For those companies involved in the production of both sterile and highly potent products, Powder Systems Limited discusses the equipment challenges and innovative solutions
Aseptic filling of sterile drugs remains one of the most challenging processes in biopharmaceutical manufacturing. It requires co-ordination and interaction between personnel, product, equipment and support facilities. At the same time, the formulation of highly potent active pharmaceutical ingredients (HAPIs) is growing due to significant advances in clinical pharmacology and oncology research. Recent industry estimates put more than 40% of all new APIs in this category.
Higher potency APIs have greater effect at a lower concentration than traditional APIs, and the trend towards higher potency is reflected within the biopharmaceutical arena too. The increased potency of sterile products requires evaluation of the manufacturing process from two angles: the high containment requirements for the operator and environment safety; and the aseptic process regulations for the protection of the integrity for the finished sterile product. These are two separate approaches that not many drug manufacturers and process equipment suppliers are able to consider as a whole.
As worldwide demand rises, contract manufacturers and global pharma groups need to understand the key considerations when producing both sterile and highly potent products, as outlined below, and any use of isolation technologies needs to be understood and reviewed, preferably with the application of decades of high containment knowledge about aseptic manufacture.
Following the ISPE Risk-Mapp guidelines, an isolator is defined as a leak-tight enclosure designed to protect operators from hazardous or potent processes, or protect processes from people or detrimental external environments, or both. The containment isolator in Figure 2 protects operators from the potency through the following parameters.
The level of containment is defined by the manufacturer or consulting agents who will define the occupational exposure limit (OEL) required for specific drug manufacturing. For highly potent compounds, the isolator should ensure an OEL of 1–10µm/m3 or lower over the sampling period.
Figure 1: The Dual Isolator developed by PSL, undergoing Factory Acceptance Testing (FAT)
A high containment isolator is generally operated under negative pressure to ensure maximum operator and environment safety. In other words, should the containment envelope be breached, the outside air will be pulled inside the isolator avoiding product exposure for the operator. The negative pressure is typically –100 Pa and must be electronically controlled. For the same reason, the air in the isolator must not exchange with that of the surrounding environment. HEPA filters are used to circulate the room air with a ‘push-push’ system for safe remote change. High containment gloveboxes are usually purged with nitrogen for higher safety or for air-sensitive product requirements.
Safety features should be integrated; for example, interlocked doors and windows with safe guard gloveports after start of operation. All levels should be displayed to indicate in real time the status of the isolator (pressure, nitrogen, etc.). This type of isolator is typically classified as ISO 7 (Class 10,000 at rest, Grade C) and as part of the recommended use, all materials exiting the isolator must be cleaned or contained using rapid transfer ports (RTP) or airlocks.
Figure 2: A high containment isolator
The entire isolator must be cleanable in a reproducible and quantifiable manner to avoid cross-contamination. Swab tests and tracer substances should be used during qualification. Ergonomics are therefore an important part of the design to allow operators to reach and wipe every part of the cabinet.
To qualify the containment isolator, a series of tests needs to be performed during the Factory Acceptance Test (FAT) and Installation and Operation Qualifications on site. It is highly recommended to test the OEL level during the FAT, or once installed on site to verify that it meets the specified design OEL. A third party usually performs all the operations in the isolator using a placebo, allowing airborne particle concentrations on the operator and in the room to be measured to certify that the OEL level has been achieved.
The requirements for the isolators used with aseptic processing differ from the containment isolator technology. They must not exchange air with the surrounding environment, but work under positive pressure. The philosophy here is to protect the product from the outside, which means that in case of containment breaching the positive pressure will ‘push’ the cabinet air out to protect the product from the environment, but exposing the operator to the product. The positive pressure is typically of 50 Pa and must be electronically controlled.
Extensive sterilisation procedures have to be applied prior to production and nitrogen purge is not required. Air from the room is typically recirculated in the isolator via a HEPA filter. Uni-Directional Air Flow (UDAF) circulates the air with a required minimum 0.45m/s airflow inside the isolator. A uniform and efficient airflow system is critical for a proper aseptic environment.
