Recall of substandard medicines in Brazil during the period 2010–2018

This is a descriptive study (documentary analysis) which is retrospective and quantitative on the recall of medicines with quality deviation, registered in ANVISA's inspection and monitoring system, located on their website, from 2010 to 2018 [36].

The period of this study was chosen according to the validity of the guidelines for GMP, which were in force between 2010 and 2018. In 2019, a new set of guidelines for good manufacturing practices in Brazil was published, reflecting the entry of ANVISA into the ICH, and demonstrated their need to harmonize internal regulations with the ICH guidelines.

In this study, only medicines that had quality deviations in the manufacturing processes, unregistered/unlicensed medicines, medicines that had problems with good manufacturing practices, or that generated product recall as a preventive measure were considered (medicines that are recalled, but quality assessment is necessary after recall). Cases where industries did not have authorization to manufacture drugs and that the drugs were falsified [10] were excluded.

The data on drugs with quality deviation were obtained through the ANVISA website, using the link “subjects”/ "inspection and monitoring" / "irregular products". The file made available on the ANVISA website lists the drugs recalled in a table, where the following data are available: company name, product, lot /validity, inspection action, reason for recall, and publication in the official government journal. In the case of incomplete information or where doubts were generated, the publication in the official government journal was consulted and the data supplemented [37].

In the data collection, the drugs and the respective and different batches were counted and reported, even if it was the same drug but with different batches. When the available file read "recall of all batches on the market", this was classified as a single batch.

The medicines were classified as generic, similar, reference, new [11], herbal, biological, specific [38], radiopharmaceutical and simplified notification [39] (Table 2). Generic, similar and reference medicines were listed through an active search on the ANVISA website (lists A and B of reference medicines related to each year of study) and ANVISA's list of generics and similars. Regarding the dosage form, the medicines were divided into: solid dosage form (tablets, hard and soft capsules, pillules (sugar coated tablet), coated granules in sachet, powder for oral solution, vaginal tablets, suppositories, among others), liquid (oral solution, topical solution, syrup, suspension, among others), semi-solid (cream, ointment, lotion, gel, among others) and parenteral preparation (solution for injection, lyophilized powder for solution for injection, suspension for injection, solution for peritoneal dialysis, among others).

The medicines recalled were classified and quantified for general and specific reasons (Table 3). The specific reasons were established according to the provisions of good manufacturing practices and the Brazilian Pharmacopoeia.

For the variable “Good Manufacturing Practices”, the specific reason “nonconformities with registered medicines” was related to the following reasons: “Change of name/excipient/place of manufacture/packaging/expiry date/method of manufacture”, among others, which were registered in ANVISA with unauthorized modification.

In the “quality” item, the specific reasons were also related to the recall for more than one specific reason, for example: Appearance and content, dissolution and content, labeling and packaging, among others.

The data were stored in an Excel program file and analyzed by the statistical tools of the program, with absolute and relative frequencies being presented.

In the period of the study a total of 3,056 medicine recalls were identified (Table 4). The highest number of recalls occurred in 2013 (n = 443; 14.5%) and 2017 (n = 845; 27.7%), caused in the first case by the recall of 176 drugs from the same pharmaceutical industry, and in the second case by the recall of 514 batches of simplified notification medicines (chlorhexidine hydrochloride solution, n = 487) in different concentrations, supplied by the same laboratory.

In 2016 (n = 253), there was a high number of reference medicine recalls, caused in this case by the recall of 59 batches of indapamide prolonged-release tablets due to a change in formulation, without the prior consent of ANVISA (nonconformities with registered medicines). In relation to a similar medicine, in 2012 there was a greater number of recalls (n = 239) due to the suspension of a line of solids from a pharmaceutical industry resulting in the recall of 184 batches of different medicines. In 2013 there was a greater amount of recalls of generic medicines (n = 250) due to there being two large recalls: 54 batches of the injectable solution of imipenem and cilastatin, due to problems in the labeling, and 176 batches of injectable solution of dipyrone, due to irregularities in good manufacturing practices. In general, the medicine recall involves mainly similar (30.1%), generic (21.3%) simplified notification products (20.7%) and reference medicines (12.2%) (Table 4).

