Originally Published PMPN June 2001
When selecting packaging materials and components for solid oral drugs, drug manufacturers must balance the needs of both children and adults. Charged under the Poison Prevention Packaging Act of 1970 to design packages that help protect children from potentially toxic drugs, manufacturers must also make sure that adults who have limited dexterity can use the packages properly. Devising such a package isn't always a scientific endeavor, because manufacturers must base their selections on unpredictable factors like marketplace opinions and child testers. Add to this mix the expectations of the United States Consumer Product Safety Commission (CPSC), which hopes to eliminate child poisonings through regulation but offers manufacturers little guidance in package selection.
In this exclusive roundtable discussion moderated by Pharmaceutical & Medical Packaging News editor Daphne Allen, five packaging professionals who work for major pharmaceutical manufacturers and a representative from an industry trade association discuss the challenges of creating child-resistant, senior-friendly packaging. The participants are John Bitner, manager of package design and development, Pharmacia (Skokie, IL); D. Bruce Cohen, director, packaging technology, GlaxoSmithKline (Research Triangle Park, NC); Arthur Jaeger, director of packaging development, Merck & Company, Inc. (West Point, PA); Ken Lang, engineering, strategic improvement department, OTC drugs, Bristol Myers Squibb (Mt. Vernon, IN); Rafael Vega Feliciano, senior package engineer, Wyeth-Ayerst Pharmaceuticals, packaging services group (Philadelphia); and Peter Mayberry, executive director, Healthcare Compliance Packaging Council (Falls Church, VA). These six professionals discuss the advantages and disadvantages of using bottles and blister packages, the challenges of meeting the requirements of CPSC's package testing protocol, the difficulty of determining the toxicity level of drug products, and the need for devising a package that patients—even senior citizens with arthritic hands—will actually use at home.
How important is child-resistant packaging to you when you select packaging materials?
Cohen: Certainly for solid-dose formulations, child-resistant packaging is part of the decision. It really depends upon the toxicity level of the product and how the package is going to be presented to the marketplace. If the product is going to be a unit of dispense, then we have to take into consideration everything that's required for child resistance for that particular drug. If it has optional pack or line extensions that make it a pharmacy dispensing pack, then child resistance falls away at that point.
Is child-resistant packaging an issue that first comes up in clinical trials?
Cohen: When we get into the end of Phase II and the beginning of Phase III clinicals, we want to narrow down the packs that marketing has in mind for the product. We try to use the final marketed pack for Phase III, if it's a package that we can get at that point. If not, child-resistant packaging probably wouldn't show up until the launch.
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| "What we are trying to accomplish with the child-resistant package is to make it as intuitive as possible. And it's hard to make a blister intuitive at a high toxicity level." John Bitner manager of package design and development, Pharmacia (Skokie, IL) |
Bitner: We try to get materials into ICH stability testing that we perceive will be useful for child-resistant packaging, even though we have additional development time beyond ICH.
Vega Feliciano: One of the things we consider is cost. We need to be very aware of cost in the over-the-counter (OTC) market because our margins are smaller.
Mayberry: When a product goes from prescription to OTC status, it doesn't necessarily have to be packaged in a child-resistant format. CPSC evaluates each of those drugs case by case. But last year CPSC proposed a rule that would automatically require a child-resistant format for what it refers to as OTC-switched drugs. It accepted public comment on that proposal through November, and now it's deciding what to do based on those comments.
Did anyone here file any comments with the CPSC?
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| "Let's be more aggressive about teaching people how to properly use a child-resistant package. We need to teach the consumer that no package is 100% safe." Rafael Vega Feliciano senior package engineer, Wyeth-Ayerst Pharmaceuticals, packaging services group (Philadelphia) |
Mayberry: HCPC and the Consumer Healthcare Products Association both did. There were two other comments as well—one from a group of students in Florida and another comment from a private citizen.
Does anyone else here have any reaction to that CPSC proposal?
Cohen: The proposal would put more pressure on both the manufacturers of the components as well as the manufacturers of the drug to reduce costs as products move to OTC status.
Would it delay OTC product launches?
Jaeger: If products will be packaged in bottles, the proposal is probably not a big deal. However, if you start going into flexibles, you've got other issues: what the toxicity levels are, what the opening features look like, which patients will use the package, and how difficult will the package be to open.
