Regulatory agencies prefer injectable products to be terminally sterilized, however for some products, such as biological drugs, terminal sterilization cannot be carried out due to it adversely affecting the product. In such cases, the product must be aseptically filled in class 100 or iso-5 environment. To remove particles, vials must be washed and then depyrogenated before filling.
Previously, when products were terminally sterilized, vials were often discharged from the washer directly to the filling room. However, published in April 2018, the ISPE Baseline Guide Volume 3: Sterile Product Manufacturing Facilities1 recommends all vials be depyrogenated, even if terminally sterilized.
Depyrogenation is the process that removes pyrogens, including bacterial endotoxins, from vial surfaces. There are several different ways to do so, including the common method of using dry heat, whereby the exposure to temperatures above 250°C destroys the pyrogens. Most depyrogenation processes are designed to achieve at least a log three or log six reductions of endotoxins, the latter of which is preferred.
Batch ovens and depyrogenation tunnels are the two more common methods for depyrogenation (see Figure 1), however different risk levels accompany them. The risks involved come from the management of airflows within the tunnel. With batch oven depyrogenation, it involves the manual handling of vials and the dwell time amongst depyrogenation and filling, which this article discusses along with opportunities for mitigation.
Figure 1: Depyrogenation Tunnel.
Depyrogenation Tunnel versus Batch Oven
Vial depyrogenation can be completed with a batch oven or depyrogenation tunnel (see Figure 1). For the batch oven process, the vials are washed in the grade C or iso-7 cleanroom, placed on trays, and manually loaded into an oven situated at the interface between the preparation area and the filling line. Once the depyrogenation process is complete, the batch of depyrogenated vials is manually unloaded onto the filling line. Well-designed batch ovens have two doors, one to the preparation area and the other to the filling line isolator or cleanroom.
Vial filling can take hours and Haag2 (2011) highlights the risk of contamination due to exposure of the container’s internal surfaces during filling, citing the increased risk with open vials, even those in a Grade A environment. Vials processed in a suitable depyrogenation tunnel have a cooling process of around 15 minutes, automatically feeding the filling machine. As a result of this, the contamination risk is markedly less.
For a typical commercial filling line with a batch size of 10,000 vials and a line speed of 50 vials per minute (with an assumed 80% line efficiency), the exposure time of an open vial from when it leaves the depyrogenation tunnel, until the time of stoppering, is approximately eight minutes.
Conversely, the exposure time of the last vials of the same batch size for an oven can be 250 minutes or greater. The higher exposure time creates a 30-fold increase in risk of contamination, not including risks associated with presenting an operator to the filling area for the vial manual transfer from the oven to the filling line.
At the 2019 ISPE Aseptic Conference, Rick Friedman (Deputy Director, Science and Regulatory Policy FDA/CDER) discussed positive choices when it comes to minimizing contamination risk. He commented that all novel aseptic filling line designs should incorporate depyrogenation tunnels rather than batch ovens.
Risks Involved with Pre-sterilized Glass
An alternative to an in-house depyrogenation process is pre-sterilized glass, where the washing and glass sterilization is completed at a remote site. Vials are then double bagged and shipped to the manufacturing site. The increased complexity of the supply chain also includes fundamental risks.
To ensure they follow the proper quality standards throughout the sterilization and packing process, the glass supplier must be monitored and the film used for double bagging must be particle-free. Similarly, the washing, depyrogenation, and packaging process is programmed to reduce manual manipulation.
During the delivery process, the movement of glass on glass during shipping can generate glass particles and chips that are difficult to identify before filling. Operators must, therefore, follow special sanitization procedures during the manual unwrapping process to prevent the contamination on the outside wrappings from transferring into the vials.
Qualities to Evaluate When Selecting Depyrogenation Tunnels
For large batch applications, from a risk mitigation perspective, a depyrogenation tunnel should also be considered for smaller batch applications. Currently, vial washer and depyrogenation tunnel combinations exclusively designed for small batch applications consume minimal space, occupying as little as 8 feet / 2.5 m.
Attaining the necessary log reduction of endotoxin is the main purpose of a depyrogenation tunnel. Therefore, it is vital to evaluate the manufacturer’s airflow designs, this is to make sure that pressure fluctuations within the cleanroom and washroom do not impact the depyrogenation process.
