The U.S. is one of only a few countries in the world that requires use of CR packaging with drug products, and our laws were first implemented more than 30 years ago, when Congress passed the Poison Prevention Packaging Act of 1970 (PPPA). At the time the law was enacted, Congress was greatly concerned by the number of small children who were killed or seriously injured each year due to ingestion of dangerous household substances. Congressional intent, in fact, was directly aimed at protecting children from harmful products that they could find in the home-everything from solvents, chemicals and pesticides to Rx and OTC drugs.
In passing the PPPA, however, Congress did not specify exactly what type of packaging would be considered "child-resistant." Instead-as it does with many of the laws it passes-Congress left it to a regulatory agency, in this case originally the U.S. Food and Drug Administration (FDA) then, later, the U.S. Consumer Product Safety Commission (CPSC) to develop rules that spell out what has to be done to comply with the law. CPSC regulations on this issue can be found under Title 16, part 1700-1750 of the U.S. Code of Federal Regulations (16 CFR 1700-1750).
Covered Products
Even though CR packaging is ubiquitous in the U.S., general understanding is somewhat limited when it comes to the types of packaging formats that can be used, and which products must be in a CR format. Generally speaking, CPSC regulations require that the following drug products be dispensed by the manufacturer in primary packaging deemed to be child-resistant:
- Anything that requires a doctor''s prescription (unless it has been specifically exempted from CR requirements);
- Certain OTC products including those that contain specific amounts of aspirin, acetaminophen, ibuprofen, iron, fluoride, and several other listed substances;
- Any solid oral dosage product-pills, tablets, capsules-approved for OTC sale by FDA after January 29, 2002 which contains an active ingredient that had previously been available by prescription only (these are known as "OTC-switched" products); and
- Investigational substances being used in clinical trials if they are dispensed on an out-patient basis, and contain an amount of drug product that could be expected to cause serious injury or illness to a small child.
With regard to primary versus secondary packaging, it is important to note that the law requires the CR feature(s) to be incorporated into the container which actually stores the drug product. In other words, manufacturers cannot legally dispense a regulated product in a non-CR container that is housed inside an outer package that is deemed to be child resistant.
CR Packaging Defined
Back in 1973, the US FDA established a test protocol that is still being used to determine whether a package is legally considered to be child resistant. Under this protocol-which is now overseen by CPSC and is codified under 16 CFR 1700.20-children and adults are both given packages to open. Only those packages that successfully foil small children, but can still be opened by adults, are considered acceptable.
While anyone can conduct a protocol test, there are several commercial operations around the country that have developed tremendous expertise in this area. Unless and until a package has been put through protocol by a recognized test lab, it should not be considered to meet CPSC''s legal definition of "child resistant." Anyone interested in engaging the services of a test lab would be well advised to contact CPSC''s Division of Health Sciences for a complete list of reputable outfits.
Here is basically how the protocol works: The children''s portion of the protocol is typically done first so that passing packages can go on to be tested with adults. Each panel of children is made up of 50 kids, divided almost equally between boys and girls, such that 30% of the panelists are between the ages of 42-44 months, 40% are between the ages of 45-48 months, and the remaining 30% are between the ages of 49-51 months. Children selected for testing must not have any "obvious or overt physical or mental handicap," and no more than 20% of the kids in a panel could have previously participated in a protocol test. Parental consent forms must be obtained for all children who participate in the test.
The kids are tested in pairs at a location that is familiar to them, well lighted, and "isolated from all distractions." Provisions are made to ensure that each child can see what the other is doing, and the adult administering the test is instructed to talk with the kids to help make them feel at ease.
Without giving children the impression that they are in a race or contest-and without offering any reward-the adult begins the test by handing both kids identical packages and saying, "Please try to open this for me." The kids are then given five minutes to get the package open. If a child refuses to participate or stops trying to open the package during the course of the test, the adult is required to "gently encourage" the child to keep trying with instructions such as, "please try to open the package." The protocol further specifies that kids should be given freedom of movement so that they can "stand up, get down on the floor, or bang or pry the package." They are also not to be discouraged from using their teeth, or from talking to each other.
If both kids get the package open in the first five minutes, the test is over. If one of them succeeds, but the other does not, the successful kid is thanked, and the adult is instructed to take his/her package away.
If one or both of the kids fails to open the package in the first five minutes, the adult is required to demonstrate how the package is opened and give two specific commands: 1) "Watch me open my package," and 2) "Now you try to open your packages." After this second command, another five-minute test period begins. If one or both of the children has not used their teeth during the first part of the test, the adult is also required to say, "You can use your teeth if you want to." At the end of this second period, the adult is instructed to make three separate statements: 1) "Thank you for helping," 2) "I know I told you that you could use your teeth today, but you should not put things like this in your mouth again," and 3) "Never open packages like this when you are by yourself. This kind of package might have something in it that would make you sick."
