Pharma Focus America

Adapting Containment Strategies to Future-proof the Manufacture of Sterile Drug Products

Preparing for the Future: Upgrading Cleanroom Containment Strategies to Ensure Long-term Drug Product Sterility.

Ben Wylie, Head of Product Management & Marketing, ChargePoint Technology

ChargePoint Technology’s Ben Wylie, Head of Product Management & Marketing, explores the latest advancement in containment technology and shares his advice on how pharma companies can thrive in a fast-evolving environment.

The aseptic pharmaceutical processing market is growing at a rapid rate - its value is currently projected to increase from $62.2 billion in 2020 to $73.6 billion by 2027.

A key driver of this growth comes from heightened demand across the generic sterile injectable market. This market was worth $434.7 billion in 2022 and is expected to reach $930.3 billion by 2030, growing at a CAGR of 10%.

With this in mind, it is essential for manufacturers to take the necessary steps to ensure their facilities are equipped to handle heightened demand for sterile drug products. Containment is essential during aseptic processing, and cleanrooms and sterile processing technologies serve as critical tools to ensure that drug products remain free from contamination and safe for patient use.

But there are significant challenges for pharmaceutical manufacturers to contend with, as they must expand their capacity to meet market demand, as well as implement advanced containment strategies across their cleanrooms to maintain the integrity of their drug products and comply with rigorous new regulatory requirements.

To overcome these obstacles, manufacturers must explore innovative solutions to future-proof their investments in 2023 and beyond.

Key challenges facing sterile integrity.

Operating in such a highly regulated environment, manufacturers of sterile drug products face the challenge of ensuring that their cleanrooms and processes remain compliant with ever-evolving regulatory requirements.

One of the most significant of these regulations is Annex 1 of the Good Manufacturing Practice (GMP). These guidelines outline the principles of aseptic processing and detail the design, operation and maintenance requirements for cleanroom facilities. This includes the use of appropriate equipment and materials, as well as the proper training and gowning of the personnel handling them.

Manufacturers must follow specific guidelines, which includes the implementation of a Contamination Control Strategy (CCS), to prevent contamination. This formally documented action plan examines and identifies the critical control points (CCPs) across a production line where contamination may occur and establishes a strategy to eliminate the risk at each of these CCPs through the use of appropriate equipment, PPE and operator behaviours.

Under Annex 1, this strategy should be informed by a living document that is subject to regular review to ensure a high degree of contamination control across all cleanroom processes. It should evaluate various aspects of contamination control, such as environment and process design, facility equipment, personnel training and gowning procedures, cleaning and validation procedures, environmental monitoring and prevention testing through process simulations.

Additionally, it is crucial for manufacturers to ensure that all cleanroom team members are fully trained and up to speed with the requirements of the CCS in order to effectively carry them out and ensure they meet Annex 1 requirements.

Ensuring containment across cleanroom designs

To preserve sterile integrity and adhere to Annex 1 regulations, it is crucial for manufacturers to implement closed systems throughout their process.

Manufacturers must design their cleanroom systems to maintain sterile integrity and minimise manual interventions across aseptic manufacturing processes. Part of this includes performing comprehensive risk assessments and implementing new methods for monitoring integrity.

Traditionally, ensuring this integrity requires manufacturers to incorporate open and closed restricted access barrier systems (RABS) or isolator technologies across their cleanroom spaces. Acting as sealed cabinets, these technologies allow for interaction with drug transfer processes while keeping a physical barrier between operators and their production environments.

While isolators and RABs are highly effective at ensuring sterility there are additional factors for manufacturers to consider. These include the cost and time it takes to install, maintain, clean, and validate them after each use, which can result in production downtime and reduced productivity.

To ensure proper operation of RABS and isolator systems in cleanrooms, manufacturers must adhere to the following procedures:

● Use of properly designed equipment
● Provide management oversight of all processes
● Use a high-quality system that adheres to ISO 5 classifications in critical zones, which is the highest level of containment (equivalent to EU GMP grade A/B or US Fed. Standard 209 class 100)
● Adhere to proper gowning practices
● Allow only fully trained operators to use the RABS
● Perform high levels of disinfection
● Follow SOPs and document any cases of human intervention.

Containment technology evolving to keep up

However, recent advancements in containment technology are acknowledged by Annex 1 regulations as enabling stringent sterile integrity while eliminating the need for the strictest cleanroom standard in many production processes or the inclusion of RABs or isolators.

One of these solutions increasingly used across cleanrooms is the aseptic split butterfly valve (SBV) - a stainless steel component that consists of two components: an "active" half that connects to production line equipment and a "passive" half that attaches to the container or primary packaging.

When connected, these two halves form a single plate that allows the drug product to flow into the container from the production line, maintaining a closed environment. SBVs offer a range of key benefits for manufacturers, both in terms of improving efficiencies of RABs and isolators, as well as eliminating the need for their use altogether, in some circumstances.

For example, the integration of aseptic SBVs into isolators or RABS systems and processes has been vital in achieving high-performance containment and improving sterility assurance. Adopting this technology allows for closed handling, reducing manual intervention and resources required for cleaning and validation, while also increasing flow and yield from product transfers.

Additionally, as the latest revision to Annex 1 stipulates, drug product transfers may occur in cleanroom environments lower than a Grade B, provided that the connection device has been validated to prevent microbial contamination and has undergone a CCS review. As a result, this can streamline processes and aid in small-batch manufacturing due to their ease of use and flexibility.

Single-use variants of aseptic components such as the SBV are also becoming more common in sterile processing. Offering the same level of sterility as its stainless steel counterpart, these innovations streamline drug transfer processes further by removing the requirement for lengthy cleaning and validation procedures after use.  

Similarly, chargebags, which are single use alternatives to reusable bottles, are increasingly being used across cleanroom facilities for the storage and transport of drug product materials. These bags feature a valve that connects to the oppsing half of an SBV, allowing for the transfer of the drug product without exposure to the outside environment. Like the single-use SBV, these chargebags are intended for disposal after use, ensuring the continued sterility and integrity of the drug product material, while minimising cleaning and validation requirements.

Future-proofing containment strategies for sterile drug product manufacture.

As the industry evolves, manufacturers of sterile drug products must stay informed not only of current regulatory requirements but also the latest advancements in technology to ensure that their manufacturing processes are prepared for the future.

While technologies such as RABs and isolators will continue to be used in cleanrooms for many years, they have certain limitations. Advances in drug product transfer equipment, such as SBVs, mean that in a growing number of situations they can eliminate the need for RABs and isolators while reducing the stringency of the surrounding cleanroom environment.

As we look ahead to the cleanrooms of the future, manufacturers will be required to explore the latest innovations to ensure the longevity of their processing equipment.

Innovations such as smart factory technology can play a critical role in this process, providing real-time monitoring and control of cleanroom environments and allowing for more efficient and precise operations.

These technologies can also provide manufacturers with predictive maintenance, reducing downtime and ensuring equipment continues to operate at optimal levels.

By incorporating these technologies, drug manufacturers are better equipped to future-proof their cleanrooms and ensure their ability to meet the ever-increasing demands of the industry by producing safe and effective medications for patients.

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Author Bio

Ben Wylie

Ben Wylie is the Senior Product Manager at ChargePoint. He has joined ChargePoint in 2005 and is responsible for the day-to-day and strategic management of the product portfolio, including the development of the ChargePoint single use solutions. Ben has 14 years of experience in Pharma with a focus on marketing and product management of powder processing and containment handling

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