Table 5 shows the reasons for recall according to drug type. GMP was the main reason for the recall of these medicines with the exception of reference medicine (49.7%), specific (80.6%) and biological (68.3%), where quality was the main reason for the recall. Regarding the type of dosage form (Fig. 1), the solid dosage form (n = 1076) obtained 35.2% of recall, where tablets obtained the highest number of recalls (n = 824, 76.6%), followed by hard capsules (n = 83, 7.7%), pillules (n = 67, 6.2%) and others (n = 102, 9.5%).

The recalls with the highest impact in the liquid dosage form (n = 954) were those with topical solution (n = 547, 57.3%), followed by oral suspension (n = 182, 19.1%), oral solution (n = 99, 10.4%) and others (n = 126, 13.2%). Parenteral preparations constituted 30.0% (n = 917) of recall, where njectable solutions correspond to 64.1% (n = 588), powder for solution for injection 19.1% (n = 175), solution for peritoneal dialysis 7.8% (n = 71), and others 9.0% (n = 83). The semi-solid dosage form (n = 105) had a few recalls, with emphasis on lotion (n = 24, 22.9%), ophthalmic ointment (n = 23, 21.9%), cream gel (n = 15, 14.3%), followed by others (n = 43, 40.9%).

The general reasons that caused the recalls of medicine during the investigated period (2010–2018) were problems related to Good Manufacturing Practices (58.4%), followed by quality (40.4%) (Fig. 2A). The main specific reasons related to Good Manufacturing Practices were irregularities in health standards (76.5%) (Fig. 2B).

When assessing the reasons for recall per year, there was a greater variation in relation to good manufacturing practices: 2018 (n = 172, 55.8%), 2017 (n = 845, 80.4%), 2016 (n = 253, 65.2%), 2013 (n = 443, 50.1%), 2012 (n = 377, 72.1%); and quality: 2015 (n = 325, 61.8%), 2014 (n = 294, 62.9%), 2011 (n = 150, 59.3%) and 2010 (n = 197, 69.5%).

Regarding the general quality reason (n = 1,234), 91.6% corresponded to recall for a specific reason and 8.4% for more than one specific reason. Figure 3(A) shows the main specific reason for recall in relation to quality, where appearance (25.2%), labels (12.4%) and packaging (11.5%) were the most quality problems identified. Other reasons represented less than 1.0% of the recall, considering each test individually: pH determination (0.6%), molecular distribution (0.6%), unit dose uniformity (0.5%), related substance (0.5%), aspiration and extrusion test (0.3%), weight determination (0.2%), disintegration test (0.2%), hardness (0.2%), donor blood detected with diagnosis of Sporadic Creutzfeldt-Jakob (0.2%), friability (0.1%), Iron II limit test (0.1%), potency (0.1%) and identification of ethyl alcohol (0.1%).

Other recalls involved more than one specific reason (Fig. 3B), in which odor/pH and appearance/pH represented 1.4% of the recall lots. The following situations were identified with less than 0.1% incidence: appearance and friability; Disulfide content and limit; appearance and count of total microorganisms; Labeling, identification of markers, loss on drying, content; Assay and uniformity of unit dose; Volume and secondary packaging; Label/packaging; Labeling, content and identification; Label and package insert; appearance, Labeling analysis and packaging appearance; appearance, color and volume; appearance, pH, content and label; Content and drip test; and appearance / determination of volume / content.

Before the establishment of ANVISA in 1999, similar medicines registered in Brazil were not required to carry out pharmaceutical equivalence and relative bioavailability tests. In 2003, ANVISA published specific regulations informing about the mandatory performance of equivalence and bioavailability tests, giving a period of 10 years for certain medicines. In 2014, with the period for presentation of the tests at the time of registration coming to an end, ANVISA published RDC 58/2014, which detailed all similar medicines that had already proved their pharmaceutical equivalence and relative bioavailability [40].

