GMP"). Article 46(f) of Directive
Afterwards, Acino sent to the Commission a 2001/83/EC (as amended) stipulates that the report including a (among others) risk assessment, holder of a manufacturing authorisation is obliged which concluded that there was no risk to to comply with the principles and guidelines of patients' health. Therefore, Acino requested a GMP for medicinal products and to use as starting new examination. materials only active substances, which have been manufactured in accordance with the detailed Nevertheless, the Agency (EMA) informed the Commission that it maintained the conclusions of guidelines on GMP. the initial opinion of the CHMP and the final The inspection resulted in a report which established that manufacturing at the factory in authorisations to market medicinal products Visakhapatnam, India did not comply with the containing the active ingredient clopidogrel were rules on GMP. Such inspection reports generally varied to the effect that the Visakhapatnam site categorize the established breaches into critical, was removed from the list of production sites serious or minor. The fact that 70 manufacturing authorised to supply that active ingredient; and, standards had been re-written and that certain secondly the consignments of medicinal products initial indications were amended, was considered containing clopidogrel manufactured at that site a critical breach. may not be placed on the European Union market. Please note that it had been mentioned in the inspection report that the quality of the products Acino lodged an application with the General was not affected as a result of the re-writing of Court seeking the annulment of both the the data relating of quality and that there was no provisional and the final decisions. However, the evidence that that breach affected the health of General Court dismissed the action brought by Furthermore, eight other serious breached were The appeal revealed. In an amended version of the inspection report, the withdrawal of medicinal products In essence, the appeal with the CJEU seeks the supplied was found to be unnecessary in the General Court's assessment of the conditions for absence of any evidence that the products at application of articles 116 and 117 of Directive issue were harmful to patients. 2001/83/EC, in the light of the precautionary principle, as derived from the Court's case-law. After the hearing before the CHMP, the Commission initiated an article 20 procedure6 and Article 116 of Directive 2001/83/EC provides that finally the Commission7 adopted provisional the competent authorities shall suspend, revoke, Article 20 Regulation (EC) No 726/2004 (as amended). The decisions were adopted in accordance with the second 7 The decisions were adopted in accordance with the first subparagraph of Article 20(3) of Regulation No 726/2004 (as subparagraph of Article 20(3) of Regulation No 726/2004 (as withdraw or vary a marketing authorisation if the be justified by new elements changing the view is taken that the product is harmful under assessment of the risk in question. normal conditions of use, or that it lacks therapeutic efficacy, or that the risk-benefit The grounds of appeal and the ruling of the CJEU balance is not positive under the normal Among its first ground of appeal9, pertaining to conditions of use, or that its qualitative and disregard for the precautionary principle, Acino quantitative composition is not as declared. The holds that breach of rules of GMP cannot provision furthermore stipulates that therapeutic automatically lead to a change in the qualitative efficacy is lacking when it is concluded that and quantitative composition of the medicinal therapeutic results cannot be obtained from the product in question, and therefore the conditions medicinal product. for the application of article 116(1) of the The following article 117(1) of that directive Directive were not met. provides that Member States shall take all Furthermore, Acino holds that the correct appropriate steps to ensure that the supply of the application of the precautionary principle medicinal product is prohibited and the medicinal presupposes that there is a probability of actual product withdrawn from the market, if the view is harm to public health. Moreover, the evidence furnished by Acino that the medicinal products at (a) the medicinal product is harmful under issue were not harmful, was not taken into normal conditions of use; or account by the General Court. The CJEU ruled that since the manufacturing (b) it lacks therapeutic efficacy; or process is a factor capable of varying the (c) the risk-benefit balance is not qualitative composition of a medicinal product, favourable under the authorised conditions of the non-compliance with that process could lead to a change in the qualitative composition and therefore the Commission was entitled to take (d) its qualitative and quantitative account of the manufacturing process declared by composition is not as declared; or Acino. Moreover, the present case entailed a the controls on the medicinal product critical breach, in conjunction with eight other and/or on the ingredients and the controls at serious breaches. an intermediate stage of the manufacturing Regarding the alleged disregard for the process have not been carried out or if some precautionary principle, the CJEU states that other requirement or obligation relating to protective measures may be taken without having the grant of the manufacturing authorisation to wait until the reality and seriousness of those has not been fulfilled. risks become fully apparent.10 Further to the precautionary principle; article 8 of The General Court has also added that where it the European Convention on Human Rights on the proves to be impossible to determine with right to respect for private and family life implies certainty the existence or extent of the alleged respect for the precautionary principle. The risk because of the insufficiency, inconclusiveness precautionary principle has been developed in the or imprecision of the results of the results of the case law of the CJEU and comprises the management of the risk exceeding the level deemed acceptable for society through measures 9 Acino put five grounds of appeal forward. As some have been designed