Pharmaceutical and medical products can be broadly divided into prescription drugs, non-prescription (or over-the-counter/OTC) drugs, and hospital equipment/consumables. While these categories are partly overlapping, their requirements for the label converter are substantially different, for legal, usage and marketing reasons. The principal regulations, which the label designer or converter needs to know about, are detailed below.
DIRECTIVES AND REGULATIONS
The two main regulatory bodies are the Food & Drug Administration (FDA), for the United States, and the European Union for Europe. Other official agencies regulate drug sales in China and other countries but generally, their rules tend to approximate to those of the FDA and EU.
Label converters are not expected to know all the very complex regulations regarding the text for pharmaceutical labels but should at least be familiar with the general requirements so as to be able to discuss with their customers and understand their constraints.
For the United States, the Federal Food, Drug and Cosmetic Act (FFDCA) defines ‘labeling’ as all labels and other written, printed, or graphic matter upon any article or any of its containers or wrappers, or accompanying such article. The term 'accompanying' is interpreted liberally to mean more than physical association with the product.
Label converters wishing to get full details of US compliance requirements can consult the US Registrar Corp who (for a fee) will provide confirmation that a given label or package meets FDA requirements.
PRODUCT INFORMATION REQUIRED ON PHARMACEUTICAL LABELS/PACKAGING
Requirements will vary from country to country and product to product, but the following will generally be required:
Ingredients, active and inactive
Any specific product warnings
Directions for taking or use
Information about allergic or other reactions.
MARKET STRUCTURE – PRODUCTION, DISTRIBUTION AND MARKETING
The pharma business has seen increasing concentration in recent years as bigger firms bought up smaller ones to increase their market share. Globally, the biggest drug producers are those listed in Figure 5.1.
Figure 5.1 Top pharma companies by global sales. Source- PM Live
You will notice that despite the huge size of leading companies, the market is still not concentrated. Despite the strict regulatory framework existing in most countries, smaller pharmaceutical companies exist in their tens of thousands.
IMPORTANCE OF CONTRACT PACKERS IN PHARMA SECTOR
Many pharmaceutical companies do not pack their own products. The packing/labeling (and sometimes even the preparation of the product) is given over to specialized contract packers. This means that the label converter has to conform to the demands of both the drug company and the packer. Contract packers are frequently called upon to pack small quantities for clinical trials.
This is why many of them have invested in digital label presses. Some, like Netherlands-based Sinensis, specialize in providing short-run packing services for pharmaceutical manufacturers.
US-based Catalent has 25 packing sites covering North America, Europe, China and Japan. However, although the pharmaceutical business is global, contract packers are mostly not. GMP Pharmaceuticals for example covers mainly the Australian and New Zealand markets, Redditch Medical does business mostly in UK.
MARKETS AND PRODUCT TYPES
With few exceptions, the doctor, and not the patient chooses a prescription drug. It is therefore one of the few products for which the label/packaging has almost no marketing function. It is almost unique in that in nearly all developed countries, the ‘buyer’ either gets it free, or pays only a nominal amount.
Labels for prescription drugs therefore tend to be one or two colors only. In some countries a two-layer label enables users to peel the top layer and stick it to their reimbursement form, however with increased ‘paper-free’ transmissions this practice is on the way out.
Either the label or the packaging will need to carry a braille description (this is also the case for many OTC medicines). If braille is carried on the label it is generally done by embossing, although screen printing and digital printing are also used.
Users of non-prescription (or OTC) drugs are free to choose the products they buy, so normal competitive forces come into play. Frequently branded and supported by heavy advertising, they need to stand out on the pharmacy shelves or, if not displayed, at least be attractive in appearance when bought, or when visible in a bathroom cabinet.
The medical and hospital sector is where many label innovations find their use (see Figure 5.2).
Figure 5.2 Not just a label – August Faller has developed imaginative label solutions for the medical sector
Consumables include blood pouches, serums and indeed all products administered to, or injected into, a patient. The double or triple layer self-adhesive label, with one copy going onto the patient’s record, avoids the risk of errors when copying by hand. For blood bags, the hospital sector needs very special labeling materials due to regulatory requirements and the extreme conditions associated with blood storage and processing.
Several labelstock producers have developed laminates specifically for this use. UPM Raflatac for example have designed a range of primary blood bag label materials fully compliant with ISO 3826 standards. These labeling products use an adhesive that can tolerate temperatures from +121 deg C during steam sterilization, down to -80 deg C, as well as freezing in ethanol to -50 deg C.
Other medical equipment requiring specialty labels includes syringes and all kinds of flacon. Much ingenuity has been shown by label converters whose innovations have included ‘Needletrap’ a safety label for syringes and ‘Flexicap’ a protective pack with integrated label for the protection of dangerous fluids.
A particularly ingenious syringe label has been designed for so-called ‘auto-injector’ syringes, as used for example by those suffering from acute diabetes (Figure 5.3). As well as the usual printed information, this label comes with an anti-slip varnish to prevent slipping during injection, an integrated hologram which identifies the product as an original, and a printed QR code or Near Field Communication (NFC) chip which provides a link, via smartphone, to a website with additional product information.