A package is considered to have passed the children''s portion of the protocol if at least 85% of the kids were unable to get it open within the first five minutes, or at least 80% were unable to get it open after the demonstration/use of teeth instruction. In other words, if as many as 10 kids are able to open the package after the full 10 minutes, the package is still considered to be child resistant. Moreover, the protocol allows for "sequential" testing such that as many as four panels of 50 children can be used if the package does not definitively pass or fail the first time around. If all 200 kids are used, a package is considered to be a failure if more than 41 of them are able to get it open after the full 10 minutes.
In the adult portion of the protocol, a 100-person "senior-adult" panel is used such that 25% of the participants are between the ages of 50-54, 25% are between the ages of 55-59, and the remaining 50% are 60-70 years old. At least 70% of the participants in the 55-70 age groups must be female, and at least 18 of the participants in the 50-54 year old panel must be women as well. Not more than 24% of the senior-adult panel can be "obtained from or tested at" the same location.
The senior-adult portion of the protocol can be conducted anywhere so long as it is a "well-lighted" and "distraction-free" area. Adults are tested individually, not in pairs, and are given five minutes to read any instructions on the product label and open the package. If they are successful, they are then given a second, identical package, and must open it within one minute. There is no demonstration provided by the person administering the test, but the panelists are instructed to read any instructions printed on the package. If the package is a re-closable format (a cap-and-vial closure, for instance), adult panelists must also properly reseal the package within a one-minute period.
If an adult is unable to get the package open in the first five minutes, the protocol requires that they be given two similar packages that do not have a CR feature. Adults are then allowed one minute to open and re-secure each of these two packages (a maximum of two minutes). If they fail to do so, they are excluded from the test. Adults are also required to read and sign a consent form before they can participate in a panel. If they cannot read the form, they are excluded from the test.
A package is considered to have passed the senior-adult portion of the protocol if at least 90% of the panelists were able to open and, if necessary, properly re-secure it in the time allotted.
Unit Dose Vs. Closures
Because it is intended to protect small children, protocol testing is a rigorous process. Interestingly, however, the test has certain inherent biases that favor cap-and-vial closures over unit dose formats such a blister and strip packaging. This is true even though data collected by CPSC strongly points to the fact that unit dose formats are safer than closures when it comes to preventing accidental ingestions of drug products.
Why is this? Primarily because the protocol was developed at a time-the early 1970s-when unit dose formats were virtually non-existent in the U.S. But in the intervening years, use of blisters has become more common in the U.S. with Rx and OTC products, and unit dose formats have become highly relied upon in clinical trials, where researchers have to account for each dosage unit. This is why efforts are currently underway to get CPSC to update the protocol. For the time being, however, the law is the law.
That said, there are many different types of unit dose formats that are capable of passing the CPSC protocol, and contract organizations should always consider use of unit dose because these formats offer significant benefits to drug manufacturers and consumers alike. Manufacturers, for instance, benefit from the fact that unit dose formats can be relied upon to: 1) provide tamper evidence, 2) increase shelf life; 3) facilitate distribution; 4) increase brand awareness; 5) facilitate compliance with pharmaceutical regimens; 6) prevent counterfeiting and diversion; and 7) protect each dosage unit from the time it is manufactured until the time it is ingested.
For consumers, unit dose formats: 1) reduce the likelihood of medication errors by eliminating the need for pharmacy personnel to repackage drugs; 2) enhance portability; 3) ensure product protection for each dosage unit, and 4) offer superior child resistance.
On this last point, it is noteworthy that CPSC has not documented a single incident during the past 17 years in which a child died after ingesting a drug removed from a unit dose format, regardless of whether it was capable of passing protocol. This can be contrasted with cap-and-vial closures which have been associated with more than 40 fatalities-more than half of which involved closures capable of passing CPSC''s protocol. The reason for this is simple: if a child is able to get the top off a closure, he/she has instant access to the entire contents. But if a child gets hold of a unit dose format, he/she has to remove each unit one at a time. This slows the child down and allows time for adult intervention or for the child to lose interest.
The bottom line is that unit dose formats are safer and offer many distinct advantages over closures. While it may currently be a bit more challenging to get unit dose formats through protocol testing, manufacturers should strongly consider unit dose as their primary packaging option. Moreover, if a contracting organization or manufacturer produces drug products that could be especially dangerous to small children, they should note that unit dose formats are currently the only type of packaging capable of protecting each dosage unit. It is possible, in fact, to make unit dose formats that simply cannot be opened unless scissors or some other type of tool is used. Such formats offer the "gold standard" in child protection because they are virtually impossible for kids to open, and their CR features do not rely on adults properly re-securing the package after every use.
