FACILITY DESIGN - Holistic Facility Design in Injectable Fill-Finish Operations

INTRODUCTION

The implementation of the EU’s Annex 1 regulations has in­troduced new standards for contamination control and sterility assurance in injectable fill-finish operations, encouraging the in­dustry to adopt more advanced, automated systems that reduce human intervention. While meeting these standards is crucial, it is just one part of the larger picture. Companies need to consider a more comprehensive approach that not only ensures compli­ance but also incorporates cutting-edge technologies and prior­itizes sustainability.

FROM REACTIVE COMPLIANCE TO PROACTIVE PLANNING

A reactive approach to regulatory compliance in fill-finish operations involves retrofitting existing facilities to meet new stan­dards. While sometimes necessary, this method can lead to in­creased costs, operational inefficiencies, and potential quality risks. The introduction of Annex 1 offers an opportunity to recon­sider this approach.

Annex 1, a crucial component of the European Union’s Good Manufacturing Practice (GMP) guidelines, specifically addresses the manufacture of sterile medicinal products. Revised signifi­cantly in 2022, it sets forth stringent requirements for contami­nation control and sterility assurance in pharmaceutical manufacturing. The updated Annex 1 places a strong emphasis on quality risk management, introducing the concept of contam­ination control strategy (CCS) as a holistic approach to maintain­ing sterility throughout the manufacturing process.¹

Key aspects of Annex 1 include:

• Enhanced focus on a quality risk management approach
• Implementation of contamination control strategy (CCS)
• Increased emphasis on the use of barrier technologies and closed systems
• Stricter environmental monitoring requirements
• Greater attention to personnel training and behavior in clean­room environments

The revised Annex 1 guidance represents a paradigm shift in how sterile products are manufactured, emphasizing a proac­tive, risk-based approach rather than a reactive one. Compliance with Annex 1 is not just about meeting regulatory requirements; it is about fundamentally improving the quality and safety of ster­ile medicinal products. By reducing the risk of contamination, Annex 1 aims to enhance patient safety and product efficacy.

Rather than viewing Annex 1 compliance as a hurdle, for­ward-thinking companies are viewing it as a chance to innovate. By adopting a more holistic approach that considers compliance, technology, and sustainability from the outset, these organizations are not just meeting current standards — they are preparing for future changes as well.

HOLISTIC FACILITY DESIGN

A holistic view of facility design is central to a future-forward mindset. This approach envisions comprehensive systems engi­neered with Annex 1 compliance and future adaptability as foun­dational principles. Facilities designed with this holistic perspective incorporate several key features that set them apart from tradi­tional manufacturing sites.

First and foremost, these facilities integrate compliance into every aspect from the ground up. Annex 1 standards are not afterthoughts but are woven into the basic design, influencing everything from the overall facility layout down to individual process steps. This in­tegrated approach to compliance reduces the need for future retrofitting and ensures that regulatory requirements are met effi­ciently and effectively.

Technology readiness is another cru­cial aspect of this holistic design philoso­phy. Recognizing the rapid pace of technological advancement in the phar­maceutical industry, these facilities are de­signed with the flexibility to adopt new technologies as they emerge. This fore­sight creates spaces that can accommo­date new equipment and processes without requiring major renovations, thus future-proofing the facility against techno­logical obsolescence.

Sustainability considerations are also a key component of this holistic approach. Environmental factors are carefully consid­ered in the facility design, from the imple­mentation of energy-efficient isolator technologies to the optimization of re­source use. This focus on sustainability not only reduces the environmental impact of pharmaceutical manufacturing but can also lead to significant cost savings over the long-term.

Risk reduction is a primary focus in every aspect of these holistically designed facilities. By going beyond current regula­tory requirements and anticipating poten­tial future standards, these facilities are designed to minimize contamination risks at every stage of the manufacturing process. This proactive approach to risk management helps ensure product quality and patient safety while also preparing the facility for potential future regulatory changes.

Finally, operational flexibility is built into the core of these facilities. In an indus­try characterized by changing market de­mands and evolving regulatory landscapes, the ability to adapt quickly is a significant advantage. Facilities designed with this holistic perspective can more eas­ily adjust to new product lines, manufac­turing processes, or regulatory requirements, providing a competitive edge in a dynamic industry.

