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Are non-sterile drugs free from bacterial contamination?

Contamination of pharmaceutical products and medications by microbes poses a serious threat to patients' health. The presence of microorganisms has a direct impact on the product's integrity, pharmacological effects, and treatment adherence. Contaminated drugs can be life-threatening in many circumstances, depending on the route of delivery.

Aside from the direct impact on patients' health and safety, it's important to remember that removing pharmaceuticals from the market can harm the company's brand and reputation, resulting in a considerable reduction in profit and sales volume.

What is the difference between sterile and non-sterile drug manufacturing?

Non-sterile items are made in conditions that reduce microbiological contamination, but the techniques are not as closely regulated as those used to make sterile products.

Furthermore, unlike sterile products, there are no specific laws or criteria for the manufacture of this sort of medicine, leaving room for interpretation and execution by the manufacturing company.

And that strategy isn't always consistent.

Microorganism control in non-sterile products must therefore be approached from a global and coordinated strategy, which entails the development and implementation of adequate environmental control systems in production sites (air, water, equipment...), as well as in the raw materials used and the finished product. The danger of microbial contamination rises dramatically when these mechanisms are missing, fail, or are not validated.  

Microbiological diversity in non-sterile products. What bacteria are involved in the non-sterile product withdrawal?

While the answer to this question may appear to be a simple curiosity at first, the truth is that this information appears to be crucial when it comes to constructing efficient and stringent control points.

And why is it the case?

Because we can pinpoint the source of contamination based on the group or bacterial species found, we may take the required steps to reduce the risk of recurrence.

A study of product recalls by the Food and Drug Administration (FDA) between 2012 and 2019 established that the presence of gram-negative bacteria is the most common cause of microbiological contamination in non-sterile drugs, at 60%. While 4% corresponded to gram-positive bacteria. Contamination by gram-negative bacteria originates mainly in water and soil. Another important group is made up of fungi and yeasts. It is the second largest cause of product recalls, with 23%. Fungi and yeasts are pollutants mainly present in the environment, so they are transmitted through the air. Material from one location to another, equipment and personnel passing through unrestricted production areas also contribute to contamination due to these types of microorganisms.  

The importance of water in the production of non-sterile drugs.

When analysing the microbial species involved, 48% belonged to only three bacterial groups: Pseudomonas spp and B. cepacea and R. pickettii. These bacteria play a direct role in disease transmission through water and are a recurrent concern in water distribution systems.

While drinking water is chemically and physically treated to reduce the microbial load and the presence of pathogenic species, pharmaceutical processes in water have a more aggressive treatment to minimize the number of microorganisms, the presence of endotoxins, and the concentration of organic and inorganic compounds. 

So, how can bacteria develop in water used for pharmaceutical production if it has such a harsh treatment? The bulk of microbial groups detected in withdrew products are capable of flourishing in oligotrophic settings, hence the solution is directly related to them (with very low nutrient concentration). Cell size and metabolism alter as they grow in diverse conditions in order to adapt. Among these modifications is the ability to build bacterial colonies, or biofilms, which is a successful approach for bacteria but destructive to the industry. If adequate disinfection and maintenance plans are not performed correctly in distribution systems, they might cause major problems.  

What do the standardized Pharmacopoeia say about the control of non-sterile products?  

The three major Pharmacopoeias, the United States Pharmacopoeia (USP), the European Pharmacopoeia (EP), and the Japanese Pharmacopoeia (JP), have standardized and split microbiological control into two categories: quantitative and qualitative control. The quantity of microorganisms (mesophilic, molds, and yeasts) present in the sample is determined by quantitative control, whereas the presence of pathogen specific indicators is determined by quality control. The following species are representative of the various bacterial populations: 

• Escherichia coli. Gram -negative and indicator of fecal contamination. 
• Salmonella spp. Gram-negative and pathogen associated with gastrointestinal diseases. 
• Candida albicans. Yeast with the highest prevalence of fungal infections. 
• Clostridium. Anaerobic gram-positive, which includes several pathogenic species. 
• Pseudomonas aeruginosa. Gram-negative associated with opportunistic infections. 
• Staphylococcus aureus.  Gram-positive, associated with poor handling and personal hygiene practices. 
• Bile-tolerant bacteria. Gram-negative, belonging to the family of Enterobacteriaceae with a wide environmental distribution and several pathogenic species.

The use of these markers does not rule out the possibility of hazardous or questionable bacteria causing a problem at any time during the manufacturing process.

When other microbes not specified in the Pharmacopoeia are present, the administration route and use of a product can decide whether or not a microbiological risk exists.