Christian Dunne is Aseptic global product manager at ChargePoint.

Christian Dunne

The manufacture of sterile drug forms must be subjected to strict controls to minimize the risk of contamination by micro-organisms, endotoxins, and particles. Because the presence of something unwanted in a dosage form can pose serious risks, legislation demands that steps be taken to reduce these risks that threaten product quality and ultimately patient safety. 

	Pharmaceutical manufacturing environments are open to multiple sources of contamination from the air filtration systems to the process of materials transfer and the fact that a fully gowned operator can create more than 10,000 colony forming units an hour. As a result, measures need to be taken to ensure the safe and sterile transfer of APIs and formulation ingredients during aseptic processes. This article reviews current approaches to sterile containment and compares several sealed transfer and barrier techniques, including isolators, restricted access barrier systems (RABS), and split butterfly valve (SBV) technology. 

	Sealed transfers and barrier technologies have been designed to contain aseptic manufacturing processes. They provide a robust alternative to conventional “cleanroom only” methods of handling sterile products, ensuring that pharmaceuticals are not exposed to viable organisms or particulate contamination, while also protecting operators from potent compounds. 

	RABS have been designed to enhance the aseptic processes carried out in conventional cleanrooms. These systems put a physical barrier between operators and processing lines, while still offering the flexibility to interact with the process. To enable the use of a less restrictive barrier, RABS are required to be set up in class ISO 7 cleanrooms, which means they do not require their own bio-decontamination system. 

	Two different types of RABS are commonly used in today’s manufacturing facilities. The first are active RABs, which actively pull air from outside the cleanroom environment, filtering and extracting it so that the RABS is completely isolated. The second type are standard passive RABS that use a cleanroom’s heating, ventilation, and air conditioning (HVAC) system. 

	RABS bring their own unique advantages by enabling operators to maintain a distance from the process, while allowing the cabinet to be opened if further intervention is required. Processes can also be quickly turned around to suit different batch sizes and requirements. 

	Isolators create an airtight barrier or enclosure around an aseptic processing line, hence, providing complete separation between the product and the operator/cleanroom environment. Operators perform tasks through half-suits or glove ports, enabling manipulation to be undertaken within the space from outside the enclosure without compromising integrity.  

	The clean environment is maintained through a combination of techniques, including the use of positively pressurized chambers with closed loop control. High-efficiency particulate air (HEPA) is supplied to the chamber in a laminar flow and ensures that particulate generation is suppressed and removed efficiently, while integrated bio-decontamination systems provide a validated sterility assurance level (SAL) of 10-6 on the chamber surfaces. 

	Due to the high-performance requirements for these enclosures, integrated pressure decay tests have become the norm during start-up and prior to any bio-decontamination phase, with the leak of the chamber being a key factor in the classification of the device. More information can be found via ISO14644 (1) on leak rates for separative devices. 

	Weighing up the advantages of isolators and RABS

	Isolators and RABS both offer rigid wall environments that provide a physical and aerodynamic barrier between the operator and the sterile drug manufacturing process. While both provide an ISO 5 cleanroom environment, they each have their own unique advantages and limitations. 

	One of the major benefits that isolators have over most RABS is that the interior can be decontaminated through an automated process. This allows for repeatable and consistent high-level bio-decontamination providing increased SALs over conventional cleanroom manufacturing. Comparably, most RABS rely on the use of manual cleaning processes. 

	A limitation of isolators is that they can create difficulties in transferring materials in and out of the cabinet. This system can require a docking isolator to be connected and its interior sanitized before materials can be transferred. The qualification of hydrogen peroxide vapour systems in isolators can also be difficult. As a result, there is a need to suspend everything within the cabinet to remove any hidden surfaces. 

	In comparison to isolators, RABS can ensure faster start-up times, while also improving the ease of changeover. They can also bring increased operational flexibility and reduced validation expenditure. Isolators, however, offer the advantage of higher integrity chambers for a more robust closed solution.  

	As an alternative handling technique to these more traditional barrier techniques, many manufacturers are finding that an SBV approach can provide a more practical option in achieving assurance of product sterility. 

	SBV technology enables a product to be transferred from one container, process vessel, isolator, or RABS to another without compromising sterility. The valve consists of two parts: the active half and the passive half. Generally, the active half will be attached to the receiving vessel, with the passive half attached to the discharging drum or container, such as an intermediate bulk container (IBC) or flexible bag. When the two halves of the “butterfly” disc are brought together, a single disc is created, which allows product to flow on the internal surface of each half. When the passive and active halves are detached, the external face remains clean and can be safely exposed to the process environment. 

