Abstract
INFARMED, the Portuguese national health authority, alerts the general public and health care professionals about quality or safety issues detected in health products. The present study analyses recalls of substandard medicines in Portugal between 2005 and 2015. All 338 alerts for medicine recalls were analysed, which represents a total of 378 drugs withdrawn. Despite the fact that the total number of medicine alerts has increased during the past decade, the number of actual medicine recalls remained relatively constant. The number of batches affected in each recall varies from only one to several batches. In addition, 294 of the alerts are related to voluntary recalls, that is, those initiated by the marketing authorisation holder, whereas only 40 were mandatory recalls. There are marketing authorisation holders that have had several medicine recalls over the period studied. The main cause of product recall was the pharmaceutical dosage form, followed by packaging problems. Forty-two percent of the withdrawn medicines are from solid oral forms, a value slightly higher than that obtained for the injectables group. Finally, substandard medicines have been accessible in the Portuguese market for a period that varied between one month and over four years. The data seem to show that the number of substandard medicines in Portugal has not been increasing. However, this may be due to a variety of causes, that is, better performance of the industry, non-detection of these cases, and so on.
LAY ABSTRACT: INFARMED, the Portuguese national health authority, alerts the general public and health care professionals about quality or safety issues detected in health products. The present study analyses market recalls of substandard medicines in Portugal between 2005 and 2015. All 338 alerts for medicine recalls were analysed, which represents a total of 378 drugs withdrawn. Despite the fact that the total number of medicine alerts has increased during the past decade, the number of actual medicine recalls has remained relatively constant. In addition, 294 of the alerts are related to voluntary recalls, that is, initiated by the marketing authorisation holder, whereas only 40 were mandatory recalls. There are marketing authorisation holders that have had several medicine recalls over the period studied. It was also found that substandard medicines have been accessible in the Portuguese market for a period that varied between 1 month and over 4 years. The data seem to show that the number of substandard medicines in Portugal has not been increasing. However, this may be due to a variety of causes, that is, better performance of the industry, non-detection of these cases, and so on.
Introduction
Substandard medicines are a major public health problem throughout medicine markets all over the world (1⇓–3). Substandard medicines are those that do not meet the legally required quality specifications defined by the regulatory authorities, following from an unintentional or negligent error (2, 4). Such medicines represent the greater part of the market recalls carried out by the pharmaceutical industry.
The present study analyses Portuguese market recalls of substandard medicines between 2005 and 2015. Exposure of the population to substandard medicines carries inherent risks. Furthermore, no similar analysis of the problem of defective medicines has been identified in this setting, despite there being a significant level of data available in the public domain.
Over the past decade, hundreds of medicine alerts have been issued by INFARMED, the Portuguese medicine regulatory agency. These alerts are classified into two categories—safety and quality—and include human and veterinary medicines, herbal and homeopathic medicines, medical devices, and cosmetics, among other health products (5).
Medicine recall alerts can be further divided into voluntary recalls, that is, those initiated by the marketing authorisation holder, and mandatory recalls, those INFARMED or another regulatory agency orders (5). While safety alerts refer to precautions that the user should consider when taking the medicine, quality alerts include a variety of situations that can compromise the quality of the health product, such as the detection of substandard or falsified medicines (5). Both types of alerts can be prompted either by national or international events (5).
The present paper focuses on market recalls of substandard medicines, relying for that purpose on the systematic analysis of all medicine quality alerts specifically related to medicine recalls. The choice of analysing medicinal products instead of other health products reflects the position of the latter in the total universe of regulated products, both because they are more numerous than others but also because they are subject of a greater number of the alerts issued.
Materials/Methods
To analyse medicine recalls in Portugal between 2005 and 2015, all medicine quality alerts issued by INFARMED and posted on their website during this period were reviewed. All quality alerts were counted, as well as medicine quality alerts and medicine recall alerts.
To support the analysis, a database was created, in Excel format, which is composed of 28 different items, of which the main are Original File Number, Issue Date, Drug Name and Dosage, Generic, Commercially Available, Market Authorization Status, Market Authorization Holder, Number of Batches Affected in Each Recall, Expiration Date, Shelf Life, Time on the Market, Pharmaceutical Dosage Form, Origin of the Problem (Quality Defect), Issuing Agency, Type of Recall—Voluntary/Mandatory, and Notes.
Items such as Time on the Market reflect the time that the affected batches were on the market, that is, the time between the medicine's production date and the issue of the medicine's recall alert. This information was not in the alert and has been calculated using the following formulas:
· Expiration Date – Shelf Life = Production Date
· Alert Issuing Date – Production Date = Time on the Market
To facilitate this data analysis the following classes were created: 0–6 months, 7–12 months, 13–18 months, 19–24 months, 25–30 months, 31–36 months, and more than 36 months; and for each period of time the number of affected batches that belonged to each time range was identified.
Within the item Pharmaceutical Dosage Form because data are easier to analyse if in groups, Oral Solids, Liquids and Semi-solids, and Injectables were identified. The item Oral Solids includes tablets, capsules, and lozenges, but also powders and/or granules for oral suspension/oral solution. The item Liquids and Semi-solids includes creams, ointments, gels, cutaneous solutions, transdermal systems, eye drops, eye ointments, powders for inhalation, pressurized inhalation solutions, oral suspensions/oral solutions, syrups, oral gels, oral drops, mouth solutions, solutions for gargling, ovules, vaginal ointments, rectal suppositories, and rectal ointments. Finally, Injectables includes all medicines for parenteral administration.
Complementary data were obtained from Infomed, the medicines database from INFARMED, mainly shelf life. After the database had been created all information was organized and converted into graphics, which made the data analysis easier.
