Integration of Containment Technologies in High-Potent Aseptic Production

What are Highly Potent Substances?

In pharmaceutical production, the term “highly potent” refers to substances or drugs that possess a significant amount of power or strength even at low doses. These substances have a significant pharmacological effect even in very small quantities, which may require special handling, safety measures, and engineering controls such as containment during manufacturing, handling and administration.

Highly potent substances can include various types of active pharmaceutical ingredients (APIs), such as potent analgesics, cytotoxic drugs, hormones, immunosuppressants and certain biologics. These substances are often used in the treatment of severe diseases or conditions where precise dosing is critical. Due to their high potency, these substances pose a higher risk to workers’ health and safety if appropriate precautions are not taken. This includes the potential for occupational exposure during manufacturing processes, which can lead to adverse effects.

Therefore, pharmaceutical companies that handle highly potent substances are required to establish stringent containment measures, such as specialized facilities, engineering controls, personal protective equipment (PPE), and strict adherence to good manufacturing practices (GMP) and occupational safety guidelines. The goal of these measures is to minimize the risk of exposure to highly potent substances and ensure the safety of personnel involved in their production, handling, and administration, as well as to prevent cross-contamination and maintain product quality.

Risks in High-Potent Drug Production

The risks presented in the production of highly potent drugs can be divided into two major categories: personnel safety risks and product safety risks.

Personnel safety risks refer to the potential harm that highly potent drugs pose to personnel involved in various stages of the process. Containment technologies, along with other engineering considerations in designing the architectural layout, mechanical systems and utilities of the facility, are tailored to protect personnel from exposure to the product.

Product safety risks, on the other hand, can adversely affect the quality of the product. These risks stem from two primary sources. The first and most significant is personnel-related contamination, particularly in the case of aseptic products. The second risk is cross-contamination between different products.

Overall, it is important for pharmaceutical companies handling highly potent drugs to address both personnel safety risks and product safety risks through the implementation of appropriate containment measures, facility design and strict adherence to good manufacturing practices (GMP). By doing so, they can ensure the well-being of personnel and maintain the integrity and quality of their products.

Identifying and Assessing Risks

Identifying risks in the process of high-potent drug production requires a comprehensive assessment of the entire manufacturing process. The steps and considerations for identifying and managing risks in high-potent drug production include:

• Conduct a thorough process analysis: Begin by examining each step of the manufacturing process, from raw material handling to final product packaging. Identify all process stages, equipment, materials and personnel involved.
• Hazard identification: Identify potential hazards associated with highly potent drugs, such as toxicity, sensitization, carcinogenicity and reproductive hazards. Consider all stages of the process, including material handling, formulation, compounding, containment, filling and cleaning.
• Assess exposure pathways: Analyze the potential routes of exposure to highly potent substances, including inhalation, skin contact and ingestion. Determine which personnel or operations are at risk of exposure and evaluate the severity and likelihood of exposure in each case.
• Rank and assess the risks: Utilize the information collected from the above exercises to rank and assess the identified risks. Consider factors such as the severity of the hazard, the likelihood of exposure and the potential consequences. This step will help prioritize and focus on managing the most significant risks first.

By following these steps and considerations, pharmaceutical companies can effectively identify and manage risks associated with high-potent drug production, ensuring the safety of personnel and maintaining the quality of the final products.

Risk Ranking & Assessment

By incorporating the outcomes of the risk assessment into the facility, equipment and containment technology designs, pharmaceutical companies can proactively address the identified risks and minimize the potential for incidents or exposure to highly potent substances. This approach ensures a safer working environment for personnel and reduces the likelihood of product contamination or adverse effects.

It is important to regularly review and update the risk assessment as new information becomes available or changes are made to the manufacturing process or facility design. This helps to maintain the effectiveness of the risk mitigation measures and adapt to any evolving risks or regulatory requirements.

Case Study: Design Considerations for High-Potent Aseptic Production

In order to discuss the details of the required considerations for the design of a high-potent aseptic production line, we will present a case and its high-level process steps to explain the design process and considerations.

Consider an aseptic filling line that receives products from a dedicated formulation process. After filling the products, they are transferred to lyophilizers for further processing. The finished products are then sent off to a separate facility for inspection and final packaging.

Let’s assume the process starts with the dispensing of raw materials, including the highly potent active pharmaceutical ingredient (API), into formulation tanks. The formulation process continues with mixing and transfer of the product through sterile filtration and then directly to the dedicated filling machine.