For Grade A, the airborne particle classification of this type of isolator is ISO 4.8, dictated by the limit for particles ≥5.0µm (with minimum sample volume of 1m3 taken per sample location). The design and construction of cleanrooms and controlled environments are covered in ISO 14644. This standard stipulates the total particulate counts required for a clean environment needed to meet the defined air quality classifications.
Instead of strict cleaning procedures and contained transfer of materials, the aseptic isolator must be sterilised in a reproducible manner using vaporised hydrogen peroxide (VHP). All materials that enter into the isolator must be sterilised and must enter either directly through a decontaminating or sterilising system, or via an RTP.
For the qualification of an aseptic isolator, a series of tests should also be performed during a FAT and Installation and Operation Qualifications carried out on site. The isolator integrity is verified by leak testing, consisting of several pressure tests, such as the pressure hold test (twice the operating pressure with a loss of less than 0.5% of the total volume of the isolator per hour being acceptable), or glove pressure test, supported by physical and microbial qualifications and trend analysis.
From the brief overview given, the challenges for manufacturers looking for a suitable technology that allows the manufacture of both sterile and highly potent products are clear to see, since aseptic processing and high containment production follow dramatically different approaches.
A sterile highly potent liquid product has to be protected from the surrounding environment to avoid microbiological contamination while being contained from the operator. During normal operation with positive pressure in an aseptic isolator, these requirements are met. But in the instance of containment breaching, the operator would be exposed to the potent product. Moreover, air circulation would not be suitable for sensitive potent product during filling or handling operations.
So what would be the most suitable technology for sterile and/or high potent liquid production lines, bringing together both aseptic and containment isolators features?
Containment supplier Powder Systems Limited (PSL) has developed an alternative technology to the existing, complex solutions that consist mainly of integrating an aseptic isolator inside a containment isolator. The so-called Dual Isolator is a containment solution that enables the manufacture of sterile product under aseptic conditions and potent product under high containment operations.
Typical operations that can be carried within the Dual Isolator are:
The Dual Isolator circulates both the room air and compressed nitrogen using UDAF via inlet HEPAs. The air or nitrogen can be recirculated to minimise nitrogen or room air consumption with real-time particle monitoring. Alternatively 100% fresh air can be used.
The pressure requirement is the second critical feature of a sterile and high potency isolator. The Dual Isolator works both under positive (+50Pa) or negative (–80Pa) pressure. The pressure level is controlled via a switch or through the emergency mode. The positive pressure mode is required for aseptic operation and negative pressure mode for high potency processes. The emergency mode triggers the shutting of the valve and opens the nitrogen flow.
The containment level is guaranteed and tested to achieve less than 1µg/m3 (8h TWA with 1h sampling period) for operator safety when the isolator is operated under negative pressure and nitrogen purged for high potency operations. The isolator is designed and manufactured to comply with industry regulations such as ISO 4.8 class from the ISO 14644 standard and is cGMP certified.
The entire sterilisation cycle, from gassing, dwelling and holding to the various ventilation operations, is performed using a VHP generator located close to the isolator, as shown in Figure 3. Specific performance tests during FAT will be required as with an aseptic isolator including: a smoke test, airflow mapping, particle monitoring and microbiological test.
Figure 3: Sterilisation process configuration of the Dual Isolator
Finally, the isolator combines ergonomic features from both high potency and aseptic containment systems to bring the best technology available to the market. Design features include lift-up windows with inflatable seals for easy access and maintenance; a glove-port design for aseptic production, no dead legs, automatic leak rate and temperature monitoring.
The isolator is designed as ‘plug & play’ technology. It is mobile with flexible RTP connections with reduced footprint and remote I/O (integrated into isolator main fabrication). The use of airlock systems to sterilise materials prior to entering the isolator is also available.
All these features make the Dual Isolator a truly versatile technology, ideal for multi-product manufacturers or contract manufacturing organisations. The first systems will be installed in a European sterile formulation facility of a global contract manufacturer.
Figure 4: Internal views of the Dual Isolator showing the VHP nozzle, lateral extraction slots and rapid transfer port