Elisabeth Vachette

	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

As the biotech industry evolves, there are mounting concerns about the transportation, security, and robustness of cell-culture media, intermediate, or bulk drug substance (BDS). Safe, stable, and closed systems are needed when sterile products are shipped in single-use bags. In this article, the authors look at the limitations of the validation for a single-use shipping system and provide a perspective on what shipping validation means.

In this article, the authors look at the limitations of the validation for a single-use shipping system and provide a perspective on what shipping validation means.

Qualification and Validation of Single-Use Shipping Systems

As the biotech industry evolves, there are mounting concerns about the transportation, security, and robustness of cell-culture media, intermediate, or bulk drug substance (BDS). Safe, stable, and closed systems are needed when sterile products are shipped in single-use bags (1). In this article, the authors look at the limitations of the validation for a single-use shipping system and provide a perspective on what shipping validation means.

The increasing need for shipping product in the biotech single-use market
	

The complexity of biopharmaceutical manufacturing processes requires continuous improvement. The expansion of manufacturing capacity worldwide has resulted in the multiplication of links between production facilities as well as the increasing need for storage or transportation of media, intermediate, BDS, and drug products.

	Outsourcing to contract manufacturing organizations (CMOs) offers a solution to the capacity constraint. CMOs bring to the biopharma industry valuable technical expertise and flexible capacity and reduce the total risks associated with building internal capacity; however, a robust and validated manufacturing process (2), including product transportation between facilities, is required.

	Single-use technology (SUT) continues to expand because of its potential for reducing both capital and operating expenses (3). The growing adoption of single-use, especially in critical process steps, has increased the need for product quality, robustness, and integrity. The biotechnology industry is now expanding its implementation of single-use bags into all bioprocess steps for applications including cell-culture preparation (4), filtration (5), purification (6), storage (7), mixing (8), freeze-thaw operations (9), and fill-finish (10).

	Depending on the manufacturing process organization and the level of outsourcing, the challenge of safe and robust BDS transportation becomes a crucial step from a risk analysis point of view (11, 12).


	To comply with modern manufacturing requirements, SUT must offer similar levels of security and robustness as multi-use technology (MUT). A MUT shipping container is designed to withstand the different static and dynamic forces to which it is subjected during transportation, handling, and storage operations. The shipped product must also be protected from climatic conditions, such as temperature and humidity (13). Reusable products must:

		Be robust in terms of providing protection to the shipped product against rigorous environmental and handling conditions

Stainless-steel tanks for bulk freezing and distribution between drug substance sites and drug product sites were the processing units of choice until recently, when the technology was challenged by SUT (9, 14, 15). It is important to note that there is a simpler supply chain with SUT shippers because there is no need to manage the return of empty tanks or to clean and verify them.

	In addition to the aforementioned standard requirements, shipping with SUT requires the following additional needs:

		Maintenance of the structural integrity of the single-use bag (i.e., no leaks)

		Qualification of product in contact with the single-use material (i.e., extractable and leachable testing).

While SUT shipping can offer substantial advantages compared to MUT shipping, there are challenges with SUT shipping as summarized 

. Several considerations are related to the material of construction of SUT. Moreover, the end-users’ requirements for shipping depend largely on the application as shown in 

(TR) N°66 (16), the supply of process solutions in large-volume bags, from point of manufacture to point of use is a well-established practice that involves the following elements:

		A bag designed to fit a rigid wall outer container

		A rigid wall outer container such as a plastic drum or tote or a stainless-steel bin

		Secondary packaging materials (e.g., dunnage) and lids or other mechanical devices to suppress the fluid wave action in the bioprocess bag.

	Transportation of process solution in small-volume bags (nominal volume lower than 20 L) is also a common process that requires less complex packaging solution (16). The exception is the transportation of frozen materials that necessitates temperature-resistant materials and cold-chain logistics (17).

	Shipping systems must be qualified for their intended use through proper design and testing in consultation with a packaging engineer. The International Safe Transit Organization (ISTA) (18) and the American Society for Testing and Material (ASTM) D4169 (19) are good references for testing standard. These standards are complex with many different protocols, and the selection of a relevant protocol linked to an application is not trivial. It must be analyzed with a packaging and transport expert. The following are some key considerations for end-users:

		What is the shipping unit (size, weight, and form of construction)?

		What are the shipping routes: intercontinental (truck/air/boat), national (long-distance truck), or continental (short-distance truck)?

