In Dr. Seuss’ famous children’s book Horton Hears A Who, Horton, the highly perceptive elephant finds a minute dust speck on a flower and sets about on a frantic journey to save the microscopic inhabitants of Who-ville.
In light of some recent recalls involving particulates in parenterals, Horton, with his prodigious powers of particulate inspection would in all likelihood, command top dollar as a particulate inspection “device” at any pharmaceutical company manufacturing parenterals. Indeed, some pharma company execs might even wish for rooms full of Hortons to ensure particulate-free products.
But unfortunately for those pharma execs Horton is a fictional character, and finding particulates in parenterals is much more complicated than just hoping one of them shouts “We are here! We are here!”
Parenteral Inspection Technologies
Technologies for inspecting parenterals fall into three general categories: manual, semi-automated, and automated inspection methods.
Manual Inspection Systems - Manual inspection systems typically require the operator to physically invert, or otherwise agitate, each container to set the liquid and any contaminants into motion, and to carefully inspect each container.
Semi-Automated Inspection Systems - Semi-automated inspection systems minimize or eliminate the need to manually handle containers by conveying and then spinning the containers in order to set their contents into motion (when required), and positioning them at optimum viewing angles to the inspector. This removes the variability inherent with manual agitation of containers, and allows the inspector to focus only on visual inspection, allowing increased inspection accuracy and throughput while reducing fatigue.
Automated Inspection Systems - Automated inspection systems are generally selected over manual and semi-automated visual systems in order to increase output and improve inspection accuracy. Automated inspection machines can be categorized according to the manner in which defects are detected:
• reflected light systems for particle inspection and cosmetic inspection
• transmitted light systems for particle inspection.
Challenges of Parenteral Inspection
Compared to other drug forms, the manufacture of parenteral products is decidedly more complex. The basic manufacturing process for parenterals is usually mixing, filtering, and then packaging into a container, usually a vial or syringe that has been washed and sterilized. In most cases these operations are conducted under sterile conditions. The many steps and components involved lead to many avenues for contaminants to enter the process and the product.
According to Mike de la Montaigne, President of Eisai Machinery U.S.A., Inc., (www.eisaiusa.com) one of most important ways to ensure defect-free parenterals is to learn how particles are characterized, detected and rejected. “There are so many different types of particulates - lint, fiber, glass, pieces of stopper, and they all come in many different shapes, sizes and colors.”
fiber optic "Tyndall Effect" lighting has adjustable light intensity
controls and can be located below the product, behind the roller, or
above the product for inspection of particulate.
de la Montaigne sees several challenges to producing defect-free parenterals. “There are clear solutions, which are the easiest for both human and machine inspection. You have suspensions which are also liquids, but come in various forms and various densities, some you can’t pass light through, some you can, which presents a whole other challenge both to humans and machines. You have oily products, more viscous, which are difficult because particles tend not to move well in those solutions. You have colored solutions, whether it is a yellow or red solution, the darker the color the more difficult it is to find particulates both by an operator and a machine.”
de la Montaigne also mentions that the location of the particulate is an important variable in the inspection process as well. “Is the particle in the solution? Is it stuck to the side wall of the container, is it floating on the meniscus, has it sunk to the bottom and is so heavy that it sits on the bottom? The area or location of the particulate becomes a variable.”
Nik Seidenader, Managing Director, Seidenader Maschinenbau, Germany (www.seidenader.de) explains that to ensure defect-free parenterals you have to inspect for foreign particulates and eliminate any possibility of particulate ingress by container leakage. Seidenader explains, “When a container is coming out of sterilization and being filled, and prior to closing, it is a very vulnerable situation because you have an open container but you need to maintain sterility and a particle free environment. That’s the challenge.”
Speaking about some of the recent recalls, Seidenader offers his opinion, “Things that happened in the industry recently – a few of those were difficult to inspect out because the particles that were found in one case were in the sub-visible range of 25-30 microns. It is debatable how dangerous they were, but they were found, and it raised a big issue.”