The filling machine utilizes ready-to-use vials, which are first washed and then sterilized in a depyrogenation tunnel connected to the filling machine. After the filling process is completed, the vials are partially stoppered and sent to the freeze dryer for lyophilization. Once lyophilization is complete, the stoppers are fully applied to the vials within the lyophilizer and then sent to a capping machine. After capping, the vials are washed again and placed in trays to be transferred to another location for final packaging. It should be noted that the design allows for the bypassing of the lyophilizer if needed for liquid products.

While every case is unique based on the specific process and the toxicity of the highly potent molecule, in our example, the risks to personnel and product have been identified after conducting a risk assessment:

• Dispensing: The dispensing steps involve weighing and transferring raw materials to formulation tanks. At this stage, the highly potent API is in powder form and can become airborne in high concentrations, posing a high risk to personnel. However, the risk of product contamination by personnel is low in this step because sterile filtration has not yet occurred, and the process is not considered aseptic.
• Formulation: The formulation step involves mixing all the ingredients and transferring them to aseptic filters and the filler. The risk to personnel remains high at this stage because the operators can be exposed to the product during the formulation step. The risk of product contamination remains low as the sterilization step is further along in the process.
• Filling: The filling step involves the preparation of vials and the aseptic filling of the vials. At this point, the product is sterile and in a closed path, posing a high risk for product contamination and a low risk for personnel.

After gathering all the relevant information and assessing the risks within a cross-functional team, the facility, utilities and equipment design will ensure the mitigation of all the identified risks.

Containment Strategies

To properly address all the risks associated with the production of highly potent products, the containment strategy and design must be looked at holistically. The containment can be broken down into primary containment and secondary containment. In the following sections, we will define the primary and secondary containment for the presented case example and describe some important details to consider while designing them. It should be noted that our discussions are specific to the presented example case, and it is important to recognize that every project is different, requiring adjustments to design considerations.

Primary Containment

Primary containment is the initial step that focuses on containing the product to either protect personnel from it or safeguard the product against contamination. Various containment technologies exist to prevent product contamination, including Restricted Access Barrier Systems (RABS), Closed RABs and Isolators. Among these options, Isolators offer the highest level of protection for both personnel and the product. In the context of high-potent production, Isolators are the most reliable solution for personnel protection. While other containment technologies can still be employed for contamination control, personnel must rely on appropriate personal protective equipment (PPE), such as full-body suits with respirators, to protect themselves from highly potent substances.

Formulation Isolator

For the presented case study, the formulation isolator would serve as a containment isolator rather than being designed specifically for aseptic processing. Its primary function is to facilitate the safe transfer of highly potent powders into the mixing tanks while ensuring personnel safety. To achieve this, the isolator would operate under negative pressure.

Additional devices such as Split Butterfly Valves, Rapid Transfer Ports (RTP) and endless liners can be incorporated into the isolator to enable the transfer of products or waste in and out of the isolator without exposing personnel to risk.

Figure 1 illustrates a suitable layout for the isolator in this example case. The isolator consists of two chambers with a negative pressure cascade. Material enters the isolator through section two, which has a higher negative pressure, and then it is transferred to section one, which has the lowest negative pressure. Section one is connected to the mixing tank via a split butterfly valve. Material is weighed and dispensed in this section and waste exits through an endless liner.

Figure 1. Dispensing Isolator

The negative pressure maintained in the isolator chambers effectively prevents any powder dust from escaping the containment and posing a risk to personnel safety. This negative pressure is achieved by exhausting air from the isolator through redundant HEPA filters and pre-filtration. The filters are designed to collect any potent powder particles, preventing them from entering the surrounding environment. Safety precautions and engineering design techniques are implemented to ensure the safety of maintenance personnel during filter exchanges.

Although the isolator is not designed for aseptic processing, the incoming air to the isolator is also filtered through HEPA filters. This additional filtration step ensures the integrity of containment in case of fan failure or loss of negative pressure.

By implementing these measures, the containment system provides a robust solution for ensuring the safety of personnel and preventing the release of highly potent powder dust into the environment.

Filling Isolator

The filling isolator for the presented case example is more complex as it needs to ensure the protection of both the product and personnel simultaneously. Additionally, it handles the product in both liquid and powder forms at different stages of the process.

