RUV CLOSURES - Daikyo PLASCAP® RUV Closures: Securing Annex 1 Compliance Through Contamination-Controlled Closure Innovation

For the intended patient, any injectable therapy can be re­garded as precious, given its potential for enhancing, maintain­ing, or even prolonging life itself.

There are, however, some types of therapy that might be de­scribed as more precious than others from the point of view of their inherent sensitivity to degradation, the challenging nature of their manufacture at low volumes, and their comparatively high costs.

Advanced therapy medicinal products (ATMPs), such as cell and gene therapies, are examples of drug products that fit this definition, along with various emerging biologics and vaccines. Over many years, continued research and development efforts have resulted in a strengthened pipeline of promising treatments for a range of inherited and acquired disorders in oncology, car­diovascular disease, ophthalmology, neurological disorders and infectious disease. Indeed, the American Society of Gene and Cell Therapy (ASGCT) reported more than 4,000 gene, cell and RNA-based therapies in development in the third quarter of 2024, with momentum building around the targeting of more common dis­eases such as diabetes.¹

In many cases, these therapies show great potential in terms of patient outcomes, yet their delicate nature necessitates ex­tremely precise containment and storage conditions to ensure they retain physico-chemical integrity and deliver efficacy while closely controlling any possible contamination risk to patients.

From primary packaging specification to manufacturing processes, this translates into a series of important and interlinked decisions, which are further complicated by the need to demon­strate compliance with the revised Annex 1 of the European Union’s Guidelines for Good Manufacturing Practice for Medici­nal Products for Human and Veterinary Use (EU GMP Annex 1).² These globally accepted rules set forth a number of stringent re­quirements, making drug product manufacturers responsible for taking “all steps and precautions necessary to assure the sterility of the products manufactured within its facilities.”

A key priority introduced by Annex 1 is the need for facilities to implement a detailed Contamination Control Strategy (CCS) to define, monitor and manage any risk to product quality that might arise from microbial, endotoxin/pyrogen contamination and particulates (both visible and sub-visible). The scope of the guidelines extends to primary packaging components from a con­tamination perspective, and there is also additional focus on as­surance of Container Closure Integrity (CCI) and an expectation for in-depth understanding of the container closure system em­ployed.

Under the requirements set out by Annex 1, the stoppering and capping process takes on particular significance since it crosses into all these areas of concern. Here, the use of more tra­ditional metal-based crimp seals presents potential for contami­nation of the drug product with metallic foreign matter, while there is also a challenge to reduce process steps to a minimum and to incorporate the use of pre-sterilized ready-to-use compo­nents in alignment with the demands of a cleanroom environ­ment.

In addition, when it comes to high-value drug products produced in lower volumes, there are further important considerations around the need for components to integrate with more compact and flexible automated filling lines, which have become increasingly prevalent over the last decade. These fill-finish systems are designed to ac­commodate a range of container for­mats on a single line, in batch sizes spanning 20,000 units down to as few as 500, with rapid changeover between batches. As such, they are predicated on the use of nested vials and ready-to-use components that not only conform to standard dimensions but also perform the critical function of assuring sterility, main­taining CCI and supporting the integrity of the drug product throughout its lifecycle.

Through its long-standing partnership with Daikyo, a market-leading provider of proven quality containment solutions, West can answer this multi-faceted vial stopper­ing and capping challenge with both Crys­tal Zenith® (CZ) polymer nested vials and PLASCAP® Ready-to-Use Validated (RUV) press-fit closures.

Available in 13mm and 20mm vial crowns compliant with ISO standards, PLASCAP closures combine both stopper and polypropylene cap into a single inte­grated component providing one-step vial stoppering and sealing for serum applica­tions. In the context of Annex 1 and the re­quirement for close control over contamination risks, PLASCAP closures re­place the traditional metal crimp closures that had the potential of shedding metal particles. With PLASCAP, the elastomer stopper is combined with a polypropylene cap and the entire assembly is subject to 100% vision inspection before being sup­plied ready-to-use after E-beam steriliza­tion.

Appropriately for a closure assembly intended for applications involving sensi­tive therapies, PLASCAP closures feature a stopper that is engineered from high-per­formance D777-1 elastomer and the drug contact surface is coated with Flurotec™ barrier film, which is a highly protective barrier between the drug product and the closure. The Flurotec barrier film reduces extractables and leachables while restrict­ing absorption and adsorption, mitigating the risk of impurities and drug-product degradation and, therefore, protecting the contained therapy and supporting an ex­tended shelf-life. Moreover, Flurotec is nat­urally lubricious, limiting the potential for abrasion that may result in the generation of fewer particles.

