Child resistant and senior friendly packs for pharma packaging — A total contradiction?

Dr Erwin Pasbrig

Approximately 140,000 to 160,000 small children poison themselves – unintentionally – every year in Germany, approximately 20,000 of who need to be treated. Unfortunately, every year there are 30 to 50 fatal poisoning accidents with children in Germany (related to household cleaner, poisoning plants, fertiliser, cosmetic products and pharma products) – deaths that could be prevented.

The Pharmaceutical Association of Great Britain (PAGB) has been investigating accidents at home for years (HASS data) and has found that – poisoning accidents of children during the period 1982 until 1998 have been constantly decreasing: by 33 per cent for all children, by more than 50 per cent for children under five years of age.

In the same period the proportion of non-reclosable pharma packages has increased tremendously.1

Only from the age of three are many children able to understand rational reasons about the dangers involved or at least are willing to accept a ‘no’ and follow educational measures and thus simple safety rules. From this point onwards-educational measures become increasingly important. This is why around 90 per cent of all accidents involving swallowing of alien substances happen with small children at the age between 10 months and 4.5 years of age (approx 90 per cent), with a significant peak for children aged one to 2.5.

Picture 1: Blister packaging for sweets and pharmaceuticals

Hazardous substances for poisoning are: household cleaning agents, pharmaceuticals, stimulants, poisonous plants, fertiliser, cosmetics and oils. Leading substances for poisoning are pharma (37 per cent) followed by tobacco (20 per cent) and cleaning agents.2, 3 Children are familiar with blister packs containing sweets or chewing gum (Blister A). Thus they associate blisters with something positive. The same holds true for shapes and colours of tablets (pharma products are marked by an arrow) (Picture 1).

The history of child-resistant packages started in the US with the Code of Federal Regulations Part 1700 to 1750, subchapter E: Poison Prevention Packaging Act (PPPA), 1970 regulation. This was the introduction of the concept of having packages tested by children and adults.

An American study shows that since the introduction of child-resistant packages for prescription drugs (tablets) the mortality rate due to poisoning has been decreasing significantly. According to this analysis, approximately 460 fatal accidents were prevented due to this protective measure; in other words a reduction by 45 per cent.4 

Country-wise regulations on child resistant packages
US	1970
Canada	1975
Germany, DIN 55559	1979
Italy (only regulation, no standard)	1984
Australia	1985
The Netherlands follow DIN	1985
United Kingdom, BS 7236 CoP	1989
UK, BS8404	2003
EN 14375	2003
Korea	2007

After the start by the US there were more countries that introduced standards and legislation with regard to child-resistant packages (reclosable and non-reclosable).

With the British standard BS 8404 and the European standard (for members of the CEN) it is for the first time that tests with children and adults are requested in Europe (CR/SF packages). As the first country in Asia, Korea have implemented the request for CR/SF in 2007.

A CR/SF package is defined as: “Package designed and developed which is difficult to be opened by small children within an appropriate time but not difficult to be handled by adults”5.

According to EN 14375: “Package which complicates opening (respectively access to the content) for small children but facilitate appropriate usage by adults.”

A target range is defined which can be checked in the course of the test (maximum ‘n’ per cent children may open the package and at least ‘n’ per cent of the adults must be able to open the package) in a given time. The test is carried out with children and adults of a certain age group and gender. Depending on the opening performance the package meets the target (target range) or fails. 

Table 1: Social and demographic indications
Country	Population		Life expectancy (years)
Under 15 years (%)	Under 15 years (%)	Over 65 years	Women	Men
Europe	17.8 % (135 Mio.)	14.5% (110 Mio)	71 – 83	66 – 79
US	21 % (61.7 Mio.)	12 % (35.2 Mio.)	80	75

The necessity for CR/SF packages for pharma packages is reflected by the population development in Europe and the US (Table 1). The ratio children/adults (older than 65 years) and the life expectancy vary but the trend in all countries is the same: increasing life expectancy and decreasing birth rates.

In Europe more than 80 per cent of solid pharma are packed in blisters, in the UK approximately 60 per cent. The main reasons for this are as follows: high degree of protection of each individual dose, higher shelf life; patient compliance; hygienic storing (only individual dose is removed); safe against manipulation (tamper evidence); only one dose can be removed per opening.

Variation in regulations between Europe and the US
	Europe	US
Bottom material	Product should not be seen (e.g. opaque, dark colour)	no regulation
Toxicity	No Max eight products per blister can be removed	Yes Limitation of the number of removable products depends on toxicity
Type testing	Yes	No

CR/SF in Europe and in the US – Two distinct worlds

Regulations as to the design of CR/SF packages and the tests to be carried out vary considerably between Europe and the US.

