Medicine withholds and recalls are announced for critically defective medicines as a result of reports or complaints on the quality, safety or efficacy of a medicine that may pose threats to patient health, either voluntarily by manufacturers or market authorization holders or by regulatory authorities [31]. NMRA, the central authority for medicines regulation in Sri Lanka, launched its official online safety alert reporting system in 2018 which created an important communication tool between the manufacturers, health care professionals, and the public [25]. This decisive move led to improve the transparency of defective medicine reporting mechanism and on the other hand, it raises awareness among all stakeholders to be cautious in order to prevent recurrence of similar episodes in future. Furthermore, an understanding of different types of defects, prevalence, pharmaceutical dosage forms and therapeutic categories is important to monitor and prevent the inflow of such medicines into the market. Therefore, to determine the trends in reported defective medicines, we retrospectively reviewed the safety alerts on medicine withholds and recalls.
According to WHO, the prevalence of SM and FM is increasing worldwide, however, the relative contribution of the two sources is unknown [3]. It is assumed that developed countries with well-structured regulatory systems can be effectively excluded from this issue which is not the case. Studies from High-Income Countries (HIC) such as the UK [8], Canada [9], the USA [13, 24], and Saudi Arabia [18] have shown that the availability of SM is common. Moreover, Almuzaini T. et al., reported that ‘the problem of defective medicines reported in the UK has increased 10-fold over the 10 years from 2001 to 2011’ [8], while a Canadian study also revealed an increasing trend of recall of SM over nine consecutive years, from 2005 to 2013 [9].
However, the burden is much more on LMICs due the lack of resources including infrastructure and trained personnel to assure the quality of medicines, weak technical capacity, lack of good governance and poor supply chain management [32–34]. Recent systematic reviews also showed that SM are a significant problem in Africa and Asia [4, 34]. Consistent findings have been reported from developing countries such as India, Mongolia, and other countries. A review article by Gautam et al., stated that fake medicines accounted for 13% − 30% of the pharmaceutical market in India [5]. Pharmaceutical analysis study from seven countries of Africa and Asia reported that 21 medicines were SM out of 869 medicine samples [33]. Another pharmacopoeial analysis study conducted on collected essential medicines from pharmacy outlets in Mongolia, found that 10.1% of the total samples were substandard [35].
The current study results indicate a total of 163 defects in 143 defective medicines, of which 17 had been recalled or withheld due to multiple defects in consistent with findings from other studies conducted internationally examining on medicine recalls. Different frequencies of defective medicines such as 653, 280, 195 and 84 were reported from Canada [9], the UK [8], the USA [13] and Saudi Arabia [18] respectively. However, it should be noted that it is not possible to compare the compatibility of findings from this study with other international studies due to the difference in study periods. In spite of the frequencies reported, they defective medicines remain a challenge and pose serious negative consequences. Although it is not possible to quantify the clinical outcomes precisely, they can prolong illness and inconvenience, cause drug resistance, and resulting in financial losses [32].
In this study, the most frequently reported type of defect was contamination (36.2%). This finding is compatible with studies conducted by Almuzaini T et al [8]., AlQuadeib et al.,[18], and Freeman et al.,[24]. Results demonstrated that contamination continues to be challenging in the manufacturing process of medicines, which needs to be addressed promptly. Stability defects (25.2%) and API defects (15.9%) were also at considerable amounts, which have the potential to affect the bioavailability of the active ingredients in the systemic circulation, and in turn, leading to therapeutic failure. However, in the Canadian study reported by Almuzani T et al., the most frequent type of defect was stability issues (32%).
Parenteral preparations (44%) were found to be routinely reported as defective, which is consistent with results of a study conducted in the UK [8]. There is a serious threat to patient safety with defective parenteral preparations as they enter systemic circulation directly. It was observed that anti-infectives (42.5%) were the most reported therapeutic group in this study. In the case of anti-infectives, development of drug resistance is a major threat. Kelesidis and colleagues, have also documented that antibiotic and antiparasitic medicines appear far more likely to be substandard than the other medicines [36]. Further, they stated that antibiotics are more susceptible to degradation while transporting or storing at temperatures above 25°C with high humidity, therefore stability issues can occur in the tropical climate under real storage conditions (in warehouses or some wholesale pharmacies) [36]. Sri Lanka falls under the Climatic Zone IVb, as per categorization by WHO Expert Committee on Specifications for Pharmaceutical Preparations, which medicines are expected to be tested for stability at 30°C/75% relative humidity levels [37]. Therefore, the storage condition must be tested accordingly and maintained throughout the shelf life to prevent from deterioration.
Pharmaceutical industries and state authorities focus and devote a plenty of resources to manufacture, import and maintain the quality, safety and efficacy of medicines. For example, according to the reports of Central Bank of Sri Lanka, Sri Lanka had imported USD 595.92 million worth of medical and pharmaceutical products (LKR 110,503 million: average exchange rate in 2020 was taken as LKR 185.4306) in the year 2020 [32]. Despite, results from this study revealed that most defective medicines were imported rather than locally manufactured, and some foreign manufacturers were accountable for repetitive withholds and recalls. In a similar study done in Nigeria by Beargie SM et al., estimated that poor quality anti-malarials are responsible for 12,300 deaths and $892 million ($890-$893 million) in costs annually [7]. Medicine withholds and recalls not only a threat to patient safety, but also, a very huge economic burden to LMICs like Sri Lanka providing free public healthcare services.
According to this study, the reporting of substandard medicines in Sri Lanka is on the rise. Therefore, quality risk assessment and root cause analysis need to be done according to prescribed guidelines. A favorable supply chain management plan would need to be set up, addressing reasons for medicine withholds and recalls by relevant authorities in Sri Lanka in recent times. In addition, reporting culture should be encouraged and barriers such as lack of awareness, overcomplicated reporting systems, lack of feedback mechanism from regulatory authorities need to be addressed and regulatory policies must be tightened. It is also recommended that manufacturers, importers, suppliers or market authorization holders should be held accountable for ensuring the quality of medicines through increased awareness, education, and sanctions.
To our knowledge this is the first review done on the issue of medicine withholds and recalls in Sri Lanka by assessing the safety alerts reported on NMRA website. Thus, this study provides an important insight into the regulatory policy and practice. However, the study was limited by several factors. It should be acknowledged that an in-depth analysis was not possible as there has been no any information published about the reporter, consequences or clinical significance and the action taken following the recall or withdrawal.