The desired isolator for this case example is comprised of six sections. Three different operation modes will be discussed, highlighting the role of the isolator in each mode. Generally, all sections of the isolator are designed similarly, providing laminar airflow to achieve an ISO 5/Grade A environment for aseptic filling. Return HEPA filters are installed throughout the isolator to capture product before contaminating difficult-to-access areas which could lead to personnel exposure during maintenance activities.

However, there is one section that differs from the others, which is the last section positioned above the external vial washer. In this stage, the product is contained within fully closed containers. The purpose of containment in this section is solely to protect personnel from any aerosols generated during the washing process that could potentially be contaminated. Consequently, this particular section is designed to exhaust air directly into the outside environment.

Liquid Filling

In this mode of operation, the product is filled into vials, which are then fully stoppered and capped within the containment before leaving the isolator. The primary risk to personnel in this mode of operation is related to aerosol generation during the filling process, as well as the potential for contamination in the event of vial breakage or spilling during filling or capping. Figure 2 illustrates the pressure cascade of the different sections in this particular mode of operation.

Figure 2. Filling Isolator in Liquid Filling Mode

As depicted in Figure 2, the isolator sections are maintained at a positive pressure compared to the surrounding room in all stages where the product is open. This positive pressure is crucial for protecting the quality of the product. Simultaneously, for personnel safety, two specific sections play a significant role in containing any highly potent aerosols within the isolator.

Section one, which has a higher pressure compared to section two, where the filling process occurs, acts as a “bubble” to prevent any aerosols generated in the filling section from escaping into the room through the depyrogenation tunnel. This helps contain any potential contamination within the isolator.

Section five serves as a sink to exhaust any potential aerosols generated within the isolator. These aerosols are filtered through a HEPA filter located outside of the containment, preventing them from entering the room where the vials exit the isolator. This ensures that any potentially highly potent aerosols are effectively contained within the isolator, safeguarding personnel and maintaining product integrity.

Lyo Loading

In this operation mode, vials are filled with liquid and partially stoppered before entering the lyophilizer. As the product is not yet in a fully closed container, ensuring a laminar airflow with ISO 5/Grade A quality is essential to protect the product from contamination. Figure 3 illustrates the pressure cascade designed to achieve this objective.

Figure 3. Filling Isolator in Lyo Loading Mode

As depicted in Figure 3, all sections of the isolator maintain positive pressure relative to the surrounding room. This closed system design is implemented to ensure the protection of personnel involved in the process.

Lyo Unloading

In this operation mode, the purpose is to transfer the vials out of the lyophilizer after the freeze-drying process is complete and the vials are fully stoppered inside the lyophilizer. At this stage, the product is in powder format and contained within fully sealed vials, making personnel safety a critical factor. In the event that some vials break during the freeze-drying or stoppering process inside the lyophilizer, the powder may contaminate the exterior of other vials, posing a potential risk to anyone who comes into contact with those vials. This includes both production personnel and healthcare personnel who will handle and administer the product. To mitigate this risk, an external vial washer is used to clean the exterior of the vials.

As illustrated in Figure 4, all sections of the isolator operate under negative pressure during this operation mode while maintaining laminar airflow. The External vial washer section acts as a sink with lower pressure to reduce the risk of contamination leakage into the surrounding room. This negative pressure design helps contain any potential contaminants within the isolator, protecting personnel and maintaining product integrity.

Figure 4. Filling Isolator in Lyo Unloading Mode

Secondary Containment Measures

Secondary containment encompasses the rooms, building and HVAC system that house the high-potent drug production process. While primary containment focuses on protecting personnel and products within the processing area, secondary containment plays a crucial role in safeguarding the environment and individuals outside the processing area. The significance of secondary containment is sometimes overlooked due to the emphasis on primary containment; however, it serves as the last line of defense in protecting people and the surrounding environment, particularly in case of accidents or failures.

One could argue that the importance of secondary containment is even greater than that of primary containment. Unlike the trained process operators who are well aware of the risks and equipped to handle contamination within the processing area, individuals outside the facility may have limited knowledge or awareness of the potential hazards. Therefore, secondary containment measures become paramount in preventing any release of highly potent substances or contaminants into the external environment.

The design and implementation of secondary containment measures, including the layout of rooms, building construction, and HVAC system, are crucial to ensuring the highest level of protection. These measures are put in place to minimize the risk of any potential leakage or release of highly potent substances, thus safeguarding the external surroundings and people who may not have the same level of awareness and training as the process operators.