What packages are best at meeting child-resistance requirements?
Bitner: It depends upon the toxicity of the product, the market we're aiming for, and the regimen of the medication. If you're looking at a regimen of three tablets a day, for instance, for a chronic condition, then it's going to be very difficult to get that product into a blister. It would be much better off in a bottle.
Mayberry: There's a quirk in the regulation regarding toxicity and blisters. Under the protocol, if you're using a bottle, it's a failure if the child gets the top off, regardless of the quantity. There could be 100 tablets in the bottle. When you use unit-dose packaging, such as a blister, there is an eight-pill standard, so if during the test children open or gain access to eight tablets in the blister or to an amount that would cause serious illness or serious injury, then that's considered a failure. But CPSC doesn't define what the serious illness or serious injury is, so it's up to the manufacturers to determine the toxicity level. Such a consideration needs to be made for blisters but not for bottles.
Vega Feliciano: I don't think that it's a matter of liking one better than the other, it's a matter of what is best for your product. Some products are more suitable for blisters; some products are more suitable for bottles. There are even some products that will require a pouch because of some specific characteristic.
Jaeger: Most market research shows that, given the choice, a lot of patients seem to prefer bottles—not because they're better or worse, but because they understand them. They've seen push-and-turn caps for so long that they can use them without thinking. However, the bottle is not always appropriate.
Lang: It also depends upon what market you're trying to get into, like OTC decongestants. Everything on the shelf is in blisters.
Bitner: What we're trying to accomplish with the child-resistant package is to make it as intuitive as possible. And it's hard to make a blister intuitive at a high toxicity level. When a failure means that children can access just one tablet, a blister becomes a very difficult package to present, especially to arthritis patients or the elderly.
Cohen: On occasion we've sized the blister with the toxicity level in mind to include as few tablets as possible but still meet patient requirements. For instance, we have one product that has three tablets in a blister pack and that is the sale item. That particular regimen of three might serve a patient for a day and a half or two days, depending on their needs. But because of the toxicity levels, if a child were to get into all three, it wouldn't be harmed.
Jaeger: The access level permitted for an individual product being packaged makes a big difference. If a product has a high allowable access level, you've got a lot more options. You can go with something that's child resistant but not nearly as unfriendly to a lot of patients, especially elderly patients.
Cohen: There's a popular pack out on the market for an antibiotic that marketing wants us to use. But that particular product's toxicity level is nowhere near what's presented in the package, so therefore the package is not child resistant. It's a nice blister pack, and everybody talks about it, but we can't necessarily put every product in it because of the higher toxicity levels.
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| "When comparing blisters to bottles, it is evident that children access more units when circumventing a child-resistant closure on a bottle." Peter Mayberry executive director, Healthcare Compliance Packaging Council (Falls Church, VA) |
Mayberry: In the United Kingdom, there's effort to establish a child-resistant packaging standard for nonreclosable packaging. The draft standard was similar to the U.S. standard, and they got more than 300 complaint letters. An overwhelming majority of the complaints focused on the issue of determining toxicity. Based on that, the United Kingdom is leaning more toward a numerical amount rather than an amount determined by toxicity testing.
Cohen: But what if five is your toxicity limit? Then manufacturers are not going to use a blister with a count of eight unless they're looking for trouble.
Mayberry: There are products that are highly toxic, so you need to put them in a count of one, two, or three pills. Then there are others where a package of 30 is not likely going to cause a problem. But the vast majority is in a gray area.
Cohen: At some point, we need to have some standard test, like an ASTM method. We could put blisters through it to ensure that they meet a minimum requirement and are therefore deemed child resistant, rather than spend all the time and effort that all of us do in looking at a group of children who varies by location and ability. If you go to one test lab, test your pack, and get a failure, and then you go to a second test lab, test the same pack, and get a pass, where does that lead you? To a third test somewhere else to try to get another pass. What makes one better than the other? They're very subjective. We need some type of reproducible, mechanical, electronic, standard test.
Mayberry: John and I are both on the ASTM subcommittee D10.31 regarding child-resistant packaging, and just earlier this month at a meeting in Phoenix, it was apparent that ASTM doesn't want to look at specific aspects of the child-resistant packaging testing protocol because ASTM members doubt that CPSC will change it.
