PRIMARY CONTAINER CLOSURE SYSTEMS - In From the Cold: Realizing the Benefits of Primary Packaging Innovation for Lyophilized Drug Products

INTRODUCTION

Many in the pharmaceutical industry are well aware of the benefits of lyophilization (or freeze-drying) in ensuring the stability of certain formulations, such as proteins, monoclonal antibodies, enzymes, and vaccines.

The market also understands some of the challenges associated with lyophilization in terms of maintaining quality; namely mitigating against particulates and ensuring container closure integrity (CCI). There are challenges too in terms of managing operational efficiency and mitigating costly downtime.

The following will quickly revisit the benefits and challenges associated with lyophilization before reviewing some of the current macro influences, including the EU GMP Annex 1 revision. It will then discuss West’s design philosophy and Quality-by- Design (QBD) blueprint, before showcasing its 4040 LyoTec^® Stoppers, which help mitigate the compromises associated with the current marketed products. Finally, it will showcase data to demonstrate the efficacy of the 4040 elastomer platform.

LYOPHILIZATION – THE COMPLEXITIES & BENEFITS

There are myriad threats to a drug’s stability and integrity over time, and each of these threats has the potential to compro­mise the desired therapeutic effect and therefore the intended outcome for the patient.

Moisture is a case in point. There are some pharmaceutical substances, including proteins, monoclonal antibodies, enzymes, and vaccines, in which the solution state required for parenteral administration can itself be a catalyst for degradation through enzymatic or hydrolytic reactions. In these circumstances, the process of lyophilization, or freeze-drying, allows stability to be maintained by altering the state of the drug from a fluid to a dry powder, causing metabolic processes to halt.

Lyophilization in simple terms describes the removal of water, but the process is undoubtedly highly complex and time-intensive, with three critical stages involved: freezing, sublimation (primary drying) and desorption (secondary drying).¹ In its resultant freeze-dried cake form, the drug is more stable, meaning formulations benefit from a longer shelf- life and are easy to transport. When it then comes to administration, healthcare professionals are tasked with reconstituting the powder with a sterile diluent to form an injectable solution.

Because the benefits of lyophilization are contingent on the sustained absence of water, drugs in a dry-powder state present particular challenges in terms of being contained within a secure, low-moisture environment. Indeed, the Ancient Greek roots of the word lyophiliza­tion, which loosely translated means a love of dissolving, underline the inherently absorbent properties of the drug in this form and the ever-present risk of the stability of the lyophilized drug product being compromised through contact with moisture.²

PACKAGING MUST BE A PRIMARY CONSIDERATION

In this context, the choice of primary packaging components is crucial. Together, all elements must harmoniously contribute to safeguarding the drug product in dried form during manufactur­ing, transportation, and storage. The elastomer stopper, which fulfills the role of sealing the vial’s contents against the external environment, demands particular attention. This interface presents several theoretical moisture-related risks. This includes the potential to release residual moisture contained within the stopper itself, as well as its potential to facilitate permeation of water from the environ­ment, both as a direct conduit and via the interface between stopper and vial.

With these risks in mind, an understanding of the independent physico-chemical attributes of vial and stopper, and the interplay between these two elements, is critical in achieving the containment properties necessary to main­tain lyophilized drugs in their desiccated state.

One of the many critical quality attributes (CQAs) for stoppers in lyophilization applications is the Moisture Vapor Transmission Rate (MVTR). This value must be recorded at a low level to ensure the elastomer does not encourage the transfer of atmospheric water.

Furthermore, there must also be consideration of treatments the compo­nent will undergo during processing. This includes steam sterilization carried out in an autoclave, which involves moisture being absorbed by the stopper and removed via a drying process. It is essen­tial this final stage is optimized in “Goldilocks” conditions of no more than 8 hours and at a temperature no higher than 105°C – a criteria “just right” to sufficiently reduce moisture levels but avoid the elastomer being over-exposed to conditions that can result in degradation. It’s important to note the exact parameters for sterilization and drying will influence the resulting water content. For example, the drying cycle will need to factor in the physicochemical properties of the elastomer and the performance and efficiency of the autoclave chamber.

Dimensional fit between stopper and vial is also critical to the effective contain­ment of a lyophilized drug product. Vials are subject to a staged sealing process, and CCI can be threatened if the stopper becomes displaced at any point through pop-up. Pop-up describes the scenario in which the edge of the stopper, or the entire component, is raised above the top of the vial following stoppering, introducing the risk of contamination and exposure to moisture.

