By Trisha Gladd, Editor, Life Science Connect
If you’re subscribed to FDA recall notices like I am, then you’ve probably noticed a substantial amount filling your inbox over the last several months. Specifically, those recalls due to the presence of particulate matter in injectables, which the FDA has announced 17 of in 2014. While there is much speculation about why there has been such an increase—aging equipment, cleaning deficiencies, discrepancies between regulators, and the list goes on—what companies need to worry about most is how to protect their product and the patient by avoiding this issue altogether. But how?
Eliminate All Points Of Entry
I recently spoke to Bob Nase, vice president of quality assurance at West Pharmaceutical Services, a designer and manufacturer of pharmaceutical packaging and delivery systems, about what pharma can do to eliminate the presence of particulate matter in their products. “Try to minimize any type of human intervention in the process, both in out-processes associated with manufacturing the container closure system itself as well as in the pharmaceutical side of the business, where they're actually doing the manufacturing and the fill finish of the product,” explains Nase. “We know that humans are probably the biggest contributor to any type of contamination, whether it's microbiological contamination or particulate, so the amount of human interaction should be as limited as possible. When I do training on particulates, I always try to stress the point that if you were a particulate, how would you find your way into a solution? You have to take into consideration that particulate matter is all over, and it will find its way into that final container and the final drug product any way that it can. The key is to eliminate those points of entry.”
In the area of particulate matter, particles are categorized in two ways: extrinsic and intrinsic. Extrinsic particles would be particles that would result from the manufacturing process itself, or the environment that the product is being manufactured in. Intrinsic particles are particulate matter that is common to the container closure system or even the drug product itself. Nase says to look at the packaging system, the drug product, and also the environment as other sources for particulates. “You have to consider all of the elements of the manufacturing process and everything that goes into the final filling operation, and make sure this process is as clean as possible.”
Is Glass To Blame?
One thing that Nase says pharmaceutical companies developing new products should be aware of is the potential risks of glass-related issues, such as delamination. He encourages manufacturers to consult with their partners who are providing packaging solutions and make sure they have the lowest risk solution and that it is evaluated in the early stage. This could just be a plastic container being evaluated alongside of a glass container, but it’s important to be aware of both options when considering choices for drug packaging.
So would switching to plastic packaging substantially reduce, or even eliminate, the existence of particulates? “From our studies, if you replace the glass container with a plastic container, the chemical phenomenon between the drug and the inner surface of the glass container does not exist, because you're not getting the same interaction. Therefore, you are eliminating the problem of delamination,” explains Nase. Secondly, he adds that plastic containers are produced in a way where everything possible is done to minimize the opportunities for particle creation, from the point of how the products are made, how they're handled, to how they're treated and sterilized. “This is opposed to glass, where you produce the glass vial and then subsequently clean it through washing and cleaning practices,” he explains. “Plastic containers can be produced so they’re going to be clean from the minute they come out of the manufacturing process.”
Regardless of what type of material is used, the presence of particulates affects the safety of the product. They create a risk to the patient and can also reduce the effectiveness of the treatment.
USP <790> And The Definition Of “Essentially Free”
Recently, the U.S. Pharmacopeial Convention (USP) published USP Chapter <790>: Visible Particulates in Injection, which specifies conditions for the inspection for visible particles in injectables. At the same time, USP <790> also provides a better description of the acceptance criteria using a statistical sampling plan as to what the expectations are for the product to be “essentially free” of visible particles. The phrase “essentially free” has caused some confusion in the industry because of the assumption it means zero defects, which is a good goal but not a practical limit or specification.
John Shabushnig, principal consultant at Insight Pharma Consulting, serves on the USP Dosage Forms Expert Committee and Visual inspection of Parenterals Expert Panel. He and other colleagues with USP spent an extensive amount of time understanding different practices in the industry and then put together a stimuli to the revision process, which is a paper that describes current thinking on the topic, and that grew into USP <790>. “This chapter now provides guidance with regard to what the expectations are,” explains Shabushnig about the 0.65% AQL level specified in <790>. “Hopefully, what this document will do is help the industry at least have a common target and a common reference and also help them in their discussions with the FDA in terms of setting the acceptance criteria.”
The inspection conditions in the new chapter already exist in the European Pharmacopoeia, so this method is not something completely foreign to the industry. “Many people are already using the conditions in <790>, but there are also a lot of other ways to inspect and they’re certainly free to use them, if done so with data to support a comparable performance,” he explains about the chapter, which he says is simply an attempt to harmonize the expectations within the global industry around what is visible inspection. “What it does is provide a benchmark. It’s an agreed upon definition of what’s visible and what isn’t visible under these conditions.”
Preparation for <790> is minimal, according to Shabushnig. Using inspection stations will still do the trick, but <790> now specifies the intensity of the light under which you should perform inspection. “It specifies a black and white background, so you have contrast with light- or dark-colored particles. This is a range of lighting that is very common, and I think very well understood,” he explains. “It says you should invert or swirl the container, because you want to make the particles move. This makes them easier to see. <790> also specifies the amount of time you should look against each of the black and white backgrounds.”
Shabushnig explains that doing something different does not mean a company is wrong or out of compliance; however, what they should at least be doing at this point is assessing their inspection capability against <790> to see whether they are doing as good as or better than what are now the current expectations.
To read USP <790>, go to www.usp.org. A paid subscription is required.