Shape and colour of pharma products are marketing factors. The patient is supposed to remember the product. Thus in the US the bottom material is transparent if cold form foil (CFF; alu-alu, Panblok) is not the material of choice. Thus there is the risk that children mistake the drug for sweets. In Europe mostly opaque coloured thermoform able film or Formpack is used.

Each product which is listed or for which there is a risk that children might poison themselves by swallowing the drug has to be packed in a CR/SF package. In the US, pharmaceuticals are traditionally packed in bottles but the proportion of blisters is constantly increasing. Irrespective of the fact whether a pharma company has (a) product(s) in CR/SF on the market a test has to be carried out for a new or different amount of active substance. 

Table 2: Test criteria for CR/SF
	PPPA (1970)	EN 14375
Children (months)	30% 42 – 44 40% 45 – 48 30% 49 – 51	42 – 51; max. 200 same number per age group and gender
Adults (years)	25 of 50 – 54 (since 1997) 25 of 55 – 50 50 of 60 – 70	25 of 50 – 54 25 of 55 – 50 50 of 60 – 70 30 male, 70 female
Testing period children Testing period adults	2 x 5 minutes 1 x 5 minutes	2 x 5 minutes 5 minutes preparation 1 minute test
Criteria for target achievement Children Adults	According to stipulation > 90	< 15% more than 8 individual doses within 5 minutes without demonstration; < 20% more than 8 individual doses within 10 minutes with demonstration; > 90

The criteria for the selection of test persons and test results are defined in the regulations/standards (Table 2).

PPPA is applicable for the following products (without details and restrictions, original page 614 – 617 of PPA ):8 Aspirin, methyl salicylate, controlled drugs, iron containing drugs, dietary supplements with iron, acetaminophen, diphenhydramine.

Prescription drugs, apart from nitroglycerin, isosorbide dinitrate, anhydrous cholestyramine, pancrelipase preparations, prednisone in tablet form, mebendazole in tablet form, colestipol in powder form, conjugated estrogens tablets, norethindrone acetate tablets, erythromycin ethylsuccinate granules and tablets, cyclically administrated oral contraceptives sodium fluoride drug preparations,betamethasone tablets, all unit dose forms of potassium supplements, methylprednisolone in tablet form.

US

Most frequently used solutions for CR/SF blisters are as follows:

• Tear-open package with notch; ASTM Type VIIIE; Semi-rigid blister with tear-open notch and instruction to use scissors for opening of the package (2 x 3 = 6 cavities); Test result adults: 0.942, tested by 2 x 100 adults. 84 per cent of the adults said that the package was easy to open
• Peelable opening
• Peel-push opening

ASTM Type VIIID; Semi-rigid blister with peel-push opening (3 x 4 = 12 cavities) Test result adults: 0.961, tested by 100 adults. 81 per cent of the adults said that the package was easy to open;

As to pouches opening is carried out by means of hidden tear notches

• ASTM Type IVA; Pouch with internal (hidden) tear notch Test result adults: 0.981, tested by the first 100 of total 400 adults. 80.5 per cent of the adults said that the package was easy to open;
• ASTM Type IVC as ASTM Type IVA with instruction to use scissors for opening of the package. Test result adults: 1,000 tested by the first 100 adults. 99 per cent of the adults said that the package was easy to open.

For all packaging solutions at least two steps are required to remove the product. Thus these blisters always have a cross perforation. As the children are asked during the test to take the blister into their mouths there is always a plastic film integrated on the outside. This renders the option of biting the package through more difficult.

I do not know of any pharmaceutical in a push-through package on the US-American market which would be in compliance with the Fortschreibungsliste (list published by the German Federal Board of Health) and was tested as CR/SF.

New solutions for CR/SF use blisters that are integrated in a cardboard package (blister cards). In this case access to the product is achieved by manipulation (pushing, turning) and subsequently the product is pushed through the lidding foil.

Europe

In Europe the standard EN 14375 has been in effect since the end of 2003. This was agreed upon by the CEN member states. Members of the CEN (Comité Européen de Normalisation, Geneva) are: Belgium, Denmark, Germany, Finland, France, Greece, Ireland, Iceland, Italy, Malta, Luxembourg, Austria, The Netherlands, Norway, Portugal, Sweden, Switzerland, Slovakia, Spain, Czech Republic, Hungary, the UK. This European standard has to be changed by the individual member states into a national standard to become effective. In Germany the EN 14375 has the status of a DIN.

