Jean-Marc Cappia is vice-president of marketing for fluid management technology at Sartorius Stedim Biotech FMT, Aubagne, France.

Jean-Marc Cappia

	Current regulatory guidelines provide clear insights into end-user responsibility for validating the shipping of liquids in single-use systems. At this point, however, there is no specific expectation or dedicated regulatory guidance on the subject. 

	The US Food and Drug Administration (FDA), the European Medicines Agency (EMA) (1,2), and other regulatory bodies require that companies have qualified processes and can prove that the process will meet the quality standards of the final drug product. Guidance like the Parenteral Drug Association (PDA) technical report TR66 (3) provides following recommendation: “Shipping systems must be qualified for their intended use through proper design and testing in consultation with a packaging engineer.” 

	Drug manufacturing processes include more frequently international shipment which have to be defined.  A risk assessment of the potential impacts of vibration, handling, delays, and seasonal variation on product should be established. 

	Shipment tests can be based on international standards such as the American Society for Testing and Materials’ (ASTM) D4169 or the International Safe Transit Association (ISTA) 3 series. Shipping and packaging expertise is necessary to define the appropriate  validation level depending on the system used and the types of distribution cycles.

	ASTM D4169 (4) and ISTA 3 series (5) are both well-known standards for shipping systems. They provide standardized validation methods using a variety of simulated shipping hazards and aim to compare or evaluate the effectiveness of protective packaging and/or a packaged-product’s ability to withstand the hazards of distribution. 

 compares the main differences between ASTM and ISTA standards for pharmaceuticals.
	

	The level of severity for test conditions  must be based on real-world shipment conditions and the desired safety margin. To optimize system validation tests, end users must know the distribution cycle, schedule, duration, severity level, and acceptance criteria, each of which may differ between sites or from one product to another.  

	Packaging engineers can be instrumental in defining the system to be tested, as well as in developing the most meaningful testing programme. Testing parameters and sample configurations can only be selected once the transportation cycles and the type of impact received by the load during transportation are well understood. Developing this understanding, however, requires preliminary testing and analysis. 

	The test protocol must simulate the lifecycle phases of the shipped product. Knowledge of the product and the type of transportation used (both the means of transportation used and the sequences involved) are crucial to understanding the shipping cycle and to providing adequate safety margin during the qualification testing programme. 

	For example, ASTM D4169’s distribution cycle DC12 is representative of the typical shipment shown in 

 for loads >68.1 kg (150 lb.) or unitized shipments. DC12 includes six modular test programmes adapted to simulate each segment of the projected distribution with impact (horizontal impact, rotational flat drop, and edge drop), low pressure (representative of shipment by plane or high altitude), and vibration tests. 
	

) has been developed to clearly understand, based on testing, the behaviour of the given shipping system under real and normalized testing conditions. This approach provides data that allow a final qualification protocol to be chosen that will guarantee the system’s safety with a measurable safety margin (6). This approach for liquid shipping validation has been taken with Flexsafe3D shipping systems, shown in 

Recorded data provide snapshots of what can happen during the chosen real transportation cycles, including a variety of conditions that would be found in truck or airplane transport, or in cases that involve long-distance travel, and severe road conditions. 

	Each of the filled 100-, 200-, and 500-L Flexsafe 3D Bags in its shipping Palletank was equipped with a data logger and shipped under two real transportation cycles, as shown in 

. Under the supervision of a trained packaging engineer, the resulting data can be visualized with an event chronogram (

	For example, the recorded vibration levels provide complex and chaotic acceleration measurements over time. The vibration levels must be mathematically transferred from a time axis to a frequency axis using Fast Fourier Transform, in order to obtain the vibration level reading in a power spectral density (PSD) curve, as shown in 

. In this example, the number of vibratory events per hour varies greatly during the distribution cycle.  This is due to the fact that events are especially intense during truck transport in India and the final phases of transport on the airport tarmac.

Step 2: Testing under lab conditions, following ASTM D4169 and ISTA 3E. 

One each of a 100-, 200-, and 500-L Flexsafe 3D Bags was filled with water in its shipping palletank and equipped with a data logger. Each bag was then tested according to ASTM D4169 Levels I, II, and III and ISTA 3E requirements. Transportation configurations (with and without a pallet between the vibratory table and the palletank) were tested to define the worst-case scenario for qualification testing. 

