High-Potent Aseptic Production

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.

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.

• 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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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-potential 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 is filtered 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.

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.