For device manufacturers, there are few things worse than a product recall. Even when a specific product has not negatively impacted patient safety, managing a recall can be complicated, costly and can damage customer confidence.

Alongside failed specifications and mislabelling, one of the most common reasons for a recall is particulate contamination. The US Pharmacopeia (USP) defines this as the process by which “mobile undissolved particles become unintentionally present in a parenteral solution”. No matter the cause, this can have serious financial and reputational consequences, and lead to a host of problems.

The sources of particulate matter are varied; some originate from foreign or extraneous contaminants, such as product containers and packaging products made from materials like glass, plastic rubber, aluminium and paper. Others are inherent to an active pharmaceutical ingredient and are often caused by protein aggregation.

While all injectable drug products contain some level of particulate matter, contamination by either foreign matter or protein aggregates can create issues for patient safety, says Erwin Freund, the executive director of drug product engineering at Amgen, a US-based multinational biopharmaceutical company.

“It is an important quality attribute,” says Freund. “These particles can be non-sterile, they can be immunogenic and they can cause local reactions at the site of injection.”

Regulators are keeping up

According to Freund, while recalls do happen, the danger posed by particle contamination has been significantly reduced in recent years thanks to the attention of regulators and subsequent efforts by manufacturers to improve their inspection processes. The rise of biotherapeutic medicines in the 1980s, for example, increased the risk of contamination through aggregation, but saw a quick response from the US FDA and European counterparts.

FDA improved the clarity of the conditions under which particles should be examined. Now, we have a scientific definition of what it means for a solution to be practically free of particles.

“FDA has increased its efforts to make manufacturers introduce a particle prevention strategy that would limit, if not totally eliminate, the presence of protein particles,” explains Freund. “They expect the manufacturer to carefully analyse adverse events in clinical trials.

There is an allowance for the presence of a certain amount and type of protein particles in the final drug product, if you have demonstrated that this is the typical behaviour of the product, without impacting safety and efficacy.”

More recently, there was a sharp uptake in regulatory observations following an increase in the presence of glass particles in vials. According to a report from the manufacturer West Pharmaceutical Services, 2006–11 saw more than 20 product recalls caused by glass, resulting in 100 million units of drugs being withdrawn from the market. But the industry bounced back fast, Freund emphasises.

“This event suddenly intensified the concern that the agencies had,” he adds. “The industry rapidly learns from those specific issues and puts surveillance methods in place to apply best practices. Adverse events in the past ten years, due to particles in parenterals, have been incredibly low.”

FDA regulations governing particles have become progressively clearer in recent years. For a while, the industry struggled to understand the USP’s requirement that parenteral products should be “essentially free” of visible particulates. While this acknowledged that injectable drug products could never be totally free of particles, many felt the requirement was too vague.

However, Freund states that last year, “FDA improved the clarity of the conditions under which particles should be examined, which gets closer to the European guidelines. Now, we have a scientific definition of what it means for a solution to be practically free of particles.”

Improving inspection

More can be done in others areas. According to Freund, one major problem with current inspection processes is how invasive they are. To examine a syringe, vial, cartridge or IV bag, for example, companies must first open them and analyse the contents.

“It is a challenging procedure,” he points out. “There is work to be done to introduce non-invasive analysis, where you can examine without opening the container. These are in an early stage of technology development.”

The validation of automated inspection is tedious and takes a lot of time. Thankfully, technology is progressing and, in the future, I see more use of artificial intelligence and machine vision.

Predicting whether a protein particle may cause patient safety issues is also made difficult by unreliable animal research. As things stand, pharmaceutical companies use information that is based on injecting animals with billions of foreign particles – far larger than those used in injections on humans.

“You can easily injure an animal by infusing large numbers of particles, but the data you get is not really relevant to understanding what happens in a human,” explains Freund. “Amgen and other companies are working with academics to find out to what extent those risks are a reality. I expect, in the next few years, there will be more articles published in peer-review journals that provide more clarity to the industry on how to better predict the outcome.”

