The extent of adverse consequences that can arise from failure to comply with manufacturing requirements, together however, cannot be ignored. This was evident from the death of 120 patients in Pakistan due to contamination

of isosorbide mononitrate tablets with large doses of an antimalarial drug.16 Another of the most pronounced examples is the phenobarbital and morphine tablet recalls in Canada. Oversized tablets (ie, tablets that exceed the weight requirement) were found in both drugs, raising the risk of the patients taking as much as double the strength stated on the bottle (table 3). The Institute for Safe Medication Practices (ISMP), a non-profit organisation, stated that the US manufacturer (KV Pharmaceutical) received abnormally high reports of serious adverse events concerning overdose of these recalled tablets.17 However, owing to the lack of sufficient details, it was impossible to link the overdose events specifically to the substandard tablets. The adverse events relating to this defect have not been documented by Health Canada. It was uncertain whether the rise of substandard medicines incidents were related to improved detection by Health Canada or due to an increase of substandard

medicine production by manufacturers. The rate of increased incidence of substandard medicines could be associated with the implementation of improved detection policies and regulations by Health Canada. Introduction of Good Manufacturing Practices (GMP) inspection policy for Canadian drug establishments may be one of the explanations.18 Since 1996, there have been numerous changes in GMP guidelines and international agreements. These led Health Canada to update its policy on GMP inspection in January 2008 as a response to harmonise its GMP compliance programme with drug regulatory authorities in other countries.18 Subsequently, there has been a steady increase of incidents of substandard medicines from 2008

to 2013 (figure 2). Similarly, it has been highlighted that most of the FDA recalls were related to FDA inspectors’ visits in the USA.19 The GMP policy illustrates the procedures Health Canada follows to ensure that all drug establishments comply with GMP guidelines. This is conducted via inspections with varying cycles according to a risk-based approach to assess complaints about medicines, Cilengitide and a ranking scale of priority.18 This assessment is to ensure that these complaints are dealt with in a timely manner. The performance of Health Canada in using the risk-based approach, however, was criticised in the 2011 report of the Auditor General of Canada.20 Based on a representative sample (50) of the files that Health Canada received in 2009 and 2010 concerning drug-related complaints, only 27 were dealt with according to the established risk-based standard operating procedures for prioritising reported complaints.