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 and plungers to the drawings of the vials and syringe barrels to ensure that there is enough compression and interference between the elastomer and the glass or plastic package to create a seal. In addition, they check to make sure there isn’t too much interference or compression, which can compromise machinability during insertion. For syringes, they must also check the activation of plunger movement for the same factors. The fit can’t be too tight or too loose. It must be just right. We typically aim for a couple percentage points of compression between the rubber and the walls of the package, but optimal results may vary. For a stopper, more compression is desirable. A plunger requires less to ensure mobility up and down the barrel of the vial. It’s also important at this stage to account for blowback tolerances. Many vials are now made with blowback features, small, recessed rings inside the neck of the vial so the rubber can relax into that recess so that a little bit of back pressure isn’t going to pop it off. A corollary feature can be added to the stopper – like a protuberance that can snag into the recess in the neck of the vial. However, problems can arise when the blowback feature is mismatched with the stopper design, exacerbating the issue. More recently, there was a movement to make blowback tolerances and dimensioning for these features clearer at the specification process which enables drug manufacturers to better identify potential mismatches at the paper analysis stage.
- Next comes dry lab (or exploratory developmental) work wherein a series of practical physical tests are conducted. The pop-up test is one example. In this test, a vial is filled with water and a stopper is placed loosely on top of the vial. The tester freezes the whole system overnight. The next morning, they bring it out and insert that stopper to observe whether it pops out as the system warms up due to positive pressure inside. That cold gas in the headspace after it’s sealed and starts to warm up, goes to a higher pressure and can pop the stopper off. The test offers an effective way to assess for stopper and vial compatibility.
- Following the practical tests, CCI testing is conducted with more advanced instrumentation and, typically, placebos (drug product without the active ingredient) to ensure the package is robust and shows no leakage over the temperature range that the drug product will experience through its lifecycle. This may include cold chain testing for cryogenic or cold storage, often a very challenging barrier to success. Some drugs must stay at liquid nitrogen temperatures –185 degrees Celsius to maintain viability. However, rubber and plastic materials take on the attributes of glass at those temperatures, making it difficult to achieve an adequate seal, and requiring alternative approaches. Very careful scrutiny must be paid to CCI testing—especially with cryogenic and cold storage.
- Residual Seal Force testing can help testers understand the residual spring left in the elastomeric closures flange. The flange compresses as vertical force is applied to it during capping. By locking the skirt in that metal furl during sealing, the energy in that rubber flange is captured and causes the rubber to be in a state of compression with the glass crown finish which ensures a great seal during the product lifespan. By measuring Residual Seal Force, testers can understand if the capping force is too great and liable to create a wrinkle and fold, and ultimately, a product leak. This testing can help drug manufacturers find their sweet spot for capping force as a preventative measure to maximise seal integrity.
- Once the product is made, the shelf studies begin. These include repetitive CCI testing at frequent intervals throughout the proposed shelf life of the drug. Typically, the manufacturer will put up three lots of drug product in its field packaging and at periods of 0, 1, 2, 3, 6, 12 and 18 months, they’ll pull samples and test them for, among other things, container closure integrity. This assessment gives drug manufacturers a good idea of how the drug will fare over time on the shelf.
Working toward CCI around the World!
No matter where drugs are manufactured, pharma companies are still subject to the CCI standards of the markets they serve. This can make the whole process complicated as pharmacopoeias vary with regions. For example, markets like Japan have had extremely strict regulations around sterility for closures compared to other markets that took significant R&D to develop elastomeric closures that met the standard. In the US, the Food and Drug Administration (FDA) prefers the deterministic CCI testing versus the probabilistic CCI testing of the past. The FDA asks drug manufacturers to use deterministic CCI testing instrumentation and technology because probabilistic methods are more subjective and contain more qualitative methodology while deterministic methods are quantitative and nondestructive while giving actionable insights. There is greater certainty in the deterministic testing methodology.
It is critical that drug manufacturers comprehend the differences between the markets they serve and work closely with their suppliers who understand the nuances of different regional regulations, and of course work toward the highest standards to do no harm.