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An Analysis of Substandard Propofol Detected in Use in Zambian Anesthesia

Mumphansha, Hazel, MBChB*; Nickerson, Jason W., PhD; Attaran, Amir, DPhil; Overton, Sean§; Curtis, Sharon, PhD§; Mayer, Paul, PhD§; Bould, M. Dylan, MBChB*‖

doi: 10.1213/ANE.0000000000002226
Global Health: Original Clinical Research Report

BACKGROUND: In early 2015, clinicians throughout Zambia noted a range of unpredictable adverse events after the administration of propofol, including urticaria, bronchospasm, profound hypotension, and most predictably an inadequate depth of anesthesia. Suspecting that the propofol itself may have been substandard, samples were procured and sent for testing.

METHODS: Three vials from 2 different batches were analyzed using gas chromatography-mass spectrometry methods at the John L. Holmes Mass Spectrometry Facility.

RESULTS: Laboratory gas chromatography-mass spectrometry analysis determined that, although all vials contained propofol, its concentration differed between samples and in all cases was well below the stated quantity. Two vials from 1 batch contained only 44% ± 11% and 54% ± 12% of the stated quantity, whereas the third vial from a second batch contained only 57% ± 9%. The analysis found that there were no hexane-soluble impurities in the samples.

CONCLUSIONS: None of the analyzed vials contained the stated amount of propofol; however, our analysis did not detect additional contaminants that would explain the adverse events reported by clinicians. Our results confirm the presence of substandard propofol in Zambia; however, anecdotal accounts of substandard anesthetic medicines in other countries abound and warrant further investigation to provide estimates of the prevalence and scope of this global problem.

From the *Department of Anaesthesia, University Teaching Hospital, Lusaka, Zambia; Bruyère Research Institute, Ottawa, Ontario, Canada; Faculty of Law, University of Ottawa, Ottawa, Ontario, Canada; §John L. Holmes Mass Spectrometry Facility, Department of Chemistry and Biomolecular Sciences, University of Ottawa, Ottawa, Canada; and Anesthesiology and Pain Medicine, Children’s Hospital of Eastern Ontario, University of Ottawa, Ottawa, Canada.

Accepted for publication April 3, 2017.

Funding: None.

The authors declare no conflicts of interest.

Reprints will not be available from the authors.

Address correspondence to Jason W. Nickerson, PhD, Bruyère Research Institute, 85 Primrose Ave, Room 308-B, Ottawa, Ontario K1R 6M1, Canada. Address e-mail to jason@jasonnickerson.ca.

For approximately 6 months in 2015, anesthesia providers at hospitals throughout Zambia noted the occurrence of adverse events following the administration of 1 particular brand of propofol: Unimed Propofol Injection British Pharmacopoeia, 1% w/v (10 mg/mL), a sterile emulsion for intravenous anesthesia marketed by Unimed Pharmaceuticals Ltd (Kent, UK) and manufactured by Kwality Pharmaceuticals Ltd (Amritsar, India) (Figure 1). These incidents were noted at the University Teaching Hospital (UTH) in Lusaka, Zambia, and comprised a range of unpredictable adverse events including urticaria, bronchospasm, and profound hypotension including the requirement to begin chest compressions (Dr Feruza Ismailova, Head of Department of Anaesthesia, UTH, personal communication, February 2016). Most predictably, the propofol appeared to result in inadequate depth of anesthesia after the administration of an appropriate dose of intravenous propofol. That is, patients failed to become unresponsive to simple airway maneuvers such as a jaw thrust that would allow placement of airway devices such as a laryngeal mask (Drs Suzyo Musamara and Dr Zubair Rakhda, anesthesia residents at UTH, personal communication, February 2016). Anecdotally, some vials of the propofol appeared to have an unusual “creamy” yellow-green tint to them, and these seemed to cause more of the unpredictable side effects.