The integration of two parts into one assembly means PLASCAP closures have the advantage of reducing what were tra­ditionally two steps in fill-finish down to a single step, enhancing convenience and introducing production efficiencies through time savings. PLASCAP closures also add a valuable layer of tamper-evident security due to the inability to re-attach the flip off cap once it is removed. This design feature consists of four clips that engage with the vial crown when seated to close the sys­tem. Once these clips are engaged, they cannot be removed. Furthermore, the dis­tinctive translucent plastic cap facilitates improvements in vision inspection, sup­porting end-of-line analysis and allowing customers to confirm the closure is prop­erly seated.

An additional benefit of the PLASCAP closures is the numerous options avail­able. Multiple nested packaging configu­rations are offered including 10 x 10 for 13mm vial crowns and 8 x 6, 5 x 5, 4 x 6, 6 x 4 and 4 x 4 for 20mm vial crowns. There is a new 6×8 nested configuration of PLASCAP closures for 20mm vial crowns (which can be supplied as three nests per tub, four tubs per carton) which is compat­ible with the nested CZ 10mL vials for a complete containment solution for ATMPs and Cytiva flexible robotic filler systems.

For Cell and Gene Therapy (C&GT) applications in particular, selecting the ap­propriate packaging is crucial for manu­facturers of these treatments. CZ vials have a proven track record in this area, with many FDA-approved gene therapies utiliz­ing these polymer vials as their primary packaging. It is essential to ensure that the press-fit closures function seamlessly in tandem with the vial to ensure the compo­nents can demonstrate container closure integrity. As such, PLASCAP closures are  meticulously designed to integrate flaw­lessly with CZ polymer nested vials. The 6×8 nest configuration is the latest product offering example of this integration pro­viding a comprehensive packaging solu­tion for C&GT applications.

As with other West products, our es­tablished supply chain has been structured to provide manufacturing partners with guaranteed continuity of PLASCAP clo­sures. Components are originated, and all units are assembled and sterilized in Japan under the guidance of Daikyo Seiko to the internationally recognised quality standards of ISO 9001, ISO 13485 and ISO 11137-1. West then supplies from stock to local markets in small quantities with reduced lead-times.

For product quality and continuity of supply, PLASCAP closures are comple­mented by robust documentation and technical support. This includes critical component specifications and formulation characteristics as well as regulatory sup­port documentation. Indeed, the area of regulatory support is a particular strength at West considering our long-standing commitment to ensure activities are aligned with Annex 1. We are prepared for the impact of the revised regulations and work closely with our pharmaceutical part­ners to ensure optimal containment of valuable drug products with low contami­nation risk.

A crucial part of our approach has been the establishment of a company-wide master CCS framework to define our objectives in relation to the requirements of Annex 1. This has subsequently become established as a Standard Operating Pro­cedure (SOP) across West guiding the con­sistent manufacture and supply of high-quality packaging components for contamination-controlled sterile drug-pro­duction environments.

For our partners, this contamination-control mindset is evident in all aspects of our business, from our products and processes to our people. Moreover, our efforts in this area are designed to com­plement pharmaceutical companies’ indi­vidual approaches to CCS, creating a truly holistic end-to-end model for compliance. Key facets of this approach are the guid­ance of our skilled and knowledgeable team, who can support practical considerations around CCI and contami­nation control, and our forward-looking investment plans to continually evolve West facilities in pursuit of the very highest standards in sterile component manufac­ture.

PLASCAP closures can be seen as a manifestation of this thinking as a one-step stoppering/sealing component, sim­plifying process steps and offering ease of inspection by way of the translucent cap which allows inspectors to see the cap is correctly seated around the vial crown. Combined with the availability of multiple nest configurations, PLASCAP closures provide manufacturers of small-batch drug products – and particularly those using robotic aseptic filling machines – with a convenient and efficient closure op­tion that complies with the contamination-control guidance dictated by Annex 1.

Failure to support these therapies with an appropriate packaging solution brings enhanced risk of degraded efficacy or contamination, which can in turn carry uncomfortable financial implications for supply-chain stakeholders. Such complica­tions represent avoidable barriers to im­proved patient health outcomes.

At West, our aim is to help ensure that drug products are contained in an optimal manner befitting of their sensitivity and value. Through a commitment to innova­tion and continuous improvement, both for products and manufacturing processes, our ambition is to enhance the manufacturing supply chain and advance the availability of precious therapies to healthcare providers and patients in need.

Flurotec™, PLASCAP^® and Crystal Zenith^® are trademarks of Daikyo Seiko, Ltd. and are used under license.

REFERENCES

1. https://www.asgct.org/global/documents/asgct-citeline-q3-2024-rep­ort.aspx.
2. https://health.ec.europa.eu/document/ download/e05af55b-38e9-42bf-8495-194bbf0b9262_en?file­name=20220825_gmp-an1_en_0.pdf.

Jim Thompson is the Director of R&D at Daikyo Product Development at West Pharmaceutical Services, Inc. He has almost 40 years of medical device and pharmaceutical packaging product development experience. He has been at West since 2009 and has a BS degree in Mechanical Engineering and an MBA from Lehigh University.