When to Use rubber closures for parenteral products？

In terms of the specification for closures and the testing and sterilization requirements, the following documents are useful as starting points:

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For the manufacturing of closures, the elastomer is either natural or, as is more common, a synthetic rubber, such as butyl rubber or chlorobutyl rubber. The advantage of synthetic rubbers is that the materials are strongly resistant to permeation by oxygen or to water vapor (4).

Pharmaceutical closures, also known as stoppers or bungs, are an important part of the final packaging of pharmaceutical preparations, particularly those that are intended to be sterile. The most commonly used type of stopper is the elastomeric closure. An elastomer is any material that is able to resume its original shape when a deforming force is removed, which is known as viscoelasticity (3).

Therefore, the manufacturers and users must have confidence in the quality control and validation of closures. It is an important part of pharmaceutical manufacturing that all information on the composition and manufacturing processes for each component type must be understood.

Closures form part of the "container-closure system." Container-closures function to keep the contents of pharmaceutical preparations sterile (e.g., by providing a barrier between the neck of a vial and the vial contents) and to prevent ingress of contamination into a vial once a needle is inserted (e.g., by enabling resealing of the vial after the needle is withdrawn). The closure, together with a crimp that creates the container-closure, and the vial itself form the primary packaging or packaging component (i.e., the material that first envelops the product and holds it) (1). The ideal container-closure will have low permeability to air and moisture and a high resistance to aging (2).

Parenteral products are designed, formulated, and packaged to be sterile and to maintain sterility. One of the most important parts of the packaging of sterile drug products is the container-closure mechanism. This article examines the use of closures, for products intended for injection, in the pharmaceutical industry. The article considers the most important aspects relating to the manufacture of closures and the different physical and biological assessments required to ensure that the closures are "fit for purpose." The article does not address caps or other types of seals.

Closures that form part of the container-closure system are an important component in the packaging of sterile products. Container-closures maintain the sterility of parenteral pharmaceuticals and prevent ingress of contamination when a needle is inserted into a vial. This article describes important aspects to consider in the manufacture of closures for pharmaceutical preparations, as well as the various physical, chemical, and biological assessments required to ensure that these closures are fit for purpose.

The FDA Code of Federal Regulations (CFR) part 21 211.94 stipulates that container-closures must provide adequate protection to the product over the product shelf-life.

Before using a closure in a vial or bottle with a drug product, the closure must be assessed to determine if it is suitable for use with the product that will be filled into the glass container. The pharmaceutical manufacturer should consider the following questions relating to product compatibility, in conjunction with the manufacturer of the closure:

• Is the product absorbed by the rubber?

• Does the rubber react with the product and leach out impurities?

• At which temperature range is both closure and product stable?

• How effective is the seal integrity?

• What happens when the product and stopper are stored together over time?

Once these questions have been satisfactorily answered, the pharmaceutical manufacturer can work with the manufacturer of the closure to design the optimal closure for the vial type and product.

MANUFACTURING PROCESS

The manufacturing process for closures involves processing raw materials and auxiliary substances; weighing and mixing; followed by vulcanization. Vulcanization is a chemical process for converting rubber or related polymers into more durable materials via the addition of sulfur (or another equivalent curative) together with an accelerating agent such as 2-mercaptobenzothiazole; an activator, usually zinc oxide; fillers such as carbon black or limestone; antioxidants; and lubricants. Following vulcanization, molding and compressing occur.

There are two types of molding: compression and injection, of which the former is the most common. Compression molding is a method of molding in which the molding material, generally preheated, is first placed in an open, heated mold cavity. The mold is closed with a top force or plug member, and pressure is applied to force the material into contact with all mold areas, while heat and pressure are maintained until the molding material has cured. Injection molding is a manufacturing process for producing parts from both thermoplastic and thermosetting plastic materials. Material is fed into a heated barrel, mixed, and forced into a mold cavity where it cools and hardens to the configuration of the mold cavity.

After molding, the stages are: coating, washing, siliconization (if required, using specific, high-viscosity silicon oil), and packaging. Siliconization has several advantages in that it prevents stoppers from sticking together or onto other surfaces and can assist with the insertion of a needle through the stopper. The siliconization step is, however, a potential source of contamination. Silicone used in the preparation of rubber stoppers should meet appropriate quality control criteria and not have an adverse effect on the safety, quality, or purity of the drug product.