Architectural Design and Cleanroom Construction

The physical barrier of secondary containment consists of the cleanroom walls and ceilings that surround the process rooms. Just as the primary containment was divided into sections to achieve a pressure cascade, a similar concept is required in the design of the cleanrooms and supporting areas where the high-potent process takes place and equipment is housed. The outer wall and ceiling of the production area must be completely sealed to prevent any air leakage from the high-potent process area to the outside environment. Although achieving such a seal remains challenging, advancements in cleanroom technology have made it possible. However, many companies still prefer to have their high-potent production in separate buildings to ensure maximum containment.

However, it is feasible to have high-potent production within the same building as other production rooms if the critical task of sealing the physical barrier is properly executed. This involves adopting closed-process technologies and implementing appropriate HVAC design for the entire facility.

Another crucial factor in the design of secondary containment is the implementation of proper airlocks for material and personnel transfer in and out of the building. These airlocks should incorporate a “sink” or “bubble” pressure cascade to prevent any air movement between the inside and outside of the physical barrier. This helps maintain the integrity of the containment and prevents the escape of highly potent substances or contaminants into the surrounding environment.

HVAC Design

The HVAC design plays a crucial role in achieving containment requirements and controlling contamination in high-potent production facilities. In buildings where both high-potent and non-potent production activities occur, it is imperative that the HVAC system serving the high-potent facility is completely separate from the rest of the building. This separation is necessary to prevent the potential spread of contamination. One pass-through air concept is typically employed in such systems to minimize air recirculation and reduce the risk of contamination if a failure or exposure occurs.

Furthermore, in facilities utilizing isolator technology, the HVAC systems must be designed to accommodate the integration of isolators. It is essential to have a thorough understanding of the mechanical design of isolators and to foster close collaboration between isolator vendors and HVAC design engineers. This collaboration ensures seamless integration of both systems and ensures their proper functioning.

Figure 5 shows a sample one-line diagram for HVAC design of the presented case example.

Figure 5. One Pass-Through Air Concept

In the concept presented in Figure 5, a redundant makeup air handler system is adopted to ensure higher availability and reduce the risk of losing pressurization in cleanrooms and airlocks, which could lead to the spread of contamination outside the facility.

The makeup air handlers are responsible for supplying 100% outside air at a specified temperature and humidity to smaller local recirculation air handlers and isolator air handlers. The local air handlers recirculate the air within the cleanrooms and provide the final filtration based on the required cleanliness level of the rooms.

To prevent contamination, exhaust from the rooms and equipment is directed outside the building. Proper filtration steps are implemented to ensure that the exhaust air is free of contaminants. The integration of containment isolators has the potential to eliminate the need for additional exhaust filtration. If all process steps that generate highly potent dust or vapors are performed inside isolators, the isolator exhaust filtration can effectively remove the contaminants.

Traditionally, high-potent buildings required multiple bag-in bag-out filter setups on exhausts, which can be expensive and challenging to maintain due to their size. However, with isolator technologies, all contaminated exhaust air goes through filtration within the isolator. The isolator exhaust filters are designed with new technologies to improve efficiency and facilitate easier maintenance and replacement. This reduces the risk of personnel exposure to highly potent compounds during filter replacement.

Conclusion

Regulatory agencies worldwide are placing increasing emphasis on improving Contamination Control Strategy (CCS) in the production of sterile products. As containment technologies have evolved, regulatory expectations for implementing containment strategies in the industry have also grown. A recent development in regulations is the update to the Volume 4 EU Guidelines for Good Manufacturing Practice for Medical Products for Human and Veterinary Use – Annex 1, which will be enforced starting August 25, 2023. This document mentions Containment Control Strategy 48 times and recommends the use of containment technologies to achieve it. The U.S. Food and Drug Administration (FDA) is expected to follow suit, given its involvement in the development of Annex 1 and the compatibility of guidelines between the two regulatory bodies.

Integrating containment technologies, particularly isolators and facility designs that work together to offer robust primary and secondary containment, is crucial for the successful execution of a project and the optimization of processes. In this article, we briefly discussed the process of designing and integrating high-potent isolators into a facility’s overall planning and design. Similar considerations would apply to the design process for non-potent aseptic isolators and their supporting facilities, albeit with fewer complexities. The key to a successful project lies in close collaboration between the manufacturer, A&E (Architecture and Engineering) design firm, and equipment vendor throughout the entire project, with experts from all sides aligning on the design requirements and technical interfaces to ensure seamless integration.