Figure 1

Figure 1

Concerns about this particular brand of propofol had been reported to the Zambia Medical Regulations Authority, through the standard pharmacovigilance form (Mr Chikatula, head of pharmacy at UTH, personal communication, February 2016) but this brand of propofol remained in circulation and in clinical use nationally in Zambia for a further 6 months (Mr Wisdom Chelu, National Anaesthesia Coordinator for Zambia, personal communication, February 2016). This preparation of propofol had been bought in bulk by the Zambian Ministry of Health and was packaged with a Ministry of Health logo (Dr Lishimpi, Director of Clinical Care and Diagnostic Services at the Zambian Ministry of Health, personal communication, February 2016).

With an ongoing concern that the quality of the Unimed propofol used may have been a contributing factor in the reported adverse events, samples were procured and sent for testing at the John L. Holmes Mass Spectrometry Facility in Ottawa, Canada to quantify the amount of the active pharmaceutical ingredient (propofol) present in the vials, and to attempt to identify any excipients or contaminants present that may have contributed to the noted adverse events. These included synthetic byproducts, degradation products, and anything soluble in the hexane solvent used to extract propofol from the samples. Samples from 2 different batches of the questionable propofol were procured in Lusaka, Zambia on September 25, 2015 and were stored according to the manufacturer’s recommendations from the time of acquisition by the investigators. A total of 3 vials were analyzed (2 vials from 1 batch N-2932, and a single vial from another N-3655). As a control, the Unimed propofol was compared to a Canadian sample of Pms-propofol, marketed and manufactured by Pharmascience Inc, (Montreal, Canada). All samples were unexpired at the time of analysis. We note that we are unable to comment on the supply chain or storage of the propofol at any time before collection of these samples.

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METHODS

Extraction

A total of 1.5 mL was removed from the pharmaceutical vial and 3 aliquots of 0.5 mL were transferred to 3 separate preweighed 1.5-mL Eppendorf microcentrifuge vials then weighed again. Aliquots of 10% (v/v) of pure propofol analytical standard in hexane were added to the vials in volumes of 0, 50, and 100 µL, respectively. Hexane was added to bring total volume to 1 mL. Samples were shaken for 20 minutes. Samples were centrifuged at a temperature of 4°C and a rate of 10,000 rpm for 15 minutes. The organic top layer was transferred to separate 1.5-mL vials marked 1, 2, and 3 and 0.5 mL of fresh hexane was added to each aqueous layer. Samples were shaken for 10 minutes. Samples were centrifuged at a temperature of 4°C and a rate of 10,000 rpm for 15 minutes. The organic top layer was transferred to the vials marked 1, 2, and 3. Samples were diluted 10% and then run via gas chromatography-mass spectrometry (GC-MS).

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Gas Chromatography-Mass Spectrometry

GC-MS analysis was done on an Agilent 7820A Gas Chromatography Instrument with a wax column, coupled with an Agilent 5975 MS Detector. A total of 1 µL of sample was injected into the inlet which was heated to 250°C. The oven originally at 40°C was heated at a gradient of 8°C/min to a maximum of 220°C. Samples were analyzed in triplicate to derive the reported uncertainties.

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RESULTS

Qualitative

Samples seemed similar in color after visual inspection—no sample had the unusual “creamy” green-yellow tint that had been described to be found in some of the Unimed propofol that had been in circulation at UTH. The physical properties (ie, layer viscosity or hardness) of the fatty layer formed after the centrifugation was different for the Pharmascience and the Unimed formulations, indicating that the oil composition was different for the 2 samples. The Unimed vials had a greater resistance to oxidation than the Pharmascience equivalents, possibly due to an impurity that acts as an antioxidant.

