Mitigating fill, finish and CCI challenges for injectables
Eugene Polini, Technical Key Account Manager at , Datwyler points out that 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
Primum non nocere. First, do no harm.
The often-official motto of healthcare providers, organisations, and associations around the world sets the bar for the global pharma industry. Patient safety should always come first. However, this philosophy isn’t just relegated to guiding the practices of medical professionals and drug developers. It extends all the way down to the healthcare sector’s expectations for every component, instrument, and process orbiting the development and manufacture of medicine—especially 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 commitments to Container Closure Integrity (CCI). CCI is the ability of a container closure system to maintain the sterility of final pharma, 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 oxidiser 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 per cent oxygen outside and inside the vial, achieving the same barometric pressure. This can lead to a loss in the active pharma ingredient and prevent the delivery of the therapeutic dose.
- Inadvertent introduction of microbes: A leak in the vial of a parenteral drug package can let in more than just oxygen. There can still be the threat of microbe introductions, which can be highly dangerous depending on the microbe and the condition of the already compromised immune system of the patient. Even the pressure change of a storm could create the conditions to not just pull out, but also push in contents from the vial if there is a leak.
What can drug manufacturers do to minimise these risks?
First, we must remember that every small component, like the stoppers, plungers, and caps, have critical roles to play in preserving drug integrity as part of the parenteral drug packaging system. Stoppers are placed at the top of syringes, vials, and cartridges to seal the barrels of these containers. Plungers glide through the barrel of syringes to deliver injectable drugs smoothly and effectively. Caps often top off vials and are comprised of both metal and rubber components. All must be designed with painstaking care to ensure compatibility with the drug product they interact with. Once that bar is cleared, there are many assessments, practices, and technologies available to help drug manufacturers enhance CCI:
- It starts with a paper analysis. In this process, analysts compare drawings of components like stoppers