Reference medicines had a high frequency of recall between 2010 and 2018. This type of medicine is considered an innovative, branded medicine used by generics and similar for future registrations of medicines that are candidates for commercialization, since in pharmaceutical equivalence and bioequivalence / relative bioavailability studies, generic and similar medicines need to be compared to the reference. It is of upmost importance that these medicines maintain a constant quality and RDC No. 35/2012, deals with the criteria for inclusion and exclusion of reference medicines in Brazil [41].

Simplified notification drugs had a high recall rate. This type of product must follow the monographs of the Brazilian pharmacopoeia or other compendium recognized by ANVISA to generate the quality control analysis reports of the finished product. The fact that we have multiple recalls may be indicative of non-compliance within these rules. The renewal of authorization of this type of product occurs every five years and these results may impair its renewal [39].

Regarding the dosage form, equivalent recalls were obtained for solid, liquid and parenteral preparation, the latter being of concern because it can cause serious damage to the patient due to its direct availability in the bloodstream.

Regarding the general reasons for recall, good manufacturing practices and quality were the parameters that caused a greater number of recalls. When assessing the reasons for recall per year, it is found that there is a very high variation and fluctuation, with quality drawing a lot of attention, as there are lots of products on the market that are released outside of specifications.

When evaluating the specific reasons within the “good manufacturing practices”, the item “irregularities in the health standards”, which involves irregularities during the inspection of ANVISA and not meeting the requirements of good manufacturing practices, represents the main cause of recall, and is directly linked to the GMP regulation in Brazil and its listed requirements.

A worrying statistic is the “nonconformities with registered medicine”. Any medication to be marketed needs to be registered with the entire documented production process, this includes batch size, excipients used, among other aspects. This implies that during the period of authorization of a registered medicine the industry must follow all documents submitted to ANVISA (validation processes, stability studies, qualified suppliers, among others). Among the nonconformities, "alteration in the mode of manufacture" and "alteration of formulation" are points of concern, as they can directly affect the bioavailability of the drug, making it possible to use the medicine without any therapeutic effect. For the medicines recalled in relation to "change in the method of manufacture" or "formulation", in most cases ANVISA determine the recall of "All batches". During the period of this study, it was verified that in 2016 there was the recall of three different reference medicines due to the following nonconformities: change in the API synthesis route, change in the product composition formula, moderate change in configuration of excipient, and change in the expiration date of the drug from 24 to 36 months. These changes differed with what was approved in the initial registration of the medicine and all of them were made without prior consent from ANVISA. In 2015, for example, a specific medicine (epinephrine nasal solution) changed the API manufacturer without prior authorization from ANVISA.

Another relevant point is the large number of recalls due to a lack of “product registered”, thus showing that ANVISA is capable to identify and remove these illegal products from the market and shows that many manufacturers do not respect the current legislation in regard to producing irregular medicines and exposing the population to risks with their life and health. In this way, warning campaigns in the media could be promoted, in order to encourage the population to always check if the medication being purchased is registered with ANVISA, because currently we have seen few actions in this regard.

The aspect that involves changing packaging/label and changing the package insert are reasons that can bring great risks to the consumer's health. During this period, 49 batches were recalled due to changing the packaging/label and 19 batches due to changing the package insert. Of the recalled drugs, there were morphine tablets, a reference medicine, which were recalled due to the use of product cartridges with a concentration of 10 mg being sold in the packaging of morphine of 30 mg, demonstrating flaws in good manufacturing practices.

In relation to the general reason for quality, which is defined as the nonconformity of the quality parameters established for a product according to Brazilian Pharmacopoeia specifications, appearance showed a high occurrence of nonconformities. Even with all the process controls, according to GMP, there can be both human error as well as failures in automated processes that cause the release of batches that should have been disapproved and, consequently, not released for consumption.

