Heightened Regulatory Scrutiny for Parenterals Produces Innovation by Suppliers

by Erik Swain, Senior Editor

While parenteral packaging takes many different forms and protects many different kinds of drug products, all types have one thing in common: they are coming under more intense regulatory scrutiny, especially from FDA.

Several recent agency guidances, such as those on container-closure systems, stability, and postapproval changes, in addition to the more specific PACPAC guidance on postapproval packaging changes that is in development at the moment, have made it clear that the manufacturing and packaging of parenterals need to be considered more closely than the processes for many other forms of drugs. In these documents, the agency has classified drugs according to dosage form and route of administration and has placed many parenterals in the most sensitive categories. This leads to increased scrutiny from inspectors and stricter reporting requirements to the agency from the drug manufacturers.

Especially once PACPAC comes into play, "things considered normal for many years will be scrutinized more by FDA," says Roger Asselta, manager of pharmaceutical packaging development, Comar Inc. (Buena, NJ). "Some assumptions will be challenged. We're getting a sense of that as FDA inspects our customers. They're having to evaluate the reasons they choose certain packaging and their practices."

This is understandable, given that many drugs that end up in parenteral packaging are volatile, and parenterals often provide a complex route of administration.

"When you talk about an injectable product, it's typically a more reactive dosage form and has the potential to interact to a greater degree with primary packaging," says Fran DeGrazio, vice president of global technical support and contract lab services for West Pharmaceutical Services Inc. (Lionville, PA). "And if there is an issue with interaction, because it's a parenteral, the product ends up getting injected into the patient's system, so the route of administration gives cause for concern."

MORE SERVICES EXPECTED

As a result, drug manufacturers are relying more on their parenteral packaging suppliers to do tests to ensure there is no drug-package interaction, and to otherwise guide them through some of the new rules. "We have had to develop services to address the issue [of more specific testing]," says DeGrazio. "Our customers come to us and ask us to perform more in-depth extractable analysis for them in response to the questions and information they get from the regulatory agencies. We have developed a GMP contract service lab to help them out with these analyses. More and more customers are realizing that they need to do this type of work. We have developed analytical techniques that allow us to test extractables in a drug product."

"Perhaps the most important change is that manufacturers of parenteral containers and closures have to provide more information regarding extractables," says Tony Robertson, director of technology, Helvoet Pharma (Pennsauken, NJ). "We were already doing this for the most part. But for a number of us, it represents an opportunity to be a little more specific with our testing and to say a little bit more about our systems. More of the testing task has shifted from the users of closures and containers to the manufacturers."

He adds that while "it does add cost to some extent, once you do testing on a particular container or closure, you don't have to redo it, unless you're doing something specific to a drug manufacturer's vehicle or active. In those cases it adds additional costs, but those are usually passed on to the drug manufacturer since these are tests specific to their systems. In any event, the test procedures in the various vehicles have to be developed and validated by the drug manufacturer or their contract laboratory, which may be the component manufacturer."

PACPAC

Having these tests in place should serve suppliers well once PACPAC comes into effect. PACPAC is expected to tell drug manufacturers how specifically to go about making changes to packaging materials after a drug has hit the market, and testing should play a significant role. Suppliers who have implemented more advanced testing methods as a result of the earlier guidances may find that PACPAC won't force them to do many new things.

"My gut feeling tells me that the impact on parenterals probably will not be significant," DeGrazio says. "It will help substantially in taking the ambiguity out of the postapproval change process across all dosage forms, though. Our customers are hoping to get regulatory relief in certain instances. I would assume that this may occur in relationship to some dosage forms other than parenterals."

But because of the sensitivity of the dosage forms and complexity of the routes of administration, parenteral packaging users and suppliers shouldn't expect too much in the way of looser restrictions, says consultant Edward J. Smith, PhD, of Packaging Science Resources (King of Prussia, PA) and chair of the Parenteral Drug Association's (PDA) Packaging Science Interest Group.

"The impact is that we will have guidelines to follow that will be more defined than what we had before, and we will be more comfortable doing postapproval changes," he says. "But I don't see many less-stringent standards for parenterals. The requirements will probably be very close to current standard practices."

EASE OF PROCESSING

Another implication of the increased regulatory scrutiny is an elevated interest in ready-to-sterilize and ready-to-use closures. "Drug companies have a high interest in ready-to-use packaging materials because these materials require minimal or no preparative work on their part," Smith explains.

Frank Keim, managing director of American Stelmi Corp. (Princeton, NJ), agrees, noting that "one advantage to this type of packaging is that it eliminates the stopper in terms of site-specific stability. It's in a bag, and you use it in the same way no matter where you use it. A large percentage of our products are in a ready-to-sterilize format, and I see a great deal of interest in that."

