QRM Process

Particle Analysis for the QbD Era

ASPEX Corp. draws from its experience in other industries to provide an automated characterization solution for pharma.

The current climate of risk management and Quality by Design has pharmaceutical R&D and manufacturing professionals searching for fast, automated analysis of microparticles for raw materials, drug powders, or parenterals. ASPEX Corp. (Delmont, Penn.), in conjunction with a major pharma company, has developed an automated means of in-process particle characterization that aims to speed and simplify materials analysis for drug manufacturers.

Part scanning electron microscope, part energy dispersive spectrometer, the ASPEX Rx has a variety of applications beyond basic quality control, and also has dedicated software and compliance features.

Pharmaceutical Manufacturing spoke with applications specialist Dr. Marie Vicens and field sales director Tom Powers about current trends and their high-throughput electron beam analysis technology. Vicens also garnered attention with her presentation at the recent Rocky Mountain Conference on Analytical Chemistry, which takes a broader look at the technology behind the Rx. To view the presentation, click here.

PhM: I'd like to ask you about the current climate and what you're seeing in the industry. Are you seeing additional caution regarding particle analysis on the part of your clients?

Marie: Well, everybody is always concerned about foreign particle material.  People that have worked with us in the past have contacted us because they're looking for product quality. And many times, not only are they looking at their bulk materials, but sometimes they have to send products out for different purposes like milling, and they want to make sure that it comes back with the same quality it had the first time.

PhM: Could you paint a picture of what the landscape is for particle analysis technologies out there and how your ASPEX Rx technology fits into that?

Tom: Conventionally, there is just particle size information, which is a one-dimensional analysis. And then size and shape is an indication of multiple dimensions, so we then classify morphological differences, like when they might mill a powder: Is it more needle-like in formation than spherical?  There are laser-diffraction techniques that are conventionally employed.  Our reproducibility is superior to that sort of technology. And then we give the advantage of providing the elemental composition of each individual particle in a very rapid manner.

The USP standard, <788>, is purely particle-size-driven and that's what every one of our customers is using. But even though the landscape is size and shape, we’re also imaging each individual particle, so you get the perceived third dimension of the particle, as well as the elemental composition.

PhM: Tell us exactly what the analysis is, how it's done, and how you're able to get all those dimensions.

Tom: We have a sieving type of a process where we dynamically scan a beam across the surface. We employ a contrast mechanism where we can look at inorganic particulate on carbonaceous background, or organic particulate on a metallic background. And that's the kind of contrast mechanism that we employ. 

The competition is a very old and time-proven technique of image processing, but it's very slow.

PhM: The Rx technology is a combination of scanning electron microscope (SEM) and energy dispersive spectrometer (EDS). . . .

Marie: . . . to get the images and chemical composition.

PhM: How does this compare to what else is out there?

Tom: We're unique in the fact that we're a single-source vendor. This technology is old—we’ll say forty years old for the SEM side. As soon as we developed the SEM, the elemental analysis followed rapidly. But there typically might be two vendors out there that would do what we do as a single vendor, and then, even a third vendor that would provide a software solution; and even a fourth vendor that would provide validation services. 

We provide all these things, including IQ, OQ, and PQ, as part of a single-source solution. Clients come to us wondering what are the black flakes in the powder and we'll get them an A to Z solution.

PhM: Could give me a general picture of what your clients are asking you to do?

Marie: One of the common applications that we’ve had is companies trying to follow the guidelines of USP <788>. Before they can actually submit any data to the FDA, they need to make sure that their materials and any foreign particles are quantified and meet the criteria.

Another thing we do is look at product quality and at any other particulate contaminants that may have been mixed with the drug powder, like stainless particulates or Teflon particles. So there are two different types of client: first, the manufacturer of the product, and second, those who buy a product from a third-party vendor and want to make sure that it's clean enough, in terms of its particulate content.

PhM: How much are the FDA initiatives for PAT and Quality by Design affecting your business and driving what you do?

Marie: Right now, Quality by Design is driving our efforts. Whenever we speak, we’re highlighting the advantage of using this technology within the Quality by Design process. If a company manufactures a product and has any kind of contamination or particulate materials, they know they’ve tested it beforehand. They know what they have in their products, and then can move forward.

PhM: And have your clients been receptive to that line of thinking?

Marie: Yes. Everybody is very receptive about counting the particles, identifying the source, tracking back the source of the contamination, cleaning the process, and then moving forward. So everyone is very receptive to this technology—knowing more about your product and knowing more about your process.

PhM: So they're receptive. Are they actually implementing it?

Marie: Actually, yes. We work with different customers. Some of them are R&D; some of them just call us on a product basis when they have a couple of samples and they have contamination, and they want to consult with us and make sure that everything is fine with their product. 

But then we have a couple companies that, after they find out that we can provide information about their product and the source of the particulate material, they stay with us—we sell the system, put together a training program to validate the product on-site, and come back for additional consulting. Everybody that looks at the data wants to know more. They feel that there's a lot of information that they can use to improve their process.

Tom: We’ve already had numerous occasions where manufacturers have used this data to support a new launch through the FDA for a final product evaluation, such as when they were changing the drug to a new delivery method.

PhM: Do you get the sense that there are a lot of companies out there that really aren't aware of some of the technologies like your own, that can actually help them implement QbD and not just be used as a reactive technology?

Tom: That's correct. And we've really done what we feel is a more than adequate job of automating a traditional manual methodology. For some companies, it is purely just a research tool where they might look at one particle, even though we can give enumerations of tens of thousands, if not hundreds of thousands, of particles.

PhM: Just for clarification's sake, explain exactly why you'd qualify this as automated technology.

Marie: Well, basically, once you develop the methods, the only thing that you need to do is set up your sample in the system and hit go. There's a template that has everything. So by automated, we mean that the system actually can find every particle in the sample, size it, take an image, get an elemental composition, classify, and create a report. Totally automated.

PhM: And this can be done at any scale of production?

Marie: Yes. It can work for a few milligrams or bulk. As long as we can dissolve it and filter it, we should be able to do the analysis.

Tom: We've had scenarios where it's been the research wing that's initially contacted us, and we develop a method and then transfer it to their manufacturing divisions. So it's been through every phase from product launch all the way through final production.

PhM: One of the whole ideas of QbD is to be able to use it in all of these different environments. And so anybody that's developing a product and hoping to scale it up is going to be aided by this technology.

Tom: Absolutely. And we're really playing off our successes in other industries where we’ve supported QbD. It really came out of the automotive industry, and we've supported the automotive industry with similar cleanliness and contamination applications.

PhM: It's funny that you bring that up, because many pharma QbD experts can’t help but talk about the automotive industry. So I think you're seeing a lot of ideas and a lot of technologies migrating over to pharma.

Tom:  I would certainly agree with that.

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