	Decontamination is able to take place in a closed environment using SBV. A gap is created between the discs when the two halves are connected, which enables hydrogen peroxide gas to be flushed through. Chemical indicators are used to validate the process and ensure that full coverage of the enclosure is obtained. Biological indicators also ensure a six-log reduction in microbiological contamination has been achieved. 

	The SBV approach offers manufacturers a closed handling method that reduces the resource associated with cleaning and validating large areas and minimizes the need for manual intervention, all while achieving the necessary SAL. By reducing cleaning requirements, the technique results in less downtime. 

	Depending on the gassing system used, processing times when employing SBV technology can range between four and 30 minutes, which represents a significant time-saving in comparison to conventional airlock systems or isolators that generally require four to six hours. The aseptic SBV also makes it possible to downgrade the surrounding cleanroom environment because of the integrity of the approach, again generating further time and cost savings. 

	The key to advanced aseptic processing is the elimination and absolute control of all sources of contaminants, including human-generated contaminants. The selection of an appropriate barrier containment technique will be dependent on several factors, including the requirements of individual manufacturing facilities and the types of products being processed. Choosing the right contamination control platform requires considerable research into what a product needs for an effective process design. 

	While ease of decontamination and a high degree of sterility assurance can be readily achieved using isolators, RABS bring increased operational flexibility and speed of changeover which appeals to manufacturers that need to adapt to varying requirements from different customers. Aseptic SBV technology not only complements and works in harmony with these solutions, but can, in many circumstances, eliminate the need for other methods. 

	For manufacturers who require high-speed commercial manufacture, barrier isolation technologies may make business sense. For smaller batch sizes, a more flexible RABS solution may be more suited to the process. 

	ISO 14644-7: Cleanrooms and Associated Controlled Environments-Part 7: Separative Devices (Clean Air Hoods, Gloveboxes, Isolators, and Mini-Environments) (2004), www.iso.org/obp/ui/#iso:std:iso:14644:-7:ed-1:v1:en.


	Vol. 30, No. 7
	July 2018
	Pages: 27–29

	When referring to this article, please cite it as C. Dunne, "Aseptic Transfer Technology: Weighing Up the Advantages of Varying Approaches for Sterile Drug Manufacturing," 

	Christian Dunne is global product manager for ChargePoint AseptiSafe.

Articles

The author reviews current approaches to sterile containment and compares several sealed transfer and barrier techniques, including 
isolators, restricted access barrier systems, and split butterfly valve technology.


Aseptic Transfer Technology: Weighing Up the Advantages of Varying Approaches for Sterile Drug Manufacturing

Pharmaceutical manufacturing environments are open to multiple sources of contamination from the air filtration systems to the process of materials transfer and the fact that a fully gowned operator can create more than 10,000 colony forming units an hour. As a result, measures need to be taken to ensure the safe and sterile transfer of APIs and formulation ingredients during aseptic processes. This article reviews current approaches to sterile containment and compares several sealed transfer and barrier techniques, including isolators, restricted access barrier systems (RABS), and split butterfly valve (SBV) technology.

Pharmaceutical Technology’s Biologics and Sterile Drug Manufacturing 2018 

 Biologics and Sterile Drug Manufacturing 

	When referring to this article, please cite it as C. Dunne, “Aseptic Transfer Technology: Weighing Up the Advantages of Varying Approaches for Sterile Drug Manufacturing,” 

Pharmaceutical Technology Biologics and Sterile Drug Manufacturing 

Choosing the right contamination control platform requires considerable research into what a product needs for an effective process design.

	Several techniques can be used to help ensure product sterility assurance during the transfer of pharmaceutical powders from one process stage to the next using an intermediate container (e.g., vessel or bag). One of these is split butterfly valve (SBV) technology. The ChargePoint AseptiSafe bio SBV traditionally uses hydrogen peroxide (H

) gas to bio-decontaminate and remove contamination on the two mating surfaces of the valve before the product is transferred. As shown in 

, the two halves of the valve create a sealed chamber by partially docking the two disc faces, allowing a decontamination to take place in a closed environment. This prevents further contamination from taking place after the decontamination process is finished, unlike the traditional sporicidal spray and wipe approach, which is generally carried out in an unsealed environment where further contamination could occur.