To preserve air quality, the highest air quality area is the filling suite, which should always be at a higher pressure relative to the lower grade areas. The pressure cascade fluctuates when the doors open or close and the air handling systems modulate due to the hysteresis between set points.
Pressure changes can affect the performance of a poorly designed depyrogenation tunnel, some of which are designed to chute pressures from the filling suite to the cool zone. Each of the zones (cooling zone, hot zone, and infeed zone) has air incoming from the filling room and exiting towards the preparation area (see Figure 2). Fluctuations in filling area static pressures can upturn the ingress of cold air into the hot zone from the cold zone, in order to prevent the heat absorption needed for the log 3 or 6 endotoxin reduction.
Figure 2: Cascading air from the Clean Room through the hot zone. Blue Zone = cooling zone, Red Zone = Hot depyrogenation zone, Orange Zone = pre-heat zone.
More sophisticated tunnel designs over pressurize the hot zone in relationship to the infeed and cool zone of the tunnel, therefore insuring that the vials will always be exposed to the proper temperature for the correct duration (see Fig 3). Such designs have a vial conveyor return underneath the hot zone, creating an air pathway from the cool zone into the infeed zone. A fan that drives fresh air from the preparation room through a pre-filter into the hot zone is sometimes present.
Figure 3: Over Pressurized Hot Zone. Blue Zone = cooling zone, Red Zone = Hot depyrogenation zone, Orange Zone = pre-heat zone.
Airflow is monitored as the fan speed is varied to combat any increase in pressure from the filling room. While less sophisticated units typically only control between 10 and 15 Pascals, efficiently designed tunnels with overpressurization of the hot zone can control the process with filling room cascades of 70 Pascals.
Another benefit to over-pressurization of the hot zone is the natural temperature gradient that happens as hot zone air mixes with the cooler air from the adjacent zones. This provides a gradual temperature change minimizing the risk of glass cracking caused by thermal shock.
Considering tunnel designs where the air velocity profile is across the vial transfer belt, the velocity is directly proportional to temperature, therefore vital quality-wise in minimizing the temperature variation during the thermic process. Tunnels with uniform control of air velocity across the transfer belt have healthier process control and batch homogeneity.
Rather than single-sided, tunnels with air returns on both sides have less variation in air velocities across the transfer belt (see Figure 4). Some of these designs combine airflow controls that compensate for this pressure gradient and fabricate a very reliable airflow across the width of the belt (see Figure 5), creating the best results, eliminating cold spots, and providing consistent depyrogenation results.
Figure 4: (Left) Double-sided return (Right) Single-sided return.
Figure 5: Single-sided return with Velocity Compensation.
In situ monitoring for non-viable particle counts in the depyrogenation tunnel should be considered. Most depyrogenation tunnel designs provide particle counting in infeed and cooling zones. Only one manufacturer offers the ability to monitor the non-viable particle counts in the hot zone. Air from the hot zone journeys to the particle counter via a heat exchanger, avoiding damage to the sensor. The process records particle counts for 5 seconds in the cool zone, hot zone, and infeed zone, and then repeats the cycle throughout the batch. This offers a full in situ particle monitoring of all three zones for optimum, in-process, quality control.
The main focus must be patient safety when producing injectable products. The drug manufacturing and packaging process are multifaceted, however, the industry has made noteworthy advancements in the reduction of product contamination risk.
Automation is easily justified for large-scale production processes. The smaller batches generally have been produced with manual processes and are susceptible to contamination risk. Personnel is the most common source of particles and contamination in an aseptic process and automation has greatly reduced the contamination risk here.
With further development of biologic medicines and personalized drugs driving down batch size requirements, equipment suppliers have offered exceptional robotic filling equipment for slower line speeds.
When selecting the washed and depyrogenated vial supply for slow speed applications, quality concerns must be measured. Automatic vial washers and depyrogenation tunnels are currently available to cater to the high-value small batch size applications. For the selection of equipment, size, throughput, and air handling designs are vital considerations in providing suitable sterility assurance.
References and Further Reading
- Baseline Guide Vol 3: Sterile Product Manufacturing Facilities, April 2018, ISPE. https://ispe.org/publications/guidancedocuments/sterile-product-manufacturing-facilities-third-edition
- Mattias Haag, 2011, Calculating And Understanding Particulate Contamination Risk. Pharmaceutical Technology Europe, Volume 23, Issue 3
- Produced from materials originally authored by John Erdner from SP Scientific.
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