Primum non nocere. First, do no harm.
This sentence, often considered as the official motto of healthcare providers, organisations, and associations around the world, sets the bar for the global pharmaceutical industry. Patient safety should always come first. However, this philosophy doesn’t just boil down to guiding the practices of medical professionals and drug developers. It extends all the way towards the healthcare sector’s expectations for every component, instrument, and process orbiting the development and manufacture of medicine – with an emphasis on parenteral drugs. Injectable therapies are some of the most highly sensitive drugs that require the most rigorous protective measures to ensure no particles, microbes or oxidisation jeopardises formulation integrity.
These high standards aren’t reachable without serious commitment to Container Closure Integrity (CCI). CCI is the ability of a container closure system to maintain the sterility of final pharmaceutical, biological and vaccine products throughout their shelf life. It is also a regulatory requirement upon which to qualify closure designs. In the case of parenteral drugs, CCI aims to avoid adulteration of the drugs packaged in vials, syringes, and cartridges. Even though these types of packaging systems are sealed in a hermetic manner, there are still many risks to mitigate.
What Factors Threaten CCI?
CCI is subject to many threats from the ambient environment. Vials, cartridges, and syringes are often packaged one of two ways. The industry preference is with terminal sterilisation wherein the entire packaging system is sterilised. Alternatively, drug manufacturers can package drugs with components that have been sterilised individually, assembled, then filled aseptically by filtering the drug product through a 0.2-micron filter. However, drugs filled and packaged using either method are still subject to a few potential risks around leaks due to CCI failure:
- Loss of aqueous solvent due to vaporisation
If the drug is in an aqueous medium, any hole in the vial can accelerate vaporisation. That can translate to a loss of solvent. Not only can that issue compromise the formulation and patient health, but the disappearance of a labeled ingredient can land drug manufacturers on the wrong side of the law and potentially find professionals close to the product manufacture in jail. This is because it is illegal to sell a mislabeled drug in most countries around the world.
- Oxidisation
Oxygen is, obviously, a potent oxidizer that must be excluded from the packaging system of parenteral drugs. Otherwise, the presence of oxygen can lead to the breakdown of fats, lipids, proteins, and other ingredients, compromising the drug formulation and impact of the dosage. For example, in a 5mL vial, there are typically 3 mLs of liquid drug product and 2 mLs of gas that sits above it. Drug manufacturers blanket their product with either nitrogen or argon to exclude any oxygen from the package. A leak would cause equilibration between the contents of the container and the outside environment. The oxygen-rich environment outside the vial will try to seep into the vial interior and equilibrate so it’s 18% oxygen outside and inside the vial, achieving the same barometric pressure. This can lead to a loss in the active pharmaceutical ingredient and prevent the delivery of the therapeutic dose.