In lyophilization, stoppers are initially inserted partially into the vial opening following aseptic filling to provide the vent that allows for sublimation during the lyophilization process. The stopper must remain secure in this position throughout the freeze-drying process until the lyophilizer shelves are lowered to fully seat the stopper in the vial. It must continue to remain fully seated during transportation from the lyophilization chamber to the crimping station, where the long-term seal is achieved.

Pop-up can be driven by many factors, including when the plug diameter of the stopper is too big and there is a resulting increase in the insertion force required to seat the stopper accurately. It can also be triggered during the lyophilization process when stoppers stick to the lyo shelves of the lyophilization chamber at the point they are raised. This adhesion can lead to the stopper being improperly seated, impacting CCI prior to capping. Ultimately, it can result in drug spills within the lyophilizer, with costly wasted drug product, production down­time, and the need to undertake clean-up procedures.

It is clear then that all attributes of a primary packaging system must combine to form an uncompromisingly secure environment; one that not only protects the lyophilized drug product itself, but also consistently mitigates the risk of contami­nation by particulates, safeguards sterility, and mitigates potential risk to patient safety.

DON’T FREEZE UNDER THE PRESSURE OF EU GMP ANNEX 1

In recent years, regulatory authorities have implemented changes to drug manufacturing regulations with a view to enforcing these objectives. Most recently, in August 2022, the European Commis­sion published the final revised version of EU GMP Annex 1 relating to the Manufac­ture of Sterile Medicinal Products for human and veterinary use. The updated Annex 1 is scheduled to come into force on August 25, 2023, (with the specific exception of Chapter 8.123, which relates to product transfer for lyophilizers and takes effect from August 25, 2024).³

The updated guidance remains faithful to the original structure of Annex 1, but goes into far greater depth in certain areas, as well as introducing the requirement to implement a Contamina­tion Control Strategy. Patient safety might be at the root of this change, but it also addresses the fact that particulates and sterility are a major cause for costly product recalls.

Despite the current focus on EU Annex 1, the European Union is not the only territory where the bar of expectation is being raised when it comes to regulatory standards for particulates. The pharma­copeia of the US, Japan, and China also place emphasis on the eradication of visible foreign matter, and updates to risk management and compliance guidance in recent years point to an underlying ambition among regulators to manifest a future essentially free from particles. Indeed, on average, 34% of FDA recalls for approved injectable products were attributed to issues with foreign particulates or a lack of sterility that stemmed from the container closure being sub-optimal.^4,5

WEST’S QUALITY-BY-DESIGN PHILOSOPHY

At West Pharmaceutical Services, we translate challenges around improving contamination control and maintaining drug product stability into strategic objectives. To our organization, they form the starting point for the development of innovative components and systems designed with the future in mind, ensuring our pharmaceutical partners are equipped with solutions that fit into their current supply chains and workflows, while meeting the ever-more stringent demands of the evolving regulatory landscape.

A case in point is West 4040 LyoTec vial stoppers, which have been developed directly in response to the CCI risks and processing challenges pharmaceutical partners are facing for lyophilized drug products. This platform was realized through the principles of QbD, using a systematic, science-based approach to meet highly targeted market-driven objectives. Not only are product features designed to meet Quality Target Product Profile (QTPP) goals, there is also consideration of performance within manufacturing environments. This all-encompassing approach provides a platform for the mitigation of development risk, ensuring variables are closely controlled, choices are backed by robust data, and the resulting innovation delivers the impact expected without compromise.

West’s continued use of QbD principles mean the properties of the 4040 LyoTec stopper, from the raw materials to the milling and compounding processes, are collectively focused on reducing the extractables and leachables (E&L) profile as well as addressing risks associated with fragmentation/coring and particulates, which are further mitigated through a validated wash process. The product is engineered to a tighter moisture-specifica­tion standard and, aligned to our emphasis on data, every batch is analyzed and certified, with particulate levels shown to be consistently low and warranted to the Westar™ Select process specifications for our high-quality, industry-proven stoppers.

Extensive consideration has also been given to how the stopper can be integrated into global supply chains. For this reason, West’s 4040 LyoTec stoppers are designed to be universally compatible with European blow back, no blow back, and American blow back ISO glass vial types in 13-mm and 20-mm formats.