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GC-MS Results

Figure 2

Figure 2

Figure 3

Figure 3

The chromatograms for the Unimed and Pharmascience Propofol emulsions were identical (Figure 2), each showing a single peak at 11.2 minutes. This component was confirmed to be propofol in both cases by comparison of the mass spectra with that in the Wiley mass spectrometry database (Figure 3). The presence of only 1 peak indicates that there were no chemically similar impurities in the samples. Although all the analyzed medicines contained propofol, its concentration was found to differ between samples. The 2 vials from batch N-2932 contained only 44% and 54% (±11% and 12%, respectively) of the stated quantity, while the third vial from batch N-3655 contained only 57% (±9%). In sum, none of the Unimed products contained the stated amount of propofol.

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DISCUSSION

The British Pharmacopoeia states that the propofol content should be within 95.0% and 105.0% of the stated amount. The quantity of propofol found in the 3 vials relative to the labeled amount was 44%, 57%, and 54%, far from the stated amount, with the remainder seemingly comprising water and oils. Used clinically, such a gravely substandard product has the potential for serious consequences resulting from inadequate anesthesia including awareness, coughing, or moving during surgery, breath-holding, laryngospasm, and difficult direct laryngoscopy, intubation, or laryngeal mask placement due to high airway tone. Depending on the medical procedure in which these occur, injury or death could foreseeably result. To our knowledge, this is the first published report of evidence of substandard medications in anesthesia. We note that we do not have data that allows us to comment on the cause of this substandard medication, because we have no information on the supply chain and storage of this drug before we collected our samples.

To avoid harm to patients, we notified the World Health Organization’s Substandard, Falsified and Counterfeit Surveillance and Monitoring department as well as the Zambian Ministry of Health of our findings promptly, in February 2016. At the time of submission, 8 months later, their investigation (including additional laboratory analysis) was still underway. Following notification of our results, Unimed propofol was removed from circulation by the Ministry of Health. Propofol, like other essential medicines, plays a unique role in the provision of safe anesthetic care. In particular, there was a shortage of thiopentone in Zambia at this time, and although ketamine was widely available as an intravenous induction agent, the latter drug is certainly not an ideal agent for induction of anesthesia in all cases. For this reason, anesthesia providers are faced with an impossible decision: remove and reject all the propofol from operating theaters and, consequently, eliminate perhaps the most commonly used anesthetic medicine from clinical practice, or risk administering a dangerous formulation. Forcing health professionals to make this decision is clearly not in the best interest of patients nor public health and does little to build confidence in the quality of health systems. The only solution is developing a comprehensive understanding of the anesthetic medicine market and supply chains and effectively regulating it.

Our results are insufficiently powered to suggest the scale or extent to which substandard anesthesia and perioperative medicines are affected, given that our analysis consists of only 3 vials of propofol that were selected based on reported problems. However, we believe that this case report constitutes the first quantitative evidence that a problem with anesthetic medicine quality exists. We note, however, that anecdotal accounts of poor-quality anesthetics have existed for years, although we are unaware of these claims or rumors having been substantiated or quantified.1

Unlike most other substandard medicines, the presence of an anesthetic containing subtherapeutic quantities of the active pharmaceutical ingredient is more likely to be detected at the point of use, because the intended effect of an anesthetic is rapid, visible, and obvious: either the medicine produces anesthesia as it should, or it does not, and there is little to confound that observation. What this study proves is that for anesthetics, anecdotal observations of poor drug quality deserve credence, because the formulation of propofol in question that was clinically suspect was confirmed upon laboratory analysis to be grievously substandard. Given the analysis presented here and other anecdotal observations of poor-quality anesthetic medicines, there is a clear need for further investigations of the kind we performed, but with larger sample sizes representative of the anesthetic medicine market. Because no robust studies of anesthetic medicine supply chains within health systems have been conducted,2 relatively little is known about the prevalence of poor-quality anesthetic or analgesic medicines in use beyond anecdotal and ad hoc reports. A 2015 alert from the World Health Organization identified falsified diazepam tablets circulating in the Democratic Republic of the Congo which contained no diazepam, but rather 25 mg of haloperidol,3 and reports of poor-quality anesthetic medicines have been anecdotally documented online4 and by researchers,5 with harms ranging from the predictable (a lack of surgical anesthesia and awareness during surgery) to the unpredictable (including atropine-like effects). The common issue in these poor-quality anesthetics is, regrettably, that they all stand to cause harm to patients, as we report here and in previous analyses of other medicines.6