The peel-push opening that is frequently used in the US has not found a market in Europe. According to the opinion of the pharma companies no opening feature, which is unknown to the user, is to be offered. These companies fear that this would lead to a competitive disadvantage and market shares might be lost. Furthermore, the blister for a peel or peel push version becomes larger (perforation and tear-open tab = unsealed area). This causes a decreased machine output and increased requirement for packaging material, thus it is more expensive than a push-through package complying with the Fortschreibungsliste (Picture 2).

Presently, the development of a mechanical test, which would result in as little involvement of children in the tests as possible, is being discussed. Nevertheless, the test has to reflect reality and has to be validated.

Picture 2: Blister with peel-push opening

Germany

The Arzneimittelgesetz (German Medicines Law) stipulates the products which have to be packed in a child-resistant package.

According to the regulation of an edition according § 28 Arzneimittelgesetz (Child-resistant packages for pharmaceuticals) dated February 12, 19829 and September 17, 198410 the formulations listed hereunder may only be sold in the following containers:

1. Push-through packages (blister packages) with individual dose packaging under exclusive use of opaque or dark coloured material, or
2. Sealed strip packages with individual dose packaging under exclusive use of opaque or dark coloured material, or
3. Container with safety closure (closure system with combined features (e.g. push and twist at the same time) which complicate opening by children.
4. For pharmaceutical such as unit dose powders or granulates single dose envelopes or single dose pouches are sufficient.
5. As to liquid pharmaceuticals these containers comply with the regulation if they have inserts that cannot be removed by children without destroying the container. After the package has been opened and shaken, squeezed or tampered with once not more than 0.5 ml of the liquid may flow out if the liquid drug has to be taken in drops. In other cases not more than 2 ml may flow out.

The containers mentioned under a, b and c have to comply with DIN 55559.

Standards stipulate test procedures but not what the package needs to looks like. Packaging solutions, which have been tested successfully, were registered at the BFArM (Bundesinstitut für Arzneimittel und Medizinprodukte, German Institute for Pharmaceuticals and Medical Products) and are then entered in the Fortschreibungsliste (Table 3). This list does not have to be complete as only those items are listed which are registered by pharmaceutical companies or packaging manufacturers.

Table 3: Fortschreibungsliste (type testing) for child-resistant blisters11
BAFArM No.	Lidding foil	Bottom (1)	Remark
9 (1980)	lacquer/Al 25 µm soft/HSL	cross perforation, 0.7 mm width of perforation
14 (19981) 30 (1985)	50 g/m² coated paper/Al 9 µm/HSL	250 µm PVC 250 µm PVC/PVDC
15 (1981) 30 (1985)	35 g/m² glassine paper/Al 9 µm/HSL	250 µm PVC 250 µm PVC/PVDC
17 (1981) 30 (1985)	lacquer/ Al 30 µm/HSL	250 µm PVC 250 µm PVC/PVDC	pyramid-shaped embossing design
23 (1982) 30 (1985)	lacquer/Al 25 µm soft/HSL	250 µm PVC 250 µm PVC/PVDC	cross perforation, 1.1 mm width of perforation
31 (1985)	50 g/m² paper/Al 7 µm /HSL	250 µm PVC	250 µm PVC
42 (1991)	50 g/m² paper/Al 7 µm /HSL	300 µm PP	250 µm PVC
43 (1991)	40 g/m² paper/Al 7 µm /HSL	300 µm PP	250 µm PVC
48 (1996)	23 µm PET/Al 20 µm /HSL	25 oPA/60 Al/60 PP	Peel-push
49 (1993)	70 – 100 µm Purelay-Lid	300 µm PP	300 µm PP
52 (1999)	50 g/m² paper/Al 9 µm /HSL (PVC)	250 µm PVC/51 µm Aclar	250 µm PVC/51 µm Aclar
(1) = dark coloured or opaque;

Material combinations past test according to the previous DIN 55559 still have to be tested according to the adult test in order to be compliant to DIN EN 14375.

Type testing (Fortschreibungsliste) is valid for the tested package and in a sense for the product packed. Nevertheless there is no such regulation that the tests have to be repeated dependant of the geometry of the filling good. BS 8404 accepts the material combinations approved by the DIN standard.

Changes of the material combination (e.g. 25 µm Al soft and COC, cross perforation) ask for a new test. Reason for this is mainly the distinct stiffness of bottom materials. For example for reclosable containers the largest and the smallest are tested and it is assumed that the intermediate sizes will also comply with the criteria for CR/SF if it passes the tests. Reason for type testing: the number of children who have to participate in the tests is decreased.