To verify this compatibility, helium leak CCI testing was performed across all formats using 4040 LyoTec stoppers in conjunction with ISO 2R and 10R tubular vials. For both non-aged stoppers and stoppers aged in ambient conditions, across all vial types, the tested containers exceeded the minimum Kirsch Limit requirement for CCI of 6×10-6 mbar L/s.

While this compatibility between vial and stopper is, of course, fundamental to maintaining the integrity of the drug product, the stopper must also be consid­ered in the context of manufacturability.

As such, the 4040 LyoTec stopper incorporates optimized drying properties to improve steam sterilization and its igloo design is proven to be effective at limiting the disruption caused by stoppers joining together, or twinning, in the feeder bowl. This risk is further reduced, along with risks of clumping and sticking, due to the stopper’s B2-Coating, which provides a low-particle alternative to conventional silicone oil. Additional benefits are also realized through the incorporation of FluroTec™ film on the top surface of the stopper closure, which has been shown to play an integral role in reducing adhesion to the lyo shelves.

Finally, to assess the risk of pop-up, oxygen-headspace analysis has been conducted using vials of all blowback geometries. These tests confirmed the 4040 LyoTec stoppers maintained CCI without capping for 24 hours in all formats of the vials tested.

Taken together, the combined results of all these tests illuminate how the 4040 LyoTec stoppers can be seen to tackle major factors behind compromised CCI while also avoiding manufacturing down­time by reducing instances in which drug product is lost and clean-up procedures hamper production efficiency and jeopardize employee safety.

To provide a complete system for assured CCI and efficient manufacturabil­ity, West can also combine 4040 LyoTec stoppers with Corning® Valor® Glass vials from Corning Incorporated. Compared to conventional vials, the Valor Glass product significantly reduces the risk of damage and breakage during low temperature processes, such as lyophilization, deliver­ing benefits for productivity and employee safety. This is the result of a chemical strengthening process that imparts compressive stress on the glass surface to levels that typically exceed the tensile stresses generated during the freezing or ice nucleation processes. A low coefficient of friction (COF) coating is applied to the exterior of the containers, improving damage resistance, machinability, and reducing particulate generation. Such properties not only offer enhanced protection for high-value drugs, but they may also allow for more aggressive and faster lyophilization cycles in some cases.

SUMMARY

Upon reflection, the fact these various manufacturability and containment challenges need to be overcome at all provides evidence of the complexity involved in lyophilization. However, in a market where moisture-intolerant biologics and more complex therapies continue to grow in share, the ability to transform parenteral solutions into dry powders remains a potent weapon against destabilization and degradation.

For pharmaceutical companies, the future of lyophilization will therefore continue to be defined by assurances of CCI and the need to control contamination in the face of increased regulatory oversight. Armed with world-class product innovation that draws on QbD principles, West has shown how it is possible to source components that answer lyophilization’s short-term challenges while providing a pathway to satisfy the functionality, performance, and safety demands of tomorrow.

REFERENCES

1. https://www.fda.gov/inspections-complia­nce-enforcement-and-criminal-investiga­tions/inspection-guides/lyophilization-parenteral-793.
2. https://link.springer.com/book/ 10.1007/978-1-4939-2383-0.
3. https://www.gmp-compliance.org/gmp-news/finalised-the-revised-eu-annex-1-is-published.
4. https://www.fda.gov/vaccines-blood-biol­ogics/safety-availability-biologics/recalls-biologics, accessed February 14, 2023.
5. https://www.fda.gov/drugs/drug-safety-and-availability/drug-recalls, accessed February 14, 2023.

Neal Higgins is a Consultant Program Manager at West Pharmaceutical Services. One of his many roles is to assist customers in process-related activities involving West products. He is also a member of the Purdue University LyoHub, an industry-focused consortium to advance the science and technology of lyophilization. He has spent 30 years in the pharmaceutical industry, where he held various SME and leadership roles in Parenteral Fill/Finish Operations as well as Delivery Device Research & Development. At the time of his retirement from Eli Lilly in 2017, he was the Global R&D System Lead Engineer for all vial systems. His broad range of knowledge and experience in aseptic processing combined his knowledge of primary container closure systems provides valuable insights and solutions for customers.