Figure 5.3 Syringe label from Schreiner Medipharm
Hygiene, inventory accuracy, patient safety: medical facilities and hospitals have to follow many regulations regarding clinical practice and keep track of their medical equipment at the same time. For this, RFID labels are being used, particularly in hospitals and clinics.
In a Danish dental clinic, RFID tracking of dental instruments is said to improve patient safety and hygiene. Instruments can be tracked continuously from the time of entry into the system, through their use and processing, and can even be sterilized (without harming the label).
For label converters, the importance of the hospital/medical sector must not be underrated. Hospitals and health services are quite rightly more concerned about reliability than cost. Having established a relationship of trust with a label supplier, they are reluctant to change. That is the reason why so many world-class label converters (CCL, Reynders, Schreiner Medipharm and others) all have a division devoted exclusively to meeting the needs of this sector.
Pharma and medical labels can be of many types, but self-adhesive and to a lesser extent sleeve labels dominate. Frequently all component parts of a label (paper/film, backing, adhesive, inks, coatings) must conform to strict specifications. Peelable (multi-layer) self-adhesives, as mentioned above, are increasingly used for hospital applications. In many countries, blister foil packs are the primary packaging for pills, and these are generally printed on the same flexo or digital presses as for labels.
PRINT TECHNOLOGIES, INKS AND ADHESIVES
All print technologies can be used for pharma/medical labeling. Increasingly, digital printing is being used because of the need for short-run test batches of drugs, or for individualized labels for hospital use. However for nearly all label applications in this field the biggest hazard is migration. Harmful substances which might be tolerated in inks or adhesives used for other purposes cannot be tolerated where there could be a risk to a patient’s health.
WHAT IS SPECIAL ABOUT PHARMACEUTICAL AND MEDICAL LABELING?
Special features can be grouped under four main headings:
Labels must be able to withstand rough handling, so they must be scuff-proof, but also water- and humidity-proof. This means that the inks must be fully water-resistant, even when patients drop their medicines into the bath. This applies equally to the labelstock/adhesive used, which must resist humidity and ageing. The typeface (font) needs to be legible for the intended user (who might be an elderly person with impaired eyesight). In Europe and many other regions braille lettering is compulsory (see box). Both EU and US regulations stipulate font size and legibility. For the EU in addition a directive (Article 63(1) of Directive 2001/83/EC) required that ‘labelling and package leaflet shall appear in the official language or languages of the Member State where the product is placed on the market’. This requirement has greatly increased the use of multi-page or booklet labels with one page for each language.
In both pharmacy and hospital usage, labels may come into contact with hazardous or corrosive liquids, and must remain legible under even extreme exposure. The print must be indelible, and must not fade with age or exposure to sunlight.
The same problems arise as in the food sector; only here the conditions can be even more extreme. Sterilization, frequently by autoclave, is a well-known difficulty, requiring the label converter to use only heat- and moisture-resistant adhesives and inks for an environment with temperatures over 100 deg C.
In some cases sterilization may also use extremely cold temperatures, and storage – of vaccines for example – may mean the label has to resist weeks or even months of cool or cold temperatures which may go down to minus 80 deg C where the physical properties of adhesive, film and paper can alter. This is a major challenge for the label converter. However, as described above, major labelstock manufacturers have developed materials suitable for these extremes, and inks are also available for such specific applications.
This is the ultimate danger with all labeling and packaging in the medical sector. Harmful substances can permeate through the label and into the contents which is why here, as in the food sector, migration of chemical substances in the ink or adhesive of the label can cause problems.
However in the case of most solid pharmaceuticals (e.g. pills) the substance itself is encased in a blister pack which is itself rarely labeled. More important among potential contaminants is sunlight, which can pass through the label and adversely affect the product. However other forms of contamination can occur when labels are applied, for example, to blood bags.
THE BATTLE AGAINST COUNTERFEITERS
The above risks concern problems which may happen accidentally in pharmaceutical labeling. More frequent, unfortunately, are the problems of fighting against deliberate counterfeiting (worldwide, Viagra is said to be the most frequently counterfeited medical product – see Figure 5.4).
Other commonly counterfeited products include antibiotics, cancer drugs, anti-malaria pills and treatments said to cure conditions ranging from hair loss to obesity or depression.
Figure 5.4 Pharmaceutical products most commonly counterfeited
In some developing countries medical authorities reckon that more than half the pharmaceuticals in circulation are counterfeit. As a result millions of people are at risk of buying drugs that in the best case will not cure them and may even do deadly harm. Labels and packaging have a vital role to play in fighting this menace. Methods (see figure 5.6) include:
Overt (visible) brand protection involves visible/tactile security features that can be easily read by the public and by pharmacy employees. This involves holograms, special colors, hard-to-copy digital watermarking, 3D features, encrypted RFID, smart-phone-readable QR codes and above all reliable, tamper-evident closures (Figure 5.5)
Covert (invisible or masked) brand protection using invisible inks or other security features needing UV light, special penlights or other special equipment to detect. Covert protection also includes the use of special papers or cartonboard containing taggants
Forensic security features: this category includes highly complex security features needing scientific evaluation. Since such tests mostly need time to be completed, such forensic protection is generally reserved for high-value items with a high risk of counterfeiting.
