The State of Inspection
By Marie Redding
Millions of pharmaceutical products have been affected by recalls this year. Reasons have included the presence of particulates in a syringe, packaging the wrong product (such as a tablet containing the wrong dosage); out-of-spec products, and contamination by a foreign substance. Although many of these issues were caught at the wholesale level, others weren’t—and some had the potential to cause life-threatening issues for end-users or consumers.
“Even a simple mislabeling issue can be very serious in our industry. When patients take medication, they rely on what the box says,” says Christoph Lehmann, director, Uhlmann VisioTec. “It is far too easy for a mix-up to occur, so many more safeguards need to be in place,” he adds.
There are times when a recall is unavoidable, even with inspection systems in place.
One recent major recall was Johnson & Johnson’s issue with the chemical TBA, which was reported to have migrated into packaging from wooden pallets. “There’s no existing vision inspection system capable of determining whether there’s been contamination like this,” says Jon Donovan, product manager, Symetix.
Other recalls have been linked to different contaminants, such as metal from fractured tablet press dies. “Accordingly, with tablet press rooms being the location of choice for inspection, this leaves the possibility for numerous other pieces of downstream process equipment to introduce foreign objects into the product,” says Ray Spurgeon, product manager, Eriez Magnetics.
And in one recall, a tablet press problem led to a tablet with double the thickness, according to Donovan. “Many of our customers are using vision inspection systems to prevent this type of issue from occurring,” he says.
There are also packaging-related recalls, which can stem from issues related to bottles being molded incorrectly, and this can affect the integrity of the package and product.
Tom McLean, general manager, Mettler-Toledo CI-Vision, describes a few of the many checks that are done with Mettler-Toledo CI-Vision’s turnkey vision system on a plastic bottle before filling.
“We check the bottle’s integrity, the validity of the opening, and we inspect the threads—if they’re not formed correctly, the cap won’t seal tightly. A cap on a pharmaceutical bottle must also be in the proper position or the safety seal won’t be correct. We inspect the bottle’s surface, because if there are any gauges or splits, then the inner foil seal won’t be airtight, and we also check for contamination of the plastic,” says McLean.
Are Inspection Technologies Utilized?
So many different types of inspection systems exist to help drug manufacturers increase quality standards. In light of recent recalls, one might assume that there’s a huge demand for inspection equipment and new inspection technologies, but this hasn’t been the case, some suppliers say.
“I wish I could say every pharma company has been running out to get inspection equipment, but they’re just not—the pharma industry is notoriously slow-moving,” says Donovan. “There are many new inspection technologies, and they’re not flying off shelves,” he adds.
Donovan says that many pharma companies still don’t have the inspection equipment capable of performing complete, 100% inspections—especially for solid-dose drugs. “Potato chips are 100% inspected before they reach the packaging line, but not pharma. When you look at other industries, such as food and chemicals, the pharmaceutical industry is behind in terms of modern technology,” he says.
However, Donovan points out that not too long ago, the technology to perform 100% inspection of solid doses in drug manufacturing didn’t exist, so many pharma manufacturers still use procedures that were in place earlier, such as manual testing and performing quality checks by pulling a statistical sample from each lot code.
McLean feels differently. He says many pharmaceutical manufacturers have been switching to automated inspection systems at much faster rates over the past few years. “Some of the largest pharma companies are more receptive to new technologies,” he says.
McLean believes more pharma companies will continue to show an increased interest in inspection systems. “Companies realize that they can save a lot of money and possibly prevent a costly recall by adding any type of inspection process to a line. It’s not worth risking an entire shipment being sent back due to one bad package—and, the return on investment is 6 to 9 months,” he says.
According to McLean, a manual inspector on a high-speed line is able to inspect approximately 10% of product, while automated vision inspection can achieve 100%. “You’re guaranteed that no rejects will get through,” he says. “Large pharma companies understand this drastic improvement in inspection, so for most, revalidating processes in order to put in an automated inspection system hasn’t been an issue,” adds McLean.
Mettler-Toledo CI-Vision has been offering its customers a turnkey vision system to inspect packaging for almost 16 years, and now the technologies have become more precise, according to McLean. “We can now find things like much smaller defects in a bottle’s threads, and much smaller plastic contamination issues,” he explains.