Bitner: We've got a protocol that's worked for 30 years. We've cut the number of pharmaceutical-related deaths dramatically to one to two per year.
Mayberry: Yes, but there are data that show there are still thousands of poisonings every year supposedly involving child-resistant closures for bottles or vials. There have been more than 5 million calls to poison prevention centers over the past 17 years involving children 6 years old and younger who ingested prescription or OTC drugs, as documented by the American Association of Poison Control Centers.
Bitner: Those calls may be more prevalent because of education. Patients know that some of these medications can be poisonous and they know who to call now. There are also more poison prevention centers in the country.
Mayberry: We asked CPSC for all its data from 1983 through October of 2000 regarding accidental exposures to prescription drugs or OTC drug products by children 6 years old or younger. What we got back were reams of data. There were hundreds of instances where children were sent to the hospital because they supposedly got these products out of child-resistant bottles, and there were 365 deaths over that period of time. Yet, there were 33 documented cases involving blisters in which children accessed drugs, and of those there were only two—two in 17 years—where child-resistant blisters were involved.
Bitner: Or documented to be involved.
Mayberry: But when comparing blisters to bottles, it is evident that children access more units when circumventing a child-resistant closure. There were 11 instances where children gained access to between 41 and 50 tabs. There are 5 instances where children gained access to between 61 and 75 tabs.
Jaeger: Today there are more once-a-day products with higher concentrations and higher potencies. So there are a lot of products where accessing just one or two tablets may be a problem.
How do you feel about child-resistant blisters currently on the market?
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| "We need a standard test, like an ASTM method, that we could put blisters through to ensure that they meet a minimum requirement and can be deemed child resistant." D. Bruce Cohen director, packaging technology, GlaxoSmithKline (Research Triangle Park, NC) |
Cohen: It depends upon your toxicity level and what your marketing folks want. We use peel-and-push blisters for most of our child-resistant blister packages. We've had to put some of our blisters into a chipboard card in order to increase the complexity and reduce the number of child openings.
Bitner: Most are extremely difficult for a senior or a debilitated patient to operate. But if you make them too easy, children are just going to rip them apart, easily accessing the medication.
Jaeger: There aren't all that many different types of child-resistant packaging materials to choose from. I'm not talking about suppliers. If it's a blister material, one side needs to be backed with polyester. If it's a pouch, you need an adequate thickness of polyester on the outside, and the rest depends on die-cutting configuration, graphics, and opening instructions.
Bitner: You bring up a good point regarding the number of vendors. There aren't that many vendors out there with the capability, the intelligence, the resources, the mentality, and the interest to develop programs for us.
Mayberry: Some vendors have gone to the trouble of designing a more intuitive package and putting it through the child-resistant testing protocol themselves to ensure that it'll pass the protocol. They then make it available for licensing, and then no one picks it up. Fortunately, there is one intuitive package that requires cognitive ability over physical strength that has passed the protocol and won HCPC's Compliance Package of the Year Award for 2000.
Bitner: Vendor testing doesn't do us much good. We still have to test our packages. When a vendor comes to us with a child-resistant package that's passed with a given tablet, test protocol, and regimen, we still have to test it.
Jaeger: Supplier test results provide very useful information whenever we are developing new packages. However, the ultimate responsibility for ensuring package performance in the marketplace rests with the manufacturer.
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| "Protocol testing certainly meets the regulation, but it does not always give you all the information you need to ensure your package will be well received in the marketplace." Arthur Jaeger director of packaging development, Merck & Company, Inc. (West Point, PA) |
Cohen: In some cases, we have found that even when using the same bottle with different closure suppliers and the same liner, we get different results.
Bitner: As end-users, we know what we want to accomplish, but the vendor still has the greatest converting technology and the understanding of how those materials react, as well as firsthand knowledge of new developments.
Do you need more vendor support?
Bitner: Once we have a concept and engineering designs, we'll do the testing—it's our market, it's our protocol, it's our focus group. But we need more experts to show how to convert materials and how to make our concepts reality.
What are you doing to meet the needs of patients who suffer from conditions that make it difficult to open complex packages?