	Analysis of the results provides complete knowledge about the shipping system behaviour when submitted to severe physical conditions (

	Characterization tests allow the definition of which norm should be used for the final qualification by assessing the most stringent testing programme possible. Qualification tests should be established  in order to provide adequate safety margins, thus guaranteeing the reliability of the shipping system when product is shipped in real conditions. 

	Secondly, characterization tests provide the worst-case shipping conditions: depending on the configurations (e.g., with or without pallet, or using one or two systems per pallet). Results of the tests can differ significantly, especially in terms of condition severity. 

	Finally, the tests allow for a compartison of the levels of intensity between ASTM and ISTA testing. In the example (

), Physical shakes have been chosen to demonstrate the level of severity for ASTM D4169 level II and ISTA 3E for each volume (100-, 200-, and 500-L). The acceleration seen by the shipping system when submitted to these normalized tests shows clearly that ASTM D4169 level II is more stringent than ISTA 3E.
	

Step 3: Determination of the final qualification testing programme by comparing real shipping data with laboratory characterization data for the shipping systems.

Comparison of real transportation measurements and data obtained during ASTM D4169 and ISTA3E, in addition to typical transportation cycle analysis, allows the definition of an adequate testing protocol. This comparison is performed on all physical entities. The comparison is illustrated in 

, in terms of PSD, the root mean square or Grms value, and shakes for horizontal and vertical shocks. 
	

Step 4: Final qualification testing programme performed on filled Flexsafe 3D bags in their shipping Palletank according to ASTM D4169, assurance level II at 4 °C (39 °F) and 40 °C (104 °F).

In this stage, 100-, 200-, and 500-L Flexsafe 3D bags that had been gamma irradiated at 50 kilogray (kGy), were set as the worst-case level. The bags were filled with water and installed in their shipping palletank, each with a shipping kit. Four bags per volume taken from two different batches were tested under the testing protocol defined previously. Qualification tests were performed at 4 °C (39.2 °F) and 40°C (104 °F) with previously defined worst-case configurations.

	The same bags were tested after one and three years of accelerated ageing. The validation protocol was based on ASTM D4169-14.  Distribution cycles numbers 12 and 14 were selected as the closest to the normal transportation conditions in the biotech industry, as shown in 

	For each test sequence, the test method and severity level must be specified for the ASTM D4169-14 distribution cycles.  Qualification protocol choices are shown in 

. Several options are available. The best choice depends on knowledge of real transport conditions, the type of system being transported, and the severity of conditions in that mode of transport. 
	

	After ASTM tests cycles, visual inspection and dye penetration tests were used to inspect the bags for damage or leakage, and to find any system damage. The following criteria were used:  

		Visual inspection during test-no leak, no damage on the system

		Visual inspection of the emptied bag-no leak

		Dye penetration test on emptied bag-no leak.

	Results of shipping liquid-filled bags using ASTM D4169 cycle 12 & 14, level II after storage during 72 hours at 4 °C (39.2 °F) and at 40 °C (104°F) are shown in 

	Shipping is a complex and challenging function. The end-user should not simply rely on system or material vendors’ claims (e.g., of their products being “ISTA certified” or “ASTM compliant”). It is important to understand what is behind each vendor’s claim for its products. In addition, each claim should be verified to ensure that it is applicable to the intended use of the biopharmaceutical product. 

	Finally, the end-user should understand the trial conditions used in the vendor tests and compare them closely to conditions for their specific application. The acceptance criteria (for both bag and shipper), the test protocol, and trial conditions must also be closely considered.

	Shipping validation must be carefully defined. This requires close collaboration between the end-user and vendor, with parameter setting linked to actual use.

	Collecting vibration data on real shipments will help the end user and vendor to understand the physical constraints of the shipping mode and select the best protocol to replicate them in laboratory testing. The limits of the system should be defined using knowledge of the safety margin and be tested under real packaging and real transport conditions. 

Guidance for Industry Process Validation: General Principles and Practices

Guideline on Process Validation for the Manufacture of Biotechnology derived Active Substances and Data to be provided in the Regulatory Submission


	3. Parenteral Drug Association (PDA)“

Technical Report Number 66, Application of Single-Use Systems to Pharmaceutical Manufacturing

ASTM D4169: Standard Practice for Performance testing of Shipping Containers and Systems

ISTA: Guidelines for Selecting and Using ISTA Test Procedures and Guidelines, General Simulation Performance Tests


	6. Technical Report of Flexsafe 3D Bags Qualification for Liquid Shipping according to ASTM D4169 – Sartorius Stedim Biotech, Publication N°: SPT1105-e161201, Order N°: 85037-557-48, Ver.: 12|2016


	Vol. 30, No. 5
	May 2018
	Pages: 48–54

	When referring to this article, please cite it as E. Vachette, F. Bazin, M. Barbaroux, and J. Cappia, "An Integrated Approach to Shipping Liquid in Single-Use Systems," 

is vice-president of marketing for fluid management technology, all at Sartorius Stedim Biotech FMT, Aubagne, France.

