All about the box

In December 2016, a pharmacist in Northern Ireland made a tragic error when he fatally dispensed propranolol to a patient who was prescribed prednisolone. It was revealed that the two boxes were side-by-side on the pharmacy’s shelf, with similar branding and packaging. Such simple slip-ups can result in devastation and highlight packaging’s crucial role in keeping patients safe.

Here, Oliver Pittock managing director of pharmaceutical packaging supplier, Valley Northern, examines the areas of pharmaceutical packaging that require special attention, and how it can contribute towards a future of safer medication.

Even to the trained eye of a busy pharmacist, medication names such as Daptomycin and Dactinomycin, Levoxine and Lanoxin could be easily muddled — especially if they share similar dosages and are packaged in indistinguishably alike white cardboard boxes.

Incorrect dispensing is just one issue that can arise from ineffective packaging. Dangerous storage conditions, medication tampering and the production of counterfeit medicine can all occur when packaging is not as effective as it should be. But what can we do to prevent these problems before they jeopardise public health?

Storage solutions

Pharmaceutical packaging solutions have to keep medication safe not only on the store shelf, but also at home. There are many factors that lead to medication being improperly taken, ranging from patient non-adherence to combining it with alcohol or certain foods that may impact its effectiveness.

How medication is stored can also gravely impact its efficiency. Research presented in 2018 at the European Association for the Study of Diabetes (EASD) annual meeting suggests that insulin used to treat the condition is often stored at the wrong temperature in patients’ fridges at home, which could affect its potency. Many injectable drugs are highly sensitive and can perish if temperatures shift by just a few degrees.

To prevent loss of effectiveness, insulin must be stored between two and eight degrees Celsius in the refrigerator or between two and 30 degrees Celsius when carried about the person in a pen or vial.

Researchers from the association used sensors to monitor the storage temperatures of 388 diabetic patients’ insulin. Data produced by the study showed that insulin stored in the fridge was above the recommended temperature range for an average of eleven per cent of the time — just over two and a half hours a day.

Low temperatures were also an issue, with 17 per cent of the sensors recording temperatures below zero degrees Celsius. For people living with insulin-dependent diabetes, precise dosing is essential. Even a gradual loss of potency can affect the medication’s viability, which could lead to dangerous outcomes for the patient.

When considering how we should package medication with strict storage instructions, manufacturers must ensure that storage guidelines are clearly and concisely displayed on the box and in the instruction pamphlet. Without this clarity, patients could unknowingly hinder their own health.

Maintain the chain

Storage conditions must also be considered during transport. If the cold chain has to be maintained to keep medical products viable, it’s crucial that delivery services are equipped to provide the correct conditions. Vaccines are sensitive biological substances. The influenza vaccine is sensitive to freezing, while others are sensitive to heat and light.

Vaccine potency, meaning a vaccine’s ability to effectively immunise a patient, can diminish if these variables fail to be maintained. To ensure their quality, vaccines must be protected from temperature extremes.

When transporting temperature sensitive medication, appropriate validated cool boxes fitted with thermometers must be used. Vaccines sensitive to light, such as the measles-mumps-rubella (MMR) injection, should be kept in dark glass vials to protect them from light exposure. It’s also important that such vaccines are kept in secondary packaging to further protect them during storage and transportation.

Discovering desiccants

Moisture is another factor that can disrupt the safe storage of medication. When packaging medication that can be affected by moisture levels, manufacturers must consider ways of protecting it. We've all seen the silica gel sachets thrown in the box of a new pair of shoes. But did you know that desiccant sachets are crucial in controlling the moisture inside packaging, particularly for pharmaceutical products?

While we may toss away these packets from our new shoes or handbags without much deliberation, these small but mighty sachets are vitally important for protecting pharmaceutical products from moisture and humidity.

Humidity may often be to blame for untameable hair and headaches, but it can have more serious consequences on lifesaving drugs. Moisture that is retained in medication packaging or containers can cause a lot of problems, including degradation of active substances, reduction of drug potency and the development of mould and mildew.

Desiccant formulas

The two most common types of desiccants used in pharmaceutical manufacturing are silica gel and molecular sieve.

A molecular sieve is a porous material that can reduce moisture levels to almost zero and is used in applications where moisture needs to be completely removed. Initially patented in 1919 and used during World War II to dehydrate pharmaceutical supplies, silica gel uses hygroscopic salts such as calcium chloride and perchlorates to absorb up to 40 per cent of its weight in moisture — without increasing in size.

Silica gel comes in two types: a white, non-indicating version and a second version that changes colour when moisture is absorbed. The latter is particularly useful to the pharmaceutical industry, especially if medication has been in transit or storage for a long period of time. If the colour of the gel is altered, pharmacists or patients will be aware that the desiccant has stopped working, and that the medication may contain excess levels of moisture that could affect its potency.

Keep it safe

While non-indicative silica gel isn’t toxic, it could cause irritation to the throat and nose if ingested and can be considered a choking hazard. Indicative gel, however, can contain toxic ingredients such as methyl violet or cobalt dichloride and is considered a substance of very high concern (SVHC).