While he can’t speculate about what caused some of the recent recalls, Eisai’s de la Montaigne says there are ways to prevent it from recurring. “From my experience as a machine vendor/supplier one should often look at their validation. Has the machine been successfully validated? Is the machine maintained? Are we maintaining the validated state? How do you challenge a machine? How do you perform routine challenges? What is your SOP for checking that the machine is working properly and is that setting conducive to detecting particulates? Has anything changed in the process; anything new upstream for that particulate product?” According to de la Montaigne these questions are important for defect-free parenterals.
Inspection Technologies – What’s Best?
As mentioned, the industry is currently using three kinds of inspection technologies – but what is the best solution?
“We recommend a combination of automated and manual inspection,” says de la Montaigne. “Automated is not for every product. It’s a misconception that an automated machine can do everything that we need it to do – because the inspection process is product dependent and type of defect dependent."
“FDA says the final referee is a trained human inspector, but automated inspection plays a major part in our world – with certain volumes you can’t do it with humans. You need machinery.” de la Montaigne recommends automated inspection when the product is conducive to automation and that not every product will work with automated technology.
“What an automated process does is make a process more consistent. You can validate an automated inspection machine to give you a yes/no judgment more consistently than a human process will.”
“Over time the most reliable system to inspect large quantities of parenteral products is an automated system,” says Seidenader. Humans do have some advantages however. “Human operators are very flexible to change, and can build up experience.” he says. “Automated systems can not do that.” Seidenader says that in a typical production environment of long runs and big lots, automated systems are difficult to beat by human operators.
Automated inspection systems are generally selected over manual and semi-automated visual systems in order to increase output and improve inspection accuracy. Eisai's automated particle inspection machines primarily use a system using transmitted light and "Static Division"(SD) technology to detect particles in liquid.
Components – Key to Quality
While it is critically important to inspect the finished parenteral for particulates, it is also vitally important to ensure that the packaging components such as vials, syringes, closures, stoppers, etc. are also of the highest quality, sterile, and defect-free.
Fran DeGrazio, Vice President of Marketing & Strategic Business Development at West Pharmaceutical Services, (www.westpharma.com) says one of the most critical components to ensure defect-free parenterals is the cleanliness of the container closure system. “This is an area that the industry is working on,” she says. “Historically pharma and biopharma companies may have cleaned their own containers and washed their own stoppers or vials. Over the years they have moved away from doing that; it’s not their area of expertise. Companies have moved to products that are already in a ready-to-sterilize form and even to a ready-to-use form which means they are already washed and sterilized. This trend has become apparent in the last few years.”
There are other factors in addition to closure cleanliness that can have an impact on particulates DeGrazio notes. She mentions the possibility of an incompatibility with the drug and the closure that can form particulates and also interactions between the drug and glass surfaces that can add to contamination.
Seidenader echoes DeGrazio’s comments, “This (quality of components) has been neglected. There has been a great emphasis on improving filling systems and a big focus to reduce the particle burden in the process, but with increasing value of products, companies became aware than a 10 cent stopper can ruin a 100 dollar value finished product.”
Ultra clean packaging components, such as West’s NovaPure™ stoppers, can help minimize the risk of extractables in the drug solution. The application of a barrier film can minimize the potential interaction between the drug and the stopper.
What Have We Learned?
While all pharmaceuticals should be manufactured and inspected to ensure the highest quality, parenterals are special. As they are typically injected, they have the potential to go directly into the bloodstream which can result in much higher patient sensitivity and adverse reactions to contamination and particulates.
For parenteral product quality it’s important to know your products, know the potential particulates you might be dealing with and implement the appropriate inspection technologies based on your production volumes. Knowing how your inspection systems operate and allying yourself with a high-quality component supplier are also important steps to eliminate the possibility of damaging and embarrassing product recalls.