Drug Recall: What are the common causes?

Drug recall involves the removal of pharmaceutical products from the market due to safety concerns or regulatory violations. From 2012 to 2023, the FDA recorded a total of 15,710 drug recalls. The five primary reasons for these recalls were: cGMP manufacturing violations, contamination, out-of-specification (OOS) results, labeling issues, and microbial contamination.   

What is a Drug recall?

A drug recall is the removal of a pharmaceutical product from the market due to safety concerns or regulatory violations. The goal is to mitigate risks associated with defective or harmful drugs and is considered the most effective strategy to protect the public from substandard or potentially harmful products.

Recalls are typically initiated following reports of adverse events, product defects, or manufacturing errors. Companies may voluntarily recall a drug product or may be required to do so by regulatory authorities such as the FDA. The FDA’s role is to oversee the company’s recall strategy and evaluate the effectiveness of the recall.

Primary Causes of Drug Recalls

Between 2012 and 2023, a total of 15,710 recalls were recorded. The following figure provides a detailed breakdown of all FDA drug recalls.

A total of 89.52% of recalls were attributed to five primary reasons:

• cGMP manufacturing violations
• Microbial contamination
• Out-of-specification (OOS) results
• Contamination
• Labeling issues

The remaining 10.47% were due to reasons such as unapproved marketing, adverse reactions, packaging, or storage problems. The following figure shows the number of drug recalls for the five primary reasons mentioned above during the period 2012- 2023:

The chart indicates that manufacturing and microbial contamination issues were the most common causes of drug recalls.

A deeper analysis of the root causes of drug recalls reveals that:

• Labeling issues: mainly due to incorrect labeling (67.17%).
• Out-of-specification (OOS) results: Mainly attributed to underpotent and overpotent drugs (31.4%) and impurities (25.4%).
• Contamination: Primarily due to microbial contamination (40%).
• Sterility: Mainly due to a lack of sterility assurance (48.3%).
• cGMP violations: Key issues identified were process control problems, storage issues, manufacturing issues, and nitrosamine impurities, accounting for 18.10%, 15.7%, 13.6%, and 13.1% of recalls due to cGMP violations, respectively

Implications of Recall Data?

Based on FDA recall data, most recalled items were classified as Class II, and the two primary reasons for recalls were a lack of sterility assurance or cGMP violations.

• Sterility: This was a major issue in drug recalls. Recalls related to contamination accounted for approximately 37% of all drug recalls, most of which were classified as Class II hazards. Injectable drug products were frequently associated with sterility recalls. Terminal sterilization is the best option to minimize recalls due to a lack of sterility. Sterile drug products must comply with the appropriate techniques, facilities, and controls used in the manufacturing of sterile products, as outlined in FDA regulations found in Title 21, Code of Federal Regulations (CFR) Part 211, Subpart F (section 211.113).
• cGMP violations: The presence of nitrosamines in pharmaceuticals – known carcinogens found in soil and water – has received increasing attention. N-nitrosodimethylamine (NDMA) and N-nitrosodiethylamine (NDEA) have been detected in some sartan drugs, H2-receptor antagonists, and, more recently, metformin-containing drugs. Nitrosamines are classified as Class I impurities. The European Medicines Agency (EMA) has implemented a plan requiring marketing authorization holders to submit self-assessment reports for their products. This approach is used to identify any potential risks from the presence of impurities, whether in chemical or biological medicines.

The remaining three causes, microbial contamination, labeling errors, and storage issues, primarily stem from a lack of adherence to strict quality management practices or Good Manufacturing Practices (GMP) guidelines.

Corrective and Preventive Actions

Companies must ensure that employees are properly trained and understand the importance of what they are producing, provide adequate training, and establish baseline practices at the operator level for skilled workers.

Information is critical when conducting a recall. Companies must identify which batches are affected and the root cause of the recall as early as possible. Companies often broaden the scope of a recall and may recall more products than necessary, simply to be safe. For example, if a recall involves batches manufactured in the previous six months, a company may also recall batches from two months prior in case they also contain the affected component. Digital systems can link points throughout the entire production cycle, making it easier to identify the root cause of the problem and take appropriate action.

Reference:

A retrospective regulatory analysis of FDA recalls carried out by pharmaceutical companies from 2012 to 2023 – ScienceDirect