By embracing this holistic approach to facility design, pharmaceutical companies and CDMOs can create manufacturing environments that are not only compliant with current regulations but are also well-positioned to meet the challenges of the future. This forward-thinking strategy rep­resents a significant shift in how the indus­try approaches fill-finish operations, emphasizing long-term sustainability, adaptability, and excellence in pharma­ceutical manufacturing.

TECHNOLOGY INTEGRATION

While automation has been a topic of discussion in the industry for some time, holistic facility design takes this concept further. The goal is to create an integrated technological ecosystem, not just to auto­mate individual processes.

ADVANCED ISOLATOR TECHNOLOGY

A cornerstone of technological inte­gration in modern fill-finish operations is advanced isolator technology. This inno­vation represents a significant leap for­ward from traditional cleanrooms or basic restricted access barrier systems (RABS), offering a level of contamination control that is particularly well-suited to meet the stringent requirements of Annex 1.²

Modern isolators provide complete physical and aerodynamic separation be­tween operators and the critical aseptic processing area. This separation is achieved through a fully enclosed, highly controlled environment that significantly minimizes the risk of human-borne con­tamination. The isolator’s design typically includes glove ports for manipulations, transfer ports for materials, and a sophis­ticated air handling system that maintains a sterile environment.

One of the key advantages of isolator technology is its ability to maintain a con­sistent, high-quality environment. Unlike traditional cleanrooms, which can be sub­ject to fluctuations due to personnel move­ment and other factors, isolators provide a stable, controlled space that can be more easily validated and maintained. By providing a physical barrier between the product and potential sources of contam­ination, isolators address one of the primary concerns of Annex 1 regulations. Moreover, the closed nature of isolator sys­tems allows for more effective decontami­nation procedures, further enhancing sterility assurance.

Beyond compliance and risk reduc­tion, isolator technology offers significant operational and sustainability benefits. These systems typically require less energy for environmental control compared to traditional cleanrooms. The smaller vol­ume of space that needs to be maintained at critical environmental parameters (tem­perature, humidity, particulate levels) translates to reduced HVAC requirements and lower energy consumption.³

The implementation of isolator tech­nology does come with its own set of chal­lenges. The initial capital investment can be significant, and staff require specialized training to operate these systems effec­tively. Additionally, the design and valida­tion of isolator systems require careful consideration to ensure they meet all reg­ulatory requirements and operational needs.

Despite these challenges, the benefits of advanced isolator technology in meet­ing Annex 1 requirements, reducing con­tamination risks, and improving operational efficiency make it a key con­sideration for companies adopting a ho­listic approach to fill-finish operations. As the pharmaceutical industry continues to evolve, isolator technology is likely to play an increasingly important role in ensuring the quality and safety of sterile products.

EXPANDING AUTOMATION

The industry is exploring more ad­vanced automation, with robotic systems capable of performing complex tasks within isolators. These robots can handle delicate components and perform precise manipulations, further reducing the need for human intervention in critical processes.

For example, automatic bag opening systems are helping to eliminate the vari­ability and potential contamination risks associated with manual handling. These systems consistently open sterile barriers, reducing the chance of accidental contam­ination or damage to packaging materials.

ENHANCING QUALITY ASSURANCE THROUGH AI/ML

Artificial intelligence (AI) and machine learning (ML) are beginning to play a role in fill-finish operations. AI algorithms can analyze large amounts of data to identify potential quality issues before they occur, allowing for preventive actions. This shift towards more proactive quality manage­ment represents a significant step forward in ensuring product consistency and safety.

ML models have the potential to opti­mize process parameters in real-time, helping to ensure consistent product qual­ity even under varying conditions. This dy­namic process adjustment capability could help reduce waste and improve overall operational efficiency.

EVOLVING QUALITY MANAGEMENT

The holistic approach to fill-finish op­erations requires a fresh look at quality management systems. The goal is to inte­grate quality considerations into every as­pect of the operation.

Electronic batch records (EBR) systems represent an important advancement in quality management. These systems pro­vide real-time tracking of interventions, help ensure compliance with standard op­erating procedures, and maintain ac­countability throughout the manufacturing process. The digital approach can en­hance data integrity, reduce the risk of human error in documentation, and pro­vide a clear audit trail for regulatory in­spections.