Australia

In Australia the Therapeutic Goods Act 1989 is effective, Therapeutic Goods Order No. 65 “Child-Resistant Packaging for Therapeutic Goods” (non-reclosable and reclosable packages). In this regulation also the therapeutic goods are stipulated which have to be packed in a child-resistant package. As to non-reclosable packages blisters or other single unit dose packages listed it is stipulated which specific material requirements have to be fulfilled. Test procedures are defined in AS 1928-1982. In the protocol of 1996 it is described that approved packages from Canada, the US or the UK will also be approved in Australia if an appropriate test certificate is provided.

India

The Indian standard IS 14233 (1995) “Packaging – Pharmaceutical Products – Child Resistant Tamper-Proof Packaging for Solid Dosage Forms – Code of Practice” is similar to BS 7236 and describes blisters and strip packs. The test of the package is not carried out with children but is a mechanical test.

Japan

In Japan there is no regulation/standard as to CR/SF. It is up to the pharma company whether and how to pack the pharmaceuticals with protection for children.

Canada

Here the Canadian standard CSA 276 C: Drugs I is effective. According to this standard a package is child-resistant when compliant with CSA 276 (1992 last edition concerning non-reclosable packages), reclosable packages (1995), UK Standard BS 5321 and PPPA.

New Zealand

In New Zealand the standard NZS 5825 (non-reclosable and reclosable packages) is effective. Approval is granted by the Department of Health. Packages which are approved in Europe, US or Australia as child-resistant are also approved in New Zealand.

Abilities/ Difficulties of children and adults
	Abilities	Difficulties
Children	Clamping, pressing, biting, tearing, hitting, do it with perseverance, eager to learn, imitation, experimenting with pleasure, visual preferences, fundamental positive attitude	Combining, execute simultaneous and complex motions,reading, writing, strong force, semantic experience, fine-motoric motions
Adult	Combining, simultaneous motions, reading, writing, pressing, clamping, biting, tearing, pulling, hitting, semantic experience, understanding, taste preferences.	Loss of force, weak vision, low contrast perception, low comprehension of new technical subjects, uncontrollablefine-motoric motions, loss of memory, mental block,typically negative approach to new thinks.

Development and test of new solutions for CR/ SF

The pharma industry is looking for new packaging solutions for CR/ SF. Some of the existing materials have been on the market for more than 20 years. The abilities of today’s children have evolved too and thus new solutions are required. In addition to new technical solutions there is the requirement to maintain the same for the same processability while producing low costs.

The development of a package is influenced by the age specific abilities and difficulties of the user. The abilities of children and adults respectively the difficulties they have to cope with are reciprocal. This complicates the possibility to offer complex solutions. The more difficult it is for an adult to open the package the more likely it becomes that the package remains opened, or that the content is filled into a package which is not CR/SF.

In order to check the probability for compliance of the newly developed solutions with the CR/SF test according to EN 14375 all materials can be checked as to their puncture resistance or burst strength. The test device is fixed in a machine for check of tensile strength and the strength, which the plug needs to puncture the lidding foil from the inside is measured.

The heatseal lacquer can be replaced by a plastic film:

1. protective lacquer /Al 20 µm, rigid/15 µm PVC
2. protective lacquer /Al 20 µm, rigid/25 µm PVC
3. protective lacquer /Al 20 µm, rigid/30 µm PVC
4. protective lacquer /Al 20 µm, rigid/40 µm PVC
5. protective lacquer /Al 20 µm, rigid/30 µm PP

Other solution, tested successful, is the lamination of paper to the 20 µm hard tempered aluminium:- paper 40 g/m²/Al 20 µm, rigid/HSL.

Advantage of this structure is that the inner side, contact to the product, remains unchanged.

The test results in comparison to the existing specifications of CR push-through foil according to the Fortschreibungsliste are listed in Table 4. Standard push-through foil 20 µm rigid is also depicted as a comparable value with 100 per cent. Based on the results the lidding foils 1, 2 and 5 were checked at the IfKiV in Hamburg (Institute for Child-resistant Packages) as to compliance with EN 14375 and BS 8404 with respect to CR/SF. All materials passed the tests and thus can be used for packaging of products that require CR/SF features. Processing of these new solutions for CR/SF can be carried out on existing blister lines, analogous to the paper laminates. A preheating station for high speed blister lines or increased angle of contact of the sealing roller is recommendable. 

