No Direct Contact, Still Migration: How Low-Migration Pharma Labels Protect Plastic Containers

A pharmaceutical label sits on the outside of a plastic bottle. It never touches the medicine inside. So how could it possibly contaminate the drug?

This is one of the most misunderstood risks in pharmaceutical packaging. Even without direct contact, molecules from a label's adhesive, ink, or coating can travel through the plastic container wall and end up inside the drug product. This process is called migration, and it is the reason low-migration labels exist.

The Plastic Container Is Not a Perfect Wall

Glass is an excellent barrier. Plastic is not. Plastic containers - especially thin-walled LDPE bottles, COC syringes, and flexible pouches - are permeable at the molecular level. Small molecules from the outside can diffuse through the plastic and reach the contents.

This permeability is the core of the problem. A label is considered secondary packaging because it does not touch the drug directly. But regulators have recognized that secondary packaging can still be a source of contamination if its components can pass through the primary container.

Migration vs. Set-Off: Two Different Pathways

Migration is not the only way label components reach a drug. There is also set-off.

Migration is the diffusion of molecules from the cured ink, adhesive, or coating through the packaging material into the product. It happens over time and is temperature-dependent.

Set-off is different. It occurs when the printed outside surface of a label touches the unprinted inside surface of the packaging - for example, when labels are stacked or wound on a roll. Molecules transfer from the printed side to the product-contact side, and from there they can enter the drug.

Both pathways matter. A label can be designed with a perfect barrier on the printed side and still fail because of set-off. That is why low-migration labels must address both mechanisms.

The Term Does Not Mean Zero

No plastic packaging system has zero migration. The term "low-migration" is used because some amount of migration will always occur. The goal is to keep migration within the accepted limits set by regulatory authorities so that the packaging is deemed safe for use.

A low-migration label is engineered so that its components either do not migrate in significant quantities, or migrate only at levels well below the applicable safety thresholds.

Three Components Must Be Controlled

A label is made of three main parts: the face material, the adhesive, and the ink. All three must be qualified for low-migration performance.

Adhesive: This is the component in closest contact with the container, and it contains the largest number of potentially mobile substances. Low-migration adhesives such as Avery Dennison's S692NP are formulated to dramatically reduce migration risk, especially as plastic packaging replaces glass.

Ink: UV-curable inks contain photoinitiators and monomers that can migrate if they are not fully cured. Low-migration ink systems use photoinitiators and resin systems designed to minimize mobile residues.

Coatings and varnishes: Overprint varnishes and protective coatings must also be selected from low-migration grades.

The Qualification Process

Low-migration labels are not simply "better" labels. They are tested and certified. Independent institutes such as ISEGA provide certification that a label construction meets the relevant regulatory principles, including FDA 21 CFR 175.105 for adhesive components.

Testing involves extracting the label under controlled conditions and analyzing what comes out. If the migration stays within the specific and overall migration limits, the label is considered suitable.

FDA 21 CFR 175.105

This regulation covers adhesives used as components of articles intended for packaging food. For pharmaceutical labels, it provides a baseline for adhesive safety. It is important to note that compliance with 21 CFR 175.105 does not mean the adhesive is suitable for direct food contact. It applies to adhesives that are separated from the product by a functional barrier - which is exactly the situation with a label on a plastic container.

USP <661>

The United States Pharmacopeia chapter <661> provides standards for plastic packaging systems. USP <661.1> addresses plastic materials of construction, and <661.2> addresses the completed packaging system. The chapter establishes that packaging ingredients cannot adsorb onto the product surface or migrate through the packaging system in unsafe amounts.

EU 10/2011

For products sold in Europe, EU Regulation 10/2011 sets specific migration limits (SML) for individual substances and an overall migration limit (OML) of 10 mg per dm² of contact surface. Labels used on plastic containers must be evaluated against these limits.

Step 1: Identify Your Plastic Container Material

Different plastics have different permeability. Thin-walled LDPE bottles and COC syringes are more challenging than thick HDPE containers. Ask your label supplier whether their low-migration construction has been tested with your specific container material.

Step 2: Ask for the Full Construction, Not Just the Adhesive

A low-migration adhesive on a standard ink is not a low-migration label. Confirm that the face material, adhesive, ink, and any coating are all qualified as a complete system. Request the certification or test report for the full construction.

Step 3: Consider Set-Off in Your Storage and Handling

If your labels are supplied on rolls or stacked sheets, set-off is a real risk. Ask whether the label system has been evaluated for set-off, not just diffusion. The printed surface should not transfer ink components to the unprinted side under normal storage conditions.

Step 4: Test Under Realistic Aging Conditions

Migration is a time-and-temperature process. A short lab test may not reveal a problem that appears after 24 months on the shelf. Look for data from accelerated aging studies, or request that your supplier run a migration study that reflects your product's shelf life and storage conditions.

Cyclic olefin copolymer (COC) syringes are increasingly used for prefilled injectables because they offer glass-like clarity with plastic convenience. But COC is permeable, and label migration was a concern.

Schreiner MediPharm developed low-migration label concepts specifically for COC syringes, using pre-tested adhesives, materials, and inks. In a study with SCHOTT, labeled COC syringes were stored for 36 months at 25°C. After aging, the contents were analyzed for volatile, semi-volatile, and non-volatile compounds. No additional compounds were found compared to unlabeled reference syringes. The barrier properties of the COC syringe, combined with the low-migration label, prevented migration of label components into the drug product.

Q1: What does "migration" mean in pharmaceutical labeling?
A: Migration is the movement of molecules from a label's adhesive, ink, or coating through the plastic container wall and into the drug product. It can happen even when the label does not directly touch the medicine.

Q2: If the label does not touch the drug, why is migration still a risk?
A: Plastic containers are permeable at the molecular level. Small molecules from the label can diffuse through the plastic over time. Regulators recognize that secondary packaging can be a source of contamination if its components can pass through the primary container.

Q3: What is the difference between migration and set-off?
A: Migration is diffusion through the packaging material. Set-off is the transfer of ink molecules from the printed outside surface to the unprinted inside surface when labels are stacked or rolled. Set-off can then lead to migration into the product.

Q4: What is a low-migration label?
A: A low-migration label is a label constructed with a face material, adhesive, ink, and coating that have been selected and tested to keep migration within regulatory safety limits. It does not mean zero migration, but migration low enough to be considered safe.

Q5: Which regulations apply to low-migration pharmaceutical labels?
A: Key regulations include FDA 21 CFR 175.105 for adhesives, USP <661> for plastic packaging systems, and EU Regulation 10/2011 for migration limits. Suppliers often use independent certification bodies such as ISEGA to verify compliance.