Particle Risk Checklist For Pre-filled Medical Device Projects
Do you know your particle risk?
The CEO of a pharmaceutical company discovered their particle problem — too late. The pre-filled device entered the market only to be recalled when silicone oil particles rendered the drug ineffective. His leadership team came from the drug formulation side. For them, risk management meant well-run clinical trials.
The last thing they expected was invisible particles bringing their pre-filled project to a screeching halt. Some risks are preventable. Particle risk is one of them.
PARTICLE RISK #1: LARGE MOLECULES
Drug formulation has a significant impact on particle risk. Large-molecule protein-based drugs have more potential to aggregate and generate hazardous particles than small, chemically manufactured molecules.
Regulatory agencies are paying close attention because particles in pre-filled containers have been linked to:
– Reduced drug efficacy.
– Immune responses in patients.
PARTICLE RISK #2: EXCIPIENTS
Excipients used in the formulation can detrimentally affect different container materials and lubricants.
Excipient Example #1:
High pH buffers can attack glass containers to generate particles due to glass delamination.
Source: D. Haines, V. Scheumann, and U. Rothhaar, “Glass Flakes: Pre-Testing stops a big problem before it even starts,” Contract Pharma, June 2013.
Surfactants (used to stabilize biopharmaceutical formulations) may emulsify silicone oil lubricants. These oil particles can interact with the protein molecules to form protein/silicone oil complexes and aggregates.
PARTICLE RISK #3: CONTAINER CHOICE
The container you choose plays a crucial role in assessing the risk of a product recall for your pre-filled device.
There are many choices to be made, for example:
Prefilled syringes and cartridges
Glass and plastic syringes
Protein formulations
Ophthalmic applications
Catheters
All of these choices have pros and cons when it comes to particle risk. Your specific risk profile will depend on the choices you make.
PARTICLE RISK #4: LUBRICANT CHOICE
Injection devices require a lubricant or a low friction coating to enable the plunger to move through the container when delivering the drug. The lubricant in an injection device is typically overlooked, but it can have a significant impact on device performance. Common lubricants used in pre-filled devices are described below.
Option #1: Silicone Oil
Medical grade, Dow Corning 360 (DC-360) silicone oil is the most commonly used lubricant for syringes. Silicone oil has been used in the medical field for decades and provides an inert material for container lubrication. One of the pitfalls of silicone oil is that it can easily migrate from where it is applied on a syringe, which can generate unwanted sub-visible particles. The figure below shows some of the driving forces for silicone migration.
Option #2: Baked-On Silicone
Medical grade, Dow Corning 365 (DC-365) silicone emulsion is commonly used for glass cartridge lubrication. DC-365 contains 350 cSt silicone oil that is emulsified using surfactants and additives.
The emulsion is sprayed onto a glass container and then baked at temperatures exceeding 300°C. The baking process helps to remove the water of hydration on a glass syringe and forms a thinner lubricant coating than standard silicone oil. This process will reduce the particle risk in a container relative to unbaked silicone oil, but can only be used on glass containers not using staked needles (the needle glue degrades at the baking temperatures).
Trace amounts of the emulsifying additives may remain in the container after baking. The silicone oil in this process can still migrate and generate particles in the drug formulation since there is no chemical cross-linking between the silicone molecules or any chemical bonding between the oil and the glass substrate.
Option #3: Chemically Cross-linked Silicone
Some companies offer chemically cross-linked silicone oil for needle and container lubrication. The cross-linked lubricant is more stable in different chemical environments and has less of a tendency to migrate.
Chemically cross-linkable silicones contain a mixture of reactive and inert silicone oils. The cross-linking reactions may occur through additive or condensation reactions.
In certain cases, the reactive silicone oils may not completely react, and trace amounts of these components may remain in the silicone layer and can adversely affect the drug product.
Option #4: Plasma Immobilized Lubricants
Plasma immobilized or cross-linked lubricants use inert gas plasma to cross-link the lubricant, rather than the reactive functional groups used in chemical cross-linking. Plasma immobilization provides the stability of a cross-linked lubricant without adding any complex reactive groups that could degrade the drug product.
This gas plasma crosslinking method can be used with standard inert DC-360 silicone oil, without the need for any additives (TriboLink-Si®).