Bitner: At Pharmacia, we consult a panel of what we call patient partners, who are patients suffering from arthritis. Most are registered with the Arthritis Foundation and doctors, so half a dozen of them can represent hundreds of patients across the country. We run different designs by them and design packages according to their feedback. Before we go to protocol testing, we do some screening and some preliminary tests with 70- to 80-year-old people and patients with arthritis.
Jaeger: More than just CPSC protocol testing is needed. Protocol testing certainly meets the regulation, but it does not always give you the information you need to ensure your package will be well received in the marketplace.
Bitner: If a vendor comes to us and says it passed the CPSC protocol, that's not all that is necessary. We can pass the protocol with any number of different packages. But that doesn't necessarily mean that a patient or consumer is going to use that package in the home.
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| "You need to put clear, concise opening instructions regarding opening features on the package in short bullet points so seniors know how to open it." Ken Lang engineering, strategic improvement department, OTC drugs, Bristol Myers Squibb (Mt. Vernon, IN) |
Lang: You also need to put clear, concise instructions regarding opening features on the package in short bullet points so seniors know how to open it.
Are you leery of using a blister?
Mayberry: Manufacturers don't want to market products that aren't going to be popularly received, and a blister is likely going to be more difficult to open than a bottle, unless tremendous forethought is given to its design.
How do you properly balance child resistance with senior friendliness ?
Mayberry: CPSC's response is you need better packages. John mentioned earlier that you can engineer packaging that does not rely on strength as much as on cognitive ability.
Jaeger: I've heard some companies say they've resorted to instructing patients to use scissors to open packages. But you shouldn't need a tool to open the package.
Cohen: We have several packs on the market that require scissors to open, and I have no complaints that I'm aware of, as opposed to the blister packs we have that frustrate seniors.
Mayberry: Are the scissors-only packages pouches?
Cohen: A couple of them are. One pouch features a tear notch that is an open, unsealed circle within the package that you have to fold over.
Bitner: Scissors are brutal to an arthritis patient, and you certainly don't want a hemophiliac patient using scissors. We have a fantastically successful pouch that has wider heat-seal areas with big, fold-over areas where the notch is positioned on the crease so you can't miss it. A target and arrows point the child to an area that is laser scored and cut. Ninety-nine percent of the kids went right for that score and tore the opening feature off in the first five seconds of the test, disarming the package. Trying to do that same thing with a blister is more challenging.
Are there any innovations that you think should become standard, like using squeeze-and-turn closures instead of push-and-turn ones?
Bitner: Squeeze-and-turn designs are one of the most discouraging developments in the last 30 years. They are not senior friendly. Arthritis patients have a lot of trouble with that type of motion.
Cohen: We've looked into squeeze-and-turn closures for a number of reasons, including the fact that they eliminate the torque requirements for opening. They also represent a reduction in price, and there are fewer components that will end up in the trash. But as John said, people who have difficulty squeezing because of limitations in their hands or wrists find that they can open the push-and-turn closures with the palm of their hand and the top of a table. There is a new proposed cap with a one-piece, push-and-turn mechanism that may be a better compromise—it requires the same force and the same procedure that most people are used to, but it is a little less strenuous.
Mayberry: For the first five years of HCPC's existence, I never heard about anything novel with blisters—it was all peel-and-push or notch-and-tear. But over the past five years, there has been an attempt to design better blisters both child resistant and senior friendly.
What else could make your job easier?
Bitner: We need a more formal universal program of national education about poisons. Poisonings occur because of ignorance. FDA responded in a surprising and disappointing way to iron tablets, mandating for the first time in history that iron tablets above a certain level have to be in blisters because they're dangerous to children. This was based on a false assumption that blisters are inherently child resistant. If all parties concerned had made it better known that iron can present a poisonous situation, iron wouldn't have been left out for children to get into.
Mayberry: The protocol gives consumers a false sense of security. In the data that we got from CPSC there were seven instances in which children were given drug products in a bottle with a child-resistant closure as a rattle or toy because an adult believed that it was childproof.
Vega Feliciano: CPSC could do a better job educating people on how to use the package and why it's important to put it away even though it's considered child resistant. Let's be aggressive about teaching people to properly use a child-resistant package. We need to teach the consumer that no package is 100% safe.
Copyright ©2001 Pharmaceutical & Medical Packaging News