Articles

Increased use of single-use systems has led to a need to redefine safe, stable and integral systems for shipping biopharmaceuticals around the world. This article provides qualification data under international ASTM D4169 norms.

An Integrated Approach to Shipping Liquid in Single-Use Systems

Single-use technologies have transformed biopharmaceutical manufacturing by providing opportunities to reduce costs, improve flexibility, and shorten cycle times. Manufacturers of biopharmaceuticals want to maximize the benefits they can derive from single-use technologies and are becoming increasingly confident when integrating single-use assemblies into processing steps that have a greater impact on product quality. Today, the expansion of such technologies into more critical applications, such as drug substance and drug product storage, has naturally raised new challenges for the industry to address. Industry surveys show that these challenges include quality assurance, supply chain reliability, supplier change control, raw material transparency, and maintaining the integrity of assemblies (1, 2). “A lack of robustness can lead to contamination of process fluids or drug products and, subsequently, loss of time and materials,” Weibing Ding, PhD, principcal scientist, Process Development at Amgen said in a statement. The cost of bag failures could be between $100,000 to $1 million per bag.

	To avoid these costs, established suppliers of single-use bags provide assurance of container-closure integrity across the entire product lifecycle. They do this by applying quality-by-design principles, performing process validation, and ensuring process control. Quality control policies ensure the integrity of the film, the welds, and the bag chamber.

	As part of their quality risk management strategy and in accordance with International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use Q9 biomanufacturers can reduce the risk of losing high-value product and enhance patient and operator safety by performing a non-destructive point-of-use leak test on all single-use bags used in critical process steps (3). This ensures no damage occurred to the single-use bags during shipping, storage, and handling at the user site.

	In this article, a leak test method was validated to detect leaks by means of pressure decay for 2D storage bags (Flexboy 2D, Sartorius Stedim Biotech). This article describes the validation of a pressure decay test method used for the point-of-use leak test at the user site of Flexboy bags from 50 mL to 50 L with the FlexAct BT and the Sartocheck 4 plus Bag tester. A preliminary parameter study was first performed to pre-determine the test pressure, stabilization time, and test time. A complete validation study was then carried out to validate the parameters, the maximum allowable pressure decay, and the leak detection limit.

Bag integrity test hardware and instrument


	Test method development and validation were performed using the FlexAct BT system with Sartocheck 4 Plus Bag tester. The bag tester was equipped with two bag holders, each consisting of two metal plates with porous spacers. By using porous spacers, the film surface of the bag is not in direct contact with the stainless steel holder during the test. Any potential masking effect is eliminated and environmental heat transfer is reduced. The holders allow performance of the leak test with a small and reproducible inflating bag volume and at a higher test pressure. This is critical for achieving the test sensitivity and reliability required. Furthermore, the holders protect the bag from mechanical stress during the test.


	The designs of 50 mL to 50 L Flexboy 2D bags for pre-use have been adapted to meet the specific requirements of critical process applications and pre-use leak testing. This requires the installation of a sterile vent filter line to permit the performance of the test under conditions that maintain the integrity and the sterility of the system (

ASTM F2095-01: Standard Leak Test for Pressure Decay Leak Test for Nonporous Flexible Packages with and without Restraining Plates 

(4). Once the test pressure has been set and allowed to stabilize, the system measures the pressure decay and compares the result to an acceptance criteria determined during the development and validation of the method (

). The pressure decay test method developed detects defects according to the leak-rate specification on the film, welds, and ports of the bags. Because the validated test method is non-destructive, it is compatible with performing pre-use leak tests on 100% of bags used at a biologics production facility.


	The aim of the initial phase of the study was to pre-determine the stabilization time and test time parameters necessary to detect a defect reliably over the volume range of the bag configurations. The range contains bags with 10 different volumes from 50 mL to 50 L. For each of the 10 bag sizes, three non-defective test samples, and three defective test samples were prepared. Defects were introduced into film samples with a laser drill and flow calibrated hole.

	All 60 samples were tested at a fixed 300-mbar test pressure. For each test run, four different stabilization times of 60 seconds, 120 seconds, 180 seconds, and 240 seconds were used. The pressure drops were continuously measured and reported every second across the entire test time from 0 to 240 seconds during the four different stabilization time test runs.

