Packaging with Purpose: Engineering Safety for Every Dose

In the latest post in our series P.E.R.F.E.C.T.-ing the Pharmaceutical Packaging Selection Process, we evaluate Engineering Capabilities, a criterion that addresses the ease of manufacture of a given component or system.

Introduction to Engineering Capabilities and Machineability 

In the most recent post in this series, functionality is addressed. If functionality is the measure of how a component performs within a given container closure system (CCS), engineering capability (or, machinability) is a measure of how that component performs on a fill/finish line.

Packaging for Primary Packaging Components 

When components arrive at a fill/finish factory, they are typically packaged in multiple layers of bags inside of a plastic or cardboard box. In general, the innermost bag (primary bag) will not be opened outside of a sterile environment (especially if the components within are sterile), and even the second and third innermost bags will have internal standards as to the environments in which they may be opened:

• Primary bags may be basic, made of Tyvek or similar materials, and carefully cut open to access the stoppers inside. Alternatively, more expensive ported bags may be used. These primary bags boast a single “beta port” on the face of the bag. This corresponds to an “alpha port” on an otherwise enclose machine. The two ports will be opened only when they are connected, to allow the transfer of product into the fill machine while preventing exposure to external contaminants.
• Secondary bags are used to protect the primary bag from pollutants, especially in the case of a non-ported bag, since the outside of the primary bag will likely be in the same environment as the exposed stoppers for a short period of time when the bag is cut open.
• Tertiary bags may be used for additional protection. One example is the use of aluminum bags to help prevent the transfer of moisture into the packaging system.
• Quaternary bags are often used as part of a vacuum indicator to prove that sterility has been maintained through transfer. The bag is vacuum-sealed, and if it maintains the vacuum then sterility can be inferred.
• Quintenary bags may be used for the protection of quaternary bags, their vacuum indicators, and all layers of bag and product within them.
• Containing all of these bags (which can appear in many different configurations) is typically a plastic or cardboard box, which sits upon a pallet, which is shipped from the component manufacturer to the fill/finish site.

Machining Serum Stoppers

Once a serum stopper has been introduced to a fill line, it will typically make its way to a bowl feeder. This tool is used to bring the stoppers, single file, to ramps in which they will be oriented in a uniform direction. From here, they may be placed on vials in their upright position and capped with an aluminum seal.

Potential issues that may arise during stoppering with serum closures include:

• Stickiness
  • Definition: A condition in which elastomeric components cling to each other, and in which components are not easily separated by the progression of a fill/finish line.
  • Effect: Excessive stickiness can lead to jams on a line and can result in undesirable amounts of human intervention required to separate components from each other.
  • Cause: Rubber is inherently sticky. Without appropriate levels of coatings or films, components will stick together.
  • Solutions: Adding coatings and films to the components, or using these throughout the fill/finish process, can help to abate stickiness. It is also possible to manually massage bags of product to try to alleviate coupling.
• Pop-Up
  • Definition: When a stopper which has been firmly placed on a vial, but not yet capped, raises from the vial to the point that the sealing area of the stopper no longer has significant contact with the lip of the vial.
  • Effect: CCI can no longer be guaranteed in cases of pop-up.
  • Cause: Potential causes include:
    • • Improper interference fit between vial and stopper (for example, if the stopper plug is big enough that it pushes the stopper out of the vial)
      • Slippery stopper plug
        • Low stoppering forces
  • Solutions: Solutions may include:
    • • Choosing a stopper design with a smaller plug diameter, or choosing a vial with a larger opening
      • Using less lubricious coating in the sealing area of the stopper

• Definition: The transfer of material from elastomeric components to fill/finish lines, typically including a buildup of this material over time.
• Effect: Depending on the content of the residue, this could improve, worsen, or have no effect upon machinability.
• Cause: The content of the residue is often telling of the cause of its buildup, which may include:
  • • • Films or coatings applied to the elastomer.
      • Elastomeric material from the surface of a bare, uncoated or undercoated stopper. If an elastomer has no coating, or not enough coating, its movement along a fill/finish line could tear at the surface of the elastomer, leaving behind a residue from the surface of the component.
• Solutions: Depending on the source of the residue, solutions may include:
  • • • Doing nothing. If the cause of residue is the transfer of film or coating material to the fill/finish lines, this could provide lubricity to the line, which may be beneficial.
      • Cleaning the tool in between transfers. This is most appropriate if a particular tool is used with several different components and the transfer of the coating from one type of component to another is considered undesirable.
      • Purchasing components with different levels of film or coating. This could be a solution if there is too much coating on a component, leaving an undesirable amount of residue, or if there is not enough coating on a component, leading to elastomeric residue on the line.