		What is the assurance level that should be established? Level I > level II > level III

		Define the lifecycle phases of the shipped unit (storage, transport, handling, transport, use)

		What are the associated environmental conditions for each phase of the lifecycle (temperature, humidity, compression, vibration, shock, free fall, bump, and pressure)?

		What are the handling conditions (forklift, tarmac, roads)?

		What are the type of shock, shake, and vibrations associated with the shipping routes?

		What is the appropriate number of samples for validation?

		What is the adequate severity of the simulated shipping test?

		What are the acceptable safety margins?

		What are the acceptance criteria: product is damage-free, package is intact, or both?

	Based on the projected distribution, the end-user should define a test plan using the distribution cycle (DC) defined in 

 of the ASTM D 4169 (19). The DC chosen should correlate with the projected lifecycle phases of the shipped unit (20).

	In addition, many pharmaceutical or biotechnological products are temperature sensitive and require specific precaution during storage and transportation (21). Transport and storage conditions have to be determined considering the risks of product degradation (22, 23).

	PDA TR N°66 has highlighted specific factors of importance for transportation that must be considered by end-user (16). These factors are:

		Dimensional factor (i.e., volume to be shipped and dimensions of the shipper)

		Mode of transportation, whether it’s ground, air, rail, boat, or combination of more than one mode of transportation. Metrics must include hold time on tarmac.

		The associated environmental conditions (temperature, humidity, pressure, and variation)

		Functionality (i.e., forklift access, stack ability of outer container, access to fill and drain port, secondary container to collect leak)

		Room classification such as fill and drain procedure to maintain sterility

		Logistics (e.g., external shipper, cold-chain logistics).

	In addition to PDA TR66, the analysis of the regulatory requirements and relevant references can be summarized as follows:

		The transportation routes must be defined for international shipment. A risk assessment for vibration, handling, delays, and seasonal variation should be established (11).

		The suitability of the containers (compatibility, safety, robustness) and of the container-closure system (material of construction, integrity, interaction) must be defined as well as a rational for the choices of the material, the barrier properties, the compatibility, and the safety (13).

		Recommendations are given to define storage and shipping conditions, to assess risk of the environmental parameter variation, to define labeling, and to assess short-term excursion outside storage conditions according to the International Council on Harmonization (ICH) accelerated testing (24).

		Qualification and validation of the shipped product can be performed in real shipment with monitoring (25-27) or in simulated shipment according to ASTM D4169 (19) or ISTA (18).

		In addition, precautions for transport of hazardous materials and dangerous goods are also described in additional regulations. The Economic Commission for Europe has defined regulations applicable to road transportation of chemical dangerous goods (28). Part 3 of the documents lists the chemical entities considered as dangerous goods for which special precautions are required.

		The United Nations has established regulations for any type of transports (air, road) of biological and infectious substances (29).

		The International Air Transport Association has established regulations applicable to safe air transportation of dangerous goods (30).

	Shipping is indeed complex and users should verify the vendor’s claims about some regulations. It is important for the end-user to understand what is behind the claim and the relevance to its application. As discussed in this article, shipping validation protocol for mechanical constraints needs to be carefully defined with parameters setting linked to the application in close collaboration between end-users and suppliers.

	It is a requirement of the US Food and Drug Administration (FDA) (12, 31), EMA (32), the European Union (11) and other drug regulatory agencies that the process produces consistently similar and reproducible results that meet the quality standard of the product. According to FDA, validation is “Establishing documented evidence that provides a high degree of assurance that a specific process--including shipping--will consistently produce a product meeting its pre-determined specifications and quality attributes” (33). A properly designed system will provide a high degree of assurance that every process step, including shipping, has been properly evaluated before its implementation.

	In the biopharmaceutical industry, qualification and validation are intended to demonstrate that the manufacturing process provides the desired level of product quality and specifically its activity, sterility, and potency. Qualification of a shipping system and shipping equipment is part of the validation.

A SUT shipping system composed of a bag and a stainless-steel bin should ensure safe shipment (i.e., no loss of integrity and no loss of product sterility). It can be granted by the mechanical robustness of the shipper. The objective is to verify that no leaks occur during transportation. According to Tull, “Product quality can be defined in terms of the ability of a product to perform its desired function despite the stresses to which it has been exposed before and during its intended use” (23).

	Bag leakage can be analyzed following methods described in the PDA TR N°27 (34). This document, however, describes high-sensitivity methods adapted for final packaging and not necessarily for intermediate or BDS. More global test methods such as diffusion of a dye, detection of a liquid leak, or damage of the bag (films and seals) may be more relevant (35).

The authors provide their perspectives on shipping validation.