European Medicines Agency recommends transfer of manufacturing site for doxorubicin hydrochloride intended for the EU market
No new patients should be started and Caelyx manufactured at Ben Venue Laboratories should only be used to complete treatment that has already been initiated
- Date : 28 Mar 2012
- Topic : Anticancer agents & Biologic therapy
The European Medicines Agency has recommended that the manufacturing processes for the anticancer medicine Caelyx (doxorubicin hydrochloride) should be transferred from the Ben Venue Laboratories in Ohio, United States, to alternative facilities. While the transfers are ongoing, the Agency’s Committee for Medicinal Products for Human Use (CHMP) is recommending that the marketing authorisation of this medicine should be maintained because it is considered as essential for patients and no alternative suppliers or alternative formulations are currently available. The Committee also considered the fact that no concerns have been raised from the safety monitoring of this medicine. During this time, Caelyx will continue to be manufactured at the Ben Venue facility, because it is the only site where it is made for the European Union (EU) market. In the meantime, the Agency is recommending that the interim measures introduced in November and December 2011 should be continued.
For Caelyx, no new patients should be started on the medicine and Caelyx manufactured at Ben Venue should only be used to complete treatment that has already been initiated. This recommendation remains valid until the sterile filtration and aseptic filling processes have been transferred to a new manufacturing site and supply can be guaranteed from this site. This should be completed by September 2012. Following this, the marketing-authorisation holder, Janssen-Cilag International NV, should transfer the remaining steps in the manufacturing process to a new site by the end of 2014.
Whilst stocks from Ben Venue are still being used in the EU, the marketing authorisation holder of Caelyx is required to promptly inform the CHMP if they become aware of safety concerns, and submit a monthly report detailing reports on effects that could be related to sterilisation problems, such as sepsis. Healthcare professionals should monitor patients closely for such effects and report them immediately to the company.
A good-manufacturing-practice inspection revealed several shortcomings in quality-assurance processes
The review of medicines manufactured at Ben Venue Laboratories began in November 2011, after a good-manufacturing-practice (GMP) inspection revealed several shortcomings in its quality-assurance processes. These included concerns over the sterility of the filling process and possible contamination with particles.
A joint GMP inspection of the site by the United Kingdom and French medicines regulatory agencies together with the United States Food and Drug Administration 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. This inspection was 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 programme. The March inspection had already led to the restriction in the importation of some medicines to the EU from the Ben Venue site. During the November 2011 inspection, Ben Venue decided to cease all manufacture and distribution of medicines from its site.
The Agency’s CHMP, at the request of the European Commission, reviewed all centrally authorised medicines that are manufactured at this 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.
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 considered 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. Despite these concerns, no safety issues have emerged from monitoring of patients receiving Caelyx, or any other centrally authorised medicines manufactured at the facility.
Recall from the EU market
In November 2011, the CHMP considered 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.
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