It’s important to use silica gel sachets that meet international standards. Suppliers, like Valley Northern, should offer sachets containing Food and Drug Administration (FDA) approved ingredients.

Desiccant canisters or capsules are sometimes favoured, as they absorb odour as well as moisture. The canisters also feature welded end caps, meaning that they can prevent dirt and dust from entering, contaminating the contents and reducing its effectiveness.

A safer future

While it is crucial to control environmental factors such as temperature and humidity, a reduction in product potency can also be a result of more heinous actions. Counterfeiting continues to plague pharmaceuticals. Worth over £150 billion, it is the world’s largest fraud market — and it’s not just the matter of lost earnings for legitimate manufacturers that’s the issue.

Anyone, anywhere in the world, can come across medicines that are seemingly packaged correctly, but have been tampered with and, in the worst-case scenario, filled with toxic substances. Both generic and innovator medicines can be falsified, ranging from very expensive drugs produced used to treat cancer to commonly used pain relief.

In fact, statistics from the World Health Organization (WHO) estimate that up to ten per cent of all medication sold is counterfeit, with cancer and heart medication among the most reproduced. Research also shows that in developing countries, the risk of obtaining and taking counterfeited medicine is much higher than in higher-income ones.

Combatting counterfeits

On February 9, 2019, the Falsified Medicines Directive (FMD) came into place to help tackle the volume of counterfeit and intentionally tainted pharmaceutical products. Falsified medicines are those that appear to be genuine, authorised medication but may contain ingredients, including active ones, that are of poor quality or the wrong strength. As falsified medicines have not been properly evaluated to approve their quality, safety and efficiency, they could be detrimental to a patient’s health.

The directive was implemented by the European Commission and requires the more than 2,200 pharmaceutical companies that hold market authorisation to place two safety features on all new packs of prescription medicines placed on the market in Europe.

These features include a unique identifier (UI) in the form of a two-dimensional data matrix, such as a barcode, which can be scanned at various points along the supply chain to determine the medication’s authenticity. The UI must contain product details including the medication’s name, pharmaceutical form, strength, pack size and type, a national identifying code, batch number and expiry date.

By scanning the UI, wholesalers and pharmacists should be able to compare the data it produces with that stored in the National Medicines Verification System (NMVS), a digital ledger that holds all information for medical products subject to the FMD in each EU member state. Cross-referencing the packaging’s data with official records allows pharmacists to verify that the medication they are dispensing is legitimate.

The other requirement is an anti-tamper device (ATD) to prevent medication being interfered with or switched for a replica. While there are no stringent regulations as to what constitutes at ATD, typical methods include glued down packaging flaps, seals or labels that must be broken when opening, shrink or film wrap and foil blister packs.

Getting smart

To help implement the directive, and to keep medication safe and effective, pharmaceutical manufacturers must take packaging into consideration. This includes introducing smart packaging features to increase the security of these potent products.

Medication security labelling continues to evolve, ranging from void films that leave an irreversible ‘VOID’ message once a package has been opened to infrared (IR) taggants that contain special additives only detectable with IR readers. These microscopic particles contain multiple colour layers, which translate into a unique numeric code.

The particles can be loaded with additional security layers such as pattern recognition for additional complexity and changed frequently and easily to prevent counterfeiters from grasping the codes.

Holograms are another useful addition to packaging and feature micro-embossed metallised paper with two or three-dimensional holographic diffraction patterns. These patterns can be customised and registered on the International Hologram Manufacturers Association’s database for authenticity.

Digital water marks are also being increasingly used, which offer an extra layer of protection by using encoded data on the packaging that can only be verified with specialist software. The data can be captured by a webcam, smartphone or other scanning equipment, but is invisible to the human eye. 

The bespoke approach

Individually, these smart solutions deliver heighted levels of security and assurance that medication is authentic and has not been altered. However, pharmaceutical manufacturers may want to consider not only adopting a single one of these technologies but combining them to develop a customised solution. For example, using barcodes or holograms coupled with a custom void film could ensure better protection against both counterfeit medication and tampering.

Using packaging design tools, such as Valley Northern’s Custom Print Design Tool, would allow manufacturers to benefit from smart packaging features, while making sure that their packaging is easily distinguishable and recognised as the legitimate product.

Custom printing means that manufacturers can take a more bespoke approach to their packaging. This not only makes packaging look more aesthetically different and thus prevents the likelihood to mix-ups, but the method also allows manufacturers to create their own layered approach to medication security with combination of smart packaging solutions.

Medication safety is not only about what’s inside the box. To prevent devastating errors, ineffective storage and the risk of medication tampering and falsified products, pharmaceutical manufacturers must take packaging into careful consideration. The potency of medication is crucial to its safety and efficiency, and even the smallest slip either side of the margins could lead to disaster. Clear communication, regulation compliance and smart solutions should all be implemented when packaging these potent products.