Lyophilization (lyo) stoppers undergo a process similar to that of serum stoppers. However, when they are placed on a vial, they are not fully pushed down to meet the lip of the vial. Instead, they are only partially stoppered, with their vent(s) positioned to leave room for material to escape the vial system.

Once lyo stopper has been partially placed on top of a vial (typically one which contains liquid product), the entire system will be loaded into a lyophilization chamber. This chamber will expose the system to extreme temperatures and pressures to remove the moisture from the liquid product, turning it into a solid. Then, the stoppers are pushed down onto the vials by a “lyo shelf”, fully stoppering the vial and disallowing additional material transfer.

Potential issues that may arise during stoppering with lyo closures may include:

• Stickiness (See above.)
• Pop-Up (See above.)
• Residue on Lines (See above.)
• Twinning
  • Definition: When two stoppers physically entangle, typically involving the “legs” of a lyophilization stopper.
  • Effect: Twinning can lead to jams on a line and can result in undesirable amounts of human intervention required to separate components from each other.
  • Cause: The geometric design of the stopper can greatly contribute to the frequency of twinning.
  • Solutions: Excessive twinning is typically solved by changing to a different stopper design or increasing the level of coating used.

Machining Vial Seals

Upon placement of a stopper on a vial, systems are capped with vial seals. Typically, seals are placed on stoppered vials and a controlled force is placed on the seal, pushing it firmly onto the system and compressing the rubber stopper. Simultaneously, a crimper will roll along the bottom of the seal, bending it securely to fit under the lip of the vial. At this point, the vial system has been fully stoppered and capped, and container closure integrity (CCI) ought to have been achieved.

A few potential issues may be seen when machining vial seals, including the following:

• Short Skirts
  • Definition: When the skirt length of an aluminum seal is too short to sufficiently cover the height of the compressed stopper flange while maintaining a secure latch under the lip of the vial.
  • Effect: The effect of a too-short seal skirt may be lack of CCI, which is dangerous to the patient. Any systems without a proper seal should be immediately discarded.
  • Cause: There are two main causes for a too-short skirt:
    • • Improper fit between vial, stopper, and seal
      • Low crimping force
  • Solutions: Depending upon which cause is most likely (or most easily remedied), solutions may include:
    • • Changing component designs (including purchasing a seal with a longer skirt, a stopper with a shorter flange, or a vial with a shorter lip)
      • Increasing crimping forces (which will increase the compression of the stopper and push the seal skirt further down the vial lip)
• Bulging
  • Definition: The squeezing of rubber up and through the hole of the aluminum skirt of a vial seal after capping.
  • Effect: Bulging gives an undesirable aesthetic for drug administrators prior to injection. This can cause them to fear that something is wrong with the product, leading to excessive disposal of otherwise “good” product.
  • Cause: Excessive capping forces, potentially compensating for short skirt lengths.
  • Solutions: Decreasing capping forces can help, potentially in combination with a longer seal skirt.
• Wrinkles
  • Definition: Uneven lines or folds in the skirt of an aluminum seal.
  • Effect: A lack of CCI, or perceived lack of CCI, can result from excessive wrinkling. This can lead to excessive disposal of otherwise “good” product by cautious and observant drug administrators.
  • Cause: Two main causes may contribute to skirt wrinkling:
    • • Excessive skirt length.
      • Nonideal capping settings including but not limited to speed, height, and/or angle of crimping.
  • Solutions: Depending upon the cause of wrinkling, appropriate solutions may include:
    • • Using a shorter seal skirt.
      • Adjusting individual tools on the fill/finish line.
• Partial Capping
  • Definition: Short or uneven crimping of a cap onto a vial system.
  • Effect: CCI cannot be guaranteed.
  • Cause: Most potential causes of partial capping involve the settings on a given fill/finish line, including but not limited to speed, height, and/or angle of crimping.
  • Solutions: Adjustments to individual tools on the fill/finish line may be appropriate.

Machining Plungers

Plunger placement is generally performed using one of two common methods: Vacuum Placement or Vent Tube Placement. Each has advantages over the other, and each can be found in hundreds of manufacturing lines around the globe.