The mixing of raw materials and auxiliary substances involves the formulation of the stopper. A stopper is typically made up of 60% rubber, 30% fillers (which protect the physical properties of the rubber) and pigments, 5% plasticizers (which provide flexibility), 5% additional chemicals including accelerators (which help to create the cross-linkages which give the stopper its strength and hardness), activators (which are a function of the efficiency of the cross-linkages), and antioxidants (which help to avoid the degradation of the rubber).

There are different types of rubber, such as natural rubber (latex), isoprene rubber (a chemical copy of natural rubber), styrol-butadine rubber, ethylene propylene dyes monomers, silicone (polysiloxane) rubber, and halogenized butyl rubber.

QUALITY CONTROL OF CLOSURES

A number of quality control checks are required for the manufacture and release of closures. These checks include:

After the material has been mixed

• Specific gravity, which is the ratio of the weight of the molded piece to the weight of an equal volume of water

• Color, which can be checked against a color chart

• Dispersion of a vulcanized sample in relation to particle size

• Examination of the ash after burning in comparison to a reference sample

• Hardness, which can be measured in Shore Units or an equivalent standard

• Rheology of the compound, by conducting an examination of solids under conditions in which they respond with plastic flow rather than deforming elastically in response to an applied force. This is an assessment of the force necessary to rotate the material by 1°.

An important distinction is that different materials—types of rubber and formulations—have different profile and respond in different ways.

Post-compression and molding

The material is checked for rubber thickness and evenness.

Washing process

• During the loading of stoppers into a washer, the quality of the water should be checked for bioburden and endotoxin using compendial methods.

• The loading of the washer should take place in a controlled environment, usually a cleanroom, with staff appropriately gowned. Unusually for a pharmaceutical process and in keeping with cleanrooms used in the electronics industry, the cleanroom may be fitted with deionization equipment in order to avoid fibers being attracted to the rubber.

Post-washing and post-siliconization

After the stoppers have been washed, a number of quality control checks should be performed.

Mechanical and material tests

• Compression test. A compression test is performed to determine the behavior of materials subjected to compressive loads. Loading is usually done at a uniform rate (in/min).

• Hardness.

• Fragmentation.

• Penetrability (i.e., what happens when a needle passes through the stopper): Assessments can be made of the insertion force, break loose force, and extrusion force. One common issue that can arise is the generation of rubber particles cut from the closures when needles are inserted, a phenomenon sometimes referred to as coring (5).

• Assessment of dimensions and flexibility.

Many material tests are conducted by testing a selection of closures using a high-speed color sensor that examines the top, bottom- side surface, and inside of the closure.

Physical tests

• Resistance to sterilization. This requires consideration of two questions: how does the rubber of the stopper react to different types of sterilization, such as gamma irradiation, ethylene oxide, and steam sterilization, and does the stopper become more brittle over time?

• Particle testing.

Chemical tests

• Tests for extractables and leachables: Extractables are chemical substances that are obtained by exposing the packaging to a variety of solvents under exaggerated incubation conditions of time and temperature (6). Leachables differ from extractables in that they are chemical substances that migrate under normal conditions of use from the stopper into a drug product. Leachables are, therefore, a subset of extractables; all extractables are potential leachables of toxicological concern (7).

• Silicone oil determination: The effect of subvisible silicone particles should be assessed, because these can cause aggregation with proteins, and the new complex can potentially trigger an immunochemical reaction within the body of the patient receiving the drug.

Biological tests

• Cytological testing.

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• Bioburden assessment (such as <5 CFU/stopper). Some manufacturers undertake an examination for mesophilic counts while others focus on examining for thermophilic bacteria, because such microorganisms will be the most resistant to the sterilization step.

• Bacterial endotoxin testing (such as <1 EU/stopper). The testing of closures for endotoxin, using the Limulus amebocyte lysate (LAL) method, is quite difficult in terms of method validation because the endotoxin challenge to the rubber surface can prove to be tricky to recover.