Problems with labeling and packaging presented a considerable percentage in the recall of products, as these are used to protect medicines and identify them properly. This demonstrates to the manufacturer that packaging and labels must also follow all error and risk analysis standards, which are sometimes just limited to the product itself. Recall due to the presence of bacterial endotoxin represents a high risk to the consumer and releasing contaminated batches demonstrates a serious failure in the quality control of the industry. Incorrect dissolution is a problem and limits the possible therapeutic effect of the drug, because the dissolution is a fundamental step for the complete and correct absorption of the drug that was administered.

In the quality parameter, there were recalls that showed nonconformity in more than one quality test, and again, there is the question of appearance in this regard, involving appearance and pH, odor and pH, and packaging and odor, however, it was appearance that presented a greater number of recalls. The recall for more than one specific reason, related to quality, is a concern, because the industry has supplied batches with considerable quality deviations, including quality assurance and quality control, for commercialization.

The reasons for recall related to the two variables, good manufacturing practices and quality, represented a high frequency of the recalled batches. These recalls occurred in 2013 in which a reference medicine (Imipramine hydrochloride) was recalled for presenting results above the specification values for the degradation product G22358 (Quality), as well as presenting an expiration date not authorized by ANVISA.

This type of study is important in order to improve ANVISA assessment guidelines, because they identify the types of medicines recalled, the reasons and causes involved, and they can alert companies to this problem. As a regulatory agency established just over 20 years ago, its internal guidelines are constantly changing in order to improve the production and quality control of medicines in the country, seeking to guarantee the effectiveness and safety of medicines. In 2019, a new set of guidelines for good manufacturing practices in Brazil was published, reflecting the entry of ANVISA into the ICH, and demonstrated their need to harmonize internal regulatory with the ICH guidelines. This study, involving the survey of medicine recalls in Brazil in the period before entering the ICH, will be an important reference to evaluate the benefits of aligning the internal rules in accordance with the ICH documents, seeking to improve regulatory issues in the country and the regulatory convergence with other countries.

The recall of medicine becomes compulsory when errors were observed in terms of quality or good manufacturing practices. The medicine recall process is costly for the pharmaceutical industries, as the manufacturer spent money on production, had costs to place the product on the market, both with distribution and advertising, but also had costs throughout the distribution chain, and thus will have logistical and reimbursement costs for distributors and even consumers.

The industry must invest in training employees and motivate them to comply with the procedures described for the production processes, thus avoiding changes in the manufacturing process however small, so that they do not affect the quality of the product.

Manufacturers should always seek the use of mechanisms that minimize the possibility of errors and dependence on the action and attention of employees to avoid these errors. To achieve this, there has been strong investment by manufacturers in the implementation of computerized systems in pharmaceutical processes and equipment, which continuously check for possible inconsistencies and deviations and determine process parameters, significantly reducing the possibility of errors.

As an example, there is an action that has contributed considerably to the safety of the processes, which is the installation of sensors in the packaging equipment and devices that evaluate 100% of the units produced, discarding any incorrect samples through cross contamination. It is also possible to carry out a risk analysis by production line and thus enable risk mitigation or elimination actions. In addition, it is possible to implement the presence of quality inspectors within the production area to assist in the identification of critical points and also in the anticipation of possible quality deviations. [42, 43].

To help solve these problems a closer relationship needs to be developed between ANVISA and the laboratories, with an exchange of information on regulatory requirements, with explanatory guides and periodic meetings/lectures in regard to the most frequent doubts. There should also be an increase in inspections in the laboratories in order to guarantee the effectiveness and safety of medicines marketed in Brazil.

 It can be seen from the data extracted from the ANVISA website that in the case of some recalls, the agency did not report the exact number of batches recalled and the information merely said, “recall all batches” (The use of this imprecise information was present in all years included in this study). This lack of information about the exact number of batches recalled may have resulted in the reporting of a smaller number of recalls than actually occurred during those years. Another limitation was that ANVISA did not report the class of risk of the collected drugs. This is important data for the consumer and is extremely relevant in statistical research on recalls.