INK SAFETY PORTAL

Importance of Pharmaceutical Packaging

Pharmaceutical packaging is a critical part in the drug delivery system as it plays a crucial role in preserving the quality and condition of a drug from the time of production until it is administered. Depending on the type of packaging, it serves multiple purposes, from protecting the drug product from environmental conditions and physical damage during transportation and handling (e.g. the blister), to providing information about the safe and effective use of the drug (e.g. the instruction leaflet).

Therefore, the packaging serves as a medium for conveying important information about the drug, such as its name, ingredients, usage instructions, warnings, manufacturer’s details, and expiry date as well as it provides convenience in handling, transportation, storage and dispensing of the product.

Types of Pharmaceutical Packaging

Due to the EU Directive 2001/83/EC, pharmaceutical packaging can be classified into the following categories: Immediate Packaging and Outer Packaging.

Types of Pharmaceutical Packaging
Due to the EU Directive 2001/83/EC

Due to the EU Directive 2001/83/EC, pharmaceutical packaging can be classified into the following categories:

Immediate Packaging

This is the first layer of packaging which is immediately in contact with the medicinal product. Examples are Ampoules, Blisters, Bottles, Infusion bags, Sachets, Syringes and Vials:

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Outer Packaging

This is the packaging into which the immediate packaging is placed. Examples are cardboard- or paperboard-boxes around an ampoule or blister:

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These packaging boxes are therefore not in direct contact with the drug whereas the instruction leaflet / package insert is much closer to the product than the printed outer packaging:

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This means, that the gas-phase migration risk of undesirable printing ink substances from the insert can be regarded higher in comparison to the migration risk of the printed outer packaging!

Regulatory Aspects

Pharmaceutical packaging must comply with regulatory requirements to ensure the safety, efficacy and quality of the medicinal product. Regulations govern aspects such as material selection, package integrity, tamper-evidence, child-resistance, and labeling.

 

Pharmacopoeia

A pharmacopoeia (from the obsolete Greek typography pharmacopœia, meaning "drug-making"), is an official publication that contains a list of medicinal drugs along with their effects and directions for their use.

Pharmacopoeia

Pharmacopoeia and packaging are closely linked in the pharmaceutical industry. Whereas packaging is crucial for protecting the integrity and quality of medicines, a pharmacopoeia (from the obsolete Greek typography pharmacopœia, meaning "drug-making"), is an official publication that contains a list of medicinal drugs along with their effects and directions for their use. These books / files are published by government authorities or a medical or pharmaceutical society and the provisions of the pharmacopoeia are binding upon all who produce drugs and dispense them. In a broader sense, it is a reference work for pharmaceutical drug specifications.

Today, globally around 49 pharmacopoeias are existing, the largest and best known are the United States Pharmacopoeia (USP), the European Pharmacopoeia (EP) and the Japanese Pharmacopoeia (JP). Although they all provide quality standards for medicinal products, the specific standards and methods may vary between the different documents. For example, there are differences in microbiological testing methods between USP, EP and JP. It is important to note that despite these differences, all three pharmacopoeias have the same objective: to ensure the safety and efficacy of medicinal products. Furthermore, it should be pointed out, that printing inks are not in the scope of these documents.

The 11th edition of the International Pharmacopoeia (Ph. Int.) was published in 2022 by the World Health Organization (WHO) and has an online access.

It provides specifications and test methods for priority medicines of major public health importance, for example listed in the WHO Model list of Essential Medicines. The Ph. Int. focuses on monographs that are of particular relevance to low- and middle-income countries that may not have sufficient resources to develop national pharmacopoeias. It serves as reference or adaptation material for WHO member states wishing to establish pharmaceutical requirements.

 

Extractables / Lechables / Migrants

Extractables and Leachables (E/L) play a crucial role in the pharmaceutical industry. They are an impurity subset resulting from the interaction of pharmaceutical products.