Container-seal tests

Of the different test methods described, the assessment of the container-closure is arguably the most important because it indicates whether the device is at risk from extraneous microbial contamination. Pharmaceutical containers constructed of materials such as plastic and glass must be qualified and meet USP <661> Containers and <671> Containers-Permeation standards. The user will therefore need to undertake additional tests that examine the physical seal of the closure in the vial, i.e., when the stopper is fully inserted and crimped, usually by of an aluminium band. The choice to conduct a physical test or a microbial ingress test for this purpose is a matter of debate. Some practitioners argue that the physical methods of measuring the system's integrity are preferred because they are more reproducible, faster, less expensive, more reliable, and quantitative. Others argue that, as the objective is to ensure that the product is safe from microbial contamination, a microbial test is the only true test. Some opt to undertake both physical and microbial tests.

A review of industry practices suggests that failures occur with container-closure seals for a variety of reasons (8). These failures include poor quality starting materials, an improper fit of the container-closure combination, the lack of sufficient inspection as part of batch release, insufficient process monitoring or process control, the use of unreliable manual or visual inspection techniques, the use of methods that produce subjective results, and the lack of proper process validation. The latter point is addressed through the tests described below.

Physical tests include the dye test, vacuum testing, gas leakage determined using a bubble test, liquid leakage detected by atomic absorption of a copper ion tracer solution, or a helium leak rate test (9). Of these, the helium leak test is one of the most widely conducted; the objective is to detect leaks by monitoring changes in headspace gas composition or changes in total headspace pressure. This test measures the rate of helium leak from the vial as well as the actual percentage of helium that is filled within the vial. Mass spectrometry can be used to measure the rate of leakage. Mass spectrometry-based leak detection is accomplished by measuring the amount of a tracer gas that escapes from the container-closure system. Tracer egress is facilitated by a pressure difference across the container-closure barrier.

Alternative and novel test methods to assess container-closure integrity include the use of hygroscopic powder and near-infrared (NIR) spectroscopy as a means of visualization. A second example is with airborne ultrasonic technology where a sound wave is directed towards the container-closure and visualized through the creation of a high-resolution image. An alternative to ultrasound is the use of a laser diode or the utilization of high- voltage technology. These new techniques have the advantage of being non-destructive and they allow for a larger proportion of the batch to be tested, which increases the level of confidence in the integrity of the seal. These techniques are also more accurate in allowing identification of small pinholes, micro cracks and seal imperfections that cannot visually be seen.

With microbiological testing, a sterility test of the end product or a microbial ingress test can be considered. The sterility test is unsuitable because the test will only detect viable microorganisms present at the time of the test and those that are capable of growth within the culture media used. The microbial ingress test involves direct microbial challenge and is, therefore, a more robust test. The objective is to detect microbial ingress based on 1) the probability that the challenge microorganisms can find a container-closure leak, 2) the ability of the microorganisms to traverse the leak, and 3) the capability of the microorganisms to grow in the internal container environment.

The microbial ingress test can be performed in different ways. One of the key criteria is the selection of the microorganisms. It is more common to use two different microorganisms of different sizes and with different methods of motility. For example, Brevundimonas diminuta, a very small bacterium, and Escherichia coli, a bacterium with a relatively powerful motility, are often used in combination (10). The complexity with the test relates to achieving a sufficiently high microbial population.

To conduct a microbial challenge test, vials are filled with a microbiological growth medium before stoppering and crimping, and are immersed in a 35 °C bath containing magnesium ion as well as 8 to 10 logs of viable bacterial cells for 24 hours. The test units are then incubated at 35 °C for 7 or 14 days. Microbial ingress is detected by turbidity and plating on blood agar.

The described tests, or a selection thereof, should ensure that the integrity is verified over the product's shelf-life, simulating the stresses the product will be subjected to, including sterilization, handling, and storage conditions. The tests, therefore, need to be made more rigorous in order to simulate "real life" events, for example by exposing test vials to stresses of temperature and pressure conditions, which the vials are subjected to when being transported for distribution and sales. The level of confidence is increased if three different batches are assessed. Another option is to assess vials as part of a stability trial program, which includes a time point at the end of the shelf-life.

Packaging

After packaging, a selection of bags should be examined for tears as a part of the quality control assessment. The placement of the stoppers into the packaging should be undertaken within an ISO Class 8/EU GMP Grade C cleanroom for standard stoppers and in an ISO Class 5/EU GMP Grade A environment for ready-to-sterilize or ready-to-use stoppers.