When working out the risk of a particle, Freund recommends taking into account what he calls the ‘route of administration’. “The level of tolerance for particles depends on these routes,” he adds. “Among the most sensitive routes is injection in the eye. The next most sensitive is an IV injection, because you are distributing the particles straight into the system and blood flow.”

Calculating risk also depends on the specific patient in question. Are they immunocompromised? What is their level of defence? What is the volume of the injection being used?

“You need to take all of those factors into consideration,” says Freund. “There is not one rule or set of assumptions that can be applied to all cases. It really depends on a range of parameters.

You also need to document the risk assessments, so that when FDA asks for justification, you have reports or monographs.”

For biopharmaceutical companies, Freud recommends creating processes and technical reports that describe what the normal appearance of a drug product is. “If you have no protein aggregation, it is pretty straightforward,” he stresses. “But if you have some aggregation, the key is to characterise the protein product over time during stability studies and, where possible, enrich the qualitative observation with quantitative data. If you do see particles, ask, ‘Do I have any information I can provide on the shape, size and number of those protein particles, so that I know what is normal?’”

Replacing the human element

The industry is also struggling with manual and automated inspection processes. While recent USP publications have given greater clarity on how to execute a manual inspection, humans will always be fallible. Two people may produce inconsistent results, for example, and even the same person’s work may vary as time goes by. “This is not an approach that gives you completely consistent data,” Freund notes.

While automated inspection is faster and more dependable, it typically yields a higher false-rejection rate – sometimes up to 30% – thanks to the use of high-resolution cameras.

“If I have 20% false rejections, based, for example, on tiny air bubbles, I may have to manually inspect 20,000 of them,” says Freund. “The validation of automated inspection is tedious and takes a lot of time. Thankfully, technology is progressing and, in the future, I see more use of artificial intelligence and machine vision.”

With the adoption of automated inspection machines expected to continue rising, Freund recommends that companies hire machine-vision experts who not only understand the software and optics involved, but can also work closely with vendors to dictate how particular machines should be equipped.

“You need to have your engineer with experience in optics and physics dictate to the vendor the specification or the components that they are going to install,” Freund states. “If you just rely on the vendor, you are going to be dissatisfied.”

While new technologies are likely to emerge in the coming years, the ultimate objective for the industry will remain the same: reducing particles and removing risk from patients.

“Although the number of negative cases is low, we must keep raising the bar to ensure parenteral injections are as particlefree as possible,” Freund concludes.

Karl Hemmerich, president of Ageless Processing Technologies, looks at FDA regulations on packaging

FDA has several regulations on all aspects of medical devices. However, it needs to be mentioned that the regulation covering medical device packaging design (section 820.130 device packaging under subpart K – labelling and packaging control) is a single line, which only states, “Each manufacturer shall ensure that device packaging and shipping containers are designed and constructed to protect the device from alteration or damage during the customary conditions of processing, storage, handling and distribution.”

Does this mean that FDA regulation on medical device packaging design is simple, plain and broad, and can be bypassed? Not really: compliance with the medical device packaging design has to be seen in relation to two factors.

Firstly, FDA regulation on medical device packaging design has to be seen in conjunction with its twin regulation, namely section 820.120 device labelling. This is the first of the two sections on medical device labelling and packaging. This section has elaborate details on how medical devices need to be packaged and labelled. FDA has requirements in this section on the integrity, inspection, storage, operations and control number of labelling. FDA regulation on medical device packaging design has to be complied with collectively with this section.

Secondly, FDA regulation on medical device packaging design is only a set of regulations that require adherence to the device packaging design elements. Medical device packaging design manufacturers are free to use their creativity in designing device packaging.

Adherence to FDA regulation on medical device packaging design does not mean that there should be no innovation; it only means that the medical device packaging design has to be complied with. As long as this is met, manufacturers are free to design imaginatively. Perhaps, so that there is enough scope for innovation, FDA has left this area general and nonspecific, with the only requirements being that the medical device packaging design adhere to guidelines aimed at protecting it.

Source: Ageless Processing Technologies