Although they are embracing automated inspection, pharma manufacturers aren’t so willing to upgrade to new technologies that quickly, according to McLean. “If we launch a new, faster system, a pharma company typically won’t make a change if their current system is working—they’ll wait until they absolutely need it, and then they’ll revalidate the line,” he says.
Contract packagers are not as quick to adopt new machinery, according to McLean.
Peter Buczynsky, president, Pharmaworks, agrees. “Contract packagers aren’t willing to purchase any extra in-line machinery, because with every added piece of equipment, you’re risking the chance of downtime if something goes wrong with the machine. You’re also increasing the probability of finding false rejects—and contractors are paid per piece,” he says.
X-Rays versus Metal Detectors
Spurgeon of Eriez Magnetics feels the majority of pharma manufacturers are doing an adequate job with the rigid protocols that are in place to ensure repeatability and quality of products. However, in terms of inspection, Spurgeon feels that more foreign object inspection after the tablet press room is needed.
“There is a lot of process equipment after compression that can introduce contaminants into the product, and this is largely ignored,” says Spurgeon.
One improvement Spurgeon suggests to customers is to use an x-ray system after products are packaged, as this mitigates the potential for foreign objects to be introduced into pharmaceuticals. By finding contaminated products on the filling line, there’s no danger of them ever reaching the supply chain.
“X-ray machines are ideal for scanning products even after the foil safety seal has been placed on the container or the product is placed in a blister pack,” he says.
An x-ray can also detect whether or not a leaflet has been inserted into a box.
Improper conveyor design, foil packaging, liquids, conductive products, and ambient noise—all of which don’t affect x-ray machines, according to Spurgeon—can affect conventional metal detectors.
“Additionally, no degradation to the detection of metal is realized, as x-ray technology does not operate on a balanced electrical field like traditional metal detectors,” he explains.
Proofreader Use is Up
Automated proofreading solutions are another type of inspection system that is high in demand, according to Reuben Malz, president, Global Vision. This technology allows users to quickly look for differences among text files, artwork files, and printed components.
“Pharmaceutical companies are under enormous pressure to reduce costs, increase efficiency, and reduce errors. This is why we’ve seen our sales increase substantially over the past few years,” says Malz.
Global Vision offers a suite of proofreading products that include text-based, image-based, and Braille inspection technologies. “Our inspection solutions tend to be deployed throughout the entire artwork process, including upfront design, regulatory affairs, packaging development, label control, incoming QC, and production,” explains Malz.
Strict regulations, collaboration among multiple departments, multilingual text, and paper-based inspections all make proofreading a difficult task. “The more pit-stops a document makes along the corporate workflow, the more chance for errors popping up and not being noticed. Something as simple as a decimal point on packaging can have enormous consequence, particularly when considering the difference between a 3.5-mg dose and a 35-mg dose,” says Malz. For a pharmaceutical company, such an error can potentially come with a multi-million dollar price tag in recalls and lawsuits.
Despite the increased demand for automated proofreading technology, a lot of proofreading is still done manually, according to Malz. “This can be time consuming and error-prone,” Malz says. “Our biggest challenge has been educating the marketplace that such a technology is available,” Malz adds.
A Stand-Alone Re-Inspection Solution
Since all the recent recalls, Peter Buczynsky, Pharmaworks, has seen more customers purchasing as well as temporarily leasing its inspection systems—but for compliance issues after a recall, not to prevent one.
“There are certain companies that are being proactive by doing more to try to prevent issues from occurring, but a good portion of calls we receive are about adding an inspection system as a quick fix—typically when a company needs to show FDA that an issue has been resolved, so they can resume production,” Buczynsky says.
A pharma manufacturer may be required to re-inspect a particular batch. “We have a system that can perform 100% inspections in-line, or it can be used as a stand-alone system, so there’s no need to reprogram machinery or revalidate processes,” Buczynsky says. Pharmaworks reports that it has been receiving a lot of recent requests for its stand-alone systems.
“Our customers also like the fact that when they need additional inspection, you can just roll this up to your line and clamp it to your conveyor, without worrying about how to integrate or validate it with your existing machinery,” Buczynsky says.
Pharmaworks’ stand-alone inline systems inspect blisters after they are punched. They also offer systems that are integrated into the thermoformer, which inspect blisters just after sealing.
“When you just have a camera system before the seal station, an issue can happen further downstream on the packaging line, like a product jumping out of the package or getting crushed,” Buczynsky says.