For applications that require a completely silicone-free lubricant system, a plasma-immobilized, inert perfluoropolyether-based lubricant is also available (TriboGlide-DS®). To be completely transparent, these are the next-generation solutions TriboFilm Research has developed to solve the challenges posed by silicone oil.
They are not appropriate for all applications but they do offer two robust alternatives.
Option #5: Plunger Laminates
Syringes completely free of any lubricants have recently been introduced into the market and rely on a laminated plunger to provide a surface with sufficiently low friction to enable movement through the container without the need for a lubricant.
The use of laminated plungers with no lubrication is restricted to plastic syringes and cartridges because glass devices cannot cost-effectively be manufactured with dimensional tolerances tight enough to ensure container closure integrity without a lubricant.
Laminate materials that are applied to elastomer closures also stiffen these closures and this reduction in compressibility may also cause leakage. Hence the design of the container and tight dimensional tolerance required could make this a more challenging and expensive solution.
However, applications that require a completely lubricant-free system may benefit from this choice of laminated plunger syringe design.
PARTICLE RISK #5: PLUNGER LEACHABLES
All of these choices have pros and cons when it comes to particle risk. Your specific risk profile will depend on the choices you make.
One excellent case study on the U.S. Food & Drug Administration’s website recounts the Eprex® recall of 2003 which was initiated because of leachables from the elastomer formulation.
The industry now offers several coating solutions that reduce leachables from the elastomer material by providing barrier protection. If this is a source of particle risk for your device, we can suggest some alternatives for you to investigate further.
Most plungers, if not all, are lubricated with silicone oil for both lubricity and as a processing aid. The silicone oil on a plunger will lead to particles just like the oil used on the container barrel. The lubricant application method for plungers is also very imprecise and in some cases the amount of silicone extracted from the plunger is equal to or greater than that extracted from the container barrel. One way to mitigate this risk is to use the gas plasma crosslinking method (TriboLink-Si®) to immobilize the silicone oil on the plungers. In addition to lower sub-visible particles, plasma crosslinking of silicone oil increases the durability of the lubricant and improves the extrusion forces in case of syringes and cartridges.
PARTICLE RISK #6: STERILIZATION
Your sterilization method can affect the performance of the container and the lubricant.
Some sterilization methods can’t be used for certain container formats.
Common sterilization methods include ethylene oxide (ETO), radiation, autoclave, and dry heat.
Ethylene oxide is the least demanding on the container and lubricant, but it can complicate the device design. This is because the sterilizing ETO gas must be accessible so it can be fully removed from complex geometries or porous container materials.
Radiation sterilization is typically only used for plastic components and can cause some device components and lubricants to degrade. In addition to particle risk, this may also significantly alter the device's performance.
For autoclave or dry heat sterilization, the components should be able to withstand high temperatures. Even so, there is potential for degradation of the components at high temperatures — this ultimately increases the risk of particulates or drug denaturation.
One example from our experience where the sterilization process generated particles is a device that was terminally sterilized using an autoclave method. After sterilization, the number of sub-visible particles in the container jumped from a few hundred particles to a few hundred thousand. Most of these particles were silicone oil droplets that migrated off of the container. This silicone oil migration not only generated many particles but also significantly increased the plunger forces in the container. In this particular case, we mitigated these issues by cross-linking the lubricant using atmospheric plasma.
PARTICLE RISK #7: TRANSPORTATION
If your medical device must be shipped to individual customers, any agitation during shipping has the potential to generate harmful particles.
PARTICLE RISK #8: END-USE
The end use of the product can play a significant role in the risk associated with particulate contamination. When the device has a specific force requirement or moves at slow speeds, the migration of silicone oil off of the barrel and into the drug formulation will negatively affect the force performance and may cause device failures.
CASE IN POINT
One of our clients had a multi-dose bolus injector that went through numerous start-stop cycles for every container. Each time the plunger stopped, it would cause the silicone oil to migrate into the drug. This led to increasing particulate contamination with sequential injections.
As you evaluate the particle risk for your pre-filled device, we invite you to reach out to us. This framework is a good starting point, but there is a lot more we cannot cover here, and each project has its own interdependent risk factors that are unique to your situation.