	The minimum, the mean, the maximum, and the standard deviations (σ) of the measured pressure drops were calculated for the four different stabilization times separately, with non-defective and defective test samples for each different bag volume. The optimum stabilization time and test time were chosen to provide a selective test method capable of differentiating defective bags form non-defective bags (i.e., the points where the error bars [± 3 σ] from the defect is distinguished from the error bars [± 3 σ] from the non-defective measurements). Initial results showed that, for tests performed with a 120-second stabilization time and 90-second test time, a difference between the observed pressure drops of defective and non-defective test samples could be detected with a probability of 99.9%. A safety margin was then applied by doubling the stabilization and test times to avoid false positive and false negative results during normal operations. These timings were selected for the subsequent validation study.


	The purpose of the validation study was to verify the ability of the pre-established test method and test parameters to detect a defect reproducibly and accurately over the volume range of the bags. The validation study was performed with a statistically significant number of bags from different routine production lots to provide a robust validation and test method. For each of the 10-bag volumes, 32 non-defective test samples from production with representative raw material and process variability, and 32 test samples with a defect were used. This represented a total of 640 samples tested during the validation study. Every defect film sample was checked for its calibrated hole size before it was used. Tests were performed using the pre-determined test pressure of 300 mbar, stabilization time of 240 seconds, test time of 180 seconds, and a defect size.

	This study allowed the validation of the pre-established test parameters and the setting of a maximum allowable pressure decay specification at 3.1 mbar. The validated pressure decay method was capable of reliably detecting defective bags from non-defective bags with a given leak detection limit in less than 10 minutes including installation and testing.

	The 3.1 mbar maximum pressure decay specification was established with a 6σ interval of confidence for the full range of bags from 50 mL to 50 L to avoid false positive or false negative results under real testing conditions (

). The final test parameters established during these studies are provided in 

	The authors developed and successfully validated a pressure-decay leak test for 2D bags using commercially available equipment and proved that it is a robust and predictive method for the reliable detection of leaks. Using the method, non-defective bags gave results below the maximum pressure drop specification. The bags into which a defect was deliberately introduced gave results above the maximum pressure drop specification and failed the test. The method is, to the authors’ knowledge, the first point-of-use leak test capable of detecting down to 10 µm defects in 2D bags, irrespective of their volume. The sensitivity of the test is independent of 2D bag size.

	1. Aspen Brook Consulting LLC, 6th Annual Survey of the Single Use Bioprocessing Market 2014 (Aspen Brook Consulting LLC, 2014). 
	2. Bioplan Associates, 12th Annual Report and Survey of Biopharmaceutical Manufacturing Capacity and Production (Bioplan Associates, 2015).
	3. ICH, Q9 Quality Risk Management (ICH, 2005). 
	4. ASTM F2095-01: Standard Leak Test for Pressure Decay Leak Test for Nonporous Flexible Packages with and without Restraining Plates (West Conshohocken, 2001).

	Carole Langlois is senior product manager, Fluid Management Technologies; Marc Hogreve is senior engineer Integrity Testing Solutions; and Jean Marc Cappia is group VP Marketing & Product Management Fluid Management Technologies all at Sartorius Stedim Biotech.

	When referring to this article, please cite it as C. Langlois, M. Hogreve and J. Cappia, "Point-of-Use Leak Testing of Single-Use Bag Assemblies,”

The authors describe the development and validation of a highly sensitive point-of-use pressure decay test.

Point-of-Use Leak Testing of Single-Use Bag Assemblies

Aseptic processing is of great importance within the biotechnology industry because cold sterilization by membrane filtration is the only method of sterilizing biological solutions. Any heat treatment would destructively affect the drug product and target protein. To ensure sterile filtered products maintain their sterile state, an increasing number of companies are using disposable process solutions to process or store the resulting filtrate. Modern disposable connectivity allows joining the filtrate hold bag with the filling line. If the product must be transported to another facility, then the filtrate could be frozen and thawed after it reaches the filling facility. A controlled freeze–thaw process ensures protein degradation is kept to a minimum as a result of the lack of fluid movements and/or uneven protein concentration within the frozen volume. 