Complementing EBR systems, ad­vanced video monitoring and microstep analysis technologies are improving risk assessment capabilities. These tools allow for continuous process monitoring and can detect subtle deviations that might be missed by human observation. By identify­ing potential issues early, these technolo­gies contribute to more proactive quality management.

Process Failure Mode and Effects Analysis (PFMEA) is also becoming increasingly important. This systematic ap­proach to identifying potential failures is being integrated earlier in the design phase of new facilities and processes. By anticipating potential issues and designing mitigation strategies from the outset, or­ganizations can create more robust and reliable fill-finish operations.

SUSTAINABILITY AS A DESIGN CONSIDERATION

In the past, sustainability was often a secondary consideration in pharmaceuti­cal manufacturing. However, in advanced facilities, it’s becoming a more integral part of the design process, influencing var­ious aspects of the operation.

The shift to isolator technology not only enhances sterility assurance but can also reduce energy consumption. Isolators typically require smaller HVAC systems compared to traditional cleanrooms, which can lead to energy savings.

Purpose-built facilities are often de­signed with an eye towards minimizing water usage and overall utility consump­tion. By adopting lean methodologies, these facilities can reduce waste, optimize resource use, and improve overall opera­tional efficiency. This not only reduces the environmental impact but can also con­tribute to long-term cost savings.

THE POTENTIAL OF GEOGRAPHIC LOCALIZATION

Geographically optimized production is emerging as a strategy for potentially re­ducing both costs and environmental im­pact. Centrally located facilities can minimize transportation risks, which is par­ticularly important for temperature-sensi­tive biologics. Fewer touchpoints in the dis­tribution process may also reduce the risk of product tampering or diversion and could allow for quicker adaptation to mar­ket demands and supply fluctuations.

A holistic approach can extend be­yond the physical facility to encompass a range of services. Comprehensive, end-to-end services can provide a single point of contact for multiple needs, potentially sim­plifying communication and problem-solv­ing. This can allow for a more unified quality system and a cohesive approach across the production process. By reducing the need to coordinate multiple vendors, integrated services may help reduce time-to-market for new products.

PREPARING FOR FUTURE SHIFTS

While Annex 1 compliance is a cur­rent focus, a holistic mindset for facility de­sign considers potential future regulatory changes as well. This forward-thinking ap­proach aims to ensure that these facilities can adapt to new requirements without major overhauls, which could provide a competitive advantage.

The future of injectable fill-finish op­erations involves not just meeting current standards but creating adaptable, effi­cient, and sustainable operations that can evolve with the industry. By adopting a ho­listic approach that considers compliance, technology, and sustainability from the ground up, pharmaceutical companies and CDMOs can position themselves well within the industry.

Advanced fill-finish facilities represent more than just a new way of manufactur­ing; they embody an approach that prior­itizes quality, efficiency, and environmental responsibility. As the industry continues to evolve, those who embrace this holistic ap­proach find themselves well-positioned to navigate an increasingly complex and de­manding market.u

 REFERENCES

1. European Commission. (2020) “Annex 1: Manufacture of Sterile Prod­ucts.” https://health.ec.europa.eu/system/files/2020-02/2020_annex1ps_sterile_medicinal_products_en_0.pdf
2. Nieuwenhuizen, P. (2021) “Aseptic Considerations in Formulation, Fill and Finish: Choosing Between Barrier and Isolator Technologies.” Bio­process International. https://www.bioprocessintl.com/fill-finish/asep­tic-considerations-in-formulation-fill-and-finish-choosing-between-barrier-and-isolator-technologies
3. Markarian, J. (2020) “Best Practices in Using Isolator Technology. Phar­maceutical Technology.” Pharmaceutical Technology: 33-34 https://al­fresco-static-files.s3.amazonaws.com/alfresco_images/pharma/2020/02/20/341d4638-173e-44a2-8a78-e28b5d2ffe85/PharmTech_Eu­rope_Feb2020_v2.pdf.

Chad Hafer is the Director of Technical Operations at Kindeva Drug Delivery, bringing over 10 years of experience in aseptic operations. Currently, he is spearheading the design and construction of Kindeva’s aseptic injectable fill-finish facility in Bridgeton, MO. He earned a Bachelor of Science degree in Chemistry, a Master of Science degree in Project Management, and a Master of Engineering.