• Vacuum Placement
  • Description: Vacuum placement involves creating a vacuum in the CCS barrel which draws the plunger in.
  • Benefits: Vacuum placement is a gentle method of plunger placement well-suited for high-value products. It does not compress the height of the plunger and allows for minimal headspace. Limiting headspace has the added benefit of reducing the likelihood of plunger movement during shipment, maintaining sterility.
  • Drawbacks: Vacuum placement is not as fast as vent tube placement.
• Vent Tube Placement
  • Description: Vent tube placement involves pushing a plunger into the barrel of a syringe or cartridge.
  • Benefits: This is a heavily relied upon method for fill/finish and can support high-speed lines.
  • Drawbacks: As vent tube placement is a bit rougher than vacuum placement, it is more likely to allow for wrinkling or tearing of any films or coatings used on the surface of the plunger. This can risk CCI. Headspace can also become a concern, as it is generally larger than could be achieved with vacuum placement.

Potential difficulties incurred when machining plungers may include the following:

• Stickiness, Clumping, and Twinning
  • Definition: Stickiness, clumping, and twinning are all terms that refer to a group of plungers that is not easily separatable into individual components.
  • Effect: This can cause jams or delays on machining lines, as human intervention may be required to “unstick”, “unclump”, or “detwin” the product.
  • Cause: Rubber is inherently sticky. Elastomers formed without enough lubricity can sometimes stick together. When this happens at a high frequency, it can cause machining headaches.
  • Solution: Potential solutions include using additional coating for lubricity and/or altering the settings of the bowl feeder vibrations (harmonics).
• Forces, Friction, and Heat at High Speeds
  • Definition: Increased forces, friction, and/or heat at the site of plunger placement.
  • Effect: This can cause damage to the surface of the rubber component during placement, including to the film/coating (see below). High enough forces can cause vent tubes to “pop”, often requiring human intervention. If this occurs with enough frequency, line times will suffer.
  • Cause: Typically, high amounts of force (which can cause friction and high temperatures) occur at higher line speeds. Significantly high amounts of force can occur when there is not enough lubricity in a system.
  • Solution: Decrease line speeds and/or increase lubricity of the system (for example, by introducing additional amounts of coating).
• Film/Coating Wrinkles and Tears
  • Definition: A rip, split, or fold in the film or coating of a plunger.
  • Effect: Wrinkles and tears can potentially expose components to leaks and contamination, risking CCI. Even when they don’t, their appearance can cause alarm among those administering them, potentially leading to wasted product and distrust in the brand.
  • Cause: This is most often caused when a coated or laminated plunger is exposed to high amounts of friction during the machining process.
  • Solution: Using additional coating can decrease the incurrence of wrinkles and tears. Slowing down machine lines can also help.
• Plunger Tilt
  • Definition: The misalignment of a plunger within a barrel, in which the body of the plunger is at a slope compared to the barrel.
  • Effect: This can risk CCI, or appearance of CCI, due to the uncertainty of the interference between plunger and barrel. Additionally, plunger movement becomes highly variable as pushing the plunger “straight down” increases in difficulty.
  • Cause: Plunger tilt typically occurs during plunger placement.
  • Solution: Misalignment may require an adjustment in placement settings, especially if it occurs with high frequency.
• Headspace
  • Definition: The height between the bottom of a plunger (drug product side) and the top of the drug product.
  • Effect: High headspace allows for excessive plunger movement, especially during transport. This can risk CCI.
  • Cause: Large headspace is common in vent tube placement, but can be affected by variability in plunger dimensions, fill volume, and placement height.
  • Solution: Consistency is key to minimize headspace; a consistent elastomer and consistent fill volume may help,

Machining CombiSeals

CombiSeals serve as a simultaneous rubber septum and aluminum skirt for many cartridge systems. Like a rubber stopper, they provide CCI before allowing for puncture and access to drug product. Like an aluminum seal, they are crimped over the lip of a container to maintain the position of a rubber counterpart.

Machining CombiSeals is similar to machining aluminum seals, and provides many of the same challenges, including:

• Short Skirts (See above.)
• Bulging (See above.)
• Wrinkles (See above.)
• Partial Capping (See above.)

Conclusions

Overall, Engineering Capabilities can determine crucial manufacturing deliverables, such as compatible instruments or line speed. No matter how well a component performs within a given closure system, it must be able to manufacture well to be filled. In the creation of life-saving drugs, life-threatening risks must be mitigated. Though choosing appropriate elastomeric components can be difficult, Datwyler is available to help guide our clients through the selection process.

Look for the next post in the PERFECTing series, in which Container Closure Integrity will be addressed.

Sources:

https://www.futuremarketinsights.com/reports/injectable-drugs-market