In addition, biologics are commonly difficult to remove from fixed, stainless-steel equipment. The cleaning and cleaning qualification process is tedious and must be exceptionally thorough to prevent residues and potential cross-contamination. The cleaning and sterilization down-times for stainless steel vessels, transfer lines, or filter housings might require 8–10 hours and copious amounts of cleaning solutions and water-for-injection (WFI). Calculations have shown that the cleaning and sterilization process of a 1000-L vessel can cost as much as $5000, depending on the WFI costs, whereby a bag of this size is priced at $200–300. The need for shorter cycle times and reduced process-material pushed the development of disposable solutions, which require no set-up times or cleaning. Disposable mixing systems can be connected to capsule membrane filters and a hold bag. These interconnected disposable systems are gamma sterilized and ready to use.  

Another benefit of disposable equipment is the fact that the end-user does not come in contact with the product. Therefore, disposable equipment has increasing popularity in cytotoxic drug applications. The drug product is processed from one disposable process step to the next without the need to either dismantle a filter from a filter housing or clean a vessel by hand. Any time a drug product has a potential to harm the user, disposable processes are the equipment of choice.  

The first disposable units were probably filter capsule devices, which could filter small volumes without the need of a filter housing and required cleaning. These filter capsules incorporated a plastic filter housing and filter cartridge into a one-piece disposable unit (see Figure 1). Capsules nowadays are available in sizes from 100 cm

. These capsules can be assembled to other equipment and autoclaved, or the capsules are delivered presterilized by the filter manufacturer, including equipment connections (e.g., to a filtrate hold bag).  

Figure 1: Small-scale filter capsule devices. (ALL PHOTOS ARE COURTESY OF THE AUTHORS.)			

The next development was single-use sterile bags to replace glass bottles, plastic carboys, or stainless-steel containers for small-volume storage, transport of biological solutions, and growth media. Originally, blood and parenteral solution bags were adapted for process use. Because the mechanical stability had to be strengthened, specific polymeric bag films were developed. These films are laminated in various configurations to gain the mechanical strength for large-volume bags, to reduce any leachable release into the product, and to create an oxygen barrier (see Figure 2).  

The laminate combinations can vary depending on the bag design, manufacturer, and application served. Currently, bag designs are manifold and vary in volume from 20 mL to 3000 L. The assemblies are not restricted to only a bag and a filter. They can be highly complex and engineered to fit specific requirements of the end-user. For example, buffer hold bag systems are commonly a manifold of multiple bags of the same volume, which can be disconnected by tube sealers. These assemblies also contain a sample bag for quality assurance purposes. The filtered volumes can be stored or transferred to individual process steps within a facility. Large-volume systems require storage with trays, tote, or pallet systems to prevent the large liquid volume from moving. The bags within such storage systems require unfolding in a very specific manner, otherwise pressure folds will occur and could damage the polymeric film. The design of the filling and connectivity of any outlet from the bag are essential because the hold-up volume of a hold bag must be minimal.  

As mentioned, disposable systems are no longer restricted to a bag and a filter. Various equipment components are available that can be combined into a single-use system or process step. Such equipment components include: 					

Mixing systems (various designs and volumes)

Bioreactors (many designs, volumes, and agitation technologies) 

Membrane chromatography (e.g., ion exchange)

Viral clearance (e.g., filters and UV inactivation)

Other equipment solutions will soon follow as the requirements for single-use systems by the industry are more pressing and innovative. For example, work is underway to design disposable valves, pump heads, and filling systems. 

Disposable mixing systems are available from 5 to 1000 L and are most commonly used for buffer and media mixing, product compounding, or final formulation purposes. A more recent application is viral inactivation by pH shift. Such mixing bags use disposable sensor patches to determine the necessary pH levels during the inactivation period.  

Mixing methods include recirculation, pulsation of the mixing bag; use of magnetic impellers, stirrer bars, or pads; and use of a levitation mixer. The latter is unique to all others because the mixer does not come in contact with the bag material, and it floats on a magnetic field. This configuration avoids any friction of the bag material and provides fast and thorough mixing results. The various mixing technologies are useful because the applications and complexities of mixing vary. Liquid–liquid mixing has easy mixing requirements, but liquid–powder mixing can be difficult and may require careful design and mixing mode observations.  

