Manufacturing Misery in Vaccines

In 2008, a report published by an economics professor at Johns Hopkins University, in partnership with the Association of British Pharmaceutical Industry and the UK Vaccines Industry Group, predicted that the vaccines sector had the potential to enter a new golden era (1). The early part of the 20^th century had seen vaccines play a major role in combatting infectious diseases, but since the 1970s, cost pressures, mergers between companies, production setbacks and a series of high-profile liability cases have led to many manufacturers abandoning this area in favour of more profitable alternatives.

Nathan Jessop

Production perils

The potential for manufacturing issues to severely disrupt operations remains a constant headache for vaccine manufacturers. In Europe, several major manufacturers experienced such problems during 2012.

In October 2012, several EU member states suspended the use of some anti-influenza vaccines manufactured by Novartis because of suspected quality defects. Although there was no evidence of the problems impacting efficacy and safety, the authorities acted as a precautionary measure. The Italian Medicines Agency was the first to act over Novartis' Aggripal, Fluad and Influpozzi products when it received a verbal notification from Novartis. The agency subsequently warned other member states, the European Commission and the European Medicines Agency (EMA). Although Novartis provided the Italian authorities with data it believed supported the high quality, efficacy and safety of their products, other countries followed Italy's lead in banning the products (2–5). Reports of protein particulates in some vials were enough to persuade France, Austria, Germany, Spain and Switzerland to act. Canada and Singapore also followed suit.

According to Novartis, the particulates reported in the vials were all "normal and necessary components" of their influenza vaccines and that the aggregation of these proteins was not considered unusual in terms of vaccines manufacturing (6). Furthermore, Novartis stated that clinical data demonstrated similar safety and immunogenicity profiles to prior years for these products. Additional data from the ongoing seasonal vaccination campaign in Europe had also not revealed any safety signals. Nevertheless, the Italian authorities sought an explanation from Novartis as to why it had taken until October to inform them of the particulate issues, despite the company identifying such problems in July (7).

The manufacturing issues have not only proven to be damaging to Novartis' reputation, but may also represent a new financial setback for the company's vaccines unit. The unit has been underperforming financially since 2010, when it had revenues of $2.9 billion (2). In 2011, reports claimed that the company had made a $249 million operating loss on $2 billion in revenue. The 2012 manufacturing issues will inevitably dampen prospects of surpassing 2010's revenue.

The influenza vaccine manufacturing issue has led to concerns that there will be a shortage of influenza vaccines this coming winter in the UK, Germany, Switzerland and Italy, although most governments should have alternative sources and strategic reserves in place. Germany, for example, has turned to GlaxoSmithKline and Abbott to help make up any shortfall, and predictions from the German Health Ministry suggest that the number of available flu vaccines available in Germany will be 14 million, which is comparable to 2011 (5). Despite these reassurances, disruptions tend to cause controversy between governments, pharmaceutical companies and healthcare professionals about why vaccine shortages occur in the first place. With respect to the situation in Germany, pharmaceutical companies and some physicians have blamed insurance companies, whom they claim negotiate exclusive contracts with vaccine manufacturers in exchange for better rates, which puts patients at risk (5).

Other vaccine disruptions

In October 2012, Crucell, which is based in the Netherlands and provides approximately 10% of the UK's influenza vaccine stock, halted production after discovering problems with two of its product batches. The company has stated that it is continuing to conduct quality tests before releasing any more vaccine, although it has not recalled any of the stocks that have already been distributed. The manufacturing issues at Crucell are particularly frustrating for Johnson & Johnson, which finalised acquisition of the company in 2011 for $2.4 billion, with the aim of accessing the global vaccines market. The acquisition was Johnson & Johnson's largest since 2006, when it took over Pfizer's consumer unit for $16.6 billion. For now, Johnson & Johnson will be preoccupied with resolving the manufacturing issues and reassuring their existing vaccine clients before the company can pursue its intended ambitious growth plans in the sector.

Another company that has recently suffered vaccine manufacturing issues, although not for anti-influenza products, is GlaxoSmithKline. In October 2012, the company cooperated with Australia's Therapeutic Goods Administration for a voluntarily recall of six batches of Infanrix hexa, a vaccine product used to prevent diphtheria, tetanus, pertussis (whooping cough), hepatitis B, poliomyelitis (polio) and Haemophilus influenzae type b (Hib). Testing had revealed low-level contamination in certain batches dispatched between August 2011 and January 2012, although the company stressed that no reported adverse events had been directly linked to this issue. Later in October, the company recalled a single lot of the same vaccine in Canada, citing potential microbial contamination, but continuing to state that it was purely a precautionary measure (8). In November 2012, GlaxoSmithKline confirmed that the affected batches had originated from its plant in Rixensart, Belgium (9). Potential microbiological contamination had been identified in the environment where bulk antigens for some of its Infanrix Hexa, Infanrix-IPV and Infanrix- IPV/Hib vaccines were placed, but release tests (including sterility tests) on intermediates and on the final containers led to the conclusion that the final products released from the facility had not been contaminated (8). The company continues to resolve the issue, but the recall of these products may have an impact in up to 20 countries. As well as many EU Member States, countries such as Lebanon, Malaysia, Qatar, Brazil and Vietnam may be affected by short supplies of the vaccine (9).

Future

Vaccines are essential to combat a range of disease threats and the migration of companies out of the sector has worried health agencies worldwide. Efforts have been made to stimulate renewed industry interest and persuade companies that it is an ideal opportunity for them to harness scientific advances made in genetics and biotechnology. There are signs that these factors are persuading some companies to increase their activities in the vaccines sector, but as recent experience shows, manufacturers face considerable technical challenges. After a troublesome last quarter of 2012, Novartis now appears to be on the verge of resolving the manufacturing issues it has faced with its influenza vaccines. Canada and Switzerland lifted their bans in late October, followed by Singapore and then Italy in the first part of November. However, the company still needs to work with authorities in other countries to allow supplies to resume. For other companies, such as Crucell and GlaxoSmithKline, efforts to restore confidence in their vaccine expertise look likely to continue through 2013.

References

1. L. Galambos, What are the Prospects for a New Golden Era in Vaccines? (UK Vaccines Group, UK, 2008).

2. Pharmaletter website, "Novartis' flu vaccines suspended in several countries on suspected quality issues", www.thepharmaletter.com, accessed 12 Dec., 2012.

3. Fiercepharma website, "Italy bans Novartis vaccines even after company assures their safety", www.fiercepharma.com, accessed 12 Dec., 2012.

4. Reuters website, "France halts sale of Novartis flu vaccine", http://uk.reuters.com, accessed 12 Dec., 2012.

5. Deutsche Welle website, "Germany moves to cut off vaccine shortage", www.dw.de, accessed 12 Dec., 2012.

6. The Globe and Mail website, "Canada suspends distribution of Novartis flu shots", www.theglobeandmail.com, accessed 12 Dec., 2012.

7. Fiercepharma website, "Novartis plant delay, vaccine woes steal spotlight", www.fiercepharma.com, accessed 12 Dec., 2012.

8. Health Canada website, "Health Canada Endorsed Important Safety Information on Infanrix Hexa", www.hc-sc.gc.ca, accessed 12 Dec., 2012.

9. In-pharmatechnologist website, "GSK pulls vaccine batch in Canada over contamination concerns", www.in-pharmatechnologist.com, accessed 12 Dec., 2012.