Continuous Monitoring and Real-Time Release
Some experts, such as Lehmann from Uhlmann VisioTec, feel that the only real solution to preventing recalls and ensuring consumer safety is to completely eliminate conventional end-of-line testing and adopt process analytical technologies (PAT).
“PAT brings more scientific methods of inspection to the manufacturing processes, rather than relying on statistical checks. It’s a big topic right now,” says Lehmann.
Continuous monitoring systems, which can gather data in real-time during manufacturing, can take quality control and the idea of inspection to new levels, according to Lehmann.
“Near-Infrared (NIR) technology can analyze the chemical composition of a drug and can check for many issues, like particle size and humidity levels,” says Lehmann.
The benefits of PAT have been raising discussions for several years. “If the entire pharma industry were to change its manufacturing methods and move toward continuous processing, there are specific advantages, which are more consistent with other industries,” says Donovan.
“Some PAT initiatives have some bearing on inspection. It would give manufacturers better control of its processes, and possibly improve public health and safety—but the move toward it has been slow,” he adds.
Lehmann feels the industry may finally be warming up to the idea.
At a recent FDA meeting, Gerry Migliaccio of Pfizer stated that it is aggressively pursuing ways to adopt Real-Time Release (RTR), Lehmann says.
“It was exciting to hear that Pfizer made this public. It’s a very good step in the right direction, for the entire industry,” says Lehmann. “It’ll be a long process to get other companies on board, but this is a tremendous help, and a step in the right direction for the entire industry,” he says.
Lehmann feels so strongly that vision inspection alone is not enough, because this type of system relies solely on aesthetics.
“Many mistakes can happen at the processing stage, during the compression and coating of tablets, even with vision inspection systems in place. By the time a drug reaches the packaging line, a tablet can look aesthetically correct, but we have no way of knowing whether something happened further upstream,” Lehmann says.
Donovan cites one example of how implementing an application in line with RTR and PAT could be useful.
“In the production of a batch of material for a tablet press, for example, a chemical analyzer could analyze the active through continuous mixing and monitoring. This would be one part of a PAT initiative, eliminating the need to take a random sample at the end to inspect for quality,” explains Donovan.
Donovan says Symetix inspection systems are consistent with PAT, but are just one part of it—and are often used as a final check at several points throughout a production line.
“Some companies are taking a basic approach to inspection and in-line solutions by using a certain application to solve a specific issue during manufacturing,” says Donovan. For instance, using a mechanical sizer to eliminate broken tablets, preventing rejection of packages with broken tablets down the line, Donovan explains. “Pharma companies are taking small steps like this toward adopting new inspection methods,” he adds.
McLean says Mettler-Toledo CI-Vision is moving in this direction as well. “Every type of inspection system we offer is used to inspect in real-time, during production. We can then take the information we collect and send it upstream to halt a faulty process much faster, saving the company money by reducing production of bad product. So we are very much in line with PAT,” explains McLean.
As the generic drug category grows, and consolidation continues to cause increased competition among drug manufacturers, experts expect to see more companies using high-speed machinery for high-volume production. As this trend continues, the standard method of performing manual inspections using statistical samples from small lots won’t be practical anymore.
“Many OTC products are being produced now in very large volumes, using continuous coaters and high-speed bottle-filling lines,” says Donovan.
“The technologies and equipment required to handle inspection at these high speeds, and even higher—often a million doses per hour—is fairly new. We’re just now starting to see some movement toward these systems from tablet manufacturers, and we expect to see more interest soon,” he adds.
Donovan asserts that he is very much in favor of complete inspections becoming a best practice in the industry, at some point. “The companies that we’re seeing consider continuous manufacturing methods are moving slowly with smaller projects, instead of changing everything all at once,” Donovan explains.
Yet, he still predicts new manufacturing and inspection methods will one day be embraced, industry-wide. “Pharma manufacturing will modernize, as more processes that are consistent with PAT are adopted. Change is surely coming—it’ll just be painfully slow,” Donovan says.
Lehmann also feels the industry is headed for positive changes. “If more quality checks were built into production, any trends happening in the production line would be caught early. Any potential issues would be prevented and corrected before the product gets down the line to packaging.
There would be no surprises—and eventually recalls would be gone,” says Lehmann.