Rubber has become an indispensable material in the manufacture of packaging components for pharma products as the design of elastomeric seals and stoppers continues to evolve. Nevertheless, concerns remain about leaching or migration of the material into drugs. World Pharmaceutical Frontiers spoke to Diane Paskiet of West Pharmaceutical Services about how to identify, analyse and mitigate these risks.

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The history of the use of rubber as an industrial raw material reaches back three centuries, by which measure its use in pharmaceutical packaging is a relatively recent phenomenon. Only since the middle of the last century has it become a viable material for the manufacture of seals and stoppers for the packaging of drugs, particularly injectables; although their design has evolved rapidly over that time.

The applications of rubber have developed, as has the use of coatings and films to improve its barrier properties, and this process of innovation continues.

"Long after its discovery in the 1700s, the modern era of rubber chemistry really began in the 20th century, although this was mainly driven by its use in tyres," says Diane Paskiet, director of scientific affairs at West Pharmaceutical Services. "It became suited for making rubber closures from 1940, a use to which it is suited due to many properties such as its flexibility, its good performance as a barrier to gases, and the fact that it makes a good element of primary packaging for use in injectables. We are constantly evaluating market needs to guide improvements in quality that will create new rubber components suitable for use in pharmaceutical packaging."

The material used in the packaging of injectable drugs has changed a great deal since the cultivation of native South American rubber plants began in Europe. The most frequently used substance for seals and stoppers in the packaging of injectables is butyl rubber, a synthetic substance made by the polymerisation of isobutylene and isoprene. Polyisobutylene, which was first developed in the 1930s and is similar in structure to polypropylene, and is highly impermeable to air and also very flexible, was developed into butyl rubber, the largest producer of which today is ExxonMobil Chemical.

Further refinement of the raw material led to the development of halogenated butyl rubber, or halobutyl, of which there are two main variants – chlorobutyl and bromobutyl.

"Butyls have a long history of use, along with the benefits of lower leaching potential and less chance of substance migration into pharmaceutical products," says Paskiet. "Exxon estimates that over 90% of the stoppers made in the US, Europe and China are based on butyl rubber. What this means is that the raw elastomer products remain the same for rubber producers, although the formulation of rubber products is driven more by the tyre industry than by the medical or pharmaceutical industries."

Extractables and leachables

The use of halobutyls has reduced the risk of leachables due to their ease of cure and cleaner process. This has been indicated by studies in which extractables were generated under fairly aggressive conditions to reveal the chemicals with the potential to migrate.Nevertheless, the further mitigation of this risk is still a focus for the industry.

Not all extractables will be leachables, but there have been reported cases, such as Johnson and Johnson’s recall of the anaemia drug Eprex in 2003, when some batches were thought to be tainted as a result of chemical reactions with rubber stoppers. The UK’s Medicines and Healthcare Products Regulatory Agency issued an alert at the time, saying that low levels of extractables had been found in the drug, although there was no indication of a direct threat to patients’ health.

"The risk of leaching or migration has been mitigated to some extent, but we can’t say that there is no uncertainty. Applications and environments do vary a lot, but the risks can be identified and mitigated. It is hard, however, to see all of the risks," says Paskiet.

"The presence of leachables, or interaction with drugs products or excipients could cause harm to patients,"she continues. "It is vital to have packaging of consistently high quality. Packaging has a role to play in addressing the concerns over supply chain security in many ways, including tamper-evidence systems or track-and-trace systems, and rubber is part of that broader system."

"You need relevant and meaningful data in order to make the right decisions about rubber packaging components."

The future aim of manufacturers of rubber components used in injectable delivery systems is to better understand the component and its processing, and link this knowledge to the drug/biologic manufacturing process and subsequent delivery to the patient. Suppliers can contribute to this knowledge base by working together with pharmaceutical developers and manufacturers.

"The raw materials might be the same, but what we have seen in the area of stoppers and plungers for injectors is the addition of barrier films, as well as new configurations to improve functionality." notes Paskiet. "There is also more focus on increasing the efficiency of the manufacturing process, so we are seeing components supplied to manufacturers of pharmaceuticals as sterilised and ready to use. That is a growing trend because these components are verified to reliably meet quality specifications. It also means that validation of sterile components resides with the manufacturer and not with the pharmaceutical company."

