European Medicines Agency finalises review of Baxter's dialysis solutions

New recommendations to ensure continued supply and quality assurance of manufacturing processes

The European Medicines Agency's Committee for Medicinal Products for Human Use (CHMP) has completed an investigation into the production processes at Baxter's manufacturing plant in Castlebar, Ireland. This follows the detection in December 2010 of endotoxins in dialysis solutions produced at the plant, which may have led to adverse reactions in some patients undergoing peritoneal dialysis.

The products affected include Dianeal, Extraneal and Nutrineal solutions for peritoneal dialysis; and Monosol and a sodium chloride solution for haemodialysis.

The CHMP has now finalised recommendations to ensure the continued supply of these dialysis solutions in the EU while quality-improvement measures are being put in place at Castlebar to ensure the production of endotoxin-free solutions.

The Agency was made aware of the presence of endotoxins in batches of the dialysis solutions Dianeal, Extraneal and Nutrineal made in the Castlebar plant in December 2010. At the time, Baxter identified endotoxin-producing bacteria in two tanks as the root cause of the problem and removed the tanks from the production line. It also cleaned the other tanks and pipework involved in the production.

Despite these measures, endotoxins were still detected in new batches of solutions produced at the plant, causing the manufacture of these solutions to be shut down at the plant.

Due to the lack of sufficient alternative sources for dialysis solutions, the CHMP could not recall all affected products from the Castlebar plant at that time. However, the Committee aimed to reduce reliance on the plant and made recommendations in January 2011 for the use of products imported from four production sites outside the EU (in Canada, USA, Singapore and Turkey). All affected products from Castlebar were eventually recalled in stages across the EU and the supply from Castlebar stopped.

The CHMP started the current review to investigate fully the issues related to the endotoxin contamination and to make recommendations to help protect public health and to prevent future supply shortages.

The CHMP concluded that the root cause of the presence of endotoxins in the affected production lines was a combination of factors: undetected cracks in equipment may have allowed the growth of bacteria, while the design of the plant and the cleaning methods used may have allowed the contamination to spread.

The CHMP noted that improvements are being made to the Castlebar plant to ensure future production of endotoxin-free dialysis solutions. These include redesign of the plant, new cleaning regimens and the introduction of improved testing methods. The Irish medicines agency will inspect the plant again in October 2011, after which it will go through a 12-month 'requalification period', where the plant will be carefully monitored and the products will undergo rigorous testing and increased surveillance. The corrective measures being made at Castlebar will also be applied to Baxter's other manufacturing sites.

The Committee also adopted a strategy to ensure adequate supply of these life-saving products in the EU should problems reoccur in the future. In order to facilitate this, the Committee had earlier during the investigation made recommendations to formally include the production sites in Canada, USA, Turkey and Poland in the products' marketing authorisations in Europe. Currently all dialysis solutions from Baxter for the EU supply are being manufactured in those sites.

Due to the measures taken, the CHMP is reassured about the quality of Baxter's dialysis fluids. Nevertheless healthcare professionals and patients should continue to report any symptoms that suggest the development of aseptic peritonitis (e.g. cloudy effluent seen in drain bag at the end of dialysis, abdominal pain, nausea, vomiting and possibly fever) and report any cases as soon as possible.

As part of the future risk management plan, the Committee adopted proposals for a period of intense monitoring of any reports of aseptic peritonitis during the initial months of marketing new products from Castlebar.

Notes

• The European review of Baxter's dialysis solutions was conducted in the context of a formal review, initiated at the request of the European Commission under Article 31 of Directive 2001/83/EC, as amended, on 18 January 2011.
• All other opinions and documents adopted by the CHMP at their September 2011 plenary meeting will be published on Friday, 23 September 2011 at 12.00 noon on a dedicated web page.