to contain it at that level. The General rejected as unfounded or inadmissible, only a selection will be discussed within the scope of this article. Court therefore concluded that the relaxation of 10 C-236/01 Monsanto Agricoltura Italia and Others [2003], par preventive measures adopted previously had to studies conducted, but the likelihood of real harm Furthermore, Acino holds that contested to public health persists should the risk decisions exceed the Commission's power of materialise, the precautionary principle justifies the adoption of restrictive measures.11 The General Court therefore correctly applied the The CJEU remarks that in so far as it has been precautionary principle when stating that the established that the obligations connected with grounds set out in the first paragraph of article the manufacturing process are essential for the purpose of ensuring the quality of medicinal 116 of Directive 2001/83/EC aim to prevent certain risks to health, the fact remains that those products, the Commission was entitled to risks need not be specific but only potential. conclude that the medicinal products at issue did not have the declared qualitative and quantitative Acino also claimed that the conditions set out in composition and that an obligation pertaining to article 117(1)(e) of Directive 2001/83/EC were not the grant of manufacturing authorisations for satisfied. However, given that the General Court medicinal products had not been complied with. observed that non-compliance with GMP may Therefore, the contested decisions are not constitute such a potential risk of impairment of infringed by any manifest error of assessment and the qualitative composition and therefore of the Commission also clearly did not exceed the detriment to public health, it was justified in limits of its discretion. holding that the conditions for the application of article 117(1)(e) of Directive 2001/83/EC were On inter alia these grounds, the Court dismisses met in the present case. the appeal and Acino is ordered to pay to costs. With regard to the burden of evidence, the CJEU CONCLUSION
confirmed that it is not the holder of an This judgment reveals that when a breach of authorisation for a medicinal product who is GMP rules is being established, no evidence of required to adduce evidence of the effectiveness harm due to noncompliance with GMP is or safety of that medicinal product, but rather it is required in order to 1) vary the marketing the competent authority, in the present case the authorisation for the medicinal product at issue Commission, that is required to establish that one and/or 2) to order the medicinal products of the conditions set out in Articles 116 and 117 of concerned be withdrawn from the distribution Directive 2001/83 has been satisfied. In that network, including pharmacies. However, the context, the General Court stated that the burden of proof of the breach and of its potential Commission may, nevertheless restrict itself to harm initially is on the authorities. providing solid and persuasive evidence on the This judgment of the CJEU underlines that where basis of which, while not dispelling scientific subsequently it proves to be impossible to uncertainty, there can be reasonable doubt as to determine with certainty the existence or extent the declared qualitative and quantitative of the alleged risk (for which the burden of proof composition of the medicinal products at issue then shifts to the manufacturer), the and as to compliance with one of the obligations precautionary principle justifies the adoption of connected with the grant of the manufacturing restrictive measures. authorisation. It would seem that, in response, the holder should then be allowed to produce With respect to the withdrawal of the product evidence of the effectiveness and safety of the from the distribution network, the CJEU ruled medicinal product, but that was not at issue in that non-compliance with GMP may constitute this case before the CJEU. such a potential risk of impairment of the qualitative composition and therefore of detriment to public health, the General Court 11 C-129/01 Commission v. Denmark, par. 52; C-333/08 was justified in holding that the conditions for Commission v. France [2010], par. 93. the application of the article 117(1)(e) of Hanneke Later-Nijland, Directive 2001/83/EC were met. Bird & Bird The Hague, This ruling seems therefore to broaden the margin of appreciation of the Commission when The Netherlands imposing measures following established noncompliance with the rules of GMP. Pharmaceutical companies should be well aware of the status of GMP compliance in the factories where their medicinal products and/or active ingredients for their medicinal products are being manufactured. Increasing the frequency of GMP audits and mock-inspections at factories at-risk may be worthwhile, considering that e.g. a suspended marketing authorisation and a withdrawal of the medicinal products due to noncompliance with GMP will result in more serious economic loss – apart from the possible impact on the quality of the medicinal products concerned. Furthermore, it should be realised that the CHMP would recommend - upon establishment of GMP noncompliance - that the factory concerned be removed from the list of sites authorised to manufacture the pharmaceutical ingredient or product, this could, in case of dependency on one of the manufacturing factories, even lead to acute or chronic shortages of certain medicinal products. authorisation holder should notify the Agency and inform the Agency of the reasons of temporary cessation of placing the medicinal product concerned on the market.12 By way of closing remark, it should be noted that
it cannot be excluded that the abovementioned
way of reasoning will also be followed upon
breach of for instance the rules on Good
Pharmacovigilance Practice ("GVP"). Therefore,
Qualified Persons should also be well aware of
the above case law and assure that all medicinal
products are manufactured in a GXP compliant
manner: the risk on direct economic loss due to
such noncompliance seems to have increased.
12 For centrally authorised products: article 13(4) and article 14b of Regulation (EC) No 726/2004 (as amended).

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