The Lancet Oncology, Volume 9, Issue 6, Page 503, June 2008
On April 23, 2008, the Philadelphia Inquirer obtained and posted on their website the official report of the US Food and Drug Administration’s (FDA) inspection of Merck’s manufacturing facility in Montgomery County (PA, USA). The report detailed a catalogue of 49 separate failures over the past 2 years in processes that affect the quality and sterility of vaccines produced at the factory, including the new quadrivalent Human papillomavirus (HPV) vaccine (Gardasil). Because the HPV vaccine is given prophylactically to children and adolescents, the vaccine has to be safe, and perceived to be so by the general public, if there is to be widespread uptake of the vaccine.
The process failures at the facility include sterility issues, equipment maintenance and sanitation, data recording, packaging, and quality control. Specific failures associated with the manufacture of the HPV vaccine were leaks in the production line that fills vials with the vaccine and leaks in syringes dispensing the vaccine—both of which could cause contamination. The FDA report also criticised Merck for failing to re-inspect batches of the HPV vaccine that have caused serious adverse reactions. However, perhaps more alarmingly, the document notes Merck’s failure to correct defects in their processes.
Each time a pharmaceutical company detects an issue arising during the manufacturing process, the company is obliged to file a report with the FDA, who then investigate and provide recommendations on how to improve the process in an Atypical Process Report (APR). After the APR has been logged, the FDA allows 30 days for the issue to be corrected. On several occasions Merck did not meet this deadline—indeed, one APR took 18 months to rectify. No single finding in the report was sufficient to trigger a recall of the HPV vaccine or a suspension of production. However, the fact that there are so many issues that are not being rectified in a timely manner suggests both a systematic failure of process and that the FDA’s advice and financial penalties are insufficient.
Women with cervical cancer have a 5-year survival of 68%. This survival is mainly due to cervical screening programmes that detect the early precursors of cervical cancer at a treatable stage. However, there is still room for improvement, and the HPV vaccine will decrease the number of women who develop cervical cancer and will be especially useful for those individuals who have limited or no access to screening or effective treatment. As the vaccine is rolled out first to girls, and eventually to boys, public trust in the vaccine is paramount. However, worryingly, in a 2008 study of 2817 girls published in the British Medical Journal, 20% of parents did not return the consent form, and 8% refused consent for their child to be immunised with the HPV vaccine. The reasons behind the withheld consent in this study are unclear, but with some parents already cautious about consenting to their children having the HPV vaccine on moral, ethical, or religious grounds, manufacturers cannot give parents any further reason, or excuse, to doubt a vaccine by providing a substandard product. We have seen, time and again, how fragile the public’s trust of vaccines is: 10 years ago, Andrew Wakefield suggested a link between the combined measles, mumps, and rubella (MMR) vaccine and autism—a claim many experts say was unfounded—yet the repercussions are still present today.
Contamination is not a new issue, but a common concern during vaccine production, which has affected the distribution of other vaccines. For example, the widespread distribution of the polio vaccine in the 1950s was blighted when the vaccine was found to contain SV40 (a carcinogenic simian virus), and indeed, other vaccines made in Merck’s Montgomery County factory have had to be withdrawn because of contamination. However, if the HPV vaccine was to have contamination issues that cause infections at the injection site or other serious adverse events, the implications and damage caused could be far-reaching in terms of vaccine uptake and efficacy. Because full immunity to HPV needs three doses at 0, 2, and 6 months, if patients have any toxic effects at the first or second injection, this could prove a major disincentive for the individual to return and finish the course.
Public confidence in vaccines has been heavily undermined in recent times, and is only now starting to show signs of recovery. Poor quality control in the production of the HPV vaccine could seriously hamper a major step forward in the prevention of cervical cancer. Inevitably, issues occur on a busy production line, but companies should ensure that they react quickly and decisively to resolve these issues and overhaul processes satisfactorily. Vaccination is a powerful intervention, but rigorous controls need to be put in place to prevent another vaccine scandal from further undermining public confidence.