Sterilization

Closures are typically sterilized by one of two methods: steam sterilization using autoclaves and gamma irradiation. It should be noted that not all types of stoppers can be sterilized by gamma irradiation because the rubber of the stopper will become brittle from the generation of free radicals in the polymeric materials (11).

The sterilization of stoppers also requires the sterilization device to be subject to the standard tests including thermometric studies and biological indicators for steam sterilization devices and dosimeters for gamma irradiation.

CONCLUSION

The container-closure system is an essential part of the final presentation of a pharmaceutical product. It defines the closure, protection, and functionality of a container while ensuring the safety and quality of the drug product over the product shelf life. This article has addressed the important considerations for closures: the "rubber" stoppers inserted into vials of products and sealed in place. The article has focused upon the important tests, control measures, and essential aspects for ensuring that the product, in its final packaging, is fit-for-purpose prior to the administration of the drug.

Tim Sandle, PhD, Bio Products Laboratory, Dagger Lane, Elstree, WD6 3BX, United Kingdom, tim.sandle@bpl.co.uk .

REFERENCES

1. L. Solomun et al., J. Pharm. Biomed. Anal. 48 (3), 744–8 (2008).

2. W. Curry et al., AAPS PharmSciTech. 11 (4), 1572–9 (2010).

3. USP 32–NF 27 (Rockville, MD, 2009), pp. 4133–4140 .

4. E.J. Smith and R.J. Nash, "Elastomeric Closures for Parenterals," in Pharmaceutical Dosage Forms: Parenteral Medications, K.E. Avis, H.A. Lieberman, L. Lachman Eds. (Marcel Dekker, New York, 1st ed., 1992), pp. 445–507.

5. G.D. Chanana, X. Guo, K.E. Avis, et al., J. Parenter. Sci. Technol. 47 (1), 22–5 (1993).

6. I. Markovic, Am. Pharm. Rev. 9 (6), 20-27 (2006).

7. D.R. Jenke, PDA J. Pharm. Sci. Technol. 59 (4), 265–281 (2005)

8. FDA Container and Closure Integrity Testing in Lieu of Sterility Testing as a Component of the Stability Protocol for Sterile Products, (Rockville, MD, Feb. 2008).

9. L.S. Burrell, M.W. Carver, G.E. DeMuth, and W.J. Lambert, PDA J, Pharm. Sci. Technol. 54 (6), 449–55 (2000).

10. E. Kirsch et al., PDA J, Pharm. Sci. Technol. 51 (5), 195–202 (1997).

11. P. Kiang et al., J. Parenter. Sci. Technol. 46 (S2) (1992).

05.10.2022

Recommendation

7/8 May 2024

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Following the draft chapter 3.2.9. Rubber closures for containers for aqueous parenteral preparations, for powders and for freeze-dried powders (Pharmeuropa 33.2) the final version has been published in the European Pharmacopoeia (Ph. Eur.) 11.1. The supplement is now available and will become applicable as of 1 April 2023.

The general revision of the chapter 3.2.9. includes changes to the following sections:

• Definition and Scope: Rubber closures include stoppers for vials as well as needle shields and plunger stoppers for syringes, etc. The use of natural rubber latex is not permitted but dry natural rubber may be used, since the allergens are removed during processing.
• Identification: IR is maintained as the main and basic technique for rubber identification. The status of the Total Ash test changed from always necessary to only possibly needed and complementary.
• Extractable Heavy Metals: The test has been deleted to align with ICH Q3D and Ph. Eur. policy on Elemental Impurities. However, Extractable Zinc testing is still required.
• Functional Tests: The introduction has been expanded to clarify cases in which the tests for penetrability, fragmentation and self-sealing may have to be adapted or can be omitted.
• Fragmentation: The specific testing procedure for closures used for dry preparations has been removed.

Furthermore, it has been clarified that the manufacturer of the pharmaceutical preparation must obtain assurance from the supplier that the composition of the closure does not vary and that it is identical to the one used during compatibility testing. When the supplier informs the pharmaceutical manufacturer about changes made to the composition, "it is recommended to carry out a risk assessment to determine whether it is necessary to repeat the compatibility testing".

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