How does packaging affect the safety of biological products? DeGrazio: Few things are as basic as the package in assuring the quality of a biologic product. By quality, I mean concerns such as, is the package going to work the way it is supposed to keep the drug sterile? If the package has not been put together correctly, you could have a problem with sterility or toxicity. If you are not using the right components or if you have purchased some oddball componentry, there could be even a negative effect on safety from a toxicity standpoint or some kind of a sensitivity that certain patients may have to certain items. So there is a combination of ways the packaging can impact the biological product. For instance, biological products are proteins and peptides, and they have a tendency to adsorb to the container they are in. So if that protein has adsorbed to that surface, then it can't be readily removed. It's important to think about the type of coating applied to a stopper or vial because coatings can affect a product's viability.
After that, the vials go into their secondary packaging, individual cartons or whatever. To use the product, the doctor or patient has to reconstitute it, which means adding the water for injection (WFI) or saline.
Is the WFI or saline packaged with the product? Typically it is. There are several products on the market that allow the user, at the point of care, to perform the reconstitution step. The one we manufacture, for instance, is called Clip'n'Ject. It has a prefilled syringe system, containing the WFI or saline, that fits on the top of the vial of lyophilized product. The WFI from the syringe is injected into the dried product, swirled or shaken to mix, and then withdrawn back into in the same syringe, ready for injection.
Does R&D ever sit down with marketing and say, "What are your needs? How can we make this product easier to launch and sell?" From what I've seen, this does not typically happen early in the development process. Sometimes later in the cycles, marketing gets involved. With something like the Clip'n'Ject, marketing would have a real impact in making a decision about something like that. But typically, the primary package for a biological product is driven from R&D and technical standpoint.
We think marketing can and should play a bigger role in packaging decisions. After all, they are interested in seeing that a product stands out in the marketplace. A unique reconstitution system can do that, but even an aluminum seal or a plastic button can differentiate a product. It is possible now to print multi-colored art or logos, usage instructions, or dosage information right on the button or the seal.
Those components can be embossed or debossed and there is a huge selection of colors and color combinations for the plastic button and the aluminum seal. In fact, some companies are considering closure options as part of their anti-counterfeiting strategy.
We often see a disconnect between development and an understanding of market issues, even down to how the product will be used. Sometimes development doesn't know whether the stopper will need to accept a spike, to be used with a mini-bag system, or whether it will only need to handle a single needle injection. If development chooses a standard stopper and then people try to push a spike through it, the stopper will get pushed into the vial. Or even worse, healthcare workers have been known to actually remove the stopper, rendering the product non-sterile.
What do you recommend to remedy this? Do R&D people need more field research? Yes. And marketing can and should play a role in helping R&D choose the appropriate packaging, especially when it comes to the secondary add-ons that differentiate the product. But we believe both marketing and development need to start working with their packaging suppliers early in the process. They need to say: "These are my requirements. This is how this is going to be used. What's the best approach here?" That way the supplier doesn't just automatically choose whatever is in their drawer from last year.
What do you see coming down the line as improvements in technology? One of the key things is the availability of certain coatings. For instance, we have FluroTec film coating for stoppers. It is highly recommended for use with biological products because it improves compatibility, reduces adsorption, and improves overall product quality. The quality even of the closure itself is improved. Biologic products are very expensive to produce, and, by selecting the newer closure coatings, for a minimal amount of cost, the risks associated with package– drug interactions is vastly diminished.
How will RFID packaging technology affect the stability of biological products? I believe the industry will have to evaluate individual products to understand the issue. Our company has several research projects that explore the use of a variety of covert and overt technologies applied to the secondary seal. It's too early to report on those efforts.
What are manufacturers' main concerns for packaging? They want components that operate well with their filling lines and their full range of processing. If every time they run 1,000 stoppers down the line, things get stuck because they are not dimensionally correct, they have big problems. Their regulatory application and product approval can be delayed. So from a regulatory standpoint, working with a reliable package supplier with sound drug master files and applicable processes, is critical in getting drug and biologics to market. Ten years ago, everybody just said, "Hey. It's only packaging. . . I'll take whatever is in our inventory, and use that," without always understanding the magnitude of risk.
Fran DeGrazio has worked in pharmaceutical packaging for 21 years and has extensive expertise in the area of injectable drug products. DeGrazio is currently vice-president of quality assurance for West Pharmaceutical Services (which produces packaging components and does some laboratory analysis) and has responsibility for quality control for nine manufacturing facilities and the corporate analytical laboratories. In 2004, she assumed direction for the regulatory group also. She is a member of the Parenteral Drug Association (PDA), American Chemical Society (ACS), Women in Packaging, and the American Association of Pharmaceutical Scientists (AAPS).