Results
A total of 1115 quality alerts were issued between 2005 and 2015. Four hundred ninety-eight of these alerts were about medicines, the remaining 617 concerning other health products, such as medical devices, cosmetics, and body care products.
Within the 498 alerts about medicines, 338 relate to medicine recalls, corresponding to 378 drugs withdrawn from the market (Graphic 1). The distribution of medicine quality alerts over the years, as well as the number of medicine recalls that took place in each year, are presented in Graphic 2.
Total alerts issued (2005–2015).
Total medicine quality alerts and total drug recalls (2005–2015).
All medicine recall alerts were issued by INFARMED. However, in some cases, the problem had not been detected by this regulatory agency, but by other countries' health care regulators.
For most of the identified cases, the recall was voluntary (87%, which corresponds to 295 recalls), and only 12% (40 recalls) were mandatory.
The main cause of product recall was the pharmaceutical dosage form. The majority, 237 medicine recall alerts, were related to problems in pharmaceutical dosage form, with 45 alerts related to primary packaging problems, and 46 cases concerning secondary packaging problems.
A small proportion relates to regulatory affairs problems or other problems that are not directly related to quality of medicines, and one case was classified as P, because the alert did not specify whether the problem was in primary or secondary packaging. Two of the cases are classified as NA, because the alerts do not specify the problem (Graphic 3).
Defect origin.
For the commonest case for withdrawal, pharmaceutical form, most medicines withdrawn from the market are included in the item Oral Solids, which represent 45% of recalls (171 medicines), followed by Injectables, with 36%, corresponding to 137 medicines. The remaining 19% are Liquids and Semi-solids, which corresponds to 70 medicines (Graphic 4).
Affected medicinal products distribution by pharmaceutical form.
In 47% of the analysed recalls only one batch was affected. In addition, for 23% of the recalls the number of affected batches varied between 4 and 38. In a few cases (9%) all batches of the medicine were affected.
Some marketing authorisation holders have carried out several medicine recalls over the past decade. Some of these cases were repeated recalls of the same product, while others corresponded to different medicines recalled at different times. The highest share, 15 recalls, was from the Sandoz Company (Table I).
Number of Recalls per Marketing Authorisation Holder
The time period between placement of medicines on the market and the detection of substandard medicines is highly variable, ranging from a few months to more than 3 years. Only 17% of the affected batches were recalled after 6 months on the market, most of the recalls being made up to 2 years after the product was available on the market (78%). In 22% of the analysed situations, the recall occurred after the medicine had been available to the population for over 2 years.
Discussion/Conclusions
Between 2005 and 2015 a total of 1115 quality alerts were issued. It is easy to conclude that in the last decade there has been an upward trend in the total number of medicine quality alerts, but the number of medicine recalls has remained relatively constant (Graphic 2). This increase could be explained by increased production or by the regulatory agencies' and pharmaceutical industry's greater attention to quality problems of medicines. Concerning what this could represent over the last decade, medicine recall alerts have tended to be replaced by suspected falsified medicine alerts.
In Portugal, most of the alerts were prompted by INFARMED. However, some regulatory agencies from other countries such as Spain, the United Kingdom, and France have a slight relevance in this study because they have issued six alerts for medicine recalls, which served as the basis for the INFARMED's recall notice. This derives from the European Union Rapid Alert System, which facilitates information interchange between regulatory agencies.
For most of the 338 identified cases, the medicine recall was voluntary. This shows that the pharmaceutical industry has an increased concern with the quality of its products and is using analytics that allow an efficient detection of quality issues.
The main cause of product recall was the pharmaceutical dosage form, followed by packaging problems. However, in the item Others there is one curious case, a medicine recall due to an increase in the adverse effects caused. As adverse effects are reported to Pharmacovigilance systems, this case should logically have been labelled as a safety alert and not a quality alert.
The pharmaceutical dosage form analysis showed that 36% of medicines withdrawn from the market were injectables. This value is higher than expected because most of the available medicines in the market belong to the Oral Solids group. It would be expected that the latter group had a value greater than 50%, because of the size of its representation in the market, but it shows only 45%.
The large number of injectables with quality issues represents a high risk because the administration of a substandard injectable medicine to a patient can bring serious health problems. Because of the route of administration and resulting patient exposure, this should be considered a bigger problem than quality issues in tablets or other oral solid forms. On the other hand, the number of individuals potentially affected by a quality issue is higher when considering oral solid forms, because there are many more of these available in the market and their usage is proportionally higher than that for injectables.
Regarding the available data on the number of batches involved in each recall, in almost half (47%) of the analysed recalls only one batch was affected. This suggests that for a great number of medicine recalls the quality issue was an isolated defect and not a systematic error. In a small number (29), all batches of the medicine were recalled, following from a wide variety of causes. These include, for example, process contamination, legal requirements, or non-compliance with good manufacturing practices by the raw materials manufacturers.
Comparing the number of recalls carried out in the past decade by each marketing authorisation holder, collected data showed that some companies were responsible for several recalls. However, this comparison must take into account the number of different products that each holder has available on the market because a company that is responsible for a higher number of medicines is potentially more susceptible to having had more recalls during this period than a smaller one.
Detection of substandard medicines available to the population can occur at varying times after medicines have been placed on the market. In the analysed recalls, Time on the Market varied between a minimum of 1 month and a maximum of 4 years and 7 months (maximum shelf life for medicinal products is 5 years). For 62% of medicine recalls, substandard medicines were available on the market for over a year, which is considered of great relevance because of the inherent risks. However, it would be important to study each of these situations individually, considering the seriousness of the quality defect and the exposure time, and quantifying the risk associated to each case.
Conflict of Interest Declaration
The authors declare that they have no competing interests.
Acknowledgments
We would like to sincerely thank Professor Rui Loureiro for support and availability throughout this project.
- © PDA, Inc. 2018
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