All these security features have a cost, which needs to be proportional to the risk, and to the value of the product (Figure 5.6).
Figure 5.5 Essentra is one of many suppliers providing a range of tamper-evident solutions
Figure 5.6 Relative costs of authentication devices
IMPACT OF NEW EUROPEAN DIRECTIVE ON SERIALIZATION: 2011/62/EU ('FALSIFIED MEDICINES DIRECTIVE')
Serialization: what is it? Serialization means giving a unique, traceable number to each individual pack of a product, along with corresponding numbers to each carton or pallet. As an anti-counterfeit system it is not limited to pharmaceutical products, but will be used worldwide for these products which are particularly subject to counterfeiting (see Figure 5.5).
For Europeans, compliance with the ‘Falsified Medicines Directive’ (2011/62/EU) will be mandatory from 2018 and will cover all sales of pharmaceutical products in the European Union, whatever their country of origin. Large markets like China have already implemented a law that requires serialization of each single product including full traceability over the entire logistics chain. Other countries like the USA will be among many others following very soon or at least starting to think about this.
While current serialization requirements are limited to marking the unit of sale with a unique data carrier, by 2023 the process will require a product to be traceable through the entirety of its journey - from the carton/pallet through to the retail pharmacist or hospital..In the United States, the Healthcare Distribution Management Association (HDMA) is suggesting that pharmaceutical companies should begin to support this level of serialization, called aggregation, now. The problem facing the pharma label converter is that no one knows how the different markets of the world will specify the rules for serialization.
A leading company in this sector is Atlantic Zeiser, whose CEO went on record as saying that we should ‘Focus on the installation of a central serialization software and database application that is characterized by a modular architecture in order to be able to grow seamlessly with any need. This way it is possible to quickly adapt workflows and coding principles to new emerging regulations without the need of reprogramming and time-consuming revalidation’.
Another international company developing software for unique product identification (UPID) and track & trace solutions is Adents.
This company, based near Paris, has worked with Microsoft to jointly develop and market a new Cloud platform. Named Adents Prodigi, it has been hailed as the only Level 4 traceability solution that can centrally manage regulatory requirements imposed on the pharmaceutical industry.
GRAY MARKET DISTRIBUTION
A particular problem of pharmaceuticals concerns the selling of genuine goods by unauthorized persons or companies. For example, an importer in a country with artificially low prices for certain medicines may try to re-sell them in a high-price country where they will compete unfairly with the same goods sold by an authorized distributor. The brand owner may need covert protection, which can be given by special inks which change color in UV light. In many cases brand owners may just need to track cross-border movements of their products to trace trading movements which while unwanted may not be illegal.
WHO MAKES WHAT?
The constraints and regulations governing pharmaceutical labels are so strict that many converters specialize only in this end-user sector. Specialized label converters with interesting new ideas for pharmaceutical labeling include:
CCL – probably the world’s largest self-adhesive label supplier, CCL has 23 plants worldwide exclusively focused on the pharmaceutical industry. All of these plants offer serialization, plus a high level of security control.
Constantia Flexibles – also a major player. Constantia’s label division makes not just labels but the full range of packaging requirements for pharmaceuticals.
PagoPharm – based in Switzerland, makes multi-layer, security and functional labels.
Reynders Pharmaceutical Labels – this division of the leading Belgian label group is particularly specialized in anti-counterfeit features, and in fully integrated camera inspection systems.
Schreiner Medipharm – with plants in Germany and USA, has developed a range of innovative products to simplify the dispensing and administration of pharmaceuticals, particular for hospital and laboratory use. Examples are the ‘Needle trap’ (photo) and the protective closure and packaging for dangerous liquids (photo).
Securikett – this Austrian label converter, as its name implied, is specialized in security labeling and track-and-trace systems, mainly for the pharmaceutical and medical sectors. Stratus – this Franco-Belgian converter makes labels for all end-user sectors, but has six production lines reserved exclusively for pharmaceutical labels.
Autajon and August Faller – market-leading label and packaging producers based in France and Germany respectively also have plants producing folding cartons, leaflets and labels for many different products, but both strong is the pharmaceutical/medical sector.
POINTS TO REMEMBER
Strict quality compliance rules apply for pharma labels
Although leading drug companies are big, the global market is not concentrated
Labeling requirements are different for prescription drugs, OTCs and hospital/medical requirements
Many pharma labels must stand up to scuffing, to chemicals and to extremes of temperature
Serialization will, it is hoped, reduce the very widespread counterfeiting of pharmaceuticals.
Figure 5.7 The road to serialization is not straightforward! (source- GS1)
Figure 5.8 Atlantic Zeiser’s Medtracker is a tool to manage serialization