CR and Clinical Trials
In 1999 CPSC staff dropped a bombshell on contract operations involved in clinical trials by announcing that investigational substances must be dispensed in CR packages if the substance is used on an out-patient basis. According to Commission staff, this was a statement of policy rather than a new requirement because, as far as CPSC knew, packaging for clinical trials routinely utilized CR formats. In reality, however, use of CR packaging for clinical trials was not the norm, and some organizations that run clinical trials had no idea that they were supposed to be using CR formats.
When CPSC staff announced these requirements, however, practical questions were quickly raised by those who run clinical trials. Would they have to put their packages through protocol before instituting a trial? What should be done with Phase IV trials when approved drugs are being tested against competing products? Do different packages have to be used in multi-national trials where drugs are being testing in the U.S. as well as other countries that have no CR requirements?
In response to these concerns, CPSC issued a clarification in 2000 specifying that clinical trial packaging need not be put through protocol. Instead, CPSC said it would exercise its "enforcement discretion" if manufacturers use any format that contained a CR feature listed under ASTM D-3475. Moreover, CPSC staff reiterated that CR packaging is only required if the investigational substance is going into a household, and could be expected to cause serious personal injury or serious illness to a small child.
Lastly, CPSC offered a timeline for complying with the new requirement such that operators of clinical trials were given a grace period-now expired-for ensuring that CR formats were being used when necessary. Unfortunately, to the author''s knowledge, CPSC staff never publicly answered questions regarding the international implications of its policy, or concerns related to Phase IV trials.
European Efforts
Contract organizations that do business internationally should also be aware of the fact that the European standards organization, CEN, is currently considering adoption of CR standards for unit dose formats. In late November, 2002, a CEN Working Group met in Basel, Switzerland, and voted to advance a draft standard which is almost identical to a CR standard for non-reclosable packaging that is also under consideration in Britain. While the British standard-if ultimately adopted in the UK-would only apply to packaging for aspirin, acetaminophen, and substances that contain iron, the CEN standard could be used by any number of European countries for whatever drug products they deem fit.
The CEN draft, which is currently being circulated among the European Union member countries for review, calls for the establishment of a test protocol similar to that used by the U.S., but with several critical differences.
Under the CEN draft, for instance, children are not to be told that it is alright to use their teeth to open the package. The CEN version also has an objective numerical standard for determining whether a unit dose format can be considered "child resistant" (i.e., the package fails if a child is able to remove more than eight dosage units during the course of the test). This is different from the CPSC protocol which states that a unit dose format fails if a child is able to gain access to more than eight units, or "the amount that may produce serious personal injury or serious illness, whichever is lower."
In other words, in the U.S., a unit dose format fails the CPSC protocol if a child can access, say, three tablets if the manufacturer has determined that is the amount which could cause serious illness or injury. The British government and the CEN Working Group both considered adoption of this "serious personal injury or serious illness" provision, but rejected it because there is no centralized database or collection system for determining how many dosage units of each particular drug product could be expected to cause harm. Moreover, unlike the CPSC, neither of these groups wanted to leave it to the manufacturer to determine the number of dosage units that could be considered harmful-but not lethal-to a small child. This is largely due to the fact that the Europeans learned from our experience in the U.S. that such determinations are extremely subjective. One manufacturer could determine that a harmful dosage of a particular product is four pills, for example, while another manufacturer of a similar product with the same active ingredient could peg the number at nine pills.
Another difference between U.S. standards and those being forwarded in Europe is that the CEN draft would allow "type testing" such that, once a package has passed protocol, it could be used again and again without the need for further testing. This differs from the U.S. where manufacturers are responsible not only for doing the initial protocol testing when they roll out a product, but also for periodically ensuring that their packaging is still capable of passing protocol so long as the product remains on the shelf. One U.S. test lab that routinely runs CPSC protocol reviews, for instance, advises manufacturers to re-test their packages every five years even if there has never been a poisoning involving the product inside the package.
A final point is that CPSC does not require manufacturers to test their packages. Instead, the Commission monitors data such as emergency room admissions and calls to poison control centers if an effort to identify packaging that could be dangerous to small children. When CPSC identifies such packaging, which is extremely rare, the Commission has the ability to penalize the manufacturer and/or recall any product contained in those packages. Facing such potential penalties, manufacturers typically feel compelled to test their packages so-in the event CPSC enforcement personnel come knocking-the manufacturer can demonstrate that the package has passed protocol.
Indeed, any contract organization that works with drug products should be aware of their clients'' legal responsibilities so that they can help comply with the law. While some contractors may focus on FDA regulations regarding Good Manufacturing Practices and related production matters, it is imperative that they have a good understanding of CR requirements as well. If not, they could find themselves in a very sticky situation.
Courtesy: Healthcare Compliance Packaging Council