Introduction

Emergent BioSolutions manufactures a portfolio of branded protein therapeutics and contract manufactured products at its Winnipeg, Canada site. In 2016 Emergent revamped its site quality plan and decided to replace the existing conventional filling equipment.

Emergent’s example provides perspective on changing existing commercial products to a new filling line and primary packaging—a topic covered extensively by ISPE and PDA conferences in discussing the modernization of aging facilities.

“In revamping the Winnipeg site’s aseptic filling operations, the company wanted a machine that could provide superior product quality, sterility assurance and flexibility. For its own branded products and our contract manufacturing clients, we believe that Vanrx’s SA25 Aseptic Filling Workcell meets all of these requirements, and will position us well to manufacture next-generation therapies,” says Kevin Gadient, Director of Manufacturing Science & Technology at the Winnipeg site.

This case study examines Emergent’s decision criteria for and implementation of a closed gloveless robotic isolator filling nested containers and closures. It will discuss the obstacles Emergent needed to overcome, including regulatory and business risks, from the point of view of both a drug product innovator and a contract manufacturing organization.

This story was originally presented as a poster by Kevin Gadient at the 2019 PDA Annual Meeting.

Choosing technology leadership

Across the company Emergent is focused on improving its aseptic processing operations. The move is in response to changing regulatory requirements and the nature of new therapies. Today drugs are being targeted at smaller patient populations, and there is a variety of containers and delivery devices into which drugs are packaged. Many of these drugs involve significant process complexity. Simultaneously, regulators are insisting on improved sterility assurance methods and separation of operators from aseptic processes.

Emergent determined that an existing conventional filling system installed in an open Grade A cleanroom could not meet future production requirements or ensure long-term regulatory compliance. As part of a new quality plan, Emergent decided to replace their existing conventional filling system.

With Emergent and its multiple manufacturing sites targeting industry leadership for its aseptic processing operations, the Winnipeg project team elected to make a major change in both technology and approach. Vanrx’s SA25 Aseptic Filling Workcell was selected because it best met the team’s selection criteria.

Project timeline

Timeline of new filling machine into Emergent BioSolutions' Winnipeg site.

Selection criteria and decision

Emergent assembled a project team consisting of engineering, manufacturing, validation and process support functions. The team developed a User Requirement Specifications (URS) document with several primary needs, as well as additional “wants” that would add capabilities or strengthen existing ones. Five machine companies submitted proposals, with two companies providing options that met all of the core requirements.

Filling machine needs Filling machine “wants”

Sterility assurance at least equal to existing machine

Complete sterility assurance

Will not disrupt commercial supply

No changes to current primary container / closure components

Will not impact commercial product shelf life

Additional vial size filling capabilities

Will meet overall budget

Cartridge / syringe filling capabilities

Will allow the transfer of commercial products on to it

Ability to easily bring new products on to the machine

Will provide sustainability in aseptic compliance from health authorities

Selecting the SA25 Aseptic Filling Workcell

For Emergent aseptic processing has been a focus area for improvement. As a result, there was buy-in from the teams conducting the due diligence process and senior management to choose a new technology, which was called “leading the charge.”

The team determined that Vanrx’s SA25 Aseptic Filling Workcell—a closed, robotic aseptic filling machine—provided a sterility assurance advantage. It was not a system with which the project team had experience operating, so extensive due diligence was completed.

This process included comparative testing, literature review, failure mode and effects analysis (FMEA), interdepartmental strategic planning, long-term projects and forecasting, supplier relations and external negotiations.

Much of the focus of this diligence process was on the eventual transfer of licensed products on to the new technology.

The Workcell also satisfied the Emergent “wants” of flexibility for additional vial sizes, syringe and cartridge filling capability, and greater ease in bringing new products online.

Change management and project plan

Proper change management was the largest concern for the business, regulatory and quality groups, who were involved early in the overall selection process.

Emergent had compiled many years of product data on the previous filling system and current container and closure components. Since these parts of the supply chain would change, a thorough project implementation plan was needed to ensure continuity in product quality and supply.