Current single-use bioreactor systems are divided into two main categories: rocking motion and cylindrical-tank reactors with various agitation modes. Rocking motion reactors were the first to enter the biopharmaceutical industry. In this design, the cell culture is moved back and forth by a rocking platform, which allows mixing of nutrients and gas input into the liquid phase. These systems produce excellent results for shear-sensitive cell cultures and have been especially established in seed reactor applications. Rocking systems are available as a basic system without sophisticated controls. Separate systems can be connected to a control unit to measure the dissolved oxygen and pH by means of a disposable sensor. The control system can also run the gas and feed strategies, which is important when the system is used as a perfusion reactor. The working volumes of rocking reactors range from 0.2 to 500 L. Recent bioreactor developments have focused on cylindrical tank systems, which use multiple agitation methods, including sleeved or fully polymeric stirrers, vibro-mixing, orbital shaking, or gas mixing. The agitation methods and cell culture requirements determine the design for these reactors. Typical capacity volumes of these cylindrical disposable bioreactor systems range from 10 to 2000 L. These units are most commonly used with the control tower systems of reusable fermentation systems. These control towers create appropriate feed and gassing environments for the cell culture.  

Bulk raw materials are often shipped over long distances, and production processes may require a product-hold step because of downstream equipment bottlenecks. In both instances. solutions are required to prevent any protein degradation, which may occur as a result of enzymatic attack and temperature, pH, concentration, or gas conditions within the hold or transport step. To avoid such yield losses, the industry has resolved to freeze steps to keep the product stabile over a period of time. However, commonly used blast-freeze steps are uncontrolled and can result in freeze concentration, pH shifts, aggregation, ice crystals within the frozen material, or bag damages. To avoid such damaging conditions, disposable controlled freeze–thaw devices have been established. These devices contain a hold bag within a frame and a freeze–thaw module that uses heat-exchanger plates, which ensure a unified controlled freeze and thaw process. The product hold bag with the frame is transferred into the freeze–thaw module, and the heat-exchanger plates move in position, pressing against the hold bag. The heat exchanger plates therefore do not only ensure the temperature transfer, but also the uniform distribution of the liquid over the entire bag design. These units are available as small-scale trial devices with a volume of 30 mL and process scale up to 16 L. 

During the past 10 years, disposable technology innovations surfaced rapidly, and the nondisposable gaps within a biopharmaceutical process are now closing. There are still process steps or specific equipment parts that either will evolve into disposable systems or will be kept and integrated into a hybrid state. How total processes will look like in the future are only predictions, but developments of new disposable process components show the trend toward a total disposable process, at least in the small-scale volume streams (see Figure 3.)  

Figure 3: Possible disposable process stream.			

Such a process would require careful planning because the volumes within a process can change drastically, process steps require proper timing, and essential connectivity requires being qualified. In some instances, radiofrequency identification (RFID) can be used to either to track equipment or process units or to connect the required process units together. These tags will can also create appropriate and necessary shelf-life information, because gamma-irradiated polymers have limited shelf lives.  

The major items still not available as disposable units  are valves and filling lines, which are able to handle fluid volumes at high speeds. There have been attempts to design filling systems, but these have not penetrated the industry as much as the above described disposable technologies. It is only a matter of time when such disposable filling equipment will be made available.  

Innovative developments in disposable equipment enhance the safety in aseptic processing. Furthermore, these developments might create the possibility of a disposable factory. The benefits of complete disposability are relevant to all scales of bioprocesses, especially within the start-up phase. In early development, disposability reduces the need for major capital investments. As these technologies continue to develop critical factors such as drug cost, production cycle times, new product development time, and facility flexibility, all aseptic processing will be affected. 

Because most disposable devices are gamma irradiated, between 25 and 50 kGy short- and long-term, stability studies with the irradiated devices must be performed. Irradiation typically reduces the shelf life of such devices, and it must be determined what the limits are. Furthermore, the irradiation step could accelerate the degradation of the polymeric substances used, which can result in increased leachable and extractable levels. To determine the effects of irradiation and the stability of the polymer used, manufacturers subject these devices to a considerable regime of qualification tests before the device is commercialized. The qualification tests serve as a guidance by the end-user and commonly encompass, but are not limited to, the following tests: 					

Mechanical properties (tensile strength, elongation at break, seal strength, air leak test)

Gas transmission properties (ASTM D3985: oxygen, ASTM F1249: water vapor)

E.P. 3.1.7.: EVA for containers and tubing

Extractable and leachable tests with standard solutions

Gamma irradiation sterilization validation

These tests are conducted under standard settings with standard solutions. The data of these tests are available from the manufacturer.  

The authors discuss current and future disposable technologies and outline the validation and qualification steps that would be required for a possible disposable process stream.

Disposable Components in Aseptic Processing

Steaming-in-place (SIP) is a widely adopted method for the in-line sterilization of processing equipment. The main advantage of SIP relies on manipulation reduction and aseptic connections that might compromise the integrity of the downstream equipment.