	The decontamination cycle time remains an important factor as ultimately only optimal performance will be considered in-line with the commercial and technical objectives of the production facility. Current H

 decontamination cycle times have been established at 4 minutes to 20 minutes. Chlorine dioxide (CD) gas has long been used as an alternative to H

 vapor for decontamination. Previous research, such as that of M. Sawyer et al. in 2014 (1), lists the differences between the two types of bio-decontamination media in terms of a typical cycle; however, SBV technology with CD gas had not been evaluated. For any technology to be adopted within a validated production process, qualification evidence should exist to prove the technology prior to live process validation. This article describes the qualification of chlorine dioxide gas to decontaminate the ChargePoint AseptiSafe bio SBV. The qualification testing was carried out in partnership with ChlorDisys Solutions, who provide decontamination services utilizing CD gas.

	To provide optimal sterility assurance, the SBV must prove to bring about a 6 log (10

) reduction in microbiological contamination on the surface areas of the device exposed to the decontamination cycle. Typically, this reduction is validated with the use of a biological indicator (BI) and subsequent controlled laboratory analysis of bacteria culture growth.

	A cycle development and optimization study was performed to test the feasibility of CD gas to sterilize the mating surfaces to the required sterility assurance level and to perform such cycles in as short a time as possible. The study determined the compatibility of materials in contact with the CD gas, and also examined how pressure may or may not cause leaks in the system.

	Cycle development and optimization methodology

	All the testing was done with CD gas generated by ClorDiSys’ Minidox-M CD Gas Generator. CD gas was injected manually from the Minidox-M (see 

) and allowed to flow for (n) seconds through the valve assembly. The outlet valve was then closed, after which the Minidox-M valve was closed.  When the valves were closed, a high concentration of CD gas (100 mg/L) was trapped in the valve assembly.

 The following materials and equipment were used for the experiment:

		ChargePoint type: 100-mm BIO ACTIVE, Equipment No.: DE0024-02-2

		Biological indicators (BI) G. stearothermophilus spores, Crosstex Code: TCDS-06, population ≥106 (1,000,000), lot#: RU 53

		Prepared culture color-change media (NAMSA Code: GMBCP-100, lot#: GM005213)

		Incubator for incubating G. stearothermophilus spore strips

		ATI C16 PortaSense II low-level chlorine dioxide sensor.

. ClorDiSys approaches every gaseous decontamination effort as if it were to obtain a 6-log sporicidal reduction. Reducing spore counts is more difficult than reducing viruses and other organisms. Sporicidal reduction also requires humidity to soften the spore walls to enable the gas to penetrate and kill the microbes. The CD decontamination process consists of the following steps:

		Humidification to soften the spore walls

		Introduction of CD gas to reach the desired concentration

		A dwell period (i.e., exposure to the gas) in which the gas sits for a period of time to obtain the desired kill level

	The humidification range required to soften the spore walls is at least 60%, with an optimal level of 65–70%.  Lower relative humidity levels require longer exposure times or more dosage. The exposure level and time that ClorDiSys targets to obtain a 6-log sporicidal reduction is 1 mg/L (360 ppm) at 2 hours. This equates to 720 ppm-hours of dosage. ClorDiSys has demonstrated 6-log sporicidal reduction as low as 450 ppm-hours. At the end of exposure, the gas is aerated until the concentration drops to 0.1 ppm, which is the 8-hour safety level as well as the odor threshold level.

	Typical cycles are generally carried out in large rooms. In this application, the concentration levels of CD used were reduced compared to a typical cycle, due to the small size of the chamber once the valves were closed.

	A first set of experiments were performed with a fixed time gas flow. The system was connected as shown in 

with the ¼-in. ball valve open to the scrubber and one BI placed in the valve assembly.  The Minidox-M outlet valve was manually opened and gas flowed to the scrubber for 20 seconds at 20 LPM.  The ¼-in. ball valve was then closed, followed by the Minidox-M outlet valve. The BI was then tested with multiple exposure times of 1, 2, 5, and 10 minutes. Each exposure time cycle was repeated three times for three cycles, for a total of 12 cycles with 12 BIs.

	At the end of each exposure (1, 2, 5, and 10 minutes) the Minidox-M sample pump was energized and the ¼-in. ball valve was opened to blow the CD gas to the scrubber.  This aeration time required to bring the CD gas to below detectable levels was 2 minutes.

