Stopper Functionality – Key Considerations

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When selecting the appropriate rubber stopper for any respective vial containment system, there are many aspects to consider regarding the properties of the elastomeric closure. For the purposes of this discussion, the focus will be on the functional performance of the stopper and what key aspects should be considered during the assessment and selection process. Coring and fragmentation, container closure integrity, and machinability of the stoppers will be briefly reviewed.

It is also important to consider for all these assessments that they are conducted under pharmaceutically representative conditions, when possible, such as ensuring components are lubricated, washed and sterilized as intended for commercial use.

Coring and Fragmentation

A point to consider in piercing a rubber stopper with a needle is the formation of cores and fragments. Their presence in a drug is a critical concern. Both are considered particulate matter, however they are caused by different mechanisms:

1. Cores – characteristically cylindrical in shape, cores formed by the needle cannula cutting the rubber during needle penetration.
2. Fragments – characteristically small with irregular shape, fragments are formed via an abrasion of the rubber by the outside of the needle cannula during needle penetration.

If particles are small enough to be drawn into the syringe, and subsequently injected into a patient, there is a potential risk to patient safety. There is also a risk that the cores could be substantial enough that the rubber stopper is unable to seal when the needle is removed, therefore potentially exposing the drug product to environmental conditions and contamination.

These issues can be mitigated through needle and technique selection.

Needle:

• Thinner (i.e., higher gauge), e.g., 27 gauge
• Blunted bevel heel and sharp point
• Use only once
• Consistent lubrication on the needle surface

Technique:

• Puncture within the target circle on the stopper
• Insert at proper angle
• Insert needle slowly
• Do not rotate during insertion
• Note, multiple punctures increase the chance of coring and fragmentation

Container Closure Integrity

Container closure integrity (CCI) is an essential element of a drug product container system. The sterility, stability, and efficacy of a drug product over its target shelf life is directly correlated to the container system’s ability to ensure a leak rate below that of a predefined maximum allowable leak limit (MALL). This topic is detailed in USP guidance: Chapter <1207> Package Integrity Evaluation – Sterile Products. The guidance provides insights into various CCI test methods, while further emphasizing the use of deterministic methods (e.g. trace gas leak detection), where possible, and using probabilistic methods (e.g. trace liquids) only when appropriate for the application.

Selecting the appropriate test method and MALL is a critical first step when challenging a vial containment system. There are many factors to consider when selecting the method, such as the specific application and critical attributes. West has built capabilities to evaluate container systems using numerous different techniques, however Helium Leak Detection and the associated Kirsch limit (6.0 x 10-6 cm3/s) has become one of the most common methods used to assess containers systems given the effectiveness of the method, as well as the versatility for directly testing container systems in cold and cryogenic storage.

No matter the test method chosen for assessing a vial containment system, it is important to keep the following factors in mind, just to name a few:

• Compression forces applied during the crimping process
• Hardness of the rubber stopper
• Cleanliness of the sample preparation environment
• Dimensional compatibility of the vial, stopper, and seal
• Empty or filled vials (e.g., liquid presence and the type of liquid, partial pressure, gas overlay)

Machinability

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Machinability is a term used to describe the effectiveness of a component (e.g., container, stopper, plunger, or seal) processed on drug product filling line. The machinability of components can have a direct impact on the yield and processing time of the drug product, as well as on the required functional aspects of the container system.

To optimize operations and reduce risks attributed to the container system, preliminary machinability assessments are often conducted during packaging development; followed by more extensive machinability assessments during process development and validation. During these machinability assessments there are numerous key factors that should be considered:

• Dimensional compatibility of the various components of the container system
• Dimensional compatibility of the components with the equipment format (change) parts 
• Stopper characteristics, such as lubricity, hardness and center of mass
• Stopper processing parameters associated with the feeder bowl, stopper insertion, and capping
• Quality and Operation requirements and specifications (e.g., raised stopper detection specifications, drug product “time-in-solution” limits, product/process deviation rates)
• Pharmaceutically representative condition of the equipment format parts both in terms of maintenance and cleanliness

For more information on how these techniques and factors impact the process of assessing and selecting the right stopper for your drug products and processes, please visit the West Knowledge Center or contact your Technical Customer Service representative or Account Manager.

EDQM

Strasbourg, France

The European Directorate for the Quality of Medicines & HealthCare (EDQM) has published the revised general chapter on Rubber closures for containers for aqueous parenteral preparations, for powders and for freeze-dried powders (3.2.9) in European Pharmacopoeia Supplement 11.1, with an implementation date of 1 April 2023.

This general chapter is mandatory for aqueous parenteral preparations since it is referred to in the general monograph on Pharmaceutical preparations (2619) and in the dosage form monograph Parenteral preparations (0520), both of which are legally binding.

The revised chapter was first published in Pharmeuropa 33.2 for public consultation. The comments received were reviewed by the group of experts responsible for the text (Group 16) before the finalised text was adopted by the European Pharmacopoeia Commission at its 172nd session in March 2022.

The overall aim of the revision process was to update the text and bring it in line with current practices. The key changes to several sections are detailed below.

• The Definition and scope section has been changed to prohibit the use of natural rubber latex because of its allergenic potential. However, dry natural rubber is permitted since any allergens it contains are removed during processing.
• IR has been maintained as the basic identification technique for rubber, and the Total ash test has become optional and complementary. A list of other techniques that can be used is now also included.
• Acidity or alkalinity has been revised to explain how to choose the titrant depending on the colour of the indicator.
• For the Absorbance test, filtration is now prescribed for turbid or hazy solutions only.
• The test for Extractable heavy metals has been deleted to align with ICH Q3D and the Ph. Eur. policy on Elemental impurities. Rubber closures are considered to be part of the container closure system and as such, their impact on the level of elemental impurities is evaluated as part of the risk assessment for the pharmaceutical product. The test for Extractable zinc has been kept as zinc is often intentionally added during the manufacturing process and there is therefore a high probability that it will be found in rubber samples.
• The introduction to the Functional tests section has been expanded to indicate when to perform, potentially adapt or omit these tests which, due to the many different types of containers and corresponding rubber closures used, might not always be applicable.
• Fragmentation: the specific testing procedure for closures used for dry preparations has been deleted. Allowing the sample to stand for 16 h at room temperature proved unnecessary and this requirement has therefore been deleted from the procedure to ease the running of the test.

As mentioned above, the revised chapter will come into force on 1 April 2023.

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