Table 4: Values of Barrier properties of Lidding Foils for CR/SF
BAFArM No.	Lidding foil	MVTR (g/m² x d) ASTM F 1249-90 25°C; 100%r.H.	OTR (cm³/m² x d x bar) ASTM D 3985-81 25°C; 50% r.H.
14 (19981) 30 (1985	50 g/m² coated paper/Al 9 µm/HSL	(1)	(2)
15 (1981) 30 (1985)	35 g/m² glassine paper/Al 9 µm/HSL	(1)	(2)
17 (1981) 30 (1985)	lacquer/ Al 30 µm/HSL (embossed)	< 0.01	< 0.005
23 (1982) 30 (1985)	lacquer/Al 25 µm soft/HSL	< 0.01	< 0.005
31 (1985)	50 g/m² paper/Al 7 µm /HSL (PVC)	(1)	(2)
42 (1991)	50 g/m² paper/Al 7 µm /HSL (PP)	(1)	(2)
43 (1991)	40 g/m² paper/Al 7 µm /HSL (PP)	(1)	(2)
52 (1999)	50 g/m² paper/Al 9 µm /HSL (PVC)	(1)	(2)
	35 g/m² Kraft paper/Al 9 µm /HSL (PVC)	(1)	(2)
	protective lacquer/Al 20 µm, rigid/15 µm PVC	< 0.01	< 0.005
	protective lacquer /Al 20 µm, rigid/30 µm PVC	< 0.01	< 0.005
	protective lacquer /Al 20 µm, rigid/30 µm PP	< 0.01	< 0.005

A topic to be discussed is always the barrier properties of the lidding foils (Table 4) in relation to diffusion of water vapour (MVTR) and oxygen (OTR). A 20 µm thick aluminium foil is technically pinhole-free (max. 0.5 pinholes/m²; average: 0.1 pinholes/m²) and thus impermeable for gases and water vapour. A study published in the Schweizer Aluminium Rundschau 12(1) (Swiss Aluminium Review) has shown that only unconverted aluminium foil of 7 respectively 9 µm thickness results in a higher water vapour transmissibility than detection limit and depends on the number of pinholes. The values measured which resulted from lacquered and laminated aluminium foils were lower. The main amount of humidity diffuses through the thermoformed bottom foil. Results of the oxygen transmissibility rate (OTR) (2) are not available. Nevertheless the same holds true as was stated in connection with the moisture vapour transmissibility rate (MVTR).

Ansapack is producing following structures and selling under name Panchild1:

• 35 g/m² glassine paper/Al 9 µm/HSL
• 35 g/m² Kraft paper/Al 9 µm /HSL (PVC)
• protective lacquer/Al 20 µm, rigid/15 µm PVC
• protective lacquer /Al 20 µm, rigid/30 µm PVC

They were given to the German test institute IfKiV and tested successful (certificates available).

Conclusion

The application of CR/SF for non-reclosable packages is constantly increasing. Thus pharma companies, which sell their products to countries with respective regulations/standards have to process appropriate packages. Manufacturers of flexible packaging materials are requested to develop appropriate solutions. Ansapack has contributed to this request with the lidding foils mentioned. With Korea started to implement CR/SF regulations it is foreseen that other countries in Asia will follow. Nevertheless, with regard to all solutions for CR/SF it must be self-evident that child-resistant packages are only the last measure of a whole range of protective measures and they do not assume the responsibility for parents and guardians; it is still their obligation to store pharmaceuticals out of the reach of children.14

Rerefences:

1.   Tassilo Korab, presentation TATAL Exhibition Birmingham, March 2004
2. www.aponet.de
3. www.vitanet.de
4. www.optipage.de
5.   Guidance on Compliance with the Medicines (Child Safety), Regulation 2003, MHRA; John Trepper, VP Perrit Labs „Blister and Harmonisation“ May 2000
6.   DSW-datenreport “Weltbevölkerung 2004” (World Population 2004), Weltbevölkerungsbericht 2004 (Report: World Population 2004)
7.   Panblok is trade mark for cold form laminate from company Ansapack
8.   Consumer Product Safety Commission 16 CFR Ch. II (1-1-90 edition)
9.   Banz No. 36 dd. February 23, 1982, p. 1
10.   Banz No. 178 dd. September 20, 1984, p. 10683
11. www.bfarm.de/de/Arzneimittel/am_sicher/stufenpl/KISIP-Aufst.pdf
12.   “Schweizer Aluminium Rundschau” High Quality Converter Foils and Laminates with Maximum Barrier Properties – 1981
13.   Panchild is trade name of M/s Ansapack
14.   EN 14375:2003 (D), p. 3