	A second set of experiments was performed with a fixed time gas flow using the same system connection and experiment times, but the gas flowed to the scrubber for 60 seconds at 20 LPM.

	A third set of experiments was performed with an exposure time gas flow. The system was connected in the same way (see 

) with the ¼-in. ball valve open to the scrubber and one BI placed in the valve assembly.  The Minidox-M outlet valve was manually opened and gas flowed to the scrubber for 20 seconds at 20 LPM.  The ¼-in. ball valve was not closed, however, and gas was allowed to flow for the entire exposure time.  Exposure time started after 20 seconds of flow.

	The BI was then tested with the same exposure times and number of cycles as in the first experiment. At the end of exposure (1, 2, 5, and 10 minutes) the Minidox-M sample pump was energized and the ¼-in. ball valve was opened to blow the CD gas to the scrubber.  In this case, the aeration time required to bring the CD gas to below detectable levels was also 2 minutes.

	A fourth set of experiments was performed with a fixed time gas flow and pressure build up in the valve assembly.  For these cycles, the system was connected as shown in 

 with the ¼-in. ball valve open to the scrubber and one BI placed in the valve assembly.  The Minidox-M outlet valve was manually opened and gas flowed to the scrubber for 20 seconds at 20 LPM.  The ¼-in. ball valve was then closed.  The Minidox-M outlet valve was closed after pressure increased to 10 psi (68.9 KPa). The BI was then tested with the same exposure times and number of cycles as in the first experiment. At the end of exposure (1, 2, 5, and 10 minutes) the Minidox-M sample pump was energized and the ¼-in. ball valve was opened to blow the CD gas to the scrubber. Again, the aeration time required to bring the CD gas to below detectable levels was 2 minutes.

	Cycle times for the four sets of cycles varied due to the exposure time and gas flow time. The shortest cycle was the 3.3 minutes and the longest was 13 minutes. The shortest successful cycle (defined as three runs with no positive BIs) was 7.3 minutes. 

 shows the cycle data BI results. In each run, only one BI was placed in the valve assembly.  Room relative humidity during the cycles was 30-40%. In the pressure-hold test (the fourth set of tests), when the pressure within the assembly was raised, a low level chlorine dioxide gas sensor was used to measure any leakage on both sides of the valve assembly for the entire exposure time. No leaks were detected on either side. No material effects (e.g., degradation/cracking) were noticed after all testing was performed. The valve underwent a minimum of 48 cycles at 100 mg/L CD gas concentration.  The total dosage for all cycles was approximate 130,000 ppm-hrs. This total dosage is equivalent to 180 runs at a normal room concentration of 1 mg/L. Conclusion The purpose of the test was to ensure that a 6 log (10

) reduction in microbiological contamination was achieved on the exposed faces of the valve. This result was achieved on all 5- and 10-minute cycles. No biological growth was seen in any of the BIs in these cycles. The cycle times presented consistent bio decontamination at five minutes, which is faster and more consistent than was found in previous tests of H

 cycles. During the leak rate analysis, in which the gassing space was pressurized and low level readings were taken above and below the discs, no levels of gas detection were found. Considering that CD is a pure gas and therefore inherently easier to detect than H

 vapor, the results proved the process to be a robust solution that can be safely used with both CD and H

 vapor. In the future, plans call for testing the system with longer pipe runs to ensure that the fast aeration times can be maintained. Longer pipes would allow drug manufacturers to house the generator in one location within the facility and the valve in the process area without the concern of prolonged cycle times.

		M. Sawyer et al., “Got Gas? Chlorine Dioxide or Vaporized Hydrogen Peroxide: Which one is right for you?” Poster Presentation, Biosecurity Research Institute, Kansas State University, 2014, www.absaconference.org/pdf55/003Sawyer.pdf 

olid Dosage Drug Development and Manufacturing
	

	When referring to this article, please cite it as C. Dunne, "Preventing Contamination During Sterile Powder Transfer," in "Solid Dosage Drug Development/Manufacturing 2017," 

olid Dosage Drug Development and Manufacturing


	Christian Dunne is ChargePoint’s Aseptic global product manager, Tel: 44.151.728.4500, www.thechargepoint.com.

A chlorine dioxide sterilization cycle was developed for a novel split-valve aseptic powder transfer device.