European Medicines Agency gives interim recommendations to deal with shortcomings in quality assurance at Ben Venue Laboratories

Press release 22/11/2011

Precautionary recall for remaining batches of Busilvex, Velcade and Vidaza manufactured at Ben Venue. No new patients to be treated with Caelyx.

The European Medicines Agency is currently reviewing shortcomings in quality assurance identified during a good-manufacturing-practice (GMP) inspection at the Ben Venue Laboratories manufacturing site in Ohio, United States of America, and their impact on centrally authorised medicines manufactured at this site.

A joint GMP inspection of the site, where a number of sterile medicines are manufactured, by the United Kingdom and French medicines regulatory agencies together with the United States Food and Drug Administration (FDA) on 7-11 November 2011 highlighted several shortcomings in the quality-management system, particularly in relation to the aseptic filling process in the North complex of the Ben Venue facility. During the inspection, Ben Venue decided to cease all manufacture and distribution of medicines from its site, which has been the object of increased GMP surveillance, and to investigate the GMP issues identified.

The Agency's Committee for Medicinal Products for Human Use (CHMP), at the request of the European Commission, is currently reviewing all centrally authorised medicines that are manufactured at the site to determine the risk to human health and to decide on appropriate regulatory action. The Agency is also in contact with the regulatory authorities of the European Union (EU) Member States on the impact of this issue on non-centrally authorised products. There will be a co-ordinated national approach to these products, taking the same principles into account as for the centrally authorised medicines.

As a first step the Committee considered whether the identified GMP issues could have compromised the quality of the centrally authorised oncology medicines Busilvex, Caelyx, Velcade, Vidaza and the antiviral medicine Vistide, manufactured in the North complex, where the quality assurance issues identified posed the greatest risk, and the potential impact of a restricted supply in the EU.

The Committee conducted a product-specific benefit/risk assessment for each medicine, covering released and quarantined batches and reviewed the need for urgent interim measures.

As precautionary measure, the CHMP concluded that the potential risk of batch contamination due to the shortcomings in quality management at the North complex means that only medicines which are absolutely essential to meet patients' needs can be used and which are currently not available from another source. A lower level of risk applies to products for which terminal sterilisation is in place.

For Caelyx, for which Ben Venue is the only manufacturing source, the CHMP considers the product to be essential only for patients already on treatment. It recommended that supplies should be available to maintain these patients on Caelyx but no new patients should be started on treatment with Caelyx until further notice. The CHMP advised that healthcare professionals should monitor treated patients intensively and immediately notify any relevant safety concerns that could be evidence of a quality assurance problem (particularly any cases of sepsis or suspected sepsis, such as acute pyrexia). The marketing authorisation holder, Janssen, has been asked to circulate a communication to healthcare professionals to reinforce these messages, requesting them to enhance monitoring and report any suspected adverse reaction or complaints that could be evidence of a quality assurance problem with the aseptic filling process. The CHMP will review the situation on a continuous basis.

The CHMP considers the supply of Busilvex, Velcade and Vidaza from Ben Venue no longer essential, as alternative manufacturers are currently supplying the EU market. In addition, recalling batches of these medicines supplied by Ben Venue would not lead to product shortages. Therefore, the CHMP recommends the recall from the EU market of batches manufactured at Ben Venue for Busilvex, Velcade, and Vidaza as a precautionary measure.

The CHMP concluded that remaining supplies of Vistide, from Ben Venue, can continue to be used as this product is terminally sterilised. Alternative manufacturers of Vistide are now supplying the EU.

For each product the CHMP considered whether supply from Ben Venue remained essential to meet clinical needs, whether alternative treatment options were available, the state of current EU stock levels, the possibility of sourcing the product from alternative manufacturing sites, and whether the product is aseptically produced or terminally sterilised. The Committee noted that, to date, there have been no complaints or reports of adverse reactions brought to its attention which would indicate a lack of quality assurance associated with batches manufactured at the North facility. However, the CHMP nevertheless considered that there is a potential risk of product contamination, necessitating the interim measures described above.

The inspection process and the review for all centrally authorised medicines manufactured at the Ben Venue Laboratories plant is still ongoing and the Agency will make further updates as appropriate.


  • The November 2011 inspection of the Ben Venue Laboratories manufacturing site was conducted by the Medicines and Healthcare Products Regulatory Agency (MHRA) and the Agence française de sécurité sanitaire des produits de santé (AFSSAPS) as a follow-up to a previous inspection conducted in March 2011 that had been triggered by the European Medicines Agency as part of a re-inspection program. This inspection had already led to the restriction in the importation of some medicines to the EU from the Ben Venue site.
  • The European review of the centrally authorised medicines Angiox, Busilvex, Caelyx, Cayston, Ceplene, Ecalta, Luminity, Mepact, Soliris, Torisel, Velcade, Vibativ, Vidaza and Vistide, manufactured at the Ben Venue site in Ohio, is being conducted in the context of a formal review, initiated at the request of the European Commission under Article 20 of Regulation (EC) No 726/2004, on 17 November 2011. More information on these medicines can be found in the relevant European public assessment reports (EPARs).
  • The Agency is working closely with international regulatory partners and in particular the FDA, the Therapeutic Goods Administration and Health Canada, in order to coordinate actions to address the GMP deficiencies at Ben Venue Laboratories manufacturing site and to share information on the impact of these quality findings for the global product supply.

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