Alongside these efforts there is a strong focus on developing a scientific approach to understanding the likelihood of extractables and leachables, and a process for identifying compounds of concern, with the Product Quality Research Institute (PQRI) among those playing a central role. The objective is to generate data that can clarify how materials will perform under certain stresses in order to inform developers in choosing the most appropriate materials for the intended use. For Paskiet, it is essential to pinpoint the potential for an extractable to leach into the drug product, and
for the impact that leachable will have on the drug’s stability, efficacy and safety to be scientifically evaluated.

"Rubbers have complex extractable profiles. The cure process can create trace reactions and by-products. Usually, extractables and leachables come out slowly over time, but that process can be accelerated by stresses such as sterilisation. The entire packaging system can yield leachables, so there may be a cumulative effect, and migration rates vary with different materials and configurations," she explains.

"A lot depends on the type of material, the thickness and configuration of the components, and the presence of coatings or a barrier film when exposed to varying temperatures and pressures. Many factors can accelerate migration. So, when it comes to leachables you have to look at the entire shelf life of the product. Some variation is inevitable, but you must understand the potential for leachables and the impact on the patient. They may only be at trace levels, but you still need to have relevant and meaningful data in order to make the right decisions about rubber packaging components."

"We need a science-based approach to mitigating risk and this must include packaging as part of the target profile. Risk assessments feed into the design of packaging components."

Understanding the impact of processing parameters and environmental stresses on elastomeric components is a complex task. It requires that each type of rubber component and material be assessed on its unique merits and risks. Yet the work to build up a bank of data will, in the long run, justify the choice of material arrived at by pharmaceutical companies and their suppliers.

"Different rubber products behave differently," says Paskiet. "There is no single optimum rubber material for every medicine on the market. So, each must be looked at in relation to the drug to ensure that the choice of material is compatible with the final drug product. You have to look at the drug, the manufacturing process, extremes of temperature during transport, the length of storage and many other factors."

The role of packaging suppliers is central to any work being done to understand and limit the risk posed by extractables.

"The right approach to risk is to understand the supplier’s capabilities and its control of GMP [good manufacturing practice] processes and audits. It is very important to be assured of quality. Suppliers play an integral role in the supply of safe medicines. It is about the selection of components early in the pharmaceutical process in order to identify and mitigate the risks," believes Paskiet.

Embrace extractables early

Whatever innovations may arise in terms of materials, coatings and designs of elastomeric seals and stoppers, Paskiet has a key piece of advice for pharmaceutical companies when it comes to developing a strategy to combat leachables and extractables. She firmly recommends that drug manufacturers look at the issue of extractables early in the development process to define the optimum packaging for the final product.

Extractables and leachables have been a primary consideration for qualifying packaging intended for pharmaceutical use for nearly two decades, and, as medicines and their delivery systems become more complex, it is important to consider these issues early in light of factors such as dosage form, materials, configurations and dosing. Paskiet advocates the potential impact of extractables be considered on a case-by-case basis.

"There is no single optimum rubber material for every medicine on the market so each must be looked at in relation to the drug. "

The future will see the development of a scientific understanding of materials and products. The packaging side is something that will be looked at when companies are manufacturing a drug, at which point they must consider how packaging will protect the drug and minimise interaction. You can’t readily backtrack to put this right once the drug is ready to put on the market. We are already seeing more people look at elastomeric packaging in this way," says Paskiet.

Among the drivers of this new approach to packaging are changes to the ‘Good Manufacturing Practice Guide for Active Pharmaceutical Ingredients and the recommendations of the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use’ (ICH).

"The GMP is being modernised and regulators’ expectations are changing in terms of ICH requirements and risk management. The goal is to identify the risk early on in the manufacturing process. Coupled with the development of new delivery devices and novel therapies, there is a growing need to look at the packaging aspect early on. Packaging products must work well with the medicines," Paskiet adds.

Elastomeric packaging products also have to be assessed in line with GDP [good distribution practice], which is essential to the quality of drug products It aims to ensure that products are consistently stored, transported and handled under suitable conditions as required by the marketing authorisation or product specification.

"Companies have to look far beyond the development of a drug," says Paskiet. "Each innovation faces unique challenges, but all innovations face the same high quality expectations. We need a science-based approach to mitigating risk and this must include packaging as part of the target profile. Risk assessments feed into the design of packaging components, as we have seen with the supply of sterile and ready-to-use components that mitigate risks and share responsibility with drug manufacturers."

She concludes: "Companies need to get meaningful data to identify critical control points and to ensure quality. So, rubber should be looked at in light of the broader processes for product quality. It is important to encompass the input of all stakeholders – including patients – in identifying risks and to work closely with packaging suppliers. It is all about patient safety and the delivery of quality medicine. That is the common goal and the benchmark for success."