A detailed project implementation plan was built along the RASCI model (Responsible, Accountable, Support, Consult With and Inform) outlining which functions were responsible for each area of project execution and their obligations to collaborate or communicate with each other.

The project plan covered key areas such as facility construction, equipment commissioning and validation, quality assurance, quality control, contract manufacturing client relations, regulatory affairs, and container-closure supply & quality.

The switch to pre-sterilized components made it a requirement of the project to work with multiple groups to approve new primary packaging components, as the current components are not available in these formats.

The transition to new primary packaging components

 

One of the key concerns of the project was to avoid interruption to the supply of commercial products. Nested containers and closures represent a change in terms of the production process. It was recognized early that these components are important to the sterility assurance and flexibility aspects of the gloveless isolator.

To mitigate the risk of interruption, the project team had to understand the impact of new vials, stoppers and closures on product shelf life. This meant analyzing product characteristics as they related to storage conditions and expiry dates, including low temperature storage.  The new containers, stoppers and press-fit closures showed equivalency to the existing ones.

The other concern was the machinability of the new vials and closures within the filling machine. In the existing conventional filling suite, a larger-than-needed size of vial was used because multiple products could be filled into the same size. With the new filling machine, a more appropriately sized vial could be selected, and multiple vial sizes could be filled without the need for change parts. Switching to a smaller vial meant that labelling and cartoning was also changed to accommodate the new formats across various sizes.

Another difference introduced to product packaging was the use of press-fit vial closures with integrated stoppers. These are supplied in a pre-sterilized nest by the supplier as a requirement of the gloveless isolator’s aseptic process. This combination of vial and press-fit closure met Emergent’s requirements, including those for container-closure integrity, low temperature storage and shelf life.

Facility implications

The project team appreciated that the gloveless isolator is designed to minimize the integration aspects of facilities and installation. The unit arrived assembled and is standalone, requiring only compressed air, single-phase 240 VAC power and an external exhaust. Its total footprint is 4’9” x 13’8” x 7’9” (1.8 x 4.1 x 2.4m), meaning it could be installed into a small cleanroom in comparison to other filling operations.

The team constructed a cleanroom using an underused area of the facility, consisting of a small Grade D corridor, and Grade C gowning room and filling suite. Pre-sterilized containers and closures are brought from the warehouse to the filling suite by the pallet when needed.

The Workcell has minimal supporting requirements and fit in a filling suite totalling 538 square feet (50 square metres), which is adjacent to 355 square feet (33 square metres) of cleanroom entrance and egress space.

Process implications

Many aspects of the aseptic process within the gloveless robotic isolator are different from the alternatives that were researched by the project team.

The Workcell provides a highly automated handling, filling and closing process. The project team spent extra time to understand how the process worked, and how areas of risk were mitigated in the process flow. Implementation of the Workcell post-installation has focused on process development and product recipes—work which is ongoing.

Though the system is closed when in operation, the project team implemented contamination control specifications, and engineering and administrative controls to reduce particle introduction and bioburden contamination in the Workcell’s interior.

There are a couple of significant differences for operators in the new filling suite. Gowning qualification is no longer required. Minimal aseptic technique is required, and there are much fewer areas for potential failure during the process. Operators have said that their job is much less physical than in the conventional filling suite. As a side effect, it has taken operators additional time to learn the Human-Machine Interface (HMI) and how recipes control different process parameters.

Currently, the site has four “super users” split between filling, maintenance and validation functions, with future plans to roll out training on the Workcell to standard users.

Key lessons from the implementation of a gloveless robotic isolator

There are many differences in implementing a gloveless robotic isolator into a production facility. These differences affect facility design and production processes, as well as requiring close regulatory attention if existing commercial products will be transferred into the new technology and primary packaging.

The key lesson from this experience was to involve supporting groups such as quality assurance, regulatory affairs, quality control and analytical development early on in the process. This helped the larger project team better understand and solve obstacles. It was important that each group understood the risks and benefits of choosing a new aseptic filling technology.