It should not be surprising, unfortunately, that substandard anesthetics exist in Zambia given their prevalence throughout sub-Saharan Africa and other world regions. When there are substandard medical products on the market in other therapeutic areas, there is little reason to suspect that the anesthetic medicine supply chain would not be similarly affected. Nor can it be assumed that the laws and law enforcement that are insufficient to interdict one kind of substandard therapy would not fail for others too. Where prevalence data do exist, there is considerable cause for alarm: a meta-analysis of high-quality studies examining antimalarials in Asia and Africa found that 35% of the medicines sampled were substandard and 20% and 36% of the medicines from sub-Saharan Africa and Asia, respectively, were classified as falsified, defined as having been fraudulently manufactured with no, or the wrong, active pharmaceutical ingredient.7 If the prevalence of poor quality or falsified anesthetics is comparable to other therapeutic areas, this signals a significant weakness that must be addressed to reliably improve access to safe and effective anesthetic and surgical care.

Of course, further studies are needed to understand whether substandard anesthetics prevail in other African and low- and middle-income countries. Relatively little has been documented concerning anesthetic and analgesic medicine supply chains in those settings, except that the barriers to accessing many of these medicines are complex and exist at multiple levels, exacerbated by the onerous national and international controls that the “war on drugs” has placed on narcotic and psychotropic medicines.8 , 9 Beyond this, there is a need to understand other possible failures in the anesthetic medicine supply chain that could contribute to medicine degradation. Temperature, exposure to sunlight, and other environmental variables may be relevant factors outside the manufacturing process that could contribute to inadequate amounts of active ingredient in medicines, for example (however, no known degradation byproducts were observed in the analyses performed in this study). Previous studies of medicines that are sensitive to environmental conditions, such as uterotonic medicines, have identified storage as a possible contributing factor in poor-quality medicines.10 A 2012 study of 185 samples of injectable oxytocin and 118 samples of ergometrine injectables and tablets by the Ghanaian Food and Drug Administration found that almost all the injectables were stored improperly, outside the recommended storage conditions.11 Furthermore, the recommended storage conditions on over half of the sampled Ghanaian products were not consistent with the recommendations of either the United States Pharmacopeia or the British Pharmacopeia. To fully understand the barriers to accessing high-quality anesthetic medicines, an analysis of supply chains, including storage facilities and processes, is necessary. Absent this, a critical element for scaling up access to high-quality anesthetic care remains poorly understood.

Our results serve as a warning that poor-quality medicines with the potential to harm patients exist on international markets. Further work must be done not just to identify, intercept, and combat these potentially lethal medicines before they reach patients, but also to understand the policies that influence the availability of anesthetic and analgesics.

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DISCLOSURES

Name: Hazel Mumphansha, MBChB.

Contribution: This author helped with data collection, suspect medicine identification, and editing of the article.

Name: Jason W. Nickerson, PhD.

Contribution: This author helped with interpretation of the results, wrote the first draft of the article.

Name: Amir Attaran, DPhil.

Contribution: This author helped with interpretation of the results, editing of the article.

Name: Sean Overton.

Contribution: This author helped conducted laboratory analysis, interpretation of the results, and editing of the article.

Name: Sharon Curtis, PhD.

Contribution: This author helped conducted laboratory analysis, interpretation of the results, and editing of the article.

Name: Paul Mayer, PhD.

Contribution: This author helped conducted laboratory analysis, interpretation of the results, and editing of the article.

Name: M. Dylan Bould, MBChB.

Contribution: This author helped with data collection, suspect medicine identification, and editing of the article.

This manuscript was handled by: Angela Enright, MB, FRCPC.

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REFERENCES

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