By the same token, Asselta says, "there is a renewed interest in glass as a packaging material because its strengths, such as being impermeable, chemically durable, and easily cleaned and sterilized, are gaining attention."

CLOSURE INNOVATIONS

Closure manufacturers are also working on other fronts to make their products simpler to process and more compliant with regulations.

"There is no resting on your laurels in this business," Robertson says. "It is important to develop barriers to protect the drug products, whether it be adding a liner or laminate or formulating a new rubber compound. You must formulate clean compounds."

There are two general categories of coatings that can be applied to rubber stoppers to reduce extractables, explains DeGrazio. "One emphasizes lubricity, replacing liquid silicone oil," she says. "Ours, for example, is a cross-lined silicone coating that dramatically lowers the degree of extractable silicone and functions in processing like a silicone oil. The second is barrier coatings. We have fluoroelastomer films that decrease extractables and increase compatibility. These are used for more-sensitive products."

USP 381

Another regulatory development is the recent revision of United States Pharmacopeia (USP) 381, a test for elastomeric closures for injections. (The document appears on p. 1108 in vol. 26, no. 4 of the Pharmacopeial Forum, July-August 2000.) It sets limits for a closure's turbidity, reducing agents, extractable lead, extractable zinc, pH change, total extractables, and UV absorbance.

PDA will submit comments on the revision because it differs from the organization's proposal to USP, Smith says.

"We wanted a two-tier system modeled on the European Pharmacopoeia (EP) and the International Organization for Standardization (ISO)," he says. "In our proposal, about 90% of the products would have fallen into the more-stringent Type I requirements, but the others (Type II elastomers) would have faced less-stringent ones. They came up with a one-tier system with fairly high test limits that include virtually all elastomeric closures on the market. It might not be as meaningful as it could be."

At PDA's annual meeting, December 4–5, 2000, in Philadelphia, the Packaging Science Interest Group resolved to persuade USP to adopt a two-tiered system, whether it be PDA's proposal or EP's current standard. Because the limits are so high in USP's proposal, Smith said, "drug companies would essentially need to develop their own limits anyway."

Nonetheless, DeGrazio says, "I don't anticipate it to cause significant issues for most closure manufacturers. There will be no impact on newly developed elastomeric formulations. The potential impact is on very old formulations that would be higher in extractables. But we feel the vast majority of them should be able to meet the requirements. That test serves as a very general screening. It's not the type of testing that you will use much once you choose your closure and develop your product. At that point you need to get into more-specific extractable testing."

EASE OF USE

While regulatory concerns have produced innovation in terms of ease of processing, the marketplace has produced innovation in terms of ease of use. One way this has been manifested is in a jump in demand for prefilled syringes.

"I think a lot of the interest is coming from home-care and self-care applications," says Jeff Turns, senior vice president, Vetter Pharma-Turm (Yardley, PA). "If you are giving an injection to yourself, it is easier to do if the proper dose is prepared for you. I think both the drug manufacturers and those who market syringes presume that the home-care and self-care markets will grow faster than the hospital market."

Regardless, he says, the outlook is positive because "there are more injectable chronic therapies now than there were even five years ago, and there are several products in the pipeline that may come to market in prefilled syringes."

Another source of innovation is coming from suppliers who "are trying to build devices that deliver respiratory drugs in a shorter amount of time," says Al Infusino, director of business development, Automatic Liquid Packaging (Woodstock, IL).

"One challenge involved with that is finding a way to improve compliance by end-users who administer their own drugs," he explains. "There are different devices being developed to address this issue. For example, a lot of people have to use nebulizers for a therapy that takes as long as 20 minutes. Perhaps the phone will ring in the middle of their therapy. Interruptions such as these result in the loss of the drug, which results in a lack of patient compliance to the prescribed regimen. New therapies and devices will address some of those kinds of problems."

Also, says Ray Scheire, director of business development for Biodome America (Princeton, NJ), now part of Baxter Healthcare Corp., "end-users are looking more at functional packaging, and not just how the drug in it works. They are interested in transfer systems that simplify the delivery of drugs. A number of systems such as ours have been in the marketplace, and the trend will continue in that direction. The end-user is expecting the kind of functionality out of drug products that he gets out of toothpaste."

But, Scheire says, producing those systems is easier said than done. "There needs to be critical mass to develop new improvements. The drug companies place so much focus on the drug itself that they usually don't have the expertise in packaging to guide us in any way. Often we have to go to them and say 'Here's a better mousetrap. Would you be willing to invest in order to see this on the market?' Often they are receptive, but unless you have a proven system, very few companies are willing to be the first to take a risk on a new delivery system."

CONCLUSION

Regardless of what form a parenteral package takes, suppliers must do whatever they can to make their products easier for their drug company clients to process and for the general public to use. Those who succeed in that will have the greatest opportunities to grow in the future.

Photo by Roni Ramos