Drug Labeling and Packaging
This chapter answers parts from Section A(ii) of the 2017 CICM Primary Syllabus, which invites the exam candidate to "describe the pharmaceutics and formulation of drugs", "including packaging" among other things. The examiners attributed a L2 level of importance to this competence, which basically means you can safely ignore it. In support of this statement, the author presents the evidence that historically no written paper exam question has ever interrogated this topic. As such, the time-poor candidate can safely move on to briefly skim through the enantiomerism chapter, becayse that was the only aspect of pharmaceutics to ever merit an SAQ in the primaries.
To return to the topic, drug packaging and labelling is an important aspect of pharmaceutics. It determines a whole series of qualities:
- Commercial appeal
- Safety from a physico-chemical perspective
- Durability in storage and transport
- Safety from the perspective of prescribing errors
Naming of pharmaceutical agents
To borrow brevity from Kenagy and Stein (2002),
"Drug names, labels, and packages are not selected and designed in accordance with human factors principles."
To rephrase, an ideal drug name is
- Unambiguous, i.e. identifies the substance
- Unique (i.e. not duplicate or sound-alike)
- Standardised, i.e. recognisable as a member of a class of drugs
None of these principles seem to matter when you are trying to push the drug through the approval process and to market. Only later is it discovered that the poor handwriting of doctors leads nurses to confuse your arthritis drug for an antiepileptic (Hoffman et al, 2003). Of course after you have marketed under a certain brand name it is unlikely that you will ever change it.
That sounds highly critical of the industry, and of course it is, but there is also a difficulty therer which is rarely recognised. For instance, when naming a drug do you follow chemical nomenclature and base your name on the molecular structure, or do you name the drug according to its pharmacodynamic effects even though it is structurally unique from its classmates? And what if the function is not completely understood? We can't even agree on what to call the class frequently, or how to define these loose boundaries. King et al (2002) explore this problem in the realm of psychitaric drug nomenclature. Things get worse when there are entrenched cultural differences in nomenclature (eg. adrenaline vs. epinephrine).
Each drug essentially has three names, which makes matters even more confusing:
- Brand name:, eg Diprivan
- Generic name: propofol
- Molecular name: 2,6- diisopropylphenol
The WHO has a statement on "generic" names, more properly known as International Nonproprietary Names (INN). Their Guidelines on the Use of INNs (1997) is a comprehensive document. The principles of naming generic drugs are outlined in their brief guidance page.
Labeling of pharmaceutical agents
The label on a box of ampoules might read "Metoprolol", but you might be looking for metaraminol and only see the "M" in your resuscitation frenzy. Disaster may ensue. Ergo, labels are important. Geetu and Girish (2010) cite labeling as the the central cause of medication errors in the United States. In brief:
- 25% of all medication errors are attributed to name confusion
- 33% to packaging and labeling confusion
- That adds up to approximately 500,000 medication errors per year in the US
- The total cost of this is though to be approximately $300 million
To determine how this could be happening, Shrank et al (2007) evaluated a pile of drug labels from pharmacy-dispensed preparations. The following issues were identified:
- On 84% of the labels, the most prominent item was the pharmacy's logo (average font size 13.6 points)
- The font size of the drug name was much smaller (8.9 points on average)
- The instructions for use were also small (9.3 point)
- The warnings and instruction stickers were unreadably tiny (6.5 point)
The following recommendations for improvement of label safety can be made (this list is copied directly from Geetu and Girish, 2010)
- Use explicit text to describe dosage and interval in instructions.
- Use a universal medication schedule (UMS) to convey and simplify dosage and use instructions.
- Organize labels in a patient-centered manner.
- According to need, include indication for use.
- Simplify language, avoiding unfamiliar words or medical jargon.
- Improve typography, use larger, sans serif font.
- When applicable, use numeric versus alphabet characters.
- Use typographic cues (bolding and highlighting) for patient content only.
- Use horizontal text only.
- Use a standard icon system for signaling and organizing auxiliary warnings and instructions.
The Australian TGA has moved even further with this and introduced new clearer labeling rules in 2016, as a legal act (Therapeutic Goods Order No. 91 - Standard for labels of prescription and related medicines.) Human-readable guidelines are also available. The order writers have clearly absorbed all the esoteric literature on the subjectr, as their guidelines are insanely prescriptive (including, for example, a specific definition of text height, so that a minimum height of 1.5mm can be made standard).
Packaging of pharmaceutical agents
Drug packaging is more than a vehicle for branding and advertising. As per Dean (Pain & Lockhart, 2012), packaging is
" an economical means of providing protection, presentation, identification, information and convenience for a pharmaceutical product from the time of manufacture to the time of its use."
Whereas labeling problems are a source of expensive medication errors, packaging problems are a source of drug recalls. There are multiple issues to consider. For instance, a packaging design may need to possess a range of protective properties:
- Unprotected (eg. for herbal or homeopathic preparations)
- Temperature protection
- Water-sealed, to protected from degradation by humidity
- Air-sealed to prevent degradation by oxygen
- Sterile packaging to prevent contamination by microorganisms
- Photoopaque packaging to protect drugs from degradation by light
- Radioopaque packaging to prevent radiation exposure of the personnel handling the substance
- Durable protective packaging to protect glass ampoules from shattering in transport
- Role in dosing (eg. the plastic body of a metered dose inhaler can be viewed as a form of packaging)
Other issues which must be considered:
- Protection against counterfeiting
- Interaction of drug packaging with the drug
- Leeching of active ingredient into the packaging
- Adsorption or absoprtion of packaging components into/onto the drug
Excellent example of major packaging problems are drugs like sodium nitroprusside (which should not be exposed to light) and paraldehyde (which will happily dissolve its way out of any plastic container). So important is the problem of packaging-drug interaction that experimental interaction studies to explore it are an expensive part of drug manufacture (Feenstra et al, 2014). Terminology like "packaging-drug partition coefficient" are used to describe the slow creep of packaging polymers into the coated tablet.