Extractables / Lechables / Migrants
A crucial role in the pharmaceutical industry

Extractables and Leachables (E/L) play a crucial role in the pharmaceutical industry. They are an impurity subset resulting from the interaction of pharmaceutical products with their packaging, drug delivery systems and manufacturing components. Proper E/L assessments are required by health authorities which should enable the pharmaceutical manufacturer to choose manufacturing, storage and administration materials that do not pose an undue risk for patients with regard to leaching.

In 2013, the United States Pharmacopoeia published the USP NF subchapters 1663 “Assessment of Extractables associated with pharmaceutical packaging/delivery systems” and 1664 “Assessment of Drug Product Leachables associated with pharmaceutical packaging/delivery systems”, which establish critical dimensions for extractable and leachable assessments respectively. The definitions in the 2 subchapters are as follows:

Extractables are organic and inorganic chemical entities that are released from a pharmaceutical packaging/delivery system, packaging component, or packaging material of construction and into an extraction solvent under laboratory conditions…. Extractables themselves, or substances derived from extractables, have the potential to leach into a drug product under normal conditions of storage and use and thus become leachables.”

Leachables are foreign organic and inorganic chemical entities that are present in a packaged drug product because they have leached into the packaged drug product from a packaging/delivery system, packaging component, or packaging material of construction under normal conditions of storage and use or during accelerated drug product stability studies. Because leachables are derived from the packaging or delivery system, they are not related to either the drug product itself or its vehicle and ingredients…..Leachables are typically a subset of extractables or are derived from extractables.”

Moreover, in both chapters there is also a reference to migrants:

Migrants are also foreign organic and inorganic chemical entities that are present in a packaged drug product because they have leached into the packaged drug product from a packaging/delivery system, packaging component, or packaging material of construction under normal conditions of storage and use or during accelerated drug product stability studies….. Regardless of whether a substance is a leachable or a migrant, it is still a foreign substance in the packaged drug product and thus it must be impact assessed in the same manner.”

This means, that all foreign substances in pharmaceutical packaging, regardless of whether they are extractables, leachables or migrants must be evaluated similar regarding their safety for human health.

 

Exposure Evaluation and SoC

As explained in the previous chapter, the migration of substances in printed pharmaceutical packaging must be carefully monitored and transparency about the potentially present migrants is pivotal.

Exposure Evaluation and SoC

As explained in the previous chapter, the migration of substances in printed pharmaceutical packaging must be carefully monitored and transparency about the potentially present migrants is pivotal. A possibility for the exposure evaluation would be the “worst case calculation” (WCC) model if it covers the real exposure scenario of pharma applications with sufficient certainty.

For food contact materials the default conditions are, that a person of 60 kg weight eats 1 kg of food packed in 6 dm2 of material every day (the so called “EU cube”):

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An exemplary WCC of a potential migrant which is present in the dried ink film with 3% would result under Siegwerk standard conditions (3 g/m2 dry ink, 100% area coverage) in a maximum migration into the food of 5.4 mg/kg (ppm).

A corresponding worst case calculator is available here.

For pharma packaging, the consumption conditions depend very much on the application. As comparison, in an example case of a pharma blister a corresponding assumption could be that a person of 60 kg weight swallows 3 pills of 2 g packed in 0.06 dm2 of material every day. The WCC of a migrant under the above mentioned conditions would lead to a maximum migration from the reverse printed side into the pills of 54 µg/kg (ppb), whereas the maximum migration from a heat seal lacquer, which is in direct contact to the print and applied with 8 g/m2 would be 144 µg/kg (ppb). For this example calculation it was taken into consideration, that the daily intake are only 6 g of pills and not 1 kg.

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This means, that the calculated limit of exposure is in this example case 5-15 times higher than 10 ppb, which is a typical threshold of concern limit in FCM applications. Hence, only a specially selected range of printing inks with a transparent disclosure of migrating substances should be used for each respective pharma application.

Siegwerk is informing its customers about all potentially migrating substances which are present in a printing ink for NPH (Nutrition, Pharma, Hygiene) packaging applications in its Statement of Composition (SoC). Even if the information in the Siegwerk SoC refers to FCM it can also be applied to pharmaceutical applications as it reflects a “worst worst case” scenario in comparison